title: Characterization of a new degradation product of nifedipine formed on catalysis by atenolol: A typical case of alteration of degradation pathway of one drug by another.
abstract: An increasing interest is being shown throughout the world on the use of fixed-dose combinations of drugs in the therapy of select diseases, like cardiovascular diseases, due to their multiple advantages. Though the main criterion for combining drugs in a single dosage form is the rationale, but consideration like stability of formulation is equally important, due to an added aspect of drug-drug interaction. The objective of this study was to evaluate interaction among the drugs in an antihypertensive combination of nifedipine and atenolol. Nifedipine is a known light sensitive drug, which degrades via intra-molecular mechanisms to nitro- and nitroso-pyridine analogs, along with a few minor secondary products that are formed through inter-molecular interactions amongst primary degradation products and their intermediates. Atenolol is reasonably stable weakly basic drug that is mainly hydrolyzed at acetamide terminal amide moiety to its corresponding carboxylic acid. To the best of our knowledge, there is no known information on chemical compatibility among the two drugs. The present study involved subjecting of nifedipine, atenolol and their combination to a variety of accelerated and stress conditions. HPLC studies revealed formation of a new product in the mixture of two drugs (∼2%), which was also generated from nifedipine alone, but at trace levels (<0.1%). The product was isolated by preparative chromatography and subjected to indepth studies for its characterization. Ultra-violet, FT-IR, mass spectrometric and nuclear magnetic resonance spectroscopic studies highlighted that the principal photo-degradation pathway of nifedipine was modified and diverted in the presence of atenolol. To verify the same, a study was conducted employing two other β-blockers with similar structures to atenolol, and the same product was formed in relatively higher quantity therein also. The new product is postulated to be produced as a result of rearrangement of hydroxylamine intermediate, known to be involved in the generation of nitro- and nitroso-pyridine photo-degradation products of nifedipine.
authors.affiliation: Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar 160 062, Punjab, India.
authors.forename: Tarun
authors.initials: T
authors.lastname: Handa
authors.affiliation: Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar 160 062, Punjab, India. Electronic address: ssingh@niper.ac.in.
authors.forename: Saranjit
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar 160 062, Punjab, India.
authors.forename: Inder Pal
authors.initials: IP
authors.lastname: Singh
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000737:chemistry; D001262:Atenolol / Q000737:chemistry*; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004338:Drug Combinations; D004347:Drug Interactions; D009543:Nifedipine / Q000737:chemistry*; D010782:Photolysis; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods
chemical_list: D000319:Adrenergic beta-Antagonists; D004338:Drug Combinations; D001262:Atenolol; D009543:Nifedipine
keywords: Characterization; Degradation product; Fixed-dose combination (FDC); Interaction; Nifedipine and atenolol