Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
Drug Product Science and Technology, Bristol-Myers Squibb Company, One Squib Drive, New Brunswick, New Jersey 08903, United States.
Mol Pharm. 2020 Apr 6;17(4):1261-1275. doi: 10.1021/acs.molpharmaceut.9b01272. Epub 2020 Mar 17.
Drug loading is an important parameter known to impact the release rate of a poorly soluble drug from an amorphous solid dispersion (ASD). Recent studies have shown that small increases in drug loading can dramatically reduce the drug release rate from ASDs prepared with poly(vinylpyrrolidone--vinyl acetate) (PVPVA). However, the link between drug physicochemical properties and the drug loading where the release is abruptly compromised is not well understood. This study probes the role of different factors on the relative dissolution rates of drug and polymer from PVPVA-based ASDs as a function of drug loading: (1) the impact of drug-polymer hydrogen bonding interactions on the initial dissolution rate of ASDs, investigated using two structural analogues, indomethacin (IND) and indomethacin methyl ester (INDester), (2) the influence of surface drug crystallization, observed for INDester ASDs, and (3) by changing temperature, the impact of the "wet" glass transition temperature (). Scanning electron microscopy (SEM), with or without energy dispersive X-ray (EDX) analysis, Fourier transform infrared spectroscopy (FTIR), and powder X-ray diffraction (PXRD) were utilized to study the solid-state phase behavior and/or drug enrichment on the partially dissolved ASD tablet surfaces. Nanoparticle tracking analysis (NTA) was utilized to study the solution-state phase behavior. It was found that, contrary to expectations, ASDs with drug-polymer hydrogen bonding exhibited poorer initial release at moderate drug loadings (15-25%) as compared to the non-hydrogen bonding analogue ASDs. Surface crystallization led to the deterioration of dissolution performance. Lastly, relative to experimental temperatures also appeared to play a role in the observed dissolution behavior as a function of drug loading. These findings shed light on potential mechanisms governing ASD dissolution performance and will aid in the development of optimized ASD formulations with enhanced dissolution performance.
载药量是影响无定形固体分散体（ASD）中难溶性药物释放速率的一个重要参数。最近的研究表明，载药量的微小增加可以显著降低用聚（乙烯吡咯烷酮-醋酸乙烯酯）（PVPVA）制备的 ASD 中药物的释放速率。然而，药物理化性质与释放突然受到影响的载药量之间的联系尚未得到很好的理解。本研究探讨了不同因素在载药量变化时对 PVPVA 基 ASD 中药物和聚合物相对溶出速率的影响：（1）使用两种结构类似物吲哚美辛（IND）和吲哚美辛甲酯（INDester），研究药物-聚合物氢键相互作用对 ASD 初始溶解速率的影响；（2）观察到 INDester ASD 中的表面药物结晶的影响；（3）通过改变温度，研究“湿”玻璃化转变温度（）的影响。扫描电子显微镜（SEM），结合或不结合能量色散 X 射线（EDX）分析、傅里叶变换红外光谱（FTIR）和粉末 X 射线衍射（PXRD）用于研究固态相行为和/或部分溶解 ASD 片剂表面的药物富集。纳米粒子跟踪分析（NTA）用于研究溶液态相行为。结果发现，与预期相反，与非氢键类似物 ASD 相比，具有药物-聚合物氢键的 ASD 在中等载药量（15-25%）下表现出较差的初始释放。表面结晶导致溶解性能恶化。最后，相对于实验温度似乎也在观察到的载药量依赖性溶解行为中发挥作用。这些发现揭示了控制 ASD 溶解性能的潜在机制，并将有助于开发具有增强溶解性能的优化 ASD 配方。
