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.