Isothermal Microcalorimetry To Investigate the Phase Separation for Amorphous Solid Dispersions of AMG 517 with HPMC-AS
Isothermal Microcalorimetry To Investigate the Phase Separation for Amorphous Solid Dispersions of AMG 517 with HPMC-AS
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DOI：
10.1021/mp300714g
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发表时间：
2013-05-01
影响因子：
4.9
通讯作者：
Munson, Eric J.
中科院分区：
文献类型：
--
作者：
Calahan, Julie L.;Zanon, Roger L.;Munson, Eric J.
了解无定形药物的结晶动力学对于无定形固体分散体（ASD）制剂的开发至关重要。本文采用等温微量热法研究了不同载药量的ASD中药物AMG 517在不同温度和相对湿度条件下的相分离和结晶。采用Buchi 290微型喷雾干燥器系统生产AMG 517醋酸羟丙基甲基纤维素琥珀酸酯（HPMC-AS）中的ASD。ASD的特点是使用调制差示扫描量热法（mDSC）和扫描电子显微镜（SEM）之前的等温微量热法评价，和结晶度进行了测量，使用F-19固态核磁共振光谱（SSNMR），之前和之后的结晶。HPMC-AS聚合物的存在显著减缓了HPMC-AS中AMG 517 ASD的结晶，表明ASD制剂的物理稳定性增强。通过等温微量热法在玻璃化转变温度（T-g）附近的温度下观察到两相结晶，表明富药物相和可混溶ASD相。F-19 SSNMR显示ASD中仅发生药物的部分结晶，表明存在未结晶的第三相，可能代表药物稳定的可溶组分。等温微量热法为监测ASD中药物的结晶提供了重要的动力学数据，并与F-19 SSNMR一起表明HPMC-AS中AMG 517的三相ASD系统。
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 F-19 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 (T-g), indicating a drug-rich phase and a miscible ASD phase. F-19 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 F-19 SSNMR, suggests a three-phase ASD system for AMG 517 in HPMC-AS.