Ester prodrugs of a potent analgesic, morphine-6-sulfate: syntheses, spectroscopic and physicochemical properties

PreechagoonD, BreretonI, Staatz, C and PrankerdR (1998) Ester prodrugs of a potent analgesic, morphine-6-sulfate: syntheses, spectroscopic and physicochemical properties. International Journal of Pharmaceutics, 163 1-2: 177-190.


Author PreechagoonD
BreretonI
Staatz, C
PrankerdR
Title Ester prodrugs of a potent analgesic, morphine-6-sulfate: syntheses, spectroscopic and physicochemical properties
Journal name International Journal of Pharmaceutics   Check publisher's open access policy
Publication date 1998
Sub-type Article
DOI 10.1016/S0378-5173(97)00381-5
Volume number 163
Issue number 1-2
ISSN 0378-5173
Start page 177
End page 190
Total pages 14
Language eng
Abstract The aim of this work is to develop 3-acyl prodrugs of the potent analgesic morphine-6-sulfate (M6S). These are expected to have higher potency and/or exhibit longer duration of analgesic action than the parent compound. M6S and the prodrugs were synthesized, then purified either by recrystallization or by semi-preparative HPLC and the structures confirmed by mass spectrometry, IR spectrophotometry and by detailed 1- and 2-D NMR studies. The lipophilicities of the compounds were assessed by a combination of shake-flask, group contribution and HPLC retention methods. The octanol-buffer partition coefficient could only be obtained directly for 3-heptanoylmorphine-6-sulfate, using the shake-flask method. The partition coefficients (P) for the remaining prodrugs were estimated from known methylene group contributions. A good linear relationship between log P and the HPLC log capacity factors was demonstrated. Hydrolysis of the 3-acetyl prodrug, as a representative of the group, was found to occur relatively slowly in buffers (pH range 6.15-8.01), with a small buffer catalysis contribution. The rates of enzymatic hydrolysis of the 3-acyl group in 10% rat blood and in 10% rat brain homogenate were investigated. The prodrugs followed apparent first order hydrolysis kinetics, with a significantly faster hydrolysis rate found in 10% rat brain homogenate than in 10% rat blood for all compounds. (C) 1998 Elsevier Science B.V. All rights reserved.
Keyword Pharmacology & Pharmacy
Morphine
Morphine-6-sulfate
3-acyl Prodrugs
Nuclear Magnetic Resonance
Lipophilicity
Hplc Capacity Factors
Hydrolysis Kinetics
Aqueous Solubility
Oil Solubility
Performance Liquid-chromatography
Partition-coefficients
Magnetic-resonance
Morphine
Morphine-6-glucuronide
Morphine-3-glucuronide
Lipophilicity
Derivatives
Retention
Phases
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article
Collection: Centre for Advanced Imaging Publications
 
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