Development of acetaminophen proline prodrug.

In this research work, proline ester prodrug of acetaminophen (Pro-APAP) was synthesized and evaluated for its stability in PBS buffer at various pH and Caco-2 cell homogenate. The Pro-APAP is more stable at lower pH than higher pH, with half-life of 120min in PBS buffer at pH 2.0, half-life of 65min at pH 5.0, and half life of 3.5min at pH 7.4, respectively. The half-life of Pro-APAP in Caco-2 cell homogenate is about 1min, much shorter than the half-life in PBS buffer at pH 7.4, indicating enzymes in the cell homogenate contribute to the hydrolysis of the ester bond. Carboxypeptidase A was incubated with Pro-APAP at pH 7.4 with half-life of 3.8min which is very close to the half life in buffer itself. This clearly indicates carboxypeptidase A is not one of the enzymes contributing to the hydrolysis of the prodrug. Physicochemical characteristics such as melting point and stability of newly synthesized prodrug were determined by MDSC technique. 2010 Elsevier Ltd. All rights reserved.