title: Molecular insight into atypical instability behavior of fixed-dose combination containing amlodipine besylate and losartan potassium.
abstract: Combination therapy with the use of fixed-dose combinations (FDCs) is evincing increasing interest of prescribers, manufacturers and even regulators, evidently due to the primary benefit of improved patient compliance. However, owing to potential of drug-drug interaction, FDCs require closer scrutiny with respect to their physical and chemical stability. Accordingly, the purpose of the present study was to explore stability behavior of a popular antihypertensive combination of amlodipine besylate (AML) and losartan potassium (LST). Physical mixtures of the two drugs and multiple marketed formulations were stored under accelerated conditions of temperature and humidity (40°C/75% RH) in a stability chamber and samples were withdrawn after 1 and 3 months. The physical changes were observed visibly, while chemical changes were monitored by HPLC employing a method that could separate the two drugs and all other components present. The combination revealed strong physical instability and also chemical degradation of AML in the presence of LST. Interestingly, three isomeric interaction products of AML were formed in the combination, which otherwise were reported in the literature to be generated on exposure of AML free base above its melting point. The same unusual products were even formed when multiple marketed FDCs were stored under accelerated conditions outside their storage packs. However, these were absent when AML alone was stored in the same studied conditions. Therefore, reasons for physical and chemical incompatibility and the mechanism of degradation of AML in the presence of LST were duly explored at the molecular level. The outcomes of the study are expected to help in development of stable FDCs of the two drugs.
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.
authors.forename: Shalu
authors.initials: S
authors.lastname: Jhajra
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar 160 062, Punjab, India.
authors.forename: Shweta
authors.initials: S
authors.lastname: Bhagat
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar 160 062, Punjab, India.
authors.forename: P V
authors.initials: PV
authors.lastname: Bharatam
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar 160 062, Punjab, India.
authors.forename: Asit K
authors.initials: AK
authors.lastname: Chakraborti
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
mesh_terms: D017311:Amlodipine / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004338:Drug Combinations; D004339:Drug Compounding; D004347:Drug Interactions; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D019808:Losartan / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure
chemical_list: D004338:Drug Combinations; D017311:Amlodipine; D019808:Losartan
keywords: Amlodipine besylate; Characterization; Fixed-dose combination (FDC); Interaction/degradation products; Losartan potassium; Stability