Study On The Quality Evaluation And Standard Of Compound Paracetamol Tablets(Ⅱ)

Compound Paracetamol tablets(Ⅱ)is an over-the-counter antipyretic and analgesic drugs,composed of Paracetamol(C8H9NO2),Propyphenazone(C14H18N2O),Caffeine(C8H10N4O2)and appropriate amount of excipients.The preparation is generally used to relieve fever caused by colds,and can also relieve symptoms such as toothache,headache,and neuralgia.Because of its fast effect of heat dissipation and pain relief,longer duration and fewer side effects than other similar drugs,it is widely used in clinical practice.At present,the only standard included in this drug at home and abroad is "National Drug Standard"-the 16 th volume of the National Standard for the Improvement of Local Standards for Chemical Drugs,but there are still some problems in the standard,such as incomplete inspection items,outdated testing methods and no relevant substance inspection.In order to cooperate with the work of the China Inspection Institute and the National Pharmacopoeia Commission,this project carried out a quality evaluation and standard study on the preparation of compound paracetamol tablets(Ⅱ)on the domestic market based on the comprehensive analysis and evaluation.It provides a certain reference contribution for the implementation of the follow-up study on the quality standard of this preparation.The main contents and conclusions are as follows:(1)A total of 166 batches of compound paracetamol tablets(Ⅱ)were selected for this project,involving 4 manufacturing companies,accounting for 80% of the number of companies that have obtained approval numbers.According to the current national standard,the quality was evaluated,and the results showed that there was little difference in tablet weight between different enterprises and batches.The dissolution results showed that the average dissolution amount of paracetamol was 97%,the average dissolution amount of propyphenazone was 94%,and the average dissolution amount of caffeine was 99%.Although the dissolution of all the samples met the 80%limit of the labeled amount,the data of box diagram showed that there was a separate outlier value in the samples from all enterprises.Similarly,the analysis of the data box chart of content determination also found that the content datas of paracetamol and propyphenazone in some enterprises were more discrete.The results showed that some enterprises had the problem of unstable production process control.And it is far from enough to control the content uniformity of this preparation based on the difference in tablet weight.Therefore,the requirement of the standard update content uniformity check item is proposed.(2)Based on the original national standard,this article established a new liquid chromatography analysis method: mobile phase A is 7m M phosphate buffer(2.4g potassium dihydrogen phosphate + 1.3g anhydrous disodium hydrogen phosphate,add water to 4000 m L,adjust the p H to 6.8): Methanol 95:5,mobile phase B is methanol,XTerra MS-C18(250×4.6mm,5μm)chromatographic column is selected for gradient elution.The mobile phase carcinogen tetrahydrofuran in the original standard is removed,the mobile phase components are simpler,the consumables are lower,and the resolution is higher.This method was used to investigate the content uniformity.The results showed that although the content uniformity results of many companies meet the A+2.2S≤15 regulations of the Pharmacopoeia,the sample batches varied greatly between batches,and there were close to the critical value.The maximum content of caffeine A+2.2S was 14.45,and the maximum content of propyphenazone A+2.2S was14.64.Therefore,it is necessary to establish the content uniformity check item in the standard.At the same time,it is suggested that the study of notch should be increased for half tablets.(3)There are no related substances inspection items in the current standards,and no systematic studies and reports on related substances have been seen.In this study,three API standards in the EP9.0,USP42-NF37,JP17 and Chinese Pharmacopoeia(2015 edition)were collected.Combined with the specific domestic market conditions,the analysis method of the relevant substance items of this compound preparation was studied.A new HPLC method was developed for the determination of five impurities,including impurity A,H of paracetamol,p-aminophenol,phenazone and impurity F of caffeine: Mobile phase A consisted of 7m M phosphate buffer(potassium dihydrogen phosphate 2.4g+ anhydrous disodium hydrogen phosphate 1.3g,adding water to4000 m L,adjusting p H to 6.8),mobile phase B consisted of methanol,and the chromatographic column was Xterra MS-C18(250×4.6mm,5μm),followed by gradient elution.The analytical method has the advantages of high specificity,well sensitivity,well accuracy,high separation degree of each impurity and principal component,high retention time and suitable peak shape stability,which can reduce the analysis operation time.(4)Combining the existing standard dissolution test items,the US Pharmacopoeia(40)"acetaminophen,caffeine tablets" dissolution test items and the Japanese Orange Book,this topic screened the dissolution methods and dissolution media of this species.A study on the dissolution curves of the three components of paracetamol,caffeine and propyphenazone was carried out.Multi-angle analysis and comparison showed and verified the reliability,accuracy and feasibility of the original standard dissolution method.The dissolution conditions were determined to be: Take 900 ml of hydrochloric acid solution(dilute hydrochloric acid 24ml→1000ml water)as dissolution medium,rotating basket method,rotating speed of 100r/min,sampling after 30 minutes,the limit is 80% of the labeled amount.At the same time,the dissolution profile measurement and the dissolution rate measurement were carried out on the samples of some enterprises.It provides a reference for the revision of the dissolution check items in the quality standard of this drug.(5)In order to strengthen the process quality control in the production,transportation,storage and sales of this preparation,this project proposed to adopt a new analysis method: terahertz time-domain spectroscopy technology,and initially established a rapid detection method of the APIs of three components in this drug.The terahertz time-domain spectras of APIs of the three components were obtained by the analysis technology of the three components;the spectras showed that the three components have suitable absorption values in the terahertz band,and there are characteristic absorption peaks,indicating that the terahertz time-domain spectroscopy technology can effectively distinguish these three effective ingredients,which can be used for qualitative analysis of this species.At the same time,through the establishment and testing of the model,a preliminary exploration and research on the caffeine composition was carried out.The caffeine quality score predicted by the model was not much different from the actual value.This work provides some references for the research of new analytical methods for this species.