Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, TU Dortmund University, Emil-Figge-Str. 70, D-44227 Dortmund, Germany.
AbbVie Deutschland GmbH & Co. KG, Global Pharmaceutical R&D, Knollstraße, D-67061 Ludwigshafen am Rhein, Germany.
Int J Pharm. 2020 Mar 15;577:119065. doi: 10.1016/j.ijpharm.2020.119065. Epub 2020 Jan 24.
In the pharmaceutical industry, polymers are used as excipients for formulating poorly water-soluble active pharmaceutical ingredients (APIs) in so-called "amorphous solid dispersions" (ASDs). ASDs can be produced via solvent-based processes, where API and polymer are both dissolved in a solvent, followed by a solvent evaporation step (e.g. spray drying). Aiming at a homogeneous API/polymer formulation, phase separation of the components (API, polymer, solvent) during solvent evaporation must be avoided. The latter is often determined by the phase behavior of polymer/solvent mixtures used for ASD processing. Therefore, this work investigates the polymer-solvent interactions in these mixtures. Suitable polymer/solvent combinations investigated in this work comprise the pharmaceutically relevant polymers poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64), and hydroxyppropyl methylcellulose acetate succinate 126G (HPMCAS) as well as the solvents acetone, dichloromethane (DCM), ethanol, ethyl acetate, methanol, and water. Based on vapor-sorption experiments demixing of solvents and polymers were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These were found to be correct for all investigated solvent/polymer mixtures. Acetone, DCM, ethanol, methanol, and water were found to be completely miscible with PVPVA64. DCM, ethanol, methanol, and water were found to be completely miscible with PVP K90, while none of the investigated solvents was appropriate for avoiding immiscibility with HPMCAS. In addition, the impact of temperature, polymer molecular weight, and solvent-mixture composition on miscibility was successfully predicted using PC-SAFT. Thus, the proposed methodology allows identifying suitable solvents or solvent mixtures relevant for solvent-based preparations of pharmaceutical ASD formulations with low experimental effort.
在制药行业中，聚合物被用作将水溶性差的活性药物成分（APIs）制成所谓的“无定形固体分散体”（ASD）的赋形剂。ASD 可以通过溶剂型工艺生产，其中 API 和聚合物都溶解在溶剂中，然后进行溶剂蒸发步骤（例如喷雾干燥）。为了获得均匀的 API/聚合物配方，必须避免在溶剂蒸发过程中组件（API、聚合物、溶剂）的相分离。后者通常由用于 ASD 加工的聚合物/溶剂混合物的相行为决定。因此，这项工作研究了这些混合物中的聚合物-溶剂相互作用。本工作中研究的合适聚合物/溶剂组合包括药用相关聚合物聚乙烯吡咯烷酮（PVP）、聚乙烯吡咯烷酮-乙酸乙烯酯共聚物（PVPVA64）和羟丙基甲基纤维素醋酸琥珀酸酯 126G（HPMCAS）以及溶剂丙酮、二氯甲烷（DCM）、乙醇、乙酸乙酯、甲醇和水。基于蒸汽吸附实验，使用受扰链统计关联流体理论（PC-SAFT）预测了溶剂和聚合物的分相。对于所有研究的溶剂/聚合物混合物，这被发现是正确的。发现丙酮、DCM、乙醇、甲醇和水与 PVPVA64 完全混溶。发现 DCM、乙醇、甲醇和水与 PVP K90 完全混溶，而没有一种研究溶剂适合避免与 HPMCAS 不混溶。此外，成功地使用 PC-SAFT 预测了温度、聚合物分子量和溶剂混合物组成对混溶性的影响。因此，该方法允许用低实验工作量识别适用于基于溶剂的药物 ASD 制剂制备的合适溶剂或溶剂混合物。
