Cocrystallization is an attractive and promising technology that can improve the physical properties of formulations of active pharmaceutical ingredients (APIs). We have developed a "nano-spot method" that can evaluate the crystalline form on the nanogram scale. In this study, the following studies were performed to obtain versatile and comprehensive improvements to the nano-spot method: modification of the sample solution, application of solvent vapor exposure to attempt the precipitation of various states of crystals, and adoption of low-frequency Raman spectroscopy. Carbamazepine was used as a model API and cocrystallization screening was examined with 12 cocrystal formers (coformers). In the case of combinations that are already known to form cocrystals, spectra similar to those of previously reported cocrystals or new spectra were obtained. It was considered that the reported cocrystals or new polymorphs were obtained. In contrast, in the case of the combination which has been reported not to form a cocrystal, the spectra were consistent with that for the physical mixture of API and coformer, suggesting that a cocrystal also did not form in this screening. In addition, the newly adopted low-frequency Raman spectroscopy enabled the high-sensitive detection of the crystalline form.
Keywords: Cocrystal; Low-frequency Raman spectroscopy; Polymorphism; Screening; Solvent vapor exposure.
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