Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmaceutical Chemistry

This thesis is concerned with the development of simple and accurate methods for the determination of a newly approved drug combination (Sacubitril and Valsartan) for the treatment of heart failure in commercially used formulation either alone or in the presence of their degradation products and/or their related impurities or in biological fluids, and the evaluation of certain drug-drug interactions and drug-food interactions of this newly approved combination (Sacubitril and Valsartan). Application of experimental design approach in optimization of RP-HPLC method for simultaneous determination of Sacubitril and Valsartan in presence of their degradation productsand forced degradation study of Sacubitril under different stress conditions was proposed. Application of RP-HPLC method to a study of the assessment of drug-drug interaction potential of concomitant use of Sacubitril/Valsartan on the pharmacokinetic of Rosuvastatin in ratsthrough in-vivo study. In addition, assessment of the influence of grapefruit juice on the activation of the prodrug Sacubitril was evaluated using rat liver S9 fraction in in-vitro study. HPLC-MS/MS method was proposed for separation and quantitation of Sacubitril and Valsartan in human plasma with some of the co-administered drugs (Chlorthalidone, Esomeprazole and Nebivolol) that are usually prescribed together according to the guidelines of heart failure treatment. Moreover, derivative ratio spectrofluorimetric method was proposed as rapid and simple methodology for resolving spectral overlap displayed by Sacubitril and Valsartan spectra.The proposed methods were validated and statistically compared with reference methods where no significant difference was found

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