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

Abstract

A deep investigation of the cocrystallization of carbamazepine form III (CBZ) with dl-tartaric acid (dl-TA) and l-tartaric acid (l-TA) has been undertaken. Different methods of synthesis (liquid-assisted grinding, solution evaporation, and mechanical/solvent-free conversion) and various stoichiometric ratios of parent components were tested. Structural and thermodynamic information from complementary characterization techniques (X-ray diffraction, differential scanning 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.