Luebbert Christian, Sadowski Gabriele
TU Dortmund, Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, Emil-Figge-Str. 70, D-44227 Dortmund, Germany.
TU Dortmund, Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, Emil-Figge-Str. 70, D-44227 Dortmund, Germany.
Int J Pharm. 2017 Oct 30;532(1):635-646. doi: 10.1016/j.ijpharm.2017.08.121. Epub 2017 Sep 1.
Active Pharmaceutical Ingredients (APIs) are often dissolved in polymeric matrices to control the gastrointestinal dissolution and to stabilize the amorphous state of the API. During the pharmaceutical development of new formulations, stability studies via storage at certain temperature and relative humidity (RH) have to be carried out to verify the long-term thermodynamic stability of these formulations against unwanted recrystallization and moisture-induced amorphous-amorphous phase separation (MIAPS). This study focuses on predicting the MIAPS of API/polymer formulations at elevated RH. In a first step, the phase behavior of water-free formulations of ibuprofen (IBU) and felodipine (FEL) combined with the polymers poly(vinyl pyrrolidone) (PVP), poly(vinyl acetate) (PVAC) and poly (vinyl pyrrolidone-co-vinyl acetate) (PVPVA64) was determined experimentally by differential scanning calorimetry (DSC). The phase behavior of these water-free formulations was modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). Based on this, the API solubility and MIAPS in the above-mentioned formulations at humid conditions was predicted in perfect agreement with the results of two-year lasting stability studies at 25°C/0% RH and 40°C/75% RH. MIAPS was predicted and also experimentally found for the FEL/PVP, FEL/PVPVA64 and IBU/PVP formulations, whereas MIAPS was neither predicted nor measured for the IBU/PVPVA64 system and PVAC-containing formulations. It was thus shown that the results of time-consuming long-term stability tests can be correctly predicted via thermodynamic modeling with PC-SAFT.
活性药物成分（API）通常溶解于聚合物基质中，以控制其在胃肠道中的溶解，并稳定API的无定形状态。在新制剂的药物研发过程中，必须通过在特定温度和相对湿度（RH）下储存进行稳定性研究，以验证这些制剂针对不必要的重结晶和水分诱导的无定形-无定形相分离（MIAPS）的长期热力学稳定性。本研究聚焦于预测在高RH条件下API/聚合物制剂的MIAPS。第一步，通过差示扫描量热法（DSC）实验测定了布洛芬（IBU）和非洛地平（FEL）与聚合物聚乙烯吡咯烷酮（PVP）、聚醋酸乙烯酯（PVAC）和聚乙烯吡咯烷酮-醋酸乙烯酯共聚物（PVPVA64）的无水制剂的相行为。使用扰动链统计缔合流体理论（PC-SAFT）对这些无水制剂的相行为进行建模。基于此，预测了上述制剂在潮湿条件下的API溶解度和MIAPS，与在25°C/0%RH和40°C/75%RH下进行的为期两年的稳定性研究结果完全一致。预测并通过实验发现FEL/PVP、FEL/PVPVA64和IBU/PVP制剂存在MIAPS，而对于IBU/PVPVA64体系和含PVAC的制剂，既未预测到也未检测到MIAPS。因此表明，通过PC-SAFT进行热力学建模可以正确预测耗时的长期稳定性测试结果。
