Carbamazepine/Tartaric Acid Cocrystalline Forms: When Stoichiometry and Synthesis Method Matter

A deep investigation of the cocrystallization of carbama(L-TA) has been undertaken. Different methods of synthesis (liquidassisted grinding, solution evaporation, and mechanical/solvent-free conversion) and various stoichiometric ratios of parent components were tested. Structural and thermodynamic information from complementary calorimetry, and thermogravimetric analysis) allowed the comparison of the CBZ multicomponent systems obtained from the two coformers, and the evaluation of the impact of the synthesis methods and the stoichiometric composition. In this study, the reproducible conditions for the crystallization by LAG of two cocrystalline forms with different stoichiometry for the carbamazepine/tartaric acid system were shown: the two cocrystals CBZ:DL-TA (1:1) and CBZ:L-TA (3:1) (isostructural of channel-like cocrystal obtained with DL-TA) were prepared by grinding stoichiometric amounts of appropriate components. Both cocrystalline forms are stable for at least two years under atmospheric conditions (uncontrolled ambient temperature and humidity). By simply mixing the parent compounds at room temperature (no solvent, no mechanical/thermal activation, no moisture intervention) the channel-like cocrystal CBZ:TA (3:1) is formed regardless of the coformer used (DL- or L-TA) or the initial ratio of the parent compounds. The spontaneous solid-solid transformation into this cocrystalline form composed of (partially) disordered coformer molecules inside CBZ-based channels is kinetically driven, i.e., it is faster with increasing temperature. Calorimetric studies of the transformation kinetics indicate that the nucleation process probably controls the cocrystallization process.

Automated summary

A comprehensive investigation into the cocrystallization of carbamazepine (CBZ) has been conducted, exploring different synthesis methods and stoichiometric compositions. Thermodynamic and structural analysis has allowed for a comparison of CBZ cocrystals obtained from different coformers, as well as an assessment of the impact of synthesis methods and stoichiometric ratios. The study has identified reproducible conditions for the crystallization of two different stoichiometries of the carbamazepine/tartaric acid system, as well as a spontaneous solid-solid transformation into a channel-like cocrystalline form. The kinetics of the transformation process suggest that nucleation likely controls the cocrystallization process.