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Detection of cocrystal formation based on binary phase diagrams using thermal analysis.

Pharmaceutical research (2012-08-22)
Hiroyuki Yamashita, Yutaka Hirakura, Masamichi Yuda, Toshio Teramura, Katsuhide Terada

Although a number of studies have reported that cocrystals can form by heating a physical mixture of two components, details surrounding heat-induced cocrystal formation remain unclear. Here, we attempted to clarify the thermal behavior of a physical mixture and cocrystal formation in reference to a binary phase diagram. Physical mixtures prepared using an agate mortar were heated at rates of 2, 5, 10, and 30 °C/min using differential scanning calorimetry (DSC). Some mixtures were further analyzed using X-ray DSC and polarization microscopy. When a physical mixture consisting of two components which was capable of cocrystal formation was heated using DSC, an exothermic peak associated with cocrystal formation was detected immediately after an endothermic peak. In some combinations, several endothermic peaks were detected and associated with metastable eutectic melting, eutectic melting, and cocrystal melting. In contrast, when a physical mixture of two components which is incapable of cocrystal formation was heated using DSC, only a single endothermic peak associated with eutectic melting was detected. These experimental observations demonstrated how the thermal events were attributed to phase transitions occurring in a binary mixture and clarified the relationship between exothermic peaks and cocrystal formation.

Product Number
Product Description

Camphor, 96%
(1R)-(+)-Camphor, 98%
D-Camphor, Pharmaceutical Secondary Standard; Certified Reference Material
(±)-Camphor, purum, synthetic, ≥95.0% (GC)
(±)-Camphor, meets analytical specification of Ph. Eur., BP, ≥95% (GC), racemic
D-Camphor, ≥97%, FG
(−)-Camphor, analytical standard
(1S)-(−)-Camphor, 99%
Camphor (racemic), European Pharmacopoeia (EP) Reference Standard
Camphor (dl), primary reference standard
(±)-Camphor, ≥95.5%
(1S)-(−)-Camphor, 95%