Coformer screening using thermal analysis based on binary phase diagrams.

Hiroyuki Yamashita, Yutaka Hirakura, Masamichi Yuda, Katsuhide Terada

文献索引：Pharm. Res. 31(8) , 1946-57, (2014)

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摘要

The advent of cocrystals has demonstrated a growing need for efficient and comprehensive coformer screening in search of better development forms, including salt forms. Here, we investigated a coformer screening system for salts and cocrystals based on binary phase diagrams using thermal analysis and examined the effectiveness of the method.Indomethacin and tenoxicam were used as models of active pharmaceutical ingredients (APIs). Physical mixtures of an API and 42 kinds of coformers were analyzed using Differential Scanning Calorimetry (DSC) and X-ray DSC. We also conducted coformer screening using a conventional slurry method and compared these results with those from the thermal analysis method and previous studies.Compared with the slurry method, the thermal analysis method was a high-performance screening system, particularly for APIs with low solubility and/or propensity to form solvates. However, this method faced hurdles for screening coformers combined with an API in the presence of kinetic hindrance for salt or cocrystal formation during heating or if there is degradation near the metastable eutectic temperature.The thermal analysis and slurry methods are considered complementary to each other for coformer screening. Feasibility of the thermal analysis method in drug discovery practice is ensured given its small scale and high throughput.