Novel Quasi-Emulsion Solvent Diffusion-Based Spherical Cocrystallization Strategy for Simultaneously Improving the Manufacturability and Dissolution of Indomethacin
Novel Quasi-Emulsion Solvent Diffusion-Based Spherical Cocrystallization Strategy for Simultaneously Improving the Manufacturability and Dissolution of Indomethacin
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DOI：
10.1021/acs.cgd.0c00876
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发表时间：
2020-10-07
影响因子：
3.8
通讯作者：
Sun, Changquan Calvin
中科院分区：
文献类型：
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作者：
Chen, Hongbo;Xu, Hongyun;Sun, Changquan Calvin
许多活性药物成分(API)的片剂配方的成功开发受到其较差的可制造性(如流动性、片性)和溶出度特性的挑战。在这里，我们报道了一种新的准乳化溶剂扩散共结晶(QESD-CC)方法，作为一种集成的晶体和粒子工程方法，成功地生成了难溶药物吲哚美辛(IMC)和甜味共结晶剂糖精(SAC)的球形共晶体聚集体。QESD-CC过程包括两个不同的步骤：(1)形成含有溶剂化IMC和SAC的瞬时乳液；(2)随后从乳液中析出IMC-SAC共晶体作为中空球形粒子。溶液H-1核磁共振分析和计算模拟研究表明，羟丙基甲基纤维素(HPMC)优先通过氢键与SAC分子相互作用，从而驱动聚合物形成壳层，稳定瞬时乳液液滴，并覆盖生成的粒子。球形QESD-CC颗粒表现出良好的流动性，而HPMC包衣和微米级的主晶导致了优异的成片性能。出色的可制造性和高共晶溶解性使高载药量片剂配方的成功开发成为可能，该片剂含有46.3wt%的IMC。
The successful development of tablet formulations of many active pharmaceutical ingredients (APIs) is challenged by their poor manufacturability (e.g., flowability, tabletability) and dissolution characteristics. Here, we report a novel quasi-emulsion solvent diffusion cocrystallization (QESD-CC) method as an integrated crystal and particle engineering approach for successful generation of spherical cocrystal agglomerates of the poorly soluble drug indomethacin (IMC) and the sweet cocrystallization agent saccharin (SAC). The QESD-CC process consists of two distinct steps: (1) formation of a transient emulsion containing solvated IMC and SAC and (2) subsequent precipitation of IMC-SAC cocrystals from the emulsion as hollow spherical particles. Solution H-1 NMR analyses and computational modeling studies indicated that hydroxypropyl methylcellulose (HPMC) preferentially interacts with the SAC molecules through hydrogen bonds, thus driving the polymer to form a shell that stabilizes the transient emulsion droplets and coats the resulting particles. Spherical QESD-CC particles exhibited excellent flowability, while the HPMC coating and microsize primary crystals led to excellent tabletability. Outstanding manufacturability and high cocrystal solubility thus enabled the successful development of a high-drug-loading tablet formulation comprising 46.3 wt % IMC.