Phase solubility diagrams and energy surface calculations support the solubility enhancement with low hygroscopicity of Bergenin: 4-Aminobenzamide (1: 1) cocrystal

Herein, we reported a new bergenin : 4-aminobenzamide ( BGN-4AM ) cocrystal with significantly enhanced solubility and low hygroscopicity probed from two aspects such as phase solubility diagrams and theoretical calculations. Compared with anhydrous BGN , BGN-4AM solubilities in water and different buffer solutions (pH = 1.2, 4.5, 6.8) increase significantly. It is noted that BGN-4AM solubility in pH = 6.8 buffer solution presents 32.7 times higher than anhydrous BGN . Interestingly, BGN-4AM (0.31 ± 0.07%) showcases lower hygroscopicity than anhydrous BGN (9.31 ± 0.16%). The predicted and experimental solubilities agree with each other when considering solubility product ( K sp ) and solution binding constant ( K 11 ) in phase solubility diagrams, indicating the solution complexes formation occurs. Further crystal surface-water interactions and Bravais, Friedel, Donnay-Harker (BFDH) analyses based on Density Functional Theory with dispersion correction (DFT- d ) methods support the enhanced solubility. The water probe demonstrates an average interaction energy of −6.48 kcal/mol on the 002 plane of BGN-4AM , and only −5.47 kcal/mol on the 011 plane of BGN monohydrate. The lower lattice energy of BGN-4AM guarantees its lower hygroscopicity than BGN monohydrate. BGN-4AM with enhanced solubility and low hygroscopicity can be a potential candidate for further formulation development.