Institute of Materia Medica, Hangzhou Medical College, 310013 Hangzhou, China.
NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, 510515 Guangzhou, China.
Mol Pharm. 2021 Jun 7;18(6):2298-2310. doi: 10.1021/acs.molpharmaceut.1c00100. Epub 2021 May 25.
(S)-carvedilol (S-CAR) is the dominant pharmacodynamic conformation of carvedilol, but its further development for extended-release formulation is restricted by its poor solubility. This study aimed to prepare and screen S-CAR salts that could be used to improve solubility and allow extended release. Five salts of S-CAR with well-known acid counterions (, phosphate, hydrochloride, sulfate, fumarate, and tartrate) were produced using similar processes. However, these salts were obtained with water contents of 1.60-12.28%, and their physicochemical properties differed. The melting points of phosphate, hydrochloride, and tartrate were 1.1-1.5 times higher than that of the free base. The solubility of S-CAR salts was promoted to approximately 3-32 times higher than that of the free base at pH 5.0-8.0. Typical pH-dependent solubilities were evidently observed in S-CAR salts, but considerable differences in solubility properties among these salts were observed. S-CAR phosphate and hydrochloride possessed high melting points, considerable solubility, and excellent chemical and crystallographic stabilities. Accordingly, S-CAR phosphate and hydrochloride were chosen for further pharmacokinetic experiments and pharmaceutical study. S-CAR phosphate and hydrochloride extended-release capsules were prepared using HPMC K15 as the matrix and presented extended release in and evaluations. Results implied that water molecules in the hydrated salt were a potential threat to the achievement of crystal stability and thermostability. S-CAR phosphate and hydrochloride are suitable for further development of the extended-release formulation.
（S）-卡维地洛（S-CAR）是卡维地洛的主要药效构象，但由于其溶解度差，其进一步开发为缓释制剂受到限制。本研究旨在制备和筛选可用于提高溶解度并允许延长释放的 S-CAR 盐。使用相似的方法生产了具有知名酸反离子（磷酸盐、盐酸盐、硫酸盐、富马酸盐和酒石酸盐）的五种 S-CAR 盐。然而，这些盐的含水量为 1.60-12.28%，其物理化学性质不同。磷酸盐、盐酸盐和酒石酸盐的熔点比游离碱高 1.1-1.5 倍。S-CAR 盐在 pH 5.0-8.0 下的溶解度提高到游离碱的约 3-32 倍。在 S-CAR 盐中明显观察到典型的 pH 依赖性溶解度，但这些盐之间的溶解度性质存在很大差异。S-CAR 磷酸盐和盐酸盐具有较高的熔点、较大的溶解度以及良好的化学和结晶稳定性。因此，选择 S-CAR 磷酸盐和盐酸盐进行进一步的药代动力学实验和药物研究。使用 HPMC K15 作为基质制备了 S-CAR 磷酸盐和盐酸盐缓释胶囊，并在 和 评估中呈现了缓释效果。结果表明，水合盐中的水分子可能对晶体稳定性和热稳定性的实现构成威胁。S-CAR 磷酸盐和盐酸盐适合进一步开发缓释制剂。
