A Study On The Crystallization Process Of Valsartan

Valsartan is an orally active specific angiotensin ? antagonist,which demonstrates high affinity to the AT1 receptor subtype.Crystallization is a key step in the process of product purification,but the research on valsartan crystallization is limited.Therefore the thermodynamic and kinetic of valsartan crystallization was studied in this article,which provides basis for the analysis,design,operation and simulation of industrial crystallizer.The solubility of valsartan in ethyl acetate was measured by a static equilibrium method at temperatures range of 278.15 to 323.15 K.The solubility data were regressed by the modified Apelblat equation,the NRTL equation,and the ?h equation.In addition,the thermodynamic parameters(including the enthalpy,entropy and Gibbs energy)were calculated by the van't Hoff analysis.The experimental data were well-correlated with the above models because the mean deviation values of these three models were 1.03%,3.87%,and 1.72%,respectively.Therefore,the modified Apelblat equation was the best choice in the correlation of the solubility data of ethyl acetate.The values of thermodynamic parameters proved that the dissolution process of valsartan in ethyl acetate was endothermic,spontaneous and entropy-driven.The main contributor to the standard molar Gibbs energy of solution is the enthalpy during the dissolution process.Furthermore,the supersolubility of valsartan in ethyl acetate was measured at different stir rate and temperature decreasing rate by the laser method.The results indicated that the metastable zone was wider under the condition of smaller stir rate,higher temperature and larger temperature decreasing rate.Meanwhile,the temperature effect was remarkable and the temperature decreasing rate had little effect on the metastable zone.According to the characteristics of the crystallization process,it was difficult to obtain the data of valsartan crystal size distribution.So in order to obtain the kineticequation parameters of the crystal growth,the kinetic data of different crystallization temperatures in ethyl acetate were determined with batch method in the condition of constant initial concentration.Meantime,the effect of temperature on kinetic data and the mechanism of crystal growth were explored.The results show that the crystallization rate of valsartan increases rapidly with the decreasing temperature at the initial stage of crystallization.During the crystal growth stage,the crystallization rate of valsartan increases with the increasing temperature.The pre exponential factor in the growth kinetics equation is 1.944×10~8;Apparent activation energy is 41.78kJ/mol;the series is 1.2729;R2 is 0.8754.Furthermore,the growth of valsartan crystal in ethyl acetate solution is controlled by the surface reaction of the crystal because the apparent activation energy is more than 40 kJ/mol.