Impurity Profiling and Degradation Behaviour of Drugs Active Against Cardiovascular Disorders

Abstract

Quality of pharmaceutical products means that the product should be free from contamination, and reproducibly delivers the therapeutic benefit to the consumer that promised in the label. Inadequate quality of pharmaceuticals can affect the performance and therapeutic efficacy of the formulation that ultimately affect to the safety of the patient. The quality of the drug product may alter during storage as some impurities may increase due to oxidation, hydrolysis, heat and humidity. The stability of pharmaceuticals at appropriate storage conditions should be monitored to derive the shelf life of the product. Proper evaluation of the quality of medicines should be assessed by performing in-vitro tests includes assay, dissolution and related substances mainly. In the current research work, related substances test methods were developed with impurity profiling for the drug products that used in cardiovascular disorders. A reverse-phase liquid chromatographic method was developed for simultaneous quantification of related substances in Ezetimibe-Simvastatin tablet dosage forms without prior separation of the drug substances. Total 15 compounds were separated along with 13 potential impurities of Ezetimibe and Simvastatin in a single method with a good resolution between all adjacent peaks. The developed method was successfully validated by all parameters as per present ICH guidelines The related substances test method was developed and validated for quantification of 15 organic impurities of Olmesartan medoxomil, Amlodipine and Hydrochlorothiazide in a combined dosage form. In the developed method, a total of 19 compounds were resolved on the C18 stationary phase by using routine solvents which are easily available at QC lab. Ion pairing HPLC method was developed for quantification of inorganic nitrite and nitrate impurities of Nitroglycerin drug substance with liquid-liquid extraction technique. Ion pairs were introduced for better retention of polar inorganic impurities and liquid-liquid extraction performed for a shorter run time. The developed method can be successfully used as an alternate to the current ion-exchange chromatographic method that is not feasible for routine analysis due to its complexity. A sensitive related substance test method was developed to analyze 9 organic impurities of Ivabradine in the tablet dosage forms. The successful separation between each nearby impurity was achieved by using a hydrophobic stationary phase. Unknown impurity, which is observed during forced degradation study, was isolated by using the preparativechromatography and characterization of the impurity was performed by using hyphenated techniques i.e., NMR spectroscopy, mass spectroscopy and IR spectroscopy. Genotoxic impurities were also evaluated in the drug product as these impurities tend to cause DNA mutation. A sensitive liquid chromatographic method was developed to analyze genotoxic impurities of Olmesartan medoxomil and Ivabradine in their combined dosage forms. The developed method can quantify the genotoxic impurities at their TTC (Threshold of Toxicological Concern) of 1.5μg/day and the method can be used as an alternate to the existing LC-MS method.