Stability of a nonaqueous trimethoprim preparation

Abstract

A nonaqueous formulation of trimethoprim for injection was prepared, and the stability of the undiluted solution (50 mg/mL) was studied. Six nonaqueous injectable solvents were used in an attempt to attain a trimethoprim concentration of 50 mg/mL; N,N-dimethylacetamide was found suitable, and a cosolvent system containing 52% N,N-dimethylacetamide and 48% propylene glycol was developed. The stability of trimethoprim 50 mg/mL in this solution after storage at temperatures of 80 degrees C, 90 degrees C, and 140 degrees C was studied using high-performance liquid chromatography. Samples were also examined visually for signs of color change or precipitation. More than 90% of the initial concentration remained after storage at 80 degrees C for 45 days. Examination of the stability data suggested that trimethoprim degradation was a zero-order process, although a first-order process could not be excluded. Extrapolation of data from an Arrhenius plot yielded a zero-order trimethoprim degradation rate constant at 25 degrees C of 0.0113% day-1. The time for 10% trimethoprim degradation at 25 degrees C would be 885 days. No precipitation was observed, but the initially colorless solution turned yellow or brown during storage. The extent of color change was associated with the degree of trimethoprim degradation. Trimethoprim, when prepared in the nonaqueous solution described, is stable at 25 degrees C. The preparation may be suitable for intravenous use.