Research On Improving The Quality Standard Of Procaterol Hydrochloride And Its Preparations

Research background and purpose:Procaterol hydrochloride belongs to the third generation ofβ₂-receptor agonists,which is clinically used to treat bronchial asthma,asthmatic bronchitis and other lung diseases.Procaterol hydrochloride raw materials and Procaterol hydrochloride tablets are subject to the quality standards of the Pharmacopoeia of the People’s Republic of China（Ch.P2020）Volume II;the current quality standards of Procaterrol hydrochloride oral solution are the national drug registration standards YBH00232021 and YBH00992010.The quality standard items of Procaterol hydrochloride and its preparations were reasonably set,but there are the following deficiencies:（1）the inspection items of related substances of Procaterol hydrochloride API only controlled the total amount of impurities,but did not control the known impurities and other single impurities;（2）the API did not control the residual solvents;（3）the inspection items of related substances were not included in Procaterol hydrochloride tablets;（4）The dissolution of tablets was determined by the small cup method,which was not conducive to the consistency evaluation;（5）The uniformity of half tablets was investigated without considering the actual situation of clinical medication;（6）There are some problems such as low sensitivity and poor durability in the determination of related substances in Procaterol hydrochloride oral solution,which still need to be optimized.According to the requirements of the National Pharmacopoeia Committee for improving the quality standard of Procaterol hydrochloride,this study intends to conduct in-depth research on the quality standards of Procaterol hydrochloride raw materials,tablets,and oral solution,and further improve and enhance them,providing scientific basis for more effective quality control of Procaterol hydrochloride and its preparations.Materials and Methods:1.The experiment applies reversed-phase high performance liquid chromatography（RP-HPLC）to optimize a method for the determination of the substances of interest in Procaterol hydrochloride and validate the proposed method.2.The experiment applies gas chromatography（GC）to establish a method for the determination of five residual solvents in Procaterol hydrochloride API and validate the proposed method.3.The experiment applies RP-HPLC to establish a method for the examination of substances related to Procaterol hydrochloride tablets and validate the proposed method.4.The experiment examines the dissolution curves of Procaterol hydrochloride tablets in different dissolution media and establishes a slurry method for the dissolution of Procaterol hydrochloride tablets.5.The experiment applies RP-HPLC to determine the uniformity of half tablet content of Procaterol hydrochloride tablets,and investigates the content uniformity and weight loss of Procaterol hydrochloride tablets by manual cutting and blade cutting.6.The experiment applies RP-HPLC to establish a method for the examination of substances related to Procaterol hydrochloride in oral solution and validate the proposed method.7.The experiment applies RP-HPLC to establish a method for the simultaneous determination of the main components of Procaterol hydrochloride oral solution and three bacteriostatic agents（sodium benzoate,ethyl hydroxybenzoate and butyl hydroxybenzoate）and validate the proposed method.Results:1.The method for the determination of the relevant substances in the raw material was optimized.The method was able to detect and effectively separate three known impurities in procaterol hydrochloride（impurity A is 5-（（1R,2R）-1-hydroxy-2-isopropylaminobutyl）-8-hydroxyquinolone,impurity B is8-hydroxyquinolone,and impurity C is 5-formyl-8-hydroxyquinolone）and other unknown single impurities.2.A GC method was established for the accurate determination of the residues of methanol,ethanol,acetone,propanal and isopropanol in Procaterol hydrochloride API.3.An RP-HPLC method was established for the examination of substances related to Procaterol hydrochloride tablets.The method was able to detect and effectively separate three known impurities in procaterol and other unknown single impurities.The limits for each impurity and the total impurity of the substances of interest in Procaterol hydrochloride tablets were formulated based on toxicological data,toxicity data predicted by computer software and influence factor tests.4.The dissolution curves of Procaterol hydrochloride tablets in four dissolution media were determined and a method for checking the dissolution was established.The method was validated by using the paddle method instead of the small cup method and the dissolution solution was determined by high performance liquid chromatography.5.The uniformity of half tablet content was examined for both manual splitting and blade splitting of Procaterol hydrochloride tablets via tablets,and the weight loss of splitting and the half tablet content after splitting were examined.The results were that the manual splitting A+2.2S value was smaller and the amount of splitting debris was smaller for Procaterol hydrochloride tablets,but the functional indentations of some products could not serve to evenly split the tablets.6.The RP-HPLC method for the examination of substances of interest in Procaterol hydrochloride oral solution was optimised.The method was effective in separating the main ingredient from three known impurities and other individual impurities,and the excipients did not interfere with the impurity examination.7.An RP-HPLC method was developed for the simultaneous determination of the main ingredient of Procaterol hydrochloride oral solution and the three inhibitors,which was calculated by external standard method,with strong method specificity and easy operation.Conclusions:In this study,the quality standard of Procaterol hydrochloride raw material was improved,the inspection method of related substances was optimized,the problem that impurity A cannot be separated from Procaterol hydrochloride at baseline was solved,and the inspection method of residual solvents was established to reduce the safety risk.A study was conducted to improve the quality standard of Procaterol hydrochloride tablets by establishing a method for the examination of relevant substances and setting reasonable limits;the method for the examination of dissolution was optimized to facilitate the consistency evaluation;the uniformity of the content of half tablets was studied to provide a reference for the enterprises to improve the process.A study was conducted to improve the quality standard of Procaterol hydrochloride oral solution.The method was optimized for the determination of impurities in the oral solution,and the problem that p-hydroxybenzoic acid and Procaterol hydrochloride could not be separated at baseline in the systemic applicability solution was solved;the method of content determination was optimized and could be applied to the examination of bacteriostatic agents at the same time,which is simple and efficient.