Study On Process Optimization And Impurities Of Doxazosin Mesylate

The synthetic process for the preparation of doxazosin mesylate was investigated experimentally and the related reaction conditions were optimized.An effective method for the detection of sulfonate genotoxic impurities in doxazosin mesylate was developed based on the test experience of detection of impurities regarding methyl methanesulfonate and methyl methanesulfonate within this product via gas chromatography and the suitable conditions for the detection of these impurities were also obtained.These results could be useful in the industrial production of high-quality doxazosin mesylate and helpful for the control of genotoxic impurities.The detail contents and results are summarized as following.(1)The synthetic process was improved and the critical process parameters were optimized by the reactions of acylation,amination,condensation and salification as well as the crystal transformation process.By the lab-scale and pilot production,the obtained preservation temperature during the main steps of synthesis process of doxazosin mesylate were 70-75 ?,10-20 ?,113-118 and ? 55-65 ?,respectively;The mole ratios of raw materials were 1:2 for 1,4-Benzodioxin-2-carboxylicacid to sulfoxide chloride,1:2.1 for 1,4-Benzodioxin-2-carboxylicacid to piperazine,1:0.78 for 1-(1,4-Benzodioxane-2-carbonyl)piperazine to 2-Chloro-4-amino-6,7-dimethoxyquinazoline,1:1.2 for doxazosin to mesylate;the pH of water phase of amination reaction was 9-10 and the salification reaction time was 5 h.(2)Under the condition of the optimized process parameters,the yields of two consecutive batches of final products in lab-scale synthesis were 93.1%,91.9%,while the yields of pilot and scale-up production batches in the pilot process were in the range of 60.6% and 75.3%.All batches met the pharmacopoeia requirements including organic impurities and total impurities,which proved that the optimized process was feasible.(3)By the analysis of the product with IR,MS,NMR and elemental analysis,the obtained doxazosin mesylate was demonstrated regarding the structure,and it was confirmed that the crystals of this product were A-type crystals by X-ray powder diffraction,differential scanning calorimeter and thermo-gravimetric analysis.(4)It was necessary to establish a gas chromatographic method for the detection of methanesulfonic acid esters genotoxic impurities,i.e.,methyl methanesulfonate and ethyl methanesulfonate,in doxazosin mesylate because of alcohol solvents used in the synthesis process.An HP-INNOWAX column(30 m×0.32 mm×0.25 ?m)was adopted with temperature raising procedure by the headspace sampler.The column temperature was programmed to be 40 for 10 minutes,and then was raised at a 30 ? ?/ min to 220 ?for 3 minutes.The temperature of the injection port was maintained at 110?,and that of the flame-ionization detector(FID)was 220?.The split ratio was 20:1,and the injection volume was 1 mL with the flow rate of 0.6 mL/min.A series of method validation results of methyl methanesulfonate and ethyl methanesulfonate were shown that the limits of quantification for Methyl methanesulfonate and ethyl methanesulfonate(the relative concentrations of 10 mg/mL in sample)were 0.0024% and 0.0014%,respectively.The detection limits were 0.0007% and 0.0004%,respectively,below the standard limit of 0.0125%.Therefore,the established method was effective and accurate to detect the quantity of methyl methanesulfonate and ethyl methanesulfonate.The impurities of methyl methanesulfonate and ethyl methanesulfonate were not observed by the detection of three batches of doxazosin mesylate produced in this work.