title: Analytical study proving alprazolam degradation to its main impurity triazolaminoquinoleine through Maillard reaction.
abstract: Triazolaminoquinoleine is rapidly formed in formulations of alprazolam tablets in presence of excipients, and its generation is speeded up with increasing temperature and humidity. The present paper deals with detailed quantitative and qualitative studies into the nonactive constituents of the formulation in order to determine the excipient (or the mixture) responsible for the degradation. Our studies have demonstrated that reducing carbohydrate excipients play a fundamental role in the generation of triazolaminoquinoleine, with lactose as the main one responsible, through a Maillard reaction. In order to demonstrate the validity of the proposed degradation mechanism, p-nitrobenzaldehyde has been employed as a model of reaction of the nucleophylic attack of amino-opened structure of alprazolam to an aldehyde to generate the first intermediate involved in Maillard reaction, a Schiff base. This model enables the identification of all the intermediates by mass spectrometry and/or nuclear magnetic resonance techniques, with the outcome of this experiment leading to a full understanding of the generation pathway. Calcium carbonate has been proposed as a possible tablet diluent replacing lactose in the pharmaceutical formulation.
authors.affiliation: Sección de Química Analítica, Facultad de Farmacia, Universidad San Pablo-CEU, Campus Montepríncipe, 28668 Boadilla del Monte, Madrid, Spain.
authors.forename: A L
authors.initials: AL
authors.lastname: Huidobro
authors.forename: C
authors.initials: C
authors.lastname: Barbas
mesh_terms: D000525:Alprazolam / Q000032:analysis* / Q000737:chemistry*; D004304:Dosage Forms; D004340:Drug Contamination; D004355:Drug Stability; D006813:Humidity; D006863:Hydrogen-Ion Concentration; D007201:Indicator Dilution Techniques; D009682:Magnetic Resonance Spectroscopy; D015416:Maillard Reaction; D013058:Mass Spectrometry; D015394:Molecular Structure; D011804:Quinolines / Q000032:analysis* / Q000737:chemistry
chemical_list: D004304:Dosage Forms; D011804:Quinolines; C465922:triazolaminoquinoleine; D000525:Alprazolam