title: Modeling Physical Stability of Amorphous Solids Based on Temperature and Moisture Stresses.
abstract: Isothermal microcalorimetry was utilized to monitor the crystallization process of amorphous ritonavir (RTV) and its hydroxypropylmethylcellulose acetate succinate-based amorphous solid dispersion under various stressed conditions. An empirical model was developed: ln(τ)=ln(A)+EaRT-b⋅wc, where τ is the crystallization induction period, A is a pre-exponential factor, Ea is the apparent activation energy, b is the moisture sensitivity parameter, and wc is water content. To minimize the propagation of errors associated with the estimates, a nonlinear approach was used to calculate mean estimates and confidence intervals. The physical stability of neat amorphous RTV and RTV in hydroxypropylmethylcellulose acetate succinate solid dispersions was found to be mainly governed by the nucleation kinetic process. The impact of polymers and moisture on the crystallization process can be quantitatively described by Ea and b in this Arrhenius-type model. The good agreement between the measured values under some less stressful test conditions and those predicted, reflected by the slope and R(2) of the correlation plot of these 2 sets of data on a natural logarithm scale, indicates its predictability of long-term physical stability of amorphous RTV in solid dispersions. To further improve the model, more understanding of the impact of temperature and moisture on the amorphous physical stability and fundamentals regarding nucleation and crystallization is needed.
authors.affiliation: Drug Product Development, Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064.
authors.forename: Donghua Alan
authors.initials: DA
authors.lastname: Zhu
authors.affiliation: School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, Wisconsin 53705.
authors.forename: George
authors.initials: G
authors.lastname: Zografi
authors.affiliation: Drug Product Development, Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064.
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.affiliation: Drug Product Development, Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064.
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Drug Product Development, Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064. Electronic address: Geoff.GZ.Zhang@abbvie.com.
authors.forename: Geoff G Z
authors.initials: GGZ
authors.lastname: Zhang
mesh_terms: D000465:Algorithms; D019380:Anti-HIV Agents / Q000737:chemistry; D002151:Calorimetry; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D004339:Drug Compounding; D004355:Drug Stability; D006813:Humidity; D007700:Kinetics; D008747:Methylcellulose / Q000031:analogs & derivatives; D008962:Models, Theoretical; D011237:Predictive Value of Tests; D019438:Ritonavir / Q000737:chemistry; D013696:Temperature
chemical_list: D019380:Anti-HIV Agents; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose; D019438:Ritonavir
keywords: amorphous; crystal growth; crystallization; isothermal microcalorimetry; mathematical model; nucleation; physical stability; solid dispersion