Crystallization For Chiral Separation And Stability Of Valsartan

The optical purity of chiral drug is one of the important product qualities.Among the various methods of enantioseparation,crystallization is one of the most attractive as it is simple and economical.In this dissertation,we take valsartan as an example to study the preferential crystallization for the separation of high-eutectic racemic compound,and to study the seeding crystallization to improve the stability of valsartan.The details are as follows:The solubility of valsartan with different optical purity in ethyl acetate and mixed solvent(ethyl acetate : ethanol=99%:1%,m:m)was measured by gravimetric method.And the ternary phase diagrams of valsartan in two solvent systems were constructed using the solubility data.The racemate valsartan was identified to be racemic compound from the ternary phase diagrams,and its eutectic point is S/R(R/S)=90%:10%.Besides,the solubility and MSZW of 91%(S)-V in two solvent systems were measured for the preferential crystallization.The initial concentration of 91%(S)-V for preferential crystallization was obtained from the ternary phase diagrams,and product with optical purity above 99% was gained by preferential crystallization from the two solvent systems,respectively.The mixed solvent system was determined to be the better solvent system of valsartan to perform preferential crystallization for its higher yield and higher success rate.This indicates that solvent have an important effect on the enantioseparation of chiral drugs.And an approach for rapid optimization of the preferential crystallization condition based on theory and experiments to obtain optically pure enantiomer products was presented.The effect of spontaneous crystallization,seeding crystallization,anti-solvent crystallization and granulation on stability of valsartan was studied in 1L reactor.The product obtained by seeding crystallization was to study the preparation adaptability.Then the product was prepared to capsule and dispersible tablet to test its chemical stability by accelerated stability test and its disintegration rate,respectively.Finally the seeding crystallization process was tested to be the suitable one for capsule and dispersible tablet.Application of process analytical technique(PAT)on crystallization was studied.On-line FTIR,turbidimeter and on-line 2D imaging system were applied to the crystallization of valsartan in this dissertation,and achieved good results,which indicates its importance for crystallization,and should be developed.