The Preformulation Stability Studies of a Proline Prodrug of Methotrexate

Ann      Stephenson; Zhiqian      Wu; Xudong      Yuan

doi:10.2174/157340612801216166

Abstract

In order to reduce toxicity of methotrexate and improve bioavailability, permeability, and explore other delivery routes, a proline prodrug of methotrexate was synthesized and preformulation stability studies were conducted under accelerated conditions to assess compound liability and possible conversion to the parent drug. Forced degradation studies showed that the prodrug will degrade in the presence of water, acid, and heat (70 °C), generating the parent compound methotrexate. It was also found that this conversion is temperature dependent. In addition, the prodrug is extremely light and oxidative labile. Therefore, future formulation studies should be light protected and stabilized by a suitable antioxidant. It was also found that the prodrug is stable in the HPLC diluent, consisting of water and acetonitrile; stored bench-top and protected from light for up to two weeks.

Keywords: Preformulation, Stability, Forced degradation, Hydrolysis, Methotrexate, Proline, Prodrug, acetonitrile, MTX, Amethopterin