Preparation And Preliminary Evaluation On Polymorphism Of Sartans

Sartans are a common class of antihypertensive drugs,which generally have polymorphism.The polymorphism of drugs affects the quality of drug substances and preparations to some extent,and then affects their bioavailability and efficacy.The study of crystal form is of great significance for the development of new drugs,optimization of crystallization process,extension of patent protection period,etc.This paper first used raw materials of losartan potassium,irbesartan,telmisartan,and candesartan cilexetil as the research objects.Their polymorphic forms were prepared and qualitative and quantitative studies are performed.In addition,the dissolution profiles of candesartan cilexetil tablets from different companies were used as one of the evaluations in vitro of the formulation.The above studies provided a certain reference value for the crystalline quality control of drugs,as follows:In the first part of the dissertation,losartan potassium formⅠand formⅢwere successfully prepared using isopropanol-cyclohexane,n-propanol,acetonitrile-water(10:1),and acetone-water(10:1)as recrystallization solvents;Irbesartan form A and form B were successfully prepared using n-propanol,dioxane,dimethyl sulfoxide-water and methylpyrrolidone-water as solvents;Telmisartan form A and form C were successfully prepared using dimethylformamide,dimethylsulfoxide,and 98%formic acid-water as solvents;Candesartan cilexetil form I,1,4-dioxane solvate,form III and form IV were successfully prepared using n-butanol,1,4-dioxane-cyclohexane,toluene and ethyl acetate-cyclohexane as solvents.The purity was determined by high performance liquid chromatography,and then powder x-ray diffraction and fourier transform infrared spectroscopy,laser micro-confocal raman spectroscopy,and differential scanning calorimetry were used to characterize them.The second part used powder x-ray diffraction method as a quantitative method.First of all,standard curves of the content of one crystal form and the ratio of the characteristic peak diffraction peak area or peak height in the mixed crystal sample were prepared by preparing a mixed crystal sample with two crystal form ratios.Then determine the content of crystal form in the sample.The results show that:Losartan potassium form III had a good linear relationship in the range of 2%to 50%(mass fraction)in the mixture of formⅠand form III.The linear relationship was good.The linear equation was y=0.0077x-0.0119,and the correlation coefficient R~2 is 0.9996;Irbesartan form B had a good linear relationship in the range of 1%to 50%(mass fraction)in the mixture of form A and form B.The linear equation was y=0.0110x+0.0039,correlation coefficient R~2 is 0.9990;Telmisartan form C had a good linear relationship in the range of 1%to 50%(mass fraction)in the mixture of form A and form C,and the linear equation was y=0.0112 x+0.0121,correlation coefficient R~2was 0.9998;candesartan cilexetil form III had a linear relationship in the range of 1%to50%(mass fraction)in the mixture of form I and form III,and the linear relationship was good,the equation was y=0.0114x+0.0064,and the correlation coefficient R~2 was0.9998.The precision,accuracy,detection limit,and stability were measured respectively.In the third part,candesartan cilexetil tablets from different companies were used as research objects.Use 0.5%sodium dodecyl sulfate solution as dissolution medium to study the dissolution behavior,It was found that when 0.5%SDS was used as the dissolution medium,it had the effect of distinguishing the dissolution performance of candesartan cilexetil tablets from different companies.The powder x-ray diffraction method was used to study the stability of the preparation.It was found that different preparation processes did not cause changes in drug crystal form,and the crystal form of candesartan cilexetil tablets from different different companies remains the same.