Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, United States.
Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, United States.
J Control Release. 2018 Jun 10;279:114-125. doi: 10.1016/j.jconrel.2018.04.014. Epub 2018 Apr 11.
The maximum achievable concentration of a drug in solution is dictated by the chemical potential of the solid form. Because an amorphous solid has a higher chemical potential than the corresponding crystal form, in the absence of phase transformations, a higher transient solubility is expected. However, the chemical potential of an amorphous drug can be reduced by mixing with another component. Therefore, upon mixing with a polymer to form an amorphous solid dispersion (ASD), the maximum solution concentration achieved can be potentially altered, in particular if the polymer is poorly soluble in the dissolution medium. Such changes in the chemical potential of the drug may be a critical factor in determining the maximum achievable solution concentration, and could alter the crystallization driving force of the drug. Therefore, the aim of this study was to gain insights into the impact of poorly soluble polymers on the "amorphous solubility" of drugs formulated as amorphous solid dispersions. Lopinavir was selected as a model drug with a low crystallization tendency, enabling determination of the amorphous solubility as a function of ASD composition. Model polymers included cellulose acetate (CA), CA phthalate (CAP), ethylcellulose (EC), Eudragit® RL PO (EUD), hydroxypropylmethylcellulose (HPMC), HPMC acetate succinate (HPMCAS), and HPMC phthalate (HPMCP). The "amorphous solubility" of the drug alone was determined and then the changes in maximum achievable concentration were measured as a function of drug loading. Drug-polymer interactions were characterized using infrared spectroscopy (IR), differential scanning calorimetry (DSC) and moisture sorption analysis. The results showed that the maximum achievable concentration ("amorphous solubility") of lopinavir varied with the extent of drug-polymer interactions, as well as the drug weight fraction in the ASD. This information is of great value when evaluating the maximum achievable concentration of amorphous systems formulated with pH responsive polymers, and should contribute to a broader understanding of drug phase behavior in the context of ASDs.
药物在溶液中的最大可实现浓度取决于固体形式的化学势。由于无定形固体具有比相应晶型更高的化学势，因此在没有相变的情况下，预计会有更高的瞬时溶解度。然而，无定形药物的化学势可以通过与另一种成分混合而降低。因此，当与聚合物混合形成无定形固体分散体（ASD）时，所达到的最大溶液浓度可能会发生变化，特别是如果聚合物在溶解介质中溶解度较差的话。药物化学势的这种变化可能是决定最大可实现溶液浓度的关键因素，并可能改变药物的结晶驱动力。因此，本研究的目的是深入了解溶解度较差的聚合物对作为无定形固体分散体配制的药物的“无定形溶解度”的影响。洛匹那韦被选为具有低结晶倾向的模型药物，能够确定 ASD 组成的无定形溶解度。模型聚合物包括醋酸纤维素（CA）、邻苯二甲酸醋酸纤维素（CAP）、乙基纤维素（EC）、Eudragit® RL PO（EUD）、羟丙基甲基纤维素（HPMC）、醋酸羟丙基甲基纤维素琥珀酸酯（HPMCAS）和邻苯二甲酸羟丙基甲基纤维素（HPMCP）。单独测定了药物的“无定形溶解度”，然后作为载药量的函数测定了最大可实现浓度的变化。使用红外光谱（IR）、差示扫描量热法（DSC）和水分吸附分析对药物-聚合物相互作用进行了表征。结果表明，洛匹那韦的最大可实现浓度（“无定形溶解度”）随药物-聚合物相互作用的程度以及 ASD 中药物的重量分数而变化。当评估用 pH 响应性聚合物配制的无定形系统的最大可实现浓度时，这些信息非常有价值，并且应该有助于更全面地了解 ASD 中药物的相行为。
