Kaur Amanpreet, Zemlyanov Dmitry, Taylor Lynne S
Department of Industrial and Molecular Pharmaceutics, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA.
Birck Nanotechnology Center, Purdue University, West Lafayette, IN 47907, USA.
J Pharm Sci. 2025 Jul 6:103894. doi: 10.1016/j.xphs.2025.103894.
Herein, the release performance of amorphous solid dispersions (ASDs) of a weakly basic drug, bedaquiline (BDQ), and a weakly acidic polymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS) was investigated in different media. In conjunction, the complexation tendency between BDQ and HPMCAS was also probed. Amorphous solid dispersions (ASDs) of BDQ were prepared at different drug loadings with LF and MF grades of HPMCAS using solvent evaporation. Drug-polymer complexation was investigated in buffers varying in pH from 5.8 to 10.5 and in biorelevant media. For these experiments, polymer concentration was quantified using colorimetry or high-performance liquid chromatography (HPLC) and evaporative light scattering detection (ELSD). The insoluble drug-polymer complex formed in some media was analyzed using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. Drug release from ASD powders was evaluated as a function of pH (1.6, 3.0, 5.0, 6.5) as well as in fasted and fed state simulated intestinal fluids. HPMCAS showed a high degree of insoluble complex formation (∼90 %) with BDQ at pH 6.0 and the extent of complexation decreased with increasing pH, or when biorelevant media was used. At pH 6.5, ASDs showed a low extent of release in buffer. Release of drug from the ASDs was considerably enhanced in biorelevant media. BDQ remained amorphous in the presence of HPMCAS for extended time periods, hence crystallization was not considered a failure mechanism. Instead, the low release extent observed in pH 6.5 buffer was attributed to the formation of an insoluble BDQ:polymer ionic complex in the ASD particle. Ionic complexation was confirmed using X-ray photoelectron spectroscopy. However, it appears that solubilizing species present in the biorelevant media disrupted the drug-polymer complexation leading to improved release. These studies highlight the convoluted nature of drug release from ASDs with enteric polymers and the need to consider the impact of the release testing conditions. Release as a function of media conditions, is in turn expected to be highly variable from drug to drug depending on the nature of the drug-polymer interactions.
在此，研究了弱碱性药物贝达喹啉（BDQ）与弱酸性聚合物醋酸羟丙甲纤维素琥珀酸酯（HPMCAS）的无定形固体分散体（ASDs）在不同介质中的释放性能。同时，还探究了BDQ与HPMCAS之间的络合倾向。使用溶剂蒸发法，以不同载药量制备了BDQ与LF和MF级HPMCAS的无定形固体分散体。在pH值从5.8到10.5变化的缓冲液以及生物相关介质中研究了药物 - 聚合物络合情况。对于这些实验，使用比色法或高效液相色谱（HPLC）和蒸发光散射检测（ELSD）对聚合物浓度进行定量。使用衰减全反射 - 傅里叶变换红外（ATR - FTIR）光谱分析在某些介质中形成的不溶性药物 - 聚合物络合物。评估了ASD粉末在不同pH值（1.6、3.0、5.0、6.5）以及空腹和进食状态模拟肠液中的药物释放情况。HPMCAS在pH 6.0时与BDQ形成了高度不溶性络合物（约90%），并且随着pH值升高或使用生物相关介质时，络合程度降低。在pH 6.5时，ASDs在缓冲液中的释放程度较低。在生物相关介质中，ASDs中药物的释放显著增强。在HPMCAS存在下，BDQ在较长时间内保持无定形状态，因此结晶不被视为失效机制。相反，在pH 6.5缓冲液中观察到的低释放程度归因于ASD颗粒中形成了不溶性BDQ：聚合物离子络合物。使用X射线光电子能谱证实了离子络合。然而，生物相关介质中存在的增溶物质似乎破坏了药物 - 聚合物络合，从而导致释放改善。这些研究突出了含肠溶聚合物的ASDs药物释放的复杂性，以及考虑释放测试条件影响的必要性。根据药物 - 聚合物相互作用的性质，不同药物的释放随介质条件的变化情况预计差异很大。
