Montelukast Sodium Preparation And Quality Standards

Asthma （allergic respiratory disease） is one of the incurable diseases of serious harm to humanhealth. Clinical major method is using drug to inhibit it. Currently there are variety of drugs used forasthma treatment and suppression, Montelukast, belonging to the leukotriene receptor antagonist, is one ofmore convenient and effective, and plays more important role in asthma treatment and suppression.Montelukast sodium（Singulair） was launched in1998by Merck in the United States for the long-termtreatment and prevention of pediatric asthma in adults and children above12months. Besides Montelukastsodium（Singulair）which are imported packing sheets and particles, the approved Montelukast sodiumpreparation of domestic manufacturers were few and can not meet the clinical needs. The research aim isfocused on the related impurity of Montelukast sodium tablets and its quality control by the moderninstrumental analysis methods to ensure its efficacy, safety and uniformity.Firstly, the published quality standards related Montelukast Sodium were summarized and itsAdvantages and disadvantages were analyzed to pointed the object of next research. Then, the tabletpreparation process was explored, its preparation formula was confirmed. On this basis, the new andperfect standards would be subsequently explored and established in the end of the research.Simultaneously, the impurity spectrum of Active Pharmaceutical Ingredient (API), MontelukastSodium and Montelukast Sodium tablets, were analyzed completely, the major related impurities, such assulfoxide, iso-sulfoxide and the cis-isomer of the tablets, which are most likely generated from API, wereisolated and identified.Then, one more reasonable method of the related substances test was established by HPLC. Method:Use Inertsil Ph-3C18column （4.6mm×250mm,5μm） with the mobile phase consisting of0.2%trifluoroacetic acid acetonitrile solution-0.2%trifluoroacetic acid with gradient elution, the flow rate was1.5mL/min; the detected wavelength was255nm; the column temperature was50℃. Result: linearregression equation was: Y=22.508x+10.789(r=1, is above0.9999); within8hours the fixed total impurityin the solution was less than1.0%; peak area RSD was0.002%, below2%, relatively stable; relatedsubstances in injection RSD was0.22%, below2%, precision well.For the impurity peak in thechromatogram of the test solution compared with the control solution chromatogram peak area of thecontent of the sulfoxide is not above1.5%; the content of cis-isomer is not above0.1%; the content of thesingle impurity whose retention time between the sulfoxide and cis-isomer impurity is not above0.05%;the content of the largest single impurity is not above0.1%; the content of total impurity not is above1.7%.Conclusion: All impurities was isolated perfectly and verified to meet the requirements.The results of the impact factor test show that the active pharmaceutical ingredient of the drug isunstable:(1)easily oxidized and generated the cis-isomer under the light,;(2)easy to absorb moisture.Suggesting that its preparation and testing process should be strictly protected from light, and avoidedusing reagents which are strong acidic, alkaline or oxidative stresses reagents, so as not to affect the quality of preparation and test results. Storage of bulk drugs and formulations should be at the room temperature(15-30℃) and the moisture shading conditions.The assay system was established by HPLC. Method: the column was inertsil Ph-3(5μm250mm×4.6mm); the mobile phase consisted of0.2%trifluoroacetic acid in acetonitrile-0.2%trifluoroacetic acidsolution (55:45); the detected wavelength was389nm; the column temperature was50℃; the flow rate was1.0mL/min. Result: the regression equation was: Y=82.334X-77.387(n=5, r=0.9999); within eight hours,the RSD of the ingredient peak area in the test solution was1.07%, below2%,; the RSD of the injectionprecision is0.23%, below1.5%; the intermediate precision is1.20%, below3.0%, the recovery rates (80%,100%,120%) are100.52%,99.62%,100.32%, in the range of98%-102%, the RSD of the nine samplesare1.31%,below2%,and the recovery rate is good. Conclusion: The destruction experiment result verifiedthat Montelukast can be well separated from the ingredient, the determination results show that the methodis accurate, fast, and good linear.Based on the above series of test results, the Standard Technical Procedure of Montelukast Sodiumpreparation was proposed; Reference to the relevant technical requirements, the quality standard ofmontelukast sodium tablets was improved, especially involved the related impurity control. The aboveresults provide adequate and reasonable support for the produce process control, the SOP and the productquality control.