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
Medicinal Chemistry
Title:The Preformulation Stability Studies of a Proline Prodrug of Methotrexate
Volume: 8 Issue: 4
Author(s): Ann Stephenson, Zhiqian Wu and Xudong Yuan
Affiliation:
Keywords: Preformulation, Stability, Forced degradation, Hydrolysis, Methotrexate, Proline, Prodrug, acetonitrile, MTX, Amethopterin
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.
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Cite this article as:
Stephenson Ann, Wu Zhiqian and Yuan Xudong, The Preformulation Stability Studies of a Proline Prodrug of Methotrexate, Medicinal Chemistry 2012; 8 (4) . https://dx.doi.org/10.2174/157340612801216166
DOI https://dx.doi.org/10.2174/157340612801216166 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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