MAILLARD REACTION OF LACTOSE AND FLUOXETINE HYDROCHLORIDE, A SECONDARY AMINE

Analysis of commercially available generic formulations of fluoxetine HCl revealed the presence of lactose as the most common excipient. We show that such formulations are inherently less stable than formulatio ns with Starch as the diluent due to the Maillard reaction between the drug, a secondary amine hydrochloride, and lactose. The Amadori rearr angement product was isolated and characterized; the characterization was aided by reduction with sodium borohydride and subsequent characte rization,of this reduced adduct. The lactose-fluoxetine HCl reaction w as examined in aqueous ethanol and in the solid state, in which factor s such as water content, lubricant concentration, and temperature were found to influence the degradation. N-Formylfluoxetine was identified as a major product of this Maillard reaction and it is proposed that N-formyl compounds be used as markers for this drug-excipient interact ion since they are easy to prepare synthetically. Many characteristic volatile products of the Maillard reaction have been identified by GC/ MS, including furaldehyde, maltol, and 2,3-dihydro-3,5-dihydroxy-6-met hyl-4H-pyran-4-one. Close similarity between the degradation products of simple mixtures and formulated generic products was found, however, at least one product decomposed at a rate nearly 10 times that predic ted from the simple models. Maillard products have also been identifie d in unstressed capsules. The main conclusion is that drugs which are secondary amines (not just primary amines as sometimes reported) under go the Maillard reaction with lactose under pharmaceutically relevant conditions. This finding should be considered during the selection of excipients and stability protocols for drugs which are secondary amine s or their salts, just as it currently is for primary amines.