Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Mol Pharm. 2013 May 6;10(5):1949-57. doi: 10.1021/mp300714g. Epub 2013 Apr 24.
Understanding the crystallization kinetics of an amorphous drug is critical for the development of an amorphous solid dispersion (ASD) formulation. This paper examines the phase separation and crystallization of the drug AMG 517 in ASDs of varying drug load at various conditions of temperature and relative humidity using isothermal microcalorimetry. ASDs of AMG 517 in hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were manufactured using a Buchi 290 mini spray dryer system. ASDs were characterized using modulated differential scanning calorimetry (mDSC) and scanning electron microscopy (SEM) prior to isothermal microcalorimetry evaluation, and crystallinity was measured using (19)F solid state nuclear magnetic resonance spectroscopy (SSNMR), before and after crystallization. The crystallization of ASDs of AMG 517 in HPMC-AS was significantly slowed by the presence of HPMC-AS polymer, indicating enhanced physical stability for the ASD formulations. A two-phase crystallization was observed by isothermal microcalorimetry at temperatures near the glass transition temperature (Tg), indicating a drug-rich phase and a miscible ASD phase. (19)F SSNMR showed that only partial crystallization of the drug occurred for the ASDs, suggesting a third phase which did not crystallize, possibly representing a thermodynamically stable, soluble component. Isothermal microcalorimetry provides important kinetic data for monitoring crystallization of the drug in the ASDs and, together with (19)F SSNMR, suggests a three-phase ASD system for AMG 517 in HPMC-AS.
了解无定形药物的结晶动力学对于开发无定形固体分散体（ASD）制剂至关重要。本文使用等温微量量热法研究了在不同温度和相对湿度条件下，不同药物负载的 AMG 517 ASD 的相分离和结晶。使用 Buchi 290 迷你喷雾干燥系统制造了 AMG 517 在羟丙基甲基纤维素醋酸琥珀酸酯（HPMC-AS）中的 ASD。在等温微量量热评估之前，使用调制差示扫描量热法（mDSC）和扫描电子显微镜（SEM）对 ASD 进行了表征，并在结晶前后使用（19）F 固态核磁共振波谱法（SSNMR）测量了结晶度。HPMC-AS 聚合物的存在显著减缓了 AMG 517 ASD 的结晶，表明 ASD 配方的物理稳定性增强。等温微量量热法在接近玻璃化转变温度（Tg）的温度下观察到两相结晶，表明存在药物丰富相和可混溶性 ASD 相。（19）F SSNMR 表明，ASD 中仅部分药物结晶，表明存在未结晶的第三相，可能代表热力学稳定的可溶性成分。等温微量量热法为监测 ASD 中药物结晶提供了重要的动力学数据，与（19）F SSNMR 一起，表明 AMG 517 在 HPMC-AS 中的 ASD 系统为三相。
