Study On Quality Of Ranitidine Hydrochloride Capsules

Ranitidine hydrochloride is a class of histamine H₂ receptor blockers.It is mainly used in the clinical treatment of gastric ulcers,duodenal ulcers,reflux esophagitis and other gastric diseases^[1].In this dissertation,researches on genotoxic impurities N,N-dimethylnitrosamine（NDMA）and photodegradable impurities in current international research hotspots have been conducted.The quality standards of the drug substance and capsules have been improved.Quality control provides the basis for testing.This research work mainly includes the following four parts:Aiming at the physical and chemical properties of NDMA,a liquid chromatography-mass spectrometry（LC-MS）method was established.The full-scan mode was used to characterize NDMA molecules,and the parent and daughter ion pairs with higher response were selected for quantification.The chromatographic column,ion source temperature,collision energy and other parameters were screened.Finally,LC-MS method was established to determine the content of NDMA in the drug substance and capsule.The results show that the method has a good linear relationship in the range of 3.174 to 634.800 ng/mL,with detection limits and quantitation limits of 1.322 ng/mL and 6.225 ng/mL,respectively.The method has the advantages of high sensitivity,strong specificity,and accurate quantification,and overcomes the shortage of false positives caused by the combination of the sample with NDMA at high temperature when using GC-MS headspace sample detection.The photodegradable impurities were studied.The photodegradable impurities were prepared by simulating sunlight with a xenon lamp.Three unknown impurity solutions were collected by liquid chromatography.After separation and purification,the structure of the impurities was estimated by LC-MS.The impurity 3 was attributed by nuclear magnetic technology Finally,the Protox data platform was used to predict the toxicity data of the three impurities.The results showed that the degradation impurity 1 was presumed to be（E）-N-methyl-N’-(2-（（（5-（（methylamino）methyl）furan-2-yl）methyl）thio）ethyl 2-nitroethylene-1,1-diamine,degradation of impurity 2 is presumed to be（E）-2-(（（1-（methylamino）-2-nitrovinyl）amino）ethane-1-Thiol;degradation impurity 3 was confirmed as（E）-3-（methylamino）-5,6-dihydro-2H-1,4-thiazin-2-one O-(（（5-（（dimethylform Amino）methyl）furan-2-yl）methyl）oxime.The toxicity data show that the three impurities are carcinogenic to varying degrees,so further toxicological studies are needed.Combined with the relevant substance inspection methods in the current standards,relevant substance inspections and methodological investigations were performed after chromatographic conditions were optimized,and residual solvent detection was performed.The results showed that the relevant substance inspection method was a C₁₈ column with a phosphate buffer as mobile phase A and acetonitrile as mobile phase B for gradient elution;the detection wavelength was 230 nm,the flow rate was 1.0 mL/min,the column temperature was 35°C,and the injection amount was 10μL;Determination of residual solvents in ethanol and1,2-dichloroethane by gas chromatography.The content determination method is the same as the related substance detection method,and the sample content is 99.98%¹00.23%.Finally,the self-made capsules were studied,and a dissolution method was established and compared with the reference preparation.The results showed that the dissolution was measured by the paddle method,and the four solutions were used as dissolution media.The dissolution method verification results were in compliance with the requirements.The influencing factor test results showed that the drug substance and capsule were stable under high temperature and high humidity The moisture absorption is relatively obvious,and the content and related substances change significantly under light conditions.The experimental results provide data support for product production and storage.