Department of Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA.
Pii Center for Pharmaceutical Technology, University of Mississippi, University, MS, 38677, USA.
AAPS PharmSciTech. 2022 Jun 17;23(6):169. doi: 10.1208/s12249-022-02319-4.
Amorphous solid dispersion (ASD) has been well known as a potential strategy to improve the bioavailability and dissolution performance of poorly water-soluble drugs. The primary concern of this approach is the long-term stability of the amorphous drug in the solid dispersion. Accurate prediction and detection of the solubility and miscibility of drug in polymeric binary system will be a milestone to the development of ASDs. In this investigation, a method based on Flory-Huggins (F-H) theory was proposed to predict and calculate the solubility and miscibility of the drug in polymeric matrix and construct the phase diagram to identify the relevance between drug loading and temperature for ASDs development. Indomethacin (Indo) was chosen as the model drug, and polyvinyl pyrrolidone vinyl acetate (Kollidon® VA 64) was used as a polymeric carrier for the ASD systems. Physical mixtures were prepared with different drug loadings (10 to 90%) and analyzed by differential scanning calorimetry (DSC). The interaction parameter χ was calculated for physical mixtures by the melting point depression and solubility parameter contribution methods. The phase diagram was constructed to investigate the impact of other parameters like drug loading, processing temperature, and Gibbs free energy of mixing (ΔG). For further validation, formulations were developed using HME to verify the accuracy of the phase diagram and to guide in the hot-melt extrusion (HME) process design space and optimization.
无定形固体分散体（ASD）已被广泛认为是提高难溶性药物生物利用度和溶解性能的潜在策略。这种方法的主要关注点是固体分散体中无定形药物的长期稳定性。准确预测和检测药物在聚合物二元体系中的溶解度和混溶性将是 ASD 发展的一个里程碑。在本研究中，提出了一种基于 Flory-Huggins（F-H）理论的方法，用于预测和计算药物在聚合物基质中的溶解度和混溶性，并构建相图以确定 ASD 发展中药物负载与温度之间的相关性。吲哚美辛（Indo）被选为模型药物，聚乙烯吡咯烷酮醋酸乙烯酯（Kollidon® VA 64）用作 ASD 系统的聚合物载体。制备了不同药物负载量（10%至 90%）的物理混合物，并通过差示扫描量热法（DSC）进行分析。通过熔点降低和溶解度参数贡献方法计算物理混合物的相互作用参数 χ。构建相图以研究其他参数（如药物负载、加工温度和混合吉布斯自由能（ΔG））的影响。为了进一步验证，使用热熔挤出（HME）制备了配方，以验证相图的准确性，并指导热熔挤出（HME）过程设计空间和优化。
