Study On Cocrystallization Process And Polymorphic Transformation Mechanism Of Ethenzamide-Saccharin Cocrystal

The curative effect of drug commonly depends on the nature of the active pharmaceutical ingredients(APIs).Cocrystallization with pharmaceutically acceptable coformers can optimize the physicochemical properties of APIs,such as solubility,dissolution rate and bioavailability.In addition,the study on pharmaceutical cocrystal polymorphism also contributes to the polymorphic screening and purification.Ethenzamide(EA)is an extremely poorly water soluble non-steroidal antiinflammatory drug with analgesic and antipyretic effects for the treatment of mild to moderate pain.Saccharin(SAC)is often employed as a pharmaceutically acceptable cocrystal former.In this study,EA and SAC were selected as the model compounds to investigate cocrystallization process and cocrystal polymorphic transformation mechanism by combination of experimental and simulative method.This paper mainly includes several parts as follows:1.The thermodynamics properties of EA were investigated.The solubility of EA in six pure solvents was determined via the gravimetric method.Five thermodynamic models were employed to correlate the experimental solubility data.The modified Apelblat model shows the best fitting result.In addition,the mixing thermodynamic properties of EA were also obtained.The results showed that the dissolution process of the EA in the six solvents was endothermic.Furthermore,the molecular modeling results give the explanation for the sequence of solubility in various solvents.2.The thermodynamics properties of EA-SAC cocrystal Form I were investigated.The ternary phase diagrams of EA-SAC in different solvents were determined by using static equilibrium methods.The effect of temperature and solvent on ternary phase diagrams was discussed.The results shoewed that the ternary phase diagram in ethyl acetate was more symmetric.In addition,the solubility of EA-SAC cocrystal was correlated by using a mathematical model.The solubility of EA-SAC cocrystal as a function of SAC concentration was calculated.These new findings are of great importance to control the cocrystallization process of EA-SAC.3.The cocrystallization process from EA and SAC to EA-SAC cocrystal was investigated.The mechanism for cocrystallization is revealed by using some on-line and off-line methods including in situ Raman spectroscopy and polarizing microscope.It is observed that this process is mainly controlled by the nucleation rate of EA-SAC cocrystal.Furthermore,kinetic parameters of the transformation process were obtained by using the Johnson-Mehl-Avrami equation.The influence of temperature and seeding on the transformation process was also studied.4.The solvent-mediated phase transformation of Form II to Form I of EA-SAC cocrystal was investigated.The transformation mechanism was analyzed by on-line and off-line tools.The results demonstrate that the transformation process consists of three steps,involving the dissolution of Form II,the nucleation and growth of Form I.The process is controlled by the nucleation and growth of Form I.The microscope photographs clearly reveal that the Form I preferably nucleates and grows on the(100)surface of Form II.The molecular simulation results indicate that higher adsorption energy makes the molecule adsorbed more strongly on the(100)surface,which are in agreement with the experimental observation.The results will be of great significance to control the formation of a desired polymorphic final product of EA-SAC cocrystal.