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Phase solubility investigation and theoretical calculations on drug-drug cocrystals of carbamazepine with Emodin, Paeonol

Dandan Huang,H.C. Stephen Chan,Yunshan Wu,Liang Li,Li Zhang,Yang Lv,Xuemei Yang,Zhengzheng Zhou

Carbamazepine ( CBZ ), a Biopharmaceutics Classification System (BCS) class II drug, is widely-used as a first line antiepileptic drug . Numbers of cocrystals have reported to regulate its poor solubility. However, the solubility behaviors are rarely discussed on theoretical calculations and phase solubility diagrams . In this study, two new drug-drug cocrystals (DDC) of CBZ with emodin ( EMO , 1: 1) and paeonol ( PAE , 1: 1) as conformers , which offer the advantages of synergetic therapy and patient compliance are reported for the first time. The solubilities in water and in pH = 1.2, 6.8 buffer solutions, demonstrating that the rank order is as follows: CBZ-PAE  >  CBZ  >  CBZ-EMO . CBZ-PAE presents the biggest solubility at 0.563 ± 0.003 mmoL/L of in water among all the investigated samples. The solubilities of all the starting materials and cocrystals in six pure organic solvents such as methanol, ethanol, 2-propanol, acetone, acetonitrile , ethyl acetate were investigated to discuss the phase solubility diagrams. The results indicate that experimental solubilities are consistent with the theoretical solubilities on consideration of solubility product ( K sp ) and solution binding constant ( K 11 ) together. The enthalpy differences between cocrystal and its coformer are calculated through the Perdew-Burke-Ernzerhof (PBE) functional with the projector augmented wave (PAW) pseudopotentials . CBZ-EMO presents the lowest enthalpy (−0.38 kcal/mol) with a highly unfavorable solvation energy (2.42 kcal/mol), resulting in unfavorable in an aqueous environment. Overall, the phase solubility diagrams and theoretical calculations support the solubility regulations on DDCs of CBZ .