The Hydrolysis of Diclofenac Esters: Synthetic Prodrug Building Blocks for Biodegradable Drug-Polymer Conjugates.

Abstract Degradation reactions on diclofenac-monoglycerides ( 3a,b ), diclofenac-( p -hydroxybenzoate)-2-monoglyceride ( 3c ), diclofenac ( 1 ), and diclofenac lactam ( 4 ) were performed at 37°C in isotonic buffer solutions (apparent pH range 1-8) containing varying concentrations of acetonitrile (ACN). The concentration remaining of each analyte was measured versus time. Diclofenac-monoglycerides and diclofenac-( p -hydroxybenzoate)-2-monoglyceride ( 3c ) were both found to undergo facile and complete hydrolysis in pH 7.4 isotonic phosphate buffer/10% ACN. Under mildly acidic, neutral or alkaline conditions, diclofenac-( p -hydroxybenzoate)-2-monoglyceride ( 3c ) had the fastest hydrolysis rate ( t 1/2  = 3.23 h at pH 7.4), with simultaneous formation of diclofenac lactam ( 4 ) and diclofenac ( 1 ). Diclofenac-monoglycerides ( 3a,b ) hydrolyzed more slowly under the same conditions, to again yield both diclofenac ( 1 ) and diclofenac lactam ( 4 ). There was also transesterification of diclofenac-2-monoglyceride ( 3b ) to its regioisomer, diclofenac-1-monoglyceride ( 3a ) across the pH range. Diclofenac was shown to be stable in neutral or alkaline conditions but cyclized to form the lactam ( 4 ) in acidic conditions. Conversely, the lactam ( 4 ) was stable under acidic conditions but was converted to an unknown species under alkaline or neutral conditions.