Characterization of Amorphous Solid Dispersions of AMG 517 in HPMC-AS and Crystallization using Isothermal Microcalorimetry.

摘要

Purpose. Recently there has been increasing interest in the development of amorphous materials, particularly on developing low solubility drugs as amorphous solid dispersions (ASDs). Understanding the crystallization rate of miscible and partially miscible ASDs is critical for the development of amorphous drugs as solid dispersions. This project focuses on examining the solid state properties of AMG 517 in HPMC-AS polymer, and stability using isothermal microcalorimetry and SSNMR.;Methods. ASDs of AMG 517 in HPMC-AS were manufactured using a Buchi 290 Mini Spray Dry system. Several techniques were used to evaluate the ASDs, including XRPD, GC, TGA, mDSC, SEM and vapor sorption. Crystallization of ASDs at elevated conditions of temperature and humidity were evaluated using isothermal microcalorimetry (TAM). Crystallinity was measured using 19F SSNMR.;Results. XRPD and mDSC evaluations demonstrated that all manufactured ASDs were amorphous. Although residual solvent contributes to the depression of Tg values of ASDs in general, significant depression of the Tg is observed which is not accounted for by residual solvent effects. Crystallization events for AMG 517 in HPMC-AS at temperature and relative humidity conditions near the Tg were observed by TAM, as long as heat flow is >1iW. At conditions below the Tg, crystallization is much slower, resulting in heat signal so low that it is difficult to identify a single crystallization event. However, SS-NMR confirms partial crystallization of HPMC-AS ASDs even for slow crystallizations below Tg. A dual mechanism was observed for crystallization of some ASDs indicating possible phase separation at higher drug loads, which was not observed by mDSC.;Conclusions. Isothermal microcalorimetry can provide important kinetic data for the crystallization of ASDs. The crystallization of ASDs of AMG 517 in HPMC-AS follows the expected trends in terms of temperature and humidity (i.e. faster crystallization at higher temperature and humidity conditions). Crystallization is significantly slowed by the presence of HPMC-AS polymer. Rate constants for ASD crystallizations aid drug load selection for maximizing stability while minimizing polymer in the formulation.