title: The Maillard reaction of bisoprolol fumarate with various reducing carbohydrates.
abstract: HPLC analysis of drug products containing bisoprolol fumarate and lactose revealed the presence of N-formylbisoprolol, which is a final product of the Maillard reaction. Formulations containing secondary amines and reducing carbohydrates are prone to the condensation of amine and carbonyl functional groups and formation of glycosylamines in pharmaceutically relevant conditions. Further rearrangement occurs in the presence of a nucleophile and leads to the formation of 1-deoxy-1-amino-2-ketose also known as the Amadori Rearrangement Product (ARP). The influence of water content, carbohydrate, and lubricant types on the reaction rate was tested. The reaction progress was monitored by HPLC and UV-Vis spectrophotometry. The structures of intermediates were confirmed by the LC/MS(2) analysis. N-formylbisoprolol - the final reaction product - was synthesised and characterised by LC/MS(2), H(1) and C(13) NMR.
authors.affiliation: Product Development Department, ICN Polfa Rzeszów S.A., 35-959 Rzeszów, Poland. Electronic address: mateusz.szalka@valeant.com.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Szalka
authors.affiliation: Department of Organic Chemistry, Rzeszów University of Technology, 35-959 Rzeszów, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Lubczak
authors.affiliation: Department of Physical Chemistry, Rzeszów University of Technology, 35-959 Rzeszów, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Naróg
authors.affiliation: Product Development Department, ICN Polfa Rzeszów S.A., 35-959 Rzeszów, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Laskowski
authors.affiliation: Department of Chemical and Process Engineering, Rzeszów University of Technology, 35-959 Rzeszów, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kaczmarski
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000737:chemistry*; D017298:Bisoprolol / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D005947:Glucose / Q000737:chemistry*; D007785:Lactose / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D015416:Maillard Reaction; D008320:Maltose / Q000737:chemistry*; D013058:Mass Spectrometry; D010084:Oxidation-Reduction; D013056:Spectrophotometry, Ultraviolet; D014867:Water / Q000032:analysis
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D014867:Water; D008320:Maltose; D005947:Glucose; D007785:Lactose; D017298:Bisoprolol
keywords: 1-Deoxy-1-amino-2-ketose; Amadori rearrangement; Bisoprolol fumarate; Excipient incompatibility; Glycosylamine; Maillard reaction