Study On The Crystallization Process Of Bezafibrate

Bezafibrate is one of the fibrate drugs used to treat hyperlipidemia.It has a better effect on lowering blood lipids and fewer adverse reactions,which shows a broad application prospect.Most of the current research on bezafibrate is the optimization of its synthesis process conditions and the exploration of pharmacological activity.However,there is no relevant data reported for bezafibrate solid-liquid phase equilibrium and crystallization process.In this paper,based on experimental operations and theoretical simulations,a comprehensive and systematic study on the crystallization process of bezafibrate was carried out.The solubility of bezafibrate were measured by using a laser dynamic monitoring method in 16 pure solvents(methanol,ethanol,ethyl acetate,n-propanol,n-butanol,1-pentanol,n-propyl acetate,iso-propanol,iso-butanol,iso-pentanol,n-butyl acetate,sec-butanol,methyl propionate,methyl ethyl ketone,cyclohexanone,and acetonitrile)and binary mixed solvents(methanol+acetonitrile and methanol+water)at temperatures ranging from 283.15 to 323.15 K under 101.3 kPa.The mole fraction solubility of bezafibrate in 16 pure solvents increases with the increasing temperature and follows the order of cyclohexanone>alcohols and methyl ethyl ketone>esters>acetonitrile.The mole fraction solubility of bezafibrate in(methanol+ acetonitrile)and(methanol+water)also increases with the increasing temperature,but the former shows a maximum value as the mole fraction of acetonitrile increases from zero to one,and the latter gradually decreases with the increase of the mole fraction of water.The solubility of bezafibrate in pure solvents was simulated using the Wilson,modified Apelblat,NRTL,and Van't Hoff model.That in(methanol+acetonitrile)was simulated using the modified Apelblat and Apelblat-Jouyban-Acree model.That in(methanol+water)was simulated using the modified Apelblat and Van't Hoff model.Since the obtained values of RD,RAD,and RMSD are very small,the selected thermodynamic models fit the solubility data well.The thermodynamic mixing properties(?mixG,?mixH,?mixS,?1?,and H1E.?)of bezafibrate solutions in pure solvents were evaluated based on the experimental solubility data and the values of the parameters of the Wilson model.The obtained values of ?mixG and ?mixH(except n-propanol at 323.26 K)are negative,indicating that the dissolution process of bezafibrate in 16 pure solvents is spontaneous and exothermic.Bezafibrate was characterized by differential scanning calorimetry(DSC)and powder X-ray diffraction(XRD).The Chi parameters,binding energy and mixing energy of the binary system were calculated by MS software to evaluate the compatibility of bezafibrate in different pure solvents.The crystal structure of bezafibrate was analyzed based on the XRD patterns of the raw bezafibrate,and the crystal habit of bezafibrate was predictd using Equilibrium morphology,BFDH,and Growth morphology models.Two methods of dilution crystallization and cooling crystallization were used to study the crystallization process of bezafibrate in methanol solvent.After analysis and comparison,it's determined to mainly study its dilution crystallization process.The crystallization process conditions examined included the initial concentration of the solution,crystallization temperature,stirring rate,dropping quantity of water,dropping rate of water,aging time and the content of crystal seeds.According to the yield and crystal habit of the crystalline product,the optimal crystallization process conditions of bezafibrate are obtained:the initial concentration of the solution is 0.020 g/mL,the stirring rate is 100 rpm,the crystallization temperature is 15?,the volume ratio of methanol to water is 1:3,the aging time is 120 min,the dropping rate of water is 2.0 mL/min,and the content of crystal seeds is 0.5%.