Improving the sublimation stability of ligustrazine with gallic acid by forming pharmaceutical cocrystal based on the Etter's rules

To improve the high sublimation characteristics of ligustrazine (TMP), an unreported ligustrazine-gallic acid pharmaceutical cocrystal (C7H6O5·2(C8H12N2)·H2O, TMP-GA) was synthesized by using a virtual cocrystal screening method based on the rules of hydrogen bonding formation (Etter's rules). The results of the molecular surface electrostatic potential (MEPS) of TMP-GA showed that the actual hydrogen bonding sites of TMP-GA were the same as the predicted ones, and the calculated ΔE was not much different from the predicted ones. The results of physicochemical properties showed that TMP-GA had better physical stability against TMP sublimation without reducing the solubility and permeability of TMP. Combined with the interaction force analysis of the crystals, the reason may be that compared with the TMP monomer pharmaceutical structure, the intermolecular hydrogen bonding of the TMP-GA pharmaceutical cocrystal is increased, the structure is more stable, and the increase in the energy required for TMP sublimation makes the tendency to sublimate of the TMP-GA significantly lower. This suggests that we can utilize the virtual cocrystal screening method based on Etter's rules to introduce suitable cocrystal formers to reduce the sublimation tendency of active pharmaceutical ingredients.