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

Feng Wang, Joshua Finnin, Cassandra Tait, Stephen Quirk, Igor Chekhtman, Andrew C. Donohue, Sarah Ng, Asha D'Souza, Russell Tait, Richard Prankerd

Research output: Contribution to journalArticleResearchpeer-review

10 Citations (Scopus)

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 (t1/2 = 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.

Original languageEnglish
Pages (from-to)773-785
Number of pages13
JournalJournal of Pharmaceutical Sciences
Volume105
Issue number2
DOIs
Publication statusPublished - 1 Feb 2016

Keywords

  • controlled release
  • diclofenac esters
  • hydrolysis
  • kinetics
  • pendent drug attachment
  • pH rate profile
  • polymeric drug delivery systems
  • prodrugs
  • stability
  • wound care

Cite this