title: 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 (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.
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria 3052, Australia.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria 3052, Australia.
authors.forename: Joshua
authors.initials: J
authors.lastname: Finnin
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria 3052, Australia.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Tait
authors.affiliation: Kimberly-Clark Corporation, Roswell, Georgia 30022.
authors.forename: Stephen
authors.initials: S
authors.lastname: Quirk
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria 3052, Australia.
authors.forename: Igor
authors.initials: I
authors.lastname: Chekhtman
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria 3052, Australia; PolyActiva P/L, Melbourne, Victoria 3000, Australia.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Donohue
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria 3052, Australia; PolyActiva P/L, Melbourne, Victoria 3000, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ng
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria 3052, Australia; PolyActiva P/L, Melbourne, Victoria 3000, Australia.
authors.forename: Asha
authors.initials: A
authors.lastname: D'Souza
authors.affiliation: PolyActiva P/L, Melbourne, Victoria 3000, Australia.
authors.forename: Russell
authors.initials: R
authors.lastname: Tait
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria 3052, Australia. Electronic address: richard.prankerd@monash.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Prankerd
mesh_terms: D004008:Diclofenac / Q000737:chemistry* / Q000378:metabolism*; D004952:Esters; D006868:Hydrolysis; D011108:Polymers / Q000737:chemistry* / Q000378:metabolism*; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D004952:Esters; D011108:Polymers; D011355:Prodrugs; D004008:Diclofenac
keywords: controlled release; diclofenac esters; hydrolysis; kinetics; pH rate profile; pendent drug attachment; polymeric drug delivery systems; prodrugs; stability; wound care