Establishment of cocrystal cocktail grinding method for rational screening of pharmaceutical cocrystals

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• 作者：Katsuhiko Yamamoto ; Shunichirou Tsutsumi ; Yukihiro Ikeda
• 关键词：CC ; cocrystal ; CCF ; cocrystal former ; API ; active pharmaceutical ingredient ; PXRD ; powder X-ray diffraction ; TG ; thermogravimetry ; DSC ; differential scanning calorimetry
• 刊名：International Journal of Pharmaceutics
• 出版年：2012
• 出版时间：1 November, 2012
• 年：2012
• 卷：437
• 期：1-2
• 页码：162-171
• 全文大小：1599 K

文摘

Cocrystals (CCs) used in the pharmaceutical industry are defined as complex crystals formed by reaction between an API and a cocrystal former (CCF); unlike salts, CCs do not show proton transfer. Recently, pharmaceutical CCs have been used to improve the drug-likeness of APIs, such as solubility and stability. Grinding is more effective for CC synthesis than crystallization from solution because in the former case, the API can predominantly interact with the CCF without being affected by solvents. However, this method is tedious because the API is ground with only one CCF at a time. We developed a cocktail cocrystal grinding (CCG) method, in which a mixture of CCFs having the same functional group was used. No false negatives/positives were observed in CCG when carbamazepine was used as the model compound. This method could be used to obtain CCs of piroxicam and spironolactone. False negatives were observed for only one compound from among three model compounds, indicating that CCG facilitates efficient CC detection and that it has higher throughput than does the conventional method. Further, CCG is fast and suitable for rational CC screening, and it helps identify the partial structure of CCFs that forms synthons with an API.