Equipe pédagogique

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1

AUBERT-POUESSEL Anne BATAILLE Bernard (responsable DFG-SP2-UE Formulation - Biopharmacie) BAYLAC Gilles BEGU Sylvie COUDANE Jean DELALONDE Michegravele DEVOISSELLE Jean-Marie DORANDEU Christophe GARRIC Xavier LEGRAND Philippe MARTI-MESTRES Gilberte MORILLE Marie NOTTELET Benjamin SHARKAWI Tahmer

Deacutepartement de Pharmacie Galeacutenique et Biomateacuteriaux

httpgalenique-biomateriauxeduumontpellierfr

Equipe peacutedagogique

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Un ancrage recherche Reacuteunion de lrsquoensemble des compeacutetences

- proceacutedeacutes chimie en solution chimie du solide - excipients fonctionnels - formes pharmaceutiques (multi-eacutechelles) - biopharmacie et - biomateacuteriaux

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Pharmacie Galeacutenique

DFGSP 2egraveme anneacutee UE Formulation ndash Biopharmacie Notions de base preacuteformulation Les formes pharmaceutiques conventionnelles Les agents de contraste en imagerie Les opeacuterations pharmaceutiques DFGSP 3egraveme anneacutee UE 5 Biotechnologies - Biopharmacie

Formes agrave libeacuteration modifieacutee Voie orale Voie parenteacuterales Voie autres

Produits issus de la biotechnologie Systegravemes theacuterapeutiques actifs

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bull Connaicirctre les diffeacuterentes eacutetapes de la mise au point drsquoun meacutedicament preacuteformulation formulation contraintes physico-chimiques lieacutees agrave lrsquoassociation de composants actifs avec des composants non actifs

bull Connaicirctre les principales formes galeacuteniques les eacuteleacutements de leur formulation de leur conditionnement et autres points critiques et controcircles associeacutes ainsi que les contraintes de biodisponibiliteacute

bull Connaicirctre les principes geacuteneacuteraux du Geacutenie des Proceacutedeacutes pharmaceutique les principales opeacuterations unitaires et opeacuterations coupleacutees conduisant agrave la mise en forme et la fabrication des meacutedicaments

DFGSP 2egraveme anneacutee UE Formulation - Biopharmacie

Objectifs peacutedagogiques

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COURS

41 h

Intituleacutes des cours 1 Preacuteformulation et physico-chimie (6 heures) 2 Grandes voies drsquoadministration et formes galeacuteniques associeacutees voie orale voie parenteacuterale voie cutaneacutee voie transmuqueuse (25 heures) 3 Principaux proceacutedeacutes et opeacuterations de mise en forme et fabrication (10 heures)

TD

75h Nombre de

seacuteances 5

Intituleacutes des seacuteances 1 Deacutemarche preacuteformulation 2 Commentaires de formulations I 3 Commentaires de formulations II 4 Isotonie 5 Meacutedicaments radiopharmaceutiques

TP

15h Nombre de

seacuteances 5

Intituleacutes des seacuteances 1 Maicirctrise de lrsquoordonnances (doses maximales doses drsquoexoneacuteration) et preacuteparations semi-solides (pommades et gels) 2 Preacuteparation de geacutelules 3 Preacuteparations de liquides sirops suspensions buvables 4 Preacuteparation de suppositoires 5 Controcircle pharmacotechnique des meacutedicaments

Programme

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PREFORMULATION

1 Geacuteneacuteraliteacutes

2 Solubiliteacute

3 Dissolution et dissolution intrinsegraveque

4 pKa et coefficient de partage

5 Etat solide et Polymorphsime

6 Stabiliteacute

7 Permeacuteabiliteacute et classification biopharmaceutique

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Rocircle de la Galeacutenique dans le deacuteveloppement de meacutedicament

RECHERCHE EXPLOITATION DEacuteVELOPPEMENT GALEacuteNIQUE

Moleacutecule Formule

Proceacutedeacute

SYNTHESE PHARMACOLOGIE TOXICOLOGIE

PREFORMULATION FORMULATION DOSE UNITAIRE POSOLOGIE TOLERANCE SECURITE DrsquoEMPLOI

PROCEDE CHANGEMENT DrsquoECHELLE LOT AMM

PRODUCTION INDUSTRIELLE COMMERCIALISATION

temps


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Genegravese et industrie du meacutedicament

Un cycle long (10 agrave 12 ans en moyenne) et aleacuteatoire

10 000 moleacutecules identifieacutees

100 moleacutecules testeacutees

10 candidats meacutedicaments

1 meacutedicament

Isolement de la moleacutecule


Etudes cliniques I II III et AMM

AMM transparence prix

Pharmacovigilance phases cliniques IV

Phase de recherche

Phase de test

Phase de deacuteveloppement

Proceacutedures administratives Phase de commercialisation

0 5 ans 10 ans 15 ans 20 ans

Deacutepocirct de brevet Expiration de brevet 10 ans de RampD


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4 grandes voies classiques

1 Lextraction drsquoune substance agrave partir de produits naturels de diffeacuterentes origines veacutegeacutetale animale ou mineacuterale

2 La synthegravese chimique 3 La creacuteation et production de substances biologiques

par les biotechnologies 4 La modeacutelisation de moleacutecules theacuterapeutiquement

actives

Phase de recherche


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n 1 Geacuteneacuteraliteacutes Phase de recherche nouvelles approches

cellule

gegravene

Rechercher des gegravenes

responsables de maladies

Identifier des

proteacuteines cibles

Tests des moleacutecules sur

les cibles

Seacutelection des PA

candidats

Creacuteer des centaines de milliers de moleacutecules

Geacutenomique proteacuteomique Chimie Criblage haut deacutebit

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Preacuteformulation

Formulation

Meacutethode de fabrication

Premiegraveres fabrication 1iers Lots cliniques

DEV

ELO

PPM

ENT

PHASE DrsquoELABORATION

Contraintes lieacutees agrave la moleacutecule


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n 1 Geacuteneacuteraliteacutes

PREFORMULATION

Etude des caracteacuteristiques du principe actif

- PHYSIQUE - CHIMIQUES - BIOLOGIQUES

- PHARMACEUTIQUES - ORGANOLEPTIQUES

Conseacutequences galeacuteniques

STABILITE

TOLERANCE

BIODISPONIBILITE

ACCEPTABILITE SE

CU

RIT

E

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Choix du meilleur deacuteriveacute

- de PA

- NATURE ION ASSOCIE

- SOLUBILITE

- COEFFICIENT DE PARTAGE

- GOUT-ODEUR-ETChellip

- PF


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Deacutefinition des caracteacuteristiques

optimales de ce deacuteriveacute

- STEREOISOMERES

- POLYMORPHISME

- DENSITE APPARENTE

- GRANULOMETRIE

- ETAT DE SURFACE

hellip



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Conditions drsquoenvironnement Ameacutelioration des caracteacuteristiques

- SOLVATATION

- PROTECTION

(IN VITROIN VIVO)

- STABILISATION

hellip

Seacutelection des excipients

- INTERACTIONS - ETAT DrsquoEQUILIBRE hellip


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Preacuteformulation = Carte drsquoidentiteacute physique et physicochimique du principe actif pureteacute solubiliteacute dissolution pKa LogP LogD eacutetat physique stabiliteacute Eacutetude du comportement et des interactions en preacutesence drsquoexcipients Aptitude agrave la formulation et aux proceacutedeacutes


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PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


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2 Solubiliteacute et strateacutegies de solubilisation

Importance des solutions en pharmacie galeacutenique

Une solution est un meacutelange homogegravene dont les constituants sont diviseacutes et disperseacutes lrsquoun dans lrsquoautre au niveau moleacuteculaire

La solution est formeacutee par un solvant en portion

majoritaire et par un soluteacute (dans la mecircme phase) Crsquoest un meacutelange HOMOGEgraveNE de 2 ou plusieurs

substances

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n 2 Solubiliteacute et strateacutegies de solubilisation

Forme pharmaceutique simple facile agrave avaler convient aux enfants aiseacutement fractionneacutee

Forme pharmaceutique homogegravene Pour ecirctre biologiquement actif un

principe actif doit ecirctre en solution Seul le principe actif dissous non ioniseacute

peut traverser les membranes


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La solubiliteacute drsquoune substance agrave une T donneacutee est la concentration de soluteacute dissous qui est en eacutequilibre avec le soluteacute non dissous

Agrave lrsquoeacutequilibre la vitesse agrave laquelle les moleacutecules de soluteacute entrent dans le solvant et la vitesse agrave laquelle les moleacutecules de soluteacute retournent dans la phase solide sont eacutegales

= EQUILIBRE STATIONNAIRE

21 Solubiliteacute


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La solution a atteint sa concentration

maximale Limite de solubiliteacute

Deacutefinition de la solubiliteacute la

concentration de la solution satureacutee

Cs mgml gl microgml microgl hellip


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Deacutetermination expeacuterimentale de la solubiliteacute

bull proceacutedeacutes utiliseacutes en recherche bull proceacutedeacutes utiliseacutes en formulation et en analyse

bull turbidimeacutetrie pheacutenomegravenes d rsquoautoassociation

bull les problegravemes de proceacutedure automatisation

bull les autres descripteurs correacutelation

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bull Les semblables dissolvent les semblables ndash Les composeacutes polaires ou semi-polaires sont solubles

dans lrsquoeau ndash Les composeacutes apolaires sont peu solubles dans lrsquoeau

bull La solubiliteacute deacutepend des caracteacuteristiques

ndash chimiques ndash eacutelectriques ndash structurelles

Les interactions solvant-soluteacute

influenccedilant les interactions entre les moleacutecules de solvant et de soluteacute

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bull De nature semblable signifie ndash les eacutenergies de coheacutesion entre les 2 espegraveces de moleacutecules sont

du mecircme type et possegravedent le mecircme genre de liaisons intermoleacuteculaires

ndash Les hydrocarbures sont insolubles dans lrsquoeau

ndash Lrsquointroduction dans la moleacutecule de groupements polaires hydrophiles tels que OH COOH CO NOH CONH2 AUGMENTENT la solubiliteacute dans lrsquoeau

ndash CH3 CH2 =CH C6H5 exercent peu drsquoinfluence sur la solubiliteacute dans lrsquoeau mais AUGMENTENT la solubiliteacute dans les solvants organiques


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bull La solubiliteacute des substances solides DIMINUE geacuteneacuteralement quand les dimensions de la moleacutecules AUGMENTENT (sauf si plusieurs groupements hydrophiles)

bull DIMINUTION de la solubiliteacute dans lrsquoeau lorsque la chaicircne hydrocarboneacutee srsquoallonge

bull DIMINUTION de la solubiliteacute dans lrsquoeau lorsqursquoil y a polymeacuterisation


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3 entiteacutes gouvernent la solubiliteacute S = f(E de packing du cristal) + (E de cavitation) + (E de solvatation) bull Eacutenergie de packing exo (rupture de lrsquoarrangement en moleacutecules isoleacutees) bull Eacutenergie de cavitation endo (rupture des liaisons H2O -gt caviteacute pour la moleacutecule hocircte) bull Eacutenergie de solvatation exo (somme des interactions favorables soluteacute-solvant)

Cas du solide dans liquide Approche theacuteorique simplifieacutee


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Proportion des nouveaux PA de solubiliteacute lt 1 mgml augmente parallegravelement avec la speacutecificiteacute de leur

action Pharmacopeacutee europeacuteenne (1992-1995) parmi les

nouveaux PA - 40 solubiliteacute lt 1 mgml - 32 solubiliteacute lt 01 mgml

La solubiliteacute un problegraveme reacutecurrent


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PA candidats (HTS) agreacuteeacutes preacutesentant des problegravemes de solubiliteacute



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22 Strateacutegies de formulation


Ajustement du pH

bull pH deacutetermineacute par le pH de solubiliteacute et le profil de pH du PA bull variables de formulation tampon force du tampon [PA] bull influence sur des [PA] agrave super saturation -gt preacutecipitation in vivo bull capaciteacute de la force tampon du sang bull formulations le plus souvent 4ltpHlt8 exception 2ltpHlt11

tampons les plus utiliseacutes bull acide citrique bull acide aceacutetique bull acide phosphorique

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Solu

bilit

eacute du

PA

Courbe

de solubiliteacute

Courbe de dilution [PA] forte

Courbe de dilution [PA] faible

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bull Stabiliteacute du PA pH ions du tampons ions d rsquoajustement du pH bull Preacutecipitation du PA agrave la perfusion [PA] utilisation du tampon force du tampon vitesse de perfusion bull Irritation isotoniciteacute vitesse de perfusion et dureacutee PA vs veacutehicule preacutecipitation du PA

Ajustement du pH en preacuteformulation des prep injectables


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Formation de sels

So solubiliteacute de la forme non ioniseacutee

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plateau

phase solide = sel

phase solide = base libre

Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1

Exemple drsquoune base faible


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PA eacutelectrolyte faible sel ioniseacute peu soluble (inf agrave 001 mgml) soluble

A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+

AH + NaOH Na+ A- + H2O

bull Sel agit comme son propre tampon

bull Base forte OH- en majoriteacute Augmente le pH dans la couche de saturation

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Utilisation de colsolvants

bull Approches empiriques deacutetermination de la solubiliteacute dans des formules deacutejagrave commercialiseacutees bull Approche systeacutematique - relation log-lineacuteaire (Yalkowski et Roseman) (systegraveme binaire ternaire et quaternaire) si deacuteviation de la lineacuteariteacute interaction solvant-solvant alors - plan d rsquoexpeacuterience


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bull Niveau acceptable deacutefinition difficile 10 agrave 100 selon les solvants et les speacutecialiteacutes bull Proportion respective choisie selon

- conditions d rsquoadministration - dose totale - population cibleacutee - dureacutee de la theacuterapie

Type de cosolvants utiliseacutes - glyceacuterol - eacutethanol - propylegravene glycol - DMA


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Utilisation de tensioactifs

Segment hydrosoluble

Segment peu soluble

Polymegravere + Ch Alkyles Polymegravere laquo random raquo Copolymegravere block Copolymegravere greffeacute

Proprieacuteteacutes

- srsquoadsorbe aux interfaces - diminue la tension interfaciale

Classification

- anionique - cationique - non-ionique


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cmc et solubilisation micellaire cmc

- solubilisation micellaire - produits apolaires - produits moyennement polaires - produits polaires


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Courbe de solubiliteacute



[tensioactif]

Solu

bilit

eacute du

PA

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Cyclodextrines Oligosaccharides cycliques dorigine naturelle - partie hydrophile externe

- partie hydrophobe de linteacuterieur de leur caviteacute

α β

hexamegravere heptamegravere octamegravere

α β γ

HP-βCD SBE-CDhellip

Utilisation de cyclodextrines


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Si le PA forme un complexe de stœchiomeacutetrie 11 avec la CD

CD PA PA

CD

]][[][

CDPACDPAKc minus

=

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PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]

si pente le 1 (PACD)

si pente gt 1 (exPA2CD)

[cyclodextrines]


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Beig A Agbaria R Dahan A (2013) Oral Delivery of Lipophilic Drugs The Tradeoff between Solubility Increase and Permeability Decrease When Using Cyclodextrin-Based Formulations PLoS ONE 8(7) e68237 doi101371journalpone0068237 httpwwwplosoneorgarticleinfodoi101371journalpone0068237


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Principe actif

cyclodextrine

Exemple de deacuteveloppement collyre

Formulation solubiliteacute (mgml) Eau pH 7 29 10 CD 159

lineacutezolide


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Solutions solides Meacutelange solide agrave tempeacuterature ambiante Composition - une matrice solide tregraves hydrosoluble pharmacologiquement inactive - un principe actif peu soluble dans lrsquoeau Obtention fusion puis meacutelange des 2 composants refroidissement et solidification Mise en forme extrusion division hellip PA agrave lrsquoeacutetat moleacuteculaire ou solide disperseacute Ex de matrice PVP-VA et PEG

Solution et dispersion solides


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PA = diclofeacutenac

diclofeacutenac + PEG6000agrave 60degC


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Vitesse de dissolution

Dispersion moleacuteculaire = solution solide

Dispersion solide amorphe Dispersion solide cristallin


Relation eacutetape physique ndash vitesse de dissolution

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Exemples de proceacutedeacutes de fabrication des dispersions solides

Dispersion solide

Lyophilisation Congeacutelation-

deacutecongeacutelation

Micro-ondes

Co-preacutecipitation

Electrospinning

Extrusion en milieu fondu

Spray-drying

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Meacutelange


Fusion (Tdeg)

refroidissement

granulation


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n 2 Solubiliteacute et strateacutegies de solubilisation Stabiliteacute physique Dispersion moleacuteculaire [PA] lt solubiliteacute crist

Dispersion moleacuteculaire [PA] gt solubiliteacute crist

Dispersion moleacuteculaire [PA] gt solubiliteacute amorph

Stabiliteacute thermodyn Seacuteparation de phase

Diffusion PA + reacuteorientation

Deacutecomposition spinodale

NB Deacutestabilisation physique possible des excipients

Cristallisation du PA (rapide)

Monophasique

biphasique

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PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


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Objectifs

Caracteacuterisation physicochimique des PA

Comparaison des formes polymorphiques

Comparaison des diffeacuterents sels

Comparaison de diffeacuterentes structures chimiques

Deacutetermination des conversions de sels

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VhCCsAD

dtdm

)( minus

=

Vitesse de dissolution = Quantiteacute de PA solubiliseacute par uniteacute de temps

Equation de Noyes et Whitney

D = coefficient de diffusion du PA dans le milieu A = surface speacutecifique du PA Cs = concentration agrave saturation du PA h = eacutepaisseur de la couche de solvant entourant chaque particule de PA C = concentration du PA agrave lrsquoinstant t V = volume du milieu de dissolution


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Importance de la granulomeacutetrie relieacute agrave A

Surface speacutecifique masse

totalesurface=A m2g-1

Ex si particules spheacuteriques

ρρπ

π3

34

43

2

rrn

rnA ==

donc diminution de la taille augmentation de A

Augmentation de la v de dissolution

Si PA peu solubles et dissolution = eacutetape limitante division ameacutelioration de la biodisponibiliteacute


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Mesures de la granulomeacutetrie - Compteur Coulter - microscopie optique coupleacutee agrave lrsquoanalyse drsquoimage (+ formes) - diffraction laser Mesures de la surface speacutecifique adsorption drsquoazote (BET)

Cas limites de la reacuteduction de taille - Agglomeacuteration donc deacutetermination taille optimale - Risque de deacutegradation (stockage in vivo) - profil pharmacotoxicologique

ESSAI SUR ECHANTILLONS DE MEME GRANULOMETRIE

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- Microcopies optique et eacutelectronique - visualiser des objets en deux dimensions - permet dappreacutecier non seulement la taille et la forme Limitations -lieacutees agrave la preacuteparation des eacutechantillons (ex particules se chevauchent) - repreacutesentation bidimensionnelle de particules tridimensionnelles

Analyse par imagerie

Microcopies optique

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Exemple drsquoanalyse drsquoimage Importance de la morphologie Cas drsquoun principe actif


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LA GRANULOMEacuteTRIE LASER norme ISO133202009 - La distribution granulomeacutetrique est deacuteduite de linteraction entre un ensemble de particules et le faisceau laser incident par lrsquoanalyse de la tache de diffraction du faisceau - 2 modes de dispersion segraveche ou humide

Analyse granulomeacutetrique par diffraction de la lumiegravere


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En cumuleacute Expression des reacutesultats

Analyse granulomeacutetrique attention agrave la meacutethode et agrave lrsquoexpression des reacutesultats


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A = cste si Cs gtgtgt C

Q=kot mgmin-1cm-2

Dissolution intrinsegraveque

Pente = vitesse de dissolution

Caracteacuteristique du PA dans les conditions du test

200 mg de PA cpeacute 100 tmin 20 min 1 litre agrave 37degC


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Cylindre rotatif Ph Eur amp USP monograph

500 ndash900 ml

Distekreg Pas monographie Ph Eur

500 ndash900 ml (mini 100 amp 200ml)


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Compacte A = 0071 cmsup2 (~15mm) Dissolution cumulative Volume minimum 15ml Deacutetection fibre optique (trajet optique 5mm)

pIONregIntrinsicDissolution


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Milieu de dissolution

Ameacutelioration

- Solutions tampons USP de pH 1 agrave 74 - Milieux simuleacutes agrave jeun (estomac intestin) nourri (estomac intestin)

dissolution intrinsegraveque en cellule agrave flux

Piston pumpMedia reservoir

Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


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n Modegravele in vitro repreacutesentant la dynamique de la digestion des lipides in vivo Contient tampon SB PL Lipase pancreacuteatique Digestion controcircleacutee par addition de CaCl2 pH gardeacute constant AG libeacutereacute quantifieacute (titrage NaOH) Eacutechantillons digeacutereacutes analytique

Modegravele de lipolyse


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Dissolution intrinsegraveque en cellule agrave flux Cellule mise au point par Merck-Serono

Th Lange Merck-Serono


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pKa et profil de solubiliteacute


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Theacuteorie du partage deacutependant du pH - Les composeacutes ionisables passent les membranes sous forme neutre - les acides faibles sont adsorbeacutes au niveau de lrsquoestomac - les bases faibles au niveau de lrsquointestin

pKa et absorption dans le TGI

acide

base


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71

Barriegravere gastrique

Plasma pH = 74

Milieu gastrique pH = 14

AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100

Exemple de lrsquoacide aceacutetylsalicylique pKa = 34

][][log

AHApKapH

minus

+=

Acide faible donc


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Exemple de lrsquoacide aceacutetylsalicylique


Donc passage favoriseacute dans lrsquoestomac Mais - Forme peu soluble donc utilisation drsquoun sel ( de v dissolution) - Forme solubiliseacutee dans le milieu acide preacutecipitation sous formes de particules tregraves fines rArr A tregraves eacuteleveacutee redissolution aiseacutee Sachant que crsquoest un eacutequilibre la forme neutre solubiliseacutee est absorbeacutee rArr deacuteplacement de lrsquoeacutequilibre et pas de pheacutenomegravene de saturation

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Deacutetermination du pKa

Titimeacutetrie classique Ex de lrsquoacide salicylique

Cas des PA complexes etou peu solubles

Potentiomeacutetrie et spectroscopie


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Coefficient de partage apparent

En biopharmacie et en geacuteneacuteral les systegravemes ne sont pas des solutions ideacuteales et aucune correction nrsquoest effectueacutee

Coefficient de partage octanoleau ou LogP eau

oct

CC P =

Ceau

Coctanol

- Le coefficient de partage est un reflet de la liposolubiliteacute drsquoun meacutedicament - Le passage des meacutedicaments agrave travers des membranes biologiques (absorption distribution et excreacutetion) et leur interaction avec les reacutecepteurs sont fonction de la liposolubiliteacute des meacutedicaments


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Coefficient de distribution logDpH

Acide faible

Base faible

AH A- + H+ eau

octanol


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Mesures sur une gamme de pH variation du Log D vs pH

Ibuprofegravene acide faible


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5 Etat solide - polymorphisme

Deacutefinition simplifieacutee du polymorphisme - Cest laptitude dune moleacutecule agrave exister agrave leacutetat solide suivant diverses structures cristallines mais conduisant bien sucircr au mecircme eacutetat thermodynamique une fois dissous agrave leacutetat fondu ou agrave leacutetat gazeux - Si la(les) structure(s) cristalline(s) contien(nent) en quantiteacute stœchiomeacutetrique (au moins en premiegravere approximation) des moleacutecules de solvants ou deau Solvateshydrates asymp PSEUDOPOLYMORPHISME

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Diffeacuterences drsquoapparence externe HABITUS

Forme amorphe

Forme cristalline

Adduits moleacuteculaires

Stoechiomeacutetriques

SOLVATESHYDRATES PSEUDOPOLYMORPHES

AMORPHE

POLYMORPHES

Diffeacuterences de structure interne

Non stoechiomeacutetriques Composeacutes drsquoinclusion

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PA

Amorphe Polymorphe

Eau - solvant Conformegravere neutre Contre-ion

Hydrate -solvate Co-cristal sel


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Exemple du paraceacutetamol

Forme 1 Forme 2

Repreacutesentation des mailles cristallines

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Conseacutequences Modification des caracteacuteristiques - point de fusion - stabiliteacute (physique chimique) - solubiliteacute V de dissolution - aptitude au process

rArr Reacutepercutions sur la biodisponibiliteacute

Meacutethodes de mise en eacutevidence des formes polymorphes

- Cristallographie Diffraction des rayons X - Morphologie Microscopie - Transition de phases Analyse thermique (TG ATD DSC) - Analyse spectrale IR Raman 13C-RMN - Caractegraveres physiques solubiliteacute point de fusion


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Chaque forme cristalline est caracteacuteriseacutee par une eacutenergie libre G (ou enthalpie libre de Gibbs) disponible pour toute reacuteaction physico-chimique possible Pour deux formes identifieacutees si G1gtG2 S1 S2 = Solubiliteacutes agrave saturation des formes cristallines 1 et 2 (agrave T et P donneacutees) J1 J2 = Vitesses intrinsegraveques de dissolution des formes cristallines 1 et 2 K1 k2 = Constantes cineacutetiques de reacuteaction des formes cristallines 1 et 2 dans tout processus physico-chimique donneacute

2

1

2

1

2

121

kkLogTR

JJLogTR

SSLogTRGGG ===∆=minus


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6 Stabiliteacute

Cause de lrsquoinstabiliteacute du PA Chimiques

- Oxydation - Hydrolyse - Photodeacutegradation ou Photolysehellip - Isomeacuterisation

Physiques - Tempeacuterature - Meacutecanique - Preacutecipitation

Sur FP Interaction(s) avec les excipients conditionnement

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6 Stabiliteacute

Tests adapteacutes en preacuteformulation eacutetat solide solutions

Tests de stress (stabiliteacute compatibiliteacute) - 20 degC - 5 degC - 25 degC 60 RH - 30 degC 60 RH and 30 degC 65 RH - 40 degC 75 RH - Photostabiliteacute - Cycles congeacutelation-deacutecongeacutelation - Tests speacutecifiques des FP (ex semi-solides)

Existence des ICH

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n 7 Permeacuteabiliteacute et classification biopharmaceutique ex de la voie orale

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Surface (m2) Longueur (cm) pH

Estomac 35 025 10-20

Duodeacutenum 19 ~35 40-55

Jeacutejunum 184 ~280 55-70

Ileacuteon 276 ~420 70-75

Colon et rectum 13 ~150 70-75

Meacutecanismes drsquoabsorption des PA

Rappels

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Test de permeacuteabiliteacute sur cellules CaCo2 microvillositeacutes Jonctions serreacutees

Monocouche cellulaire

1 2

Systegraveme automatiseacute

7 Permeacuteabiliteacute et classification biopharmaceutique ex de la voie orale

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21 jours pour - confluence - diffeacuterenciation

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ACdTdQPapp

11

0 sdotsdot=

Test permettant aussi drsquoidentifier - Un efflux actif (eacutetudebasolateral agrave apical et vice versa ratio of B-AA-B)

Si gt1 efflux actif - Inhibiteurs of efflux transporteurs drsquoefflux verapamil (inhibiteur P-gp)

Correacutelation entre Papp et absorption chez lrsquohomme

(cmsec)

A A

B B


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Tecan Genesis CPW 150 workstation

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0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007

solubiliteacute mgmlPapp

Relation solubiliteacute-permeacuteabiliteacute

Exemple de lrsquoibuprofegravene

drsquo ougrave lrsquoexistence de la BCS


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Relation solubiliteacute-permeacuteabiliteacute reprise de lrsquo exemple drsquoutilisation de CD


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solubiliteacute

perm

eacuteabi

liteacute

Classe II Faible solubiliteacute

Forte permeacuteabiliteacute

Classe I Forte solubiliteacute


Classe IV Faible solubiliteacute

Faible permeacuteabiliteacute

Classe III Forte solubiliteacute


Systegraveme de classification biopharmaceutique

Amidon et al 1995 Pharm Res

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Varma et al Current Drug Metabolism November 2004

Programme RampD integravegre la dimension biopharmaceutique

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Exemples de deacuteriveacutes de lrsquooxazolidinone

Biodisponibiliteacute chez le rat faible () modeacutereacutee () et complegravete ()

Diapositive numeacutero 1































































































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Un ancrage recherche Reacuteunion de lrsquoensemble des compeacutetences

- proceacutedeacutes chimie en solution chimie du solide - excipients fonctionnels - formes pharmaceutiques (multi-eacutechelles) - biopharmacie et - biomateacuteriaux

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COURS

41 h


TD

75h Nombre de

seacuteances 5


TP

15h Nombre de

seacuteances 5


Programme

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n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


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n




Proceacutedeacute





temps


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1 meacutedicament






Phase de recherche

Phase de test






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n





actives

Phase de recherche


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cellule

gegravene



Identifier des



les cibles


candidats



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Preacuteformulation

Formulation



DEV

ELO

PPM

ENT




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PREFORMULATION





STABILITE

TOLERANCE

BIODISPONIBILITE

ACCEPTABILITE SE

CU

RIT

E

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- de PA


- SOLUBILITE



- PF


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- STEREOISOMERES

- POLYMORPHISME

- DENSITE APPARENTE

- GRANULOMETRIE

- ETAT DE SURFACE

hellip



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- SOLVATATION

- PROTECTION

(IN VITROIN VIVO)

- STABILISATION

hellip




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DFG

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n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


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n






substances

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n




21 Solubiliteacute


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n







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atio







DFG

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eacutefor

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atio

n

DFG

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Pr

eacutefor

mul

atio








DFG

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Pr

eacutefor

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atio








DFG

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eacutefor

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atio






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atio

n




DFG

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atio

n






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Pr

eacutefor

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atio

n




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n



Ajustement du pH



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Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



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Formation de sels


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n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



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A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




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n




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n





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n



Segment peu soluble




Classification



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[tensioactif]

Solu

bilit

eacute du

PA

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n



α β


α β γ




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CD PA PA

CD

]][[][

CDPACDPAKc minus

=

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n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


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n



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n

Principe actif

cyclodextrine



lineacutezolide


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n




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atio

n




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eacutefor

mul

atio

n






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Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

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n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


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Monophasique

biphasique

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n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


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eacutefor

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n


Objectifs






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eacutefor

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atio

n

VhCCsAD

dtdm

)( minus

=





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eacutefor

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atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





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n





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atio

n




Microcopies optique

DFG

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eacutefor

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atio

n



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mul

atio

n




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mul

atio

n




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eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






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n


500 ndash900 ml




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atio

n




DFG

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Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

COURS

41 h


TD

75h Nombre de

seacuteances 5


TP

15h Nombre de

seacuteances 5


Programme

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Proceacutedeacute





temps


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






1 meacutedicament






Phase de recherche

Phase de test






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





actives

Phase de recherche


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


cellule

gegravene



Identifier des



les cibles


candidats



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Preacuteformulation

Formulation



DEV

ELO

PPM

ENT




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


PREFORMULATION





STABILITE

TOLERANCE

BIODISPONIBILITE

ACCEPTABILITE SE

CU

RIT

E

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- de PA


- SOLUBILITE



- PF


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- STEREOISOMERES

- POLYMORPHISME

- DENSITE APPARENTE

- GRANULOMETRIE

- ETAT DE SURFACE

hellip



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- SOLVATATION

- PROTECTION

(IN VITROIN VIVO)

- STABILISATION

hellip




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






substances

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




21 Solubiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

COURS

41 h


TD

75h Nombre de

seacuteances 5


TP

15h Nombre de

seacuteances 5


Programme

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Proceacutedeacute





temps


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






1 meacutedicament






Phase de recherche

Phase de test






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





actives

Phase de recherche


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


cellule

gegravene



Identifier des



les cibles


candidats



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Preacuteformulation

Formulation



DEV

ELO

PPM

ENT




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


PREFORMULATION





STABILITE

TOLERANCE

BIODISPONIBILITE

ACCEPTABILITE SE

CU

RIT

E

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- de PA


- SOLUBILITE



- PF


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- STEREOISOMERES

- POLYMORPHISME

- DENSITE APPARENTE

- GRANULOMETRIE

- ETAT DE SURFACE

hellip



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- SOLVATATION

- PROTECTION

(IN VITROIN VIVO)

- STABILISATION

hellip




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






substances

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




21 Solubiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

COURS

41 h


TD

75h Nombre de

seacuteances 5


TP

15h Nombre de

seacuteances 5


Programme

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Proceacutedeacute





temps


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






1 meacutedicament






Phase de recherche

Phase de test






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





actives

Phase de recherche


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


cellule

gegravene



Identifier des



les cibles


candidats



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Preacuteformulation

Formulation



DEV

ELO

PPM

ENT




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


PREFORMULATION





STABILITE

TOLERANCE

BIODISPONIBILITE

ACCEPTABILITE SE

CU

RIT

E

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- de PA


- SOLUBILITE



- PF


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- STEREOISOMERES

- POLYMORPHISME

- DENSITE APPARENTE

- GRANULOMETRIE

- ETAT DE SURFACE

hellip



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- SOLVATATION

- PROTECTION

(IN VITROIN VIVO)

- STABILISATION

hellip




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






substances

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




21 Solubiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Proceacutedeacute





temps


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






1 meacutedicament






Phase de recherche

Phase de test






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





actives

Phase de recherche


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


cellule

gegravene



Identifier des



les cibles


candidats



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Preacuteformulation

Formulation



DEV

ELO

PPM

ENT




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


PREFORMULATION





STABILITE

TOLERANCE

BIODISPONIBILITE

ACCEPTABILITE SE

CU

RIT

E

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- de PA


- SOLUBILITE



- PF


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- STEREOISOMERES

- POLYMORPHISME

- DENSITE APPARENTE

- GRANULOMETRIE

- ETAT DE SURFACE

hellip



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- SOLVATATION

- PROTECTION

(IN VITROIN VIVO)

- STABILISATION

hellip




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






substances

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




21 Solubiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Proceacutedeacute





temps


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






1 meacutedicament






Phase de recherche

Phase de test






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





actives

Phase de recherche


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


cellule

gegravene



Identifier des



les cibles


candidats



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Preacuteformulation

Formulation



DEV

ELO

PPM

ENT




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


PREFORMULATION





STABILITE

TOLERANCE

BIODISPONIBILITE

ACCEPTABILITE SE

CU

RIT

E

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- de PA


- SOLUBILITE



- PF


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- STEREOISOMERES

- POLYMORPHISME

- DENSITE APPARENTE

- GRANULOMETRIE

- ETAT DE SURFACE

hellip



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- SOLVATATION

- PROTECTION

(IN VITROIN VIVO)

- STABILISATION

hellip




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






substances

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




21 Solubiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






1 meacutedicament






Phase de recherche

Phase de test






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





actives

Phase de recherche


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


cellule

gegravene



Identifier des



les cibles


candidats



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Preacuteformulation

Formulation



DEV

ELO

PPM

ENT




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


PREFORMULATION





STABILITE

TOLERANCE

BIODISPONIBILITE

ACCEPTABILITE SE

CU

RIT

E

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- de PA


- SOLUBILITE



- PF


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- STEREOISOMERES

- POLYMORPHISME

- DENSITE APPARENTE

- GRANULOMETRIE

- ETAT DE SURFACE

hellip



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- SOLVATATION

- PROTECTION

(IN VITROIN VIVO)

- STABILISATION

hellip




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






substances

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




21 Solubiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





actives

Phase de recherche


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


cellule

gegravene



Identifier des



les cibles


candidats



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Preacuteformulation

Formulation



DEV

ELO

PPM

ENT




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


PREFORMULATION





STABILITE

TOLERANCE

BIODISPONIBILITE

ACCEPTABILITE SE

CU

RIT

E

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- de PA


- SOLUBILITE



- PF


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- STEREOISOMERES

- POLYMORPHISME

- DENSITE APPARENTE

- GRANULOMETRIE

- ETAT DE SURFACE

hellip



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- SOLVATATION

- PROTECTION

(IN VITROIN VIVO)

- STABILISATION

hellip




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






substances

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




21 Solubiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


cellule

gegravene



Identifier des



les cibles


candidats



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Preacuteformulation

Formulation



DEV

ELO

PPM

ENT




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


PREFORMULATION





STABILITE

TOLERANCE

BIODISPONIBILITE

ACCEPTABILITE SE

CU

RIT

E

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- de PA


- SOLUBILITE



- PF


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- STEREOISOMERES

- POLYMORPHISME

- DENSITE APPARENTE

- GRANULOMETRIE

- ETAT DE SURFACE

hellip



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- SOLVATATION

- PROTECTION

(IN VITROIN VIVO)

- STABILISATION

hellip




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






substances

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




21 Solubiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Preacuteformulation

Formulation



DEV

ELO

PPM

ENT




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


PREFORMULATION





STABILITE

TOLERANCE

BIODISPONIBILITE

ACCEPTABILITE SE

CU

RIT

E

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- de PA


- SOLUBILITE



- PF


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- STEREOISOMERES

- POLYMORPHISME

- DENSITE APPARENTE

- GRANULOMETRIE

- ETAT DE SURFACE

hellip



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- SOLVATATION

- PROTECTION

(IN VITROIN VIVO)

- STABILISATION

hellip




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






substances

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




21 Solubiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


PREFORMULATION





STABILITE

TOLERANCE

BIODISPONIBILITE

ACCEPTABILITE SE

CU

RIT

E

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- de PA


- SOLUBILITE



- PF


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- STEREOISOMERES

- POLYMORPHISME

- DENSITE APPARENTE

- GRANULOMETRIE

- ETAT DE SURFACE

hellip



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- SOLVATATION

- PROTECTION

(IN VITROIN VIVO)

- STABILISATION

hellip




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






substances

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




21 Solubiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- de PA


- SOLUBILITE



- PF


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- STEREOISOMERES

- POLYMORPHISME

- DENSITE APPARENTE

- GRANULOMETRIE

- ETAT DE SURFACE

hellip



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- SOLVATATION

- PROTECTION

(IN VITROIN VIVO)

- STABILISATION

hellip




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






substances

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




21 Solubiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- STEREOISOMERES

- POLYMORPHISME

- DENSITE APPARENTE

- GRANULOMETRIE

- ETAT DE SURFACE

hellip



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- SOLVATATION

- PROTECTION

(IN VITROIN VIVO)

- STABILISATION

hellip




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






substances

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




21 Solubiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



- SOLVATATION

- PROTECTION

(IN VITROIN VIVO)

- STABILISATION

hellip




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






substances

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




21 Solubiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






substances

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




21 Solubiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






substances

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




21 Solubiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






substances

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




21 Solubiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




21 Solubiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




21 Solubiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio







DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio








DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Ajustement du pH



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Solu

bilit

eacute du

PA

Courbe

de solubiliteacute



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


Formation de sels


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

plateau

phase solide = sel


Solu

bilit

eacute du

PA

liquide

solide

solide solide

zone 2 zone 1

zone 2 zone 1



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



A-

A-

A-

A- A-

A-

A-

A-

Na+

Na+ Na+

Na+

Na+

Na+ Na+

Na+




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Segment peu soluble




Classification



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio





[tensioactif]

Solu

bilit

eacute du

PA

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



α β


α β γ




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



CD PA PA

CD

]][[][

CDPACDPAKc minus

=

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA so

lubi

liseacute

(ST)

PA so

lubi

liseacute

(ST)

[cyclodextrines]



[cyclodextrines]


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Principe actif

cyclodextrine



lineacutezolide


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Dispersion solide



Micro-ondes


Electrospinning


Spray-drying

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

Meacutelange


Fusion (Tdeg)

refroidissement

granulation


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio









Monophasique

biphasique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PREFORMULATION


2 Solubiliteacute




6 Stabiliteacute


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Objectifs






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

VhCCsAD

dtdm

)( minus

=





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





ρρπ

π3

34

43

2

rrn

rnA ==





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




Microcopies optique

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Q=kot mgmin-1cm-2






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


500 ndash900 ml




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Ameacutelioration




Drug released

collection

HPLC dosage

Sample


Drug released

collection

HPLC dosage

Sample


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



acide

base


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

71


Plasma pH = 74


AH A- + H+

AH A- + H+

X

X ][][log4341

AHAminus

+= rArr [AH] ~99

][][log4347

AHAminus

+= rArr [A-] ~100


][][log

AHApKapH

minus

+=

Acide faible donc


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




oct

CC P =

Ceau

Coctanol



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


Acide faible

Base faible

AH A- + H+ eau

octanol


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme amorphe

Forme cristalline




AMORPHE

POLYMORPHES



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

PA

Amorphe Polymorphe




DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



Forme 1 Forme 2


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


2

1

2

1

2

121

kkLogTR

JJLogTR



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute





DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

6 Stabiliteacute



Existence des ICH

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio



Estomac 35 025 10-20






Rappels

DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



1 2



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

ACdTdQPapp

11

0 sdotsdot=




(cmsec)

A A

B B


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n


DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n

0

2

4

6

8

10

12

14

16

2 3 4 5 6 7 8 9 100

001

002

003

004

005

006

007






DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio


solubiliteacute

perm

eacuteabi

liteacute











DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



DFG

-SP-

2 B

ioph

arm

acie

Pr

eacutefor

mul

atio

n



































































































Equipe pédagogique

Documents

Transcript of Equipe pédagogique