Department of Physical Chemistry, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague 6, Czech Republic.
Faculty of Chemical Engineering, University of Chemistry and Technology, Prague, Technická 3, 166 28 Prague 6, Czech Republic.
Mol Pharm. 2021 Apr 5;18(4):1742-1757. doi: 10.1021/acs.molpharmaceut.0c01232. Epub 2021 Mar 3.
Knowledge of the active pharmaceutical ingredient (API) solubility in a polymer is imperative for successful amorphous solid dispersion design and formulation but acquiring this information at storage temperature is challenging. Various solubility determination methods have been established, which utilize differential scanning calorimetry (DSC). In this work, three commonly used DSC-based protocols [i.e., melting point depression (MPD), recrystallization, and zero-enthalpy extrapolation (Z-EE)] and a method that we have developed called "step-wise dissolution" (S-WD) were analyzed. For temperature-composition phase diagram construction, two glass-transition temperature equations (i.e., those of Gordon-Taylor and Kwei) and three solid-liquid equilibrium curve modeling approaches [i.e., the Flory-Huggins model, an empirical equation, and the perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state (EOS)] were considered. Indomethacin (IND) and Kollidon 12 PF (PVP K12) were selected as the API and polymer, respectively. An annealing time investigation revealed that the IND-PVP K12 dissolution process was remarkably faster than demixing, which contradicted previously published statements. Thus, the recrystallization method overestimated the solubility of IND in PVP K12 when a 2-h time of annealing was set as the benchmark. Likewise, the MPD and Z-EE methods overestimated the API solubility because of unreliable IND melting endotherm evaluation at lower API loadings and a relatively slow heating rate, respectively. When the experimental results obtained using the S-WD method (in conjunction with the Kwei equation) were applied to the PC-SAFT EOS, which was regarded as the most reliable combination, the predicted IND solubility in PVP K12 at = 25 °C was approximately 40 wt %. When applicable, the S-WD method offers the advantage of using a limited number of DSC sample pans and API-polymer physical mixture compositions, which is both cost- and time-effective.
了解活性药物成分 (API) 在聚合物中的溶解度对于成功设计和配制无定形固体分散体至关重要，但在储存温度下获取此信息具有挑战性。已经建立了各种溶解度测定方法，这些方法利用差示扫描量热法 (DSC)。在这项工作中，分析了三种常用的基于 DSC 的方案[即熔点降低 (MPD)、重结晶和零焓外推 (Z-EE)]和我们开发的一种称为“逐步溶解”(S-WD)的方法。为了构建温度-组成相图，考虑了两个玻璃化转变温度方程（即 Gordon-Taylor 和 Kwei 方程）和三种固液平衡曲线建模方法[即 Flory-Huggins 模型、经验方程和受扰链统计关联流体理论 (PC-SAFT) 状态方程 (EOS)]。吲哚美辛 (IND) 和 Kollidon 12 PF (PVP K12) 分别被选为 API 和聚合物。退火时间研究表明，IND-PVP K12 的溶解过程明显快于离析，这与之前发表的声明相矛盾。因此，当设定 2 小时的退火时间作为基准时，重结晶方法高估了 IND 在 PVP K12 中的溶解度。同样，MPD 和 Z-EE 方法高估了 API 的溶解度，因为在较低的 API 负载下，IND 熔融吸热的评估不可靠，并且加热速率相对较慢。当使用 S-WD 方法（与 Kwei 方程结合使用）获得的实验结果应用于被认为是最可靠组合的 PC-SAFT EOS 时，在 = 25°C 时预测的 IND 在 PVP K12 中的溶解度约为 40wt%。在适用的情况下，S-WD 方法具有使用少量 DSC 样品盘和 API-聚合物物理混合物组成的优势，这既具有成本效益又节省时间。
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