Tanaka Ryoma, Osotprasit Supisara, Peerapattana Jomjai, Ashizawa Kazuhide, Hattori Yusuke, Otsuka Makoto
Graduate School of Pharmaceutical Sciences, Musashino University, 1-1-20 Shin-machi, Nishi-Tokyo, Tokyo 202-8585, Japan.
Center for Research and Development of Herbal Health Products, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.
Pharmaceutics. 2021 Jan 4;13(1):56. doi: 10.3390/pharmaceutics13010056.
The manufacturing of solid pharmaceutical dosage forms composed of cocrystals requires numerous processes during which there is risk of dissociation into parent molecules. Resonant acoustic wet granulation (RAG) was devised in an effort to complete theophylline-citric acid (THPCIT) cocrystal formation during the granulation process, thereby reducing the number of operations. In addition, the influence of granulation liquid was investigated. A mixture of anhydrous THP (drug), anhydrous CIT (coformer), and hydroxypropyl cellulose (granulating agent) was processed by RAG with water or ethanol as a granulation liquid. The purposes were to (i) form granules using RAG as a breakthrough method; (ii) accomplish the cocrystallization during the integrated unit operation; and (iii) characterize the final solid product (i.e., tablet). The RAG procedure achieved complete cocrystal formation (>99%) and adequately sized granules (d50: >250 μm). The granulation using water (GW) facilitated formation of cocrystal hydrate which were then transformed into anhydrous cocrystal after drying, while the granulation using ethanol (GE) resulted in the formation of anhydrous cocrystal before and after drying. The dissolution of the highly dense GW tablet, which was compressed from granules including fine powder due to the dehydration, was slower than that of the GE tablet.
由共晶体组成的固体药物剂型的制造需要多个过程，在此期间存在解离成母体分子的风险。为了在制粒过程中完成茶碱 - 柠檬酸（THPCIT）共晶体的形成，从而减少操作步骤，设计了共振声学湿法制粒（RAG）。此外，还研究了制粒液体的影响。以水或乙醇作为制粒液体，通过RAG对无水THP（药物）、无水CIT（共形成物）和羟丙基纤维素（制粒剂）的混合物进行处理。目的是：（i）以RAG作为突破性方法形成颗粒；（ii）在集成单元操作过程中完成共结晶；（iii）对最终的固体产品（即片剂）进行表征。RAG程序实现了完全共晶体形成（>99%）和粒度合适的颗粒（d50：>250μm）。用水制粒（GW）促进了共晶体水合物的形成，干燥后转变为无水共晶体，而用乙醇制粒（GE）在干燥前后均导致无水共晶体的形成。由于脱水，由包含细粉的颗粒压制而成的高密度GW片剂的溶出度比GE片剂慢。
