Preparation,characterization And Properties Study Of Nateglilnide Cocrystal

As a new solid form,cocrystal is usually used in solid chemical modification.Over the past 20 years,there are more and more reports on the improvement of drug properties by pharmaceutical cocrystal.Compared to other modification methods,the cocrystal is the combination of the Active Pharmaceutical Ingredients(API)and the Co-Crystal Former(CCF)molecule through non-covalent interaction,and any API,whether acidic,basic or ionizable,may form a co-crystal.Which provides a possible way for drug modification that cannot form a salt.Nateglinide is a poorly soluble drug for the treatment of type 2 diabetes with a polymorphic form.There are carboxyl groups and substituted amino groups in the molecular structure that may form co-crystal.Nicotinamide was identified as a co-crystal ligand by design and screening.The nateglinide-nicotinamide(1:1)cocrystal was successfully prepared by dry,wet milling and slurry crystallization.The nateglinide-nicotinamide(1:1)cocrystal was successfully prepared by neat grinding,wet grinding and reaction crystallization.The formation of nateglinide cocrystal was verified by PXRD,DSC,TGA,FTIR and SEM.The cocrystal ratio was determined by PXRD.The ratio of API and CCF was determined to be 1:1 in cocrystal,and different conditions were studied.Grinding to prepare the effect of cocrystal.The effects of different grinding time and solvent types on the preparation of cocrystal by grinding were studied.The results show that the addition of liquid(ethanol,acetone)wet grinding can effectively prepare cocrystal.In order to study the change in the properties of the cocrystal relative to the single drug,the prepared nateglinide cocrystal was studied for hygroscopicity and stability study at 25 0 C/60%RH and 40 ?/75%RH.The results show that the cocrystal can exist stably for a long time and has low hygroscopicity.It can be developed as a potential drug.The dissolution test was carried out by simulating different in vivo environments,and it was found that the maximum apparent solubility of nateglinide-nicotinamide co-crystal in pH=6.8 phosphate buffer solution,pH=4.2 acetate buffer solution and pH=1 hydrochloric acid buffer solution was 1.86 times,2 times and 1.5 times respectively.compared with nateglinide,cocrystal has better solubilization in different pH environments.The dissolution model of cocrystal was established by referring to the "spring parachute model" and the PXRD characterization of the precipitate after dissolution.The cocrystal solubility product and dissociation free energy were further calculated.The dissolution and complexation properties of cocrystal in solution provide a theoretical basis for the good stability of cocrystal.Finally,the solubility data and the heat of dissolution of nateglinide and its cocrystal were calculated,and the ternary phase diagram of the cocrystal in acetonitrile solution at 293.15K and 303.15K was measured,which provided the basic data of industrial preparation of cocrystal and the design of crystallization process.