Department of Chemical Engineering, University of Chemistry and Technology, Prague, Technická 3, 166 28 Prague 6, Czech Republic; Department of Physical Chemistry, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague 6, Czech Republic.
Department of Chemical Engineering, University of Chemistry and Technology, Prague, Technická 3, 166 28 Prague 6, Czech Republic.
Int J Pharm. 2020 Nov 15;589:119845. doi: 10.1016/j.ijpharm.2020.119845. Epub 2020 Sep 12.
The preparation of an amorphous solid dispersion (ASD) is a promising strategy for improving the poor oral bioavailability of many active pharmaceutical ingredients (APIs). However, poor predictability of ASD long-term physical stability remains a prevalent problem. The purpose of this study was to evaluate and compare the predictive performance of selected models concerning solid-liquid equilibrium (SLE) curve and glass-transition temperature (T) line modeling of ibuprofen (IBU) in cellulosic polymers (i.e., hydroxypropyl methylcellulose (HPMC) and hydroxypropyl methylcellulose acetate succinate (HPMCAS)). For SLE curve modeling, an empiricalanalyticalapproach(Kyeremateng et al., 2014)and the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) equation of state (EOS) were chosen. Due to the unavailability of PC-SAFT parameters for both polymers, an approximation procedure for parametrization was applied. The Gordon-Taylor equation and Kwei equation were considered for T line determination. The impact of various computational set-ups (e.g., model parametrization or extrapolation length) on IBU solubility prediction at storage conditions was thoroughly investigated, assessed and confronted with the results from an 18-month physical stability study. IBU developed stable 20 wt% API content ASDs with both HPMC and HPMCAS.The extrapolation behavior and subsequent ASD thermodynamic stability prediction at storage conditions deduced from the aforementioned models weresignificantly different. Overall, the PC-SAFT EOS predicted higher IBU solubility in both polymers and, thus, a lower recrystallization tendency when compared to the empirical analytical approach. At higherIBU concentrations, liquid-liquid demixing inIBU-polymer systems was predicted by the PC-SAFT EOS, which was in qualitative disagreement with experimental observation.
制备无定形固体分散体（ASD）是提高许多活性药物成分（API）口服生物利用度的一种有前途的策略。然而，ASD 长期物理稳定性的可预测性仍然是一个普遍存在的问题。本研究的目的是评估和比较所选模型在评估布洛芬（IBU）在纤维素聚合物（即羟丙基甲基纤维素（HPMC）和羟丙基甲基纤维素醋酸琥珀酸酯（HPMCAS））中的固液平衡（SLE）曲线和玻璃化转变温度（T）线建模方面的预测性能。对于 SLE 曲线建模，选择了经验分析方法（Kyeremateng 等人，2014 年）和受扰链统计关联流体理论（PC-SAFT）状态方程（EOS）。由于两种聚合物都没有 PC-SAFT 参数，因此应用了参数化的近似程序。考虑了 Gordon-Taylor 方程和 Kwei 方程来确定 T 线。彻底研究、评估和对比了各种计算设置（例如，模型参数化或外推长度）对储存条件下 IBU 溶解度预测的影响，并与 18 个月物理稳定性研究的结果进行了对比。IBU 在 HPMC 和 HPMCAS 中均开发了稳定的 20wt%API 含量 ASD。从上述模型推断出的储存条件下的外推行为和随后的 ASD 热力学稳定性预测存在显着差异。总体而言，与经验分析方法相比，PC-SAFT EOS 预测了两种聚合物中更高的 IBU 溶解度，因此具有更低的重结晶趋势。在更高的 IBU 浓度下，PC-SAFT EOS 预测了 IBU-聚合物体系中的液-液相分离，这与实验观察结果在定性上不一致。
