Synthesis and hydrolytic behaviour of glycerol-1,2-diibuprofenate-3-nitrate, a putative pro-drug of ibuprofen and glycerol-1-nitrate.
Nitroxylated derivatives of non-steroidal anti-inflammatory drugs appear to offer protection against the gastrotoxicity normally associated with non-steroidal anti-inflammatory drugs, ostensibly via local production of nitric oxide. A diester of ibuprofen and glycerol-1-mononitrate has been prepared via the condensation of ibuprofen with 3-bromopropan-1,2-diol, followed by silver-(I)-nitrate-mediated nitroxylation. The release of ibuprofen from this diester has been studied in a simulated gastric fluid model with direct analysis by reverse-phase HPLC, using an acetonitrile-water (80%:20%) mobile phase containing trifluoroacetic acid (0.005%). n-Propyl ibuprofen was found to undergo pH-dependent hydrolysis, ranging from negligible hydrolysis at pH 5 to 52% hydrolysis at pH 3, over a 2-h period in this model. The ibuprofen-glycerol mononitrate diester was subjected to the most vigorous model hydrolytic conditions and was found to undergo 50 % hydrolysis during the study period. This study shows that pro-drugs of ibuprofen and glycerol mononitrate can be obtained, and can undergo degradation to the parent drugs under conditions simulating those likely to be encountered in the stomach.
Ingram
M J
MJ
School of Pharmacy and Chemistry, Liverpool John Moores University, UK.
Moynihan
H A
HA
Powell
M W
MW
Rostron
C
C
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D005750:Gastric Juice / Q000737:chemistry; D006868:Hydrolysis; D007052:Ibuprofen / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D005996:Nitroglycerin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011355:Prodrugs; C429887:glycerol-1,2-diibuprofenate-3-nitrate; C049454:glycerol-1-nitrate; D005996:Nitroglycerin; D007052:Ibuprofen