Study On The Key Quality Attributes Of Lorazepam Table

Lorazepam is a benzodiazepines sedative-hypnotics developed by the American company Wyeth.It has a central nervous system calming,hypnotic,anti-anxiety,antiepileptic and other effects and can be used as the first choice for first-line anti-epileptic status.Lorazepam was listed as China’s basic medicine.Lorazepam was widely used in clinical applications.Although it has been used for many years,it lacks a comprehensive and in-depth examination of its quality.The "12th Five-Year Plan for National Drug Safety" explicitly proposed to conduct generic drugs quality and efficacy consistency evaluation and improve the quality of drugs comprehensively.This article has conducted relevant research on the quality of generics lorazepam.The quality of medicines is related to the safety and effectiveness.Based on the critical quality attributes that affect the safety and effectiveness of lorazepam tablets,this paper aims to improve the current quality standard and provide direct ground for the evaluation of quality and efficacy consistency by the research on its related substances and in vitro dissolution.The test consists of the following two parts:First,safety research.The related substances are one of the critical quality attributes of drugs and have important influence on the safety and quality of drugs.1.The reasonableness of the chromatographic conditions of ChP related substances test on Lorazepam was investigated and compared with the USP method,it was found that the method of ChP related substances test had some advantages in durability and specificity.By calculating the relative response factor of the known impurity A~E in the USP,it is proved that the quantitative method of impurity in the current standard method of ChP on Lorazepam is reasonable.2.The impurity spectrum of lorazepam was studied.The degradation of the API of lorazepam under the conditions of acid,alkali,oxidation,heat and light was investigated,and the sources of the degradation products were analyzed.Two unknown impurities in the preparations were identified by relative retention time,UV spectrum and LC-MS / MS,respectively.In combination with the synthetic route of lorazepam,the degradation rule and the detection results of impurities in the preparations,it is suggested that in the quality standard of lorazepam,in addition to control the known impurity B,C in the ChP,We should also control the limit of the known impurity A,D,E,and increase the limit of impurity D in the quality standard of lorazepam tablets.3.The toxicity of lorazepam and its known impurity A~E was investigated by animal experiment,cell experiment and computer simulation method.The neurotoxicity test of zebrafish showed that the toxicity of lorazepam and its impurity B,impurity C to embryonic development was as follows: impurity C > impurity B > lorazepam.At the same time,the three can increase the viability of neonatal SD rat cardiomyocytes,there is no significant difference.The risk of allergy,reproductive toxicity and genetic toxicity of lorazepam and impurity A~E was predicted by ADMET Predictor software.Second,the effectiveness researchDissolution is a critical evaluation item for solid preparations.The dissolution rate not only reflects the intrinsic quality of the product,but also evaluates the consistency of the production process and has a certain correlation with the bioavailability.1.The inherent dissolution rate of Lorazepam in three domestic enterprises was investigated and it was found that there was no difference among them.The results show that the difference of Lorazepam tablets dissolution behavior in China is not directly related to the drug itself,but to the preparation of the formulation and the production process.2.An in vitro dissolution method capable of differentiating the intrinsic quality of Lorazepam was established.The dissolution test conditions were determined as: the dissolution device selected the first method(basket method),the rotation speed was 50 rpm,and 500 ml of pH 6.8 buffer solution was dissolved out of the medium.3.The similarity of sample dissolution curves in three domestic enterprises was compared in order to compare and analyze samples of different quality scientifically.The results showed that the intra-batch uniformity and inter-batch reproducibility of domestic enterprise samples were not good,suggesting that domestic enterprises should improve the stability of their production process.In this paper,the critical quality attributes of lorazepam tablets,related substances and dissolution were studied systematically and deeply in order to provide reliable experimental data for the consistency evaluation of the quality and efficacy of lorazepam in the future.It also provides the basis for the revision of the quality standard of Lorazepam in order to ensure the scientific and reasonable quality of the standard.