Comprehensive Study On The Quality Of Purinostat Dihydrochloride Bulk Drug

Purinostat dihydrochloride is a histone deacetylase?HDAC?inhibitor,and its an-titumor effect is excellent.According to the requirements of new drug research and development,the comprehensive quality of Purinostat dihydrochloride was studied from character,identification,examination and content determination in order to de-termine the analysis method of the indexes of quality control and the current quality level and provide reference for the follow-up study with the"technical guidelines of the establishment of chemical drug quality standard normalization processand"and"technical guidelines of chemical impurities research"issued by CFDA and"the 2015edition of Chinese Pharmacopoeia four".In character study,we investigated the appearance,melting point,solubility and hygroscopy of Purinostat dihydrochloride to determine its basic properties.Results:The appearance of Purinostat dihydrochloride is pale yellow amorphous powder;Odorless and bitter;Soluble in DMSO,slightly soluble in NaOH solution(0.1mol·L^-1),very slightly soluble in methanol and HC l solution(0.1mol·L^-1),and insoluble in eth-anol,acetonitrile,chloroform,acetone and ethyl acetate;a melting point of105¹09?;high hygroscopicity.Identification study mainly used chemical method,infra-red spectrum?IR?and high performance liquid chromatography?HPLC?combined with the control sample to identify Purinostat dihydrochloride by characteristic reactions,peaks in the spectra and Chromatographic retention time respectively.Results:Purinostat dihydrochloride reacted with ferric chloride solution in purplish red,faded the color of potassium permanganate solution and reacted with silver nitrate solution in white precipitate;The infra-red spectrum of Purinostat dihydrochloride is consistent with the standards';Retention time of Purinostat dihydrochloride by HPLC method is consistent with the standards'.Examination study includes general impurities inspection,residual solvents in-spection and related substances inspection.General impurities inspection was mainly investigated for sulfate,water content,ignition residue,heavy metal and arsenic salt.A method of gas chromatography for the simultaneous determination of five residual solvents,namely,pentane,ethanol,isopropanol,dichloromethane and 1,4-dioxane,were established and residual solvents were determined.In the examination of related substances,a method to separate and detect related substances by HPLC was devel-oped and validated,and the content of related substances in Purinostat dihydrochlo-ride was determined by self-contrast method without correction factor.At the same time,UPLC-MS method was used to analyze the related substances.Results:Its moisture content was 1.2%¹.6%;The average content of residue on ignition was0.17%;The content of sulfate is less than 0.025%;The content of heavy metal is not more than 20ppm;The content of arsenic is not more than 2ppm;Isopropanol and 1,4-dioxane were not detected,dichloromethane was less than 0.06%,and pentane and ethanol were more than 0.5%.By optimizing,gradient HPLC method for related sub-stances was established,which was finalized:C₁₈ column;column temperature was30?;the flow rate was 1.0mL·min^-1;acetonitrile and phosphate buffer(10 mmol·L^-1,PH=3.0)were used as mobile phase.The results showed that there was a good linear relationship between the peak area of each substance and sample size.This method had strong specificity and high sensitivity.The total impurities of the three batches were 2.58%,2.06%,and 1.61%,respectively.According to the synthesis process and the results of UPLC-MS,it is speculated that the related substa nces may be amide,carboxylic acid and ethyl ester.Content determination study is based on the determination of the related sub-stances.By adjusting the parameters of chromatographic conditions,shortening analy-sis time,and lowerng the concentration of sample solution,a high performance liquid chromatography?HPLC?method was established,optimized and validated,and the content of Purinostat dihydrochloride was determined by external standard method.The linear range of the calibration curve was 6.25²00?g·mL^-1?R2=0.9997,n=6?and the average recovery was 100.40%?RSD=1.13%,n=9?with good precision.The analysis methods established in this study can evaluate and control the quali-ty of Purinostat dihydrochloride better.These methods are specific,accurate,and se n-sitive and can be used to determine the indexes of quality control of this product,and can provide reference for the further study.