Study On Preparation, Characterization And Properties Of Oxcarbazepine Cocrystal

Pharmaceutical cocrystal is one kind of solid crystals formed by hydrogen bonds or other non-covalent bonds between host and guest molecules.The melting point,stability,hygroscopicity,solubility,dissolution rate,and bioavailability of the drug can be changed by pharmaceutical cocrystal without changing the efficacy of the drug itself,which exerts the efficacy of the drug.Oxcarbazepine(OXCBZ)is a poorly soluble drug which can't be turned into salt and has an amide functional group which may form cocrystals with other guest molecules.Oxalic acid(OA),2,5-dihydroxybenzoic acid(2,5DHBA)and salicylic acid(SA)which may form hydrogen bonds with the amide group or keto group in OXCBZ were selected as coformers.OXCBZ-OA(2:1),OXCBZ-2,5DHBA(1:1)and OXCBZ-SA(1:1)cocrystals were successfully prepared by dry grinding,wet grinding and reaction crystallization methods,respectively.The formation of these OXCBZ cocrystals was confirmed by characterizations of SEM images,PXRD,DSC,TGA,and FTIR spectra.Effects of different preparation conditions on cocrystal properties were also investigated,the results of which are beneficial to the optimization of preparation process of cocrystal.Deep realization of the intrinsic molecular structure of OXCBZ cocrystal can provide guidance for coformers screening and prediction of cocrystal structure.Materials Studio simulation software was used to study the cocrystals at molecular level,which is beneficial to understanding the nature of cocrystal formation.The surface electrostatic potentials of OXCBZ and the coformers,the binding energies of each molecule,the crystal structure of cocrystal and the location of hydrogen bond were calculated.The related properties of newly developed drugs need to be studied to ensure the effectiveness of the drug.The prepared OXCBZ cocrystal could stably exist at 25 ?/60%RH and 40 ?/75%RH,which shows good stability.In addition,the determination of solubility data and establishment of dissolution models of OXCBZ and its cocrystals can lay the foundation for the preparation of cocrystals and design of crystallizer.The solubility data of OXCBZ and its cocrystals in six solvents were determined by static method.The obtained solubility data could be fitted and predicted well by ?h model and Apelblat equation.Finally,both the dissolution mechanisms of OXCBZ-OA and OXCBZ-2,5DHBA cocrystals conformed to the "spring and parachute" model.However,it was not obvious for the process of "parachute".Meanwhile,the OXCBZ-SA cocrystal dissolved in the form of cocrystal.The maximum apparent solubilities of OXCBZ-OA and OXCBZ-2,5DHBA cocrystals were 2.6 and 4.7 times as much as that of single OXCBZ,respectively.However,the solubility of OXCBZ-SA cocrystal was similar to that of single OXCBZ.These studies provide a theoretical basis for improving the solubility and dissolution rate of drugs by forming cocrystals.