Drug-Excipient Interactions of Seproxetine Maleate Hemi-Hydrate: Isothermal Stress Methods

Abstract

Seproxetine maleate hemi-hydrate was originally formulated with pregelatinized starch, to provide 1 and 20 mg free base equivalent gelatin capsule dosage forms for storage at 25°C and 40°C. HPLC analysis after 3 months revealed the formation of a 1,4 Michael addition adduct in each case. No additional degradation products were detected. To pursue a less interactive formulation, 5 mg formulation equivalent mixtures of seproxetine maleate hemi-hydrate were prepared with pregelatinized starch, lactose, and talc; thus, three distinctly different excipient classifications. These were evaluated in additional isothermal stress experiments at 25°C, 40°C, and 50°C. The results indicated that each excipient interacted with the drug in a unique chemically and thermally dependent manner. Thus, the drug-pregelatinized starch data may be represented by an Arrhenius type relationship, with activation energy of 32 kcal/mol, and formation of the previously described adduct. However, the drug-lactose data suggest reaction with an impurity in which the equilibrium is temperature dependent. Finally, the drug-talc data correspond to either sigmoid kinetics or a threshold temperature which must be exceeded for formation of an amide. A final choice of excipient is thus complicated by having to project these three solid state reactions, of different thermal characteristics, to the shelf life of the product.