Study On Solid-Liquid Equilibrium And Crystallization Conditions Of Clotrimazole And Bifonazole

Crystallization plays a significant role in the separation and purification of pharmaceutical and chemical products.The products obtained by crystallization are characterized by high purity and quality,especially in the production of drugs,where the crystal morphology and crystal form have an effect on the solubility,bioavailability and stability of the drug,making the efficacy of the drug affected.Clotrimazole and bifonazole belong to the imidazole class of drugs,which are highly effective antifungal drugs against Candida albicans mucosal infections.In addition,clotrimazole also exhibits good anti-cancer activity and has a broad application prospect.At present,most of the studies on clotrimazole and bifonazole at home and abroad are about their principles of action and clinical application effects,but there is almost no systematic study on the solid-liquid phase equilibrium and crystallization process of bifonazole in the relevant literature.Based on this phenomenon,the solid-liquid phase equilibrium of clotrimazole and bifonazole was studied in this paper,and the solution-crystallization process of bifonazole was systematically and comprehensively studied on the basis of the theory of solid-liquid equilibrium.The main findings of this paper are as follows:The solubility of clotrimazole in alcohol and ester solvents,and the solubility of bifonazole in alcohols,esters,N,N-dimethylformamide(DMF)and acetonitrile were determined by using a laser dynamic detection device according to the needs of drug production.The results showed that the solubility of clotrimazole and bifonazole increased with the increase of temperature,and the solubility of clotrimazole in alcohol solvents was greater than that in ester solvents,and the solubility of bifonazole in different solvents followed:DMF>alcohol solvents>ester solvents>acetonitrile,which laid a theoretical foundation for the selection of suitable solvents for the preparation of drug crystals.In addition,the relationship between the solubility and temperature of clotrimazole and bifonazole in pure solvents was correlated with the aid of five thermodynamic models(Apelblat,Van’t Hoff,λh,Wilson and NRTL),and the results showed that all five thermodynamic models correlated well with the measured solubility data.The thermodynamic properties of the solution systems(ΔmixG、ΔmixH、ΔmixS、γ1∞和H1E,∞)were estimated based on Wilson model parameters and experimental values of solubility,which showed that the dissolution of both clotrimazole and bifonazole in the selected solvents was a spontaneous process..The mixing thermodynamic variables(Chi parameters,mixing energy and binding energy)of bifonazole in four solvents(DMF,n-pentanol,iso-butanol and methyl acetate)were simulated using Materials Studio software.The crystal structure of bifonazole was analyzed based on PXRD patterns to obtain information about the crystal system and cell parameters,and the crystal habit of bifonazole under vacuum was predicted using the BFDH model,and the crystal habit was obtained as a rectangular sheet.The crystallization process of bifonazole was investigated by comparing cooling crystallization and solvation crystallization to select a suitable crystallization method,and the effects of six factors,such as the initial concentration of the solution,crystallization temperature and crystallization time,on the crystallization process of bifonazole were investigated by the controlled variable method.Meanwhile,the optimum process conditions were determined using the yield and crystalline habit as indicators:the initial concentration of the solution was 0.03 g/mL,the stirring rate was 50 rpm,the crystallization temperature was 20℃,the volume ratio of the main solvent(ethanol)to the solubilizer(deionised water)was 1:3,the dropper acceleration rate of water was 1 mL/min and the crystallization time was 1 h.