Impact of Halogen Substituent Nature and Position on the Structural and Energetic Properties of Carbamazepine Cocrystals with Meta-Halobenzoic Acids: A Two-Pathway Synthesis Study.

Crystal engineering provides effective strategies to produce pharmaceutical cocrystals, aimed at enhancing the physicochemical properties of active pharmaceutical ingredients. Herein, the structural and energetic properties of carbamazepine cocrystals with meta-chlorobenzoic, meta-bromobenzoic, and meta-iodobenzoic acids are examined in depth, with particular focus on the influence of halogen substitution. A comparative assessment of solution-based crystallization and mechanochemical synthesis via liquid-assisted grinding provides insight into the viability of different synthetic methodologies. The crystallographic analysis reveals isostructurality among the three cocrystals, with lattice stability being modulated by the increasing atomic radius of the halogen substituent. Complementary techniques, including thermogravimetry, differential scanning calorimetry, Fourier transform infrared spectroscopy, and Hirshfeld surface analysis, further elucidate the intermolecular forces driving the formation of these crystalline phases. The lattice energy calculations offer a quantitative perspective on the role of halogen substitution in stabilization, enriching the understanding of fundamental crystal engineering principles relevant to pharmaceutical development.