Understanding the Formation of Indomethacin–Saccharin Cocrystals by Anti-Solvent Crystallization

Min-Jeong Lee †, Nan-Hee Chun ‡, In-Chun Wang †, J. Jay Liu §, Myung-Yung Jeong , and Guang J. Choi *‡ † Department of Smart Food & Drugs, Inje University, Gimhae, Gyeongnam 621-749, South Korea‡ Department of Pharmaceutical Engineering, Soon Chun Hyang University, Asan, Chungnam 336-745, South Korea§ Department of Chemical Engineering, Pukyong National University, 365 Sinseon-ro, Nam-gu, Busan, 608-739, South Korea

Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735, South KoreaCryst. Growth Des., Article ASAPDOI: 10.1021/cg400135aPublication Date (Web): March 8, 2013Copyright © 2013 American Chemical Society*22 Soonchunhyang-ro, Asan, Chungnam 336-745, South Korea. Tel: +82-41-530-4864. Fax: +82-41-530-3085. E-mail: guangchoi@sch.ac.kr.

Abstract

Pharmaceutical cocrystals are a novel drug form with the potential to enhance pharmaceutical properties, including the solubility and dissolution behavior for BCS class II drug substances such as indomethacin (IMC). Recently, we reported that pure indomethacin–saccharin (IMC–SAC) cocrystals were prepared via anti-solvent crystallization. In this study, we investigated the solubility behavior of IMC–SAC cocrystals and individual components in methanol–water cosolvent. Also, the phase solubility diagram (PSD) of the cocrystal was determined to increase our understanding of cocrystallization. The criterion for pure IMC–SAC cocrystal

formation was proposed and verified through supporting experiments performed with different concentrations. We also found that Scocrystal and Scocrystal/Sdrug are critical factors for the design of the cocrystallization process via anti-solvent addition. Real-time monitoring of the cocrystallization process was performed using an in-line near-infrared (NIR) system. Principal component analysis (PCA) was applied to NIR spectral analysis. Based on the PCA results, distinct differences were observed in the pathways of IMC–SAC cocrystal formation depending on the initial concentrations.