crystallization kinetics in asds · luebbert, c.; wessner, m.; sadowski, g.: mol. pharmaceutics,...

CrystallizationkineticsinASDs

DDFSummit|March13th 2019 | Berlin

ChristianLuebbert,GabrieleSadowski

LaboratoryofThermodynamics

2Dr.ChristianLuebbertDDFSummit|March13th 2019|Berlin

LaboratoryofThermodynamicsProf.Dr.G.Sadowski

Amorphous soliddispersions (ASDs)

§ ASDs:Stateof the art formulation technique for poorly water-solubleactive pharmaceuticalingredients (APIs)

crystalline API

…dissolved inpolymer

ASD

Enhancedbioavailability

APIcrystallization

Limitedlong-termstability

but:

Many ASDsmarketedbecause most new APIsarepoorly solubleinwater



Phasebehavior and long-termstability

crystallization

stable

storage

§ Phasediagrams used to estimate thecrystallization behavior inASDs

Felodipine/PVP(0%RH)

Gordon-TaylororKwei equation

PC-SAFT

long-termstudies were carried outforthreeyears



PXRD

signal[a.u.]

Felodipine/PVP(0%RH)

All predicted-stable ASDsremainedstable!

Phasebehavior and long-termstability

§ Phasediagrams used to estimate thecrystallization behavior inASDs



stability test T RHlong-term(12months) 25°C 60%accelerated (6months) 40°C 75%

Predicting the influence of humidity

§ Humidity (RH)influences phase diagram

§ Thermodynamic equilibrium:

• humidair (V)

• ASD(polymer+API)

V

L L+S

amorphous crystallized

storage



Phasebehavior and sorption profiles

crystallization

stable

sorption:

I.Water sorption inamorphous ASDII./III.:Crystallization may occur

phase diagram athighRH water sorption athighRH

Lwater

LwaterxRH g×=

I.

II.

III.

Tempe

rature



III:Phaseseparationfollowedbycrystallization

water sorption inASDsdepends ontime

Luebbert,C.;Wessner,M.;Sadowski,G.:Mol.Pharmaceutics,2018,15(2),669-678

5days

500days

phase diagram at75%RH water sorption at40°C/75%RH

Felodipine/PVP



III:Phaseseparationfollowedbycrystallization

water sorption inASDsdepends ontime


5days

500days

phase diagram at75%RH water sorption at40°C/75%RH

Felodipine/PVP

25°C/ 0%RH



Felodipine/PVAC- formulations

Felodipine/PVAC

40°C/75%RH

wwater[-]

sorption after500days storage



Felodipine/PVAC Felodipine/PVP

water sorption at40°C/75%RHwater sorption at40°C/75%RH

Influence ofpolymerhydrophilicity




Felodipine/PVAC Felodipine/PVP

water sorption at40°C/75%RHwater sorption at40°C/75%RH

Influence ofpolymerhydrophilicity


time

polymerhydrophilicity RH

water sorption

crystallization

shelf life



Crystallization kinetics ofpuresubstances

Burnettetal.:Int J.Pharm.,2006,313,23-28Li,W.andBuckton,G.:Int.J.Pharm.,2015,495,999-1004

DVS:standard method toquantify crystallization kineticsofpure substances (lactose,

griseofulvin)

amorphous

crystallizing



Time-dependent water sorption

Time-dependent water sorption innifedipine/PVACASDstored at40°C/75%RH

Nifedipine/PVAC



Water sorption vs.APIcrystallization

water sorption inamorphous/crystallizing formulation used to determine crystallinity

sorption diagram atconstant RHcrystallinity as function of time

wAP

I(L)[-]

wcrystals[-]

wwater[-]

wAPI=0.70



Crystallization as function oftime

Nifedipine/PVAC

sorption diagram atconstant RHDVSmeasurement

crystallinity




crystallization

highwAPI

Luebbert,C.;Sadowski,G.:Eur.J.Pharm.Biopharm.,2018,127,183-193

Nifedipine/PVACwNIF=0.80;75%RHwNIF =0.80;40°C

influence of wNIF




40°C/75%RH

crystallization

highwAPI highT

wNIF=0.80;75%RH


Nifedipine/PVAC

influence of temperature




40°C/75%RH

crystallization

highwAPI highT highRH

wNIF=0.80;75%RHwNIF =0.80;40°C


Nifedipine/PVAC

influence of RH



§ Johnson-Mehl-Avrami-Kolmogorow (JMAK)– equation

Ø Estimating thecrystallization velocity atdifferentstorage conditions

Modelingandpredicting thecrystallization kinetics

JMAKplot

Y t =1−exp(−ktn)

nln(k)



Crystallization constants

Crystallization constants ofASDsdetermined

influence of RHinfluence of wNIF



§ Water sorption as function oftimeviaDVSmeasurement

• HOWFASTdoes theAPIcrystallize?

§ Thermodynamic phase behavior atelevated RHviaPC-SAFT

• PredictionWHETHERAPIcrystallizes

Summary

mass fraction API[-]

Temperature

[°C]

RH

time[h]

Crystals[-]

Shelf life estimation

Thankyouforyourattention!

crystallization kinetics in asds · luebbert, c.; wessner, m.; sadowski, g.: mol. pharmaceutics,...

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