Research On The Production Process,Quality Standard And Stability Of The Quality Consistency Evaluation Of Ambroxol Hydrochloride Solution For Inhalation

Objective:By consulting the relevant documents on the selection of reference preparations published by the National Medical Products Administration(NMPA),research and development of the company’s self-made generic drug inhalation ambroxol hydrochloride solution and the original imported Italian Sanofi Boehringer Ingelheim company’s inhalation The drug consistency evaluation study using ambroxol hydrochloride solution(trade name: Mucosolvan)provides relevant experimental data for the consistency evaluation of the generic drug declaration of ambroxol hydrochloride solution for inhalation,and further improves the efficacy and quality of domestic generic drugs.In order to fully ensure the consistency of this quality and efficacy with the reference preparation Mucosolvan,referring to the reference preparation Mucosolvan,the specification,dosage form,route of administration,dosage and indications of the imitation ambroxol hydrochloride solution for inhalation are consistent with Mucosolvan.Under the premise of the same type and amount of experiments,refer to the preparation properties,p H,content,related substances,osmotic pressure and other indicators,screen the prescription process,and finally determine the preparation process and quality standards of the self-made ambroxol hydrochloride solution for inhalation.Improve the quality of domestically produced generic drugs of ambroxol hydrochloride solution for inhalation.Method:Use reverse engineering ideas to conduct reverse research on the original drug Mucosolvan,First master the information of Mucosolvan’s drug composition,prescription process,preparation conditions and other information,and prepare products with the same efficacy and quality as Mucosolvan.Through further research and optimization of the prescription,the prescription and production process parameters suitable for mass production are finally determined.High performance liquid chromatography(HPLC)was used to conduct related tests on Mucosolvan;by comparing the content determination standard of ambroxol hydrochloride solution for inhalation in the 2020 edition of The Chinese Pharmacopoeia(CHP)and the 9.0 edition of the European Pharmacopoeia(EP),found that the chromatographic conditions were basic Unanimous.Therefore,the content determination method was optimized on the Chp standard,and the content limit of ambroxol hydrochloride solution for inhalation was reasonably limited;the self-product determination method of related substances was also optimized on the Chp standard.Using the quality standard of ambroxol hydrochloride solution for inhalation,the compatibility experiment and stability experiment of the three batches of products in the laboratory test were carried out.Result:After a large number of experiments,the prescription dosage,preparation process and content of self-made ambroxol hydrochloride solution for inhalation and the determination method of related substances were finally determined.Conclusion:1.Prescription composition Ambroxol hydrochloride solution for inhalation,the specification is 2 m L: 15 mg.The ingredients are citric acid monohydrate,disodium hydrogen phosphate dodecahydrate,and sodium chloride.The prescription composition of 1000 unit dose solutions is shown in Table 1.2.Process operation1)Weighing:Weigh the prescribed amount of ambroxol hydrochloride,citric acid monohydrate,disodium hydrogen phosphate dodecahydrate,and sodium chloride;2)Liquid preparation:Add 80 % of the prescription amount of ultrapure water(the laboratory does not have water for injection,use homemade ultrapure water instead),heat to 55 ± 5 ℃,add the agony ambroxol hydrochloride,magnetic force Stir to completely dissolve,then add weighed citric acid monohydrate,magnetically stir until it is completely dissolved,then add weighed sodium chloride,magnetically stir to dissolve completely,and finally add weighed disodium hydrogen phosphate dodecahydrate,Dissolve thoroughly with magnetic stirring,pour it into a graduated cylinder and add ultrapure water to the prescription amount,stir and mix evenly,and detect the properties,p H,and content of the intermediate liquid medicine;Among them,the p H internal control range of the intermediate liquid is5.0 ± 0.2,And the content is between 7.27 ~ 7.73 mg/m L;3)Components:The Solution is filtered through 0.22 μm PES Material Filter membrane;4)Filling and sealing:The liquid medicine is filled in 2 m L medium borosilicate glass ampoule(brown),The filling volume is 2.1 m L,and nitrogen is filled while filling,the residual oxygen content of the ampoule is monitored,and the internal control is below 6 %,and the sealing is melted;5)Unilinear Sterilization at 121 ℃ for 15 min;6)Labeling.3.Traits Detection method: visual inspection method.Pharmacopoeia stipulates: The content of this product is a colorless to slightly yellowish green clear liquid.4.Differences in loading The weight difference limit is ± 10%.5.Determination of content and related substances Combined with the 2020 version of Chp,Product containing ambroxol chloride(C13H18Br2N2O·HCl)should be 95.0 %-105.0 % of the labeled amount;the established method for related substances is in compliance with the regulations for the detection of self-products of ambroxol hydrochloride solution for inhalation.