Study On The Dissolution Kinetics Of Carbamazepine "Drug-drug Co-crystals" In Solution

Carbamazepine(CBZ),a widely used first line anti-epileptic agent,is classified as a Biopharmaceutics Classification System(BCS)class Ⅱ drug.Its poor solubility,results in low bioavailability directly and high dose requirement to achieve the desired therapeutic effect.Because carbamazepine is stable in crystal form and neutral in structure,it is hard to form salts.At present,forming cocrystals is the main method to improve solubility,few studies on the dissolution kinetics of carbamazepine cocrystal in solution were reported.In this study,dissolution mechanism of carbamazepine cocrystals was discussed on experiment(phase solubility theory)and theoretical calculations(dispersion-corrected density functional theory and conductor-polarizable continuum model calculations).According to the principle of supramolecular chemistry,natural active pharmaceutical ingredients with polyhydroxyl groups were selected to form supramolecular synthons with CBZ,which were synthesized by solvent-assisted grinding method and slow solvent volatilization method.The formations of these CBZ cocrystals were confirmed by characterizations of X-ray diffraction,nuclear magnetic resonance,thermodynamic analyses and infrared spectroscopy.Moreover,the experiments of solubilities and inherent dissolution rate(IDR)were carried out.In order to investigated the dissolution behavior of CBZ cocrystals in solution,the solubilities of all started materials and CBZ cocrystals in six pure organic solvents(such as methanol,ethanol,2-propanol,acetone,acetonitrile,and ethyl acetate)were determined,respectively.Moreover,the CBZ cocrystals solubilities were measured by suspending cocrystals in varying ligands concentrations in six organic solvents.Besides,Density Functional Theory with dispersion correction(DFT-d)calculations were performed using the Perdew-Burke-Ernzerhof(PBE)function with the projector augmented wave(PAW)pseudopotentials,and solvent effect on solute molecule was treated with the conduct-like polarizable model(CPCM)Two new drug-drug cocrystals of CBZ with emodin(EMO,1:1)and paeonol(PAE,1:1)as conformers were formed.Single crystal X-ray diffraction results show that the CBZ-EMO cocrystal is determined in P 21/c space group belonging to monoclinic crystal system,and the CBZ-PAE determined in P-1 space group belonging to triclinic crystal system.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,CBZPAE cocrystal presents the biggest solubility at 133.1±0.6 μg/mL in water among all the investigated samples.The IDR results show that the dissolution rate of CBZ(53.9±1.0 μg/min/cm2)is the biggest.The phase solubility diagrams of the CBZ-EMO cocrystal have good linearity in the four organic solvents(such as ethanol,2-propanol,ethyl acetate and acetone),the rank order of solubility(mol/L)in four organic solvents is acetone(0.014±0.0004)>ethyl acetate(0.012±0.0003)>ethanol(0.0095±0.0003)>2-propanol(0.0086±0.0005);while phase solubility diagrams of the CBZ-PAE cocrystal have good linearity in three organic solvents(such as methanol,ethanol and 2-Propanol),the order rank is methanol(0.407±0.005)>ethanol(0.113±0.004)>2-propanol(0.046±0.0007).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.Phase solubility diagrams and theoretical calculations were used to explain the solubility regulation between CBZ and its cocrystals.The predicted solubilities are in consistent with experimental solubilities when taken into consideration of solubility product(Ksp)and complexion binding constant(K11).Theoretical calculations based on DFT-d principles and CPCM support the rank order of CBZ and its cocrystals.The combination of phase solubility and theoretical calculations provide an effective method to explain the solubility changes of cocrystals.