title: Solid state compatibility study and characterization of a novel degradation product of tacrolimus in formulation.
abstract: Tacrolimus is macrolide drug that is widely used as a potent immunosuppressant. In the present work compatibility testing was conducted on physical mixtures of tacrolimus with excipients and on compatibility mixtures prepared by the simulation of manufacturing process used for the final drug product preparation. Increase in one major degradation product was detected in the presence of magnesium stearate based upon UHPLC analysis. The degradation product was isolated by preparative HPLC and its structure was elucidated by NMR and MS studies. Mechanism of the formation of this degradation product is proposed based on complementary degradation studies in a solution and structural elucidation data. The structure was proven to be alpha-hydroxy acid which is formed from the parent tacrolimus molecule through a benzilic acid type rearrangement reaction in the presence of divalent metallic cations. Degradation is facilitated at higher pH values.
authors: Lek Pharmaceuticals d.d., Verovškova 57, SI-1526 Ljubljana, Slovenia. Electronic address: tanja.rozman_peterka@sandoz.com.
authors: Tanja
authors: T
authors: Rozman Peterka
authors: Lek Pharmaceuticals d.d., Verovškova 57, SI-1526 Ljubljana, Slovenia.
authors: Rok
authors: R
authors: Grahek
authors: Lek Pharmaceuticals d.d., Verovškova 57, SI-1526 Ljubljana, Slovenia.
authors: Jure
authors: J
authors: Hren
authors: Lek Pharmaceuticals d.d., Verovškova 57, SI-1526 Ljubljana, Slovenia.
authors: Andrej
authors: A
authors: Bastarda
authors: Lek Pharmaceuticals d.d., Verovškova 57, SI-1526 Ljubljana, Slovenia.
authors: Jure
authors: J
authors: Bergles
authors: Lek Pharmaceuticals d.d., Verovškova 57, SI-1526 Ljubljana, Slovenia.
authors: Uroš
authors: U
authors: Urleb
mesh_terms: D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004340:Drug Contamination; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007166:Immunosuppressive Agents / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D021241:Spectrometry, Mass, Electrospray Ionization; D013229:Stearic Acids / Q000737:chemistry; D016559:Tacrolimus / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D005079:Excipients; D007166:Immunosuppressive Agents; D013229:Stearic Acids; C031183:stearic acid; D016559:Tacrolimus
keywords: Characterization; Compatibility study; Degradation product; Tacrolimus