Application and Comparison of Cocrystallization Techniques on Trospium Chloride Cocrystals

To identify as many solid forms of active pharmaceutical ingredient (API) as possible and to monitor their cocrystallization potential, synthetic methods are needed. According to API properties (solubility, melting point, stability), suitable screening methods have to be considered. In this study, the performance of most of the commonly available cocrystallization techniques such as neat grinding, liquid-assisted grinding, slurrying, co-melting, and slow evaporation was compared. We applied them to four pharmaceutical cocrystals of trospium chloride (TCl, a muscarinic antagonist urinary antispasmodic) with adipic (AD), glutaric (GA), oxalic (OX), and salicylic acids (SA), which were identified as hits from previous slow evaporation experiments. Their structures were determined by single-crystal X-ray diffraction (TCl-SA and TCl-OX cocrystals) or from powder X-ray diffraction data (TCl-AD and TCl-GA cocrystals). Other methods to characterize the cocrystal phases were applied (1H NMR, DSC, IR, and Raman spectroscopy). Comparison of cocrystallization methods and of the prepared cocrystals was discussed.