Effect of cyclodextrins on the hydrolysis of an oxazolidine prodrug of (1R,2S)-(-)-ephedrine-cis-2-(4-methoxyphenyl)-3, 4-dimethyl-5-phenyloxazolidine.
Molecular complexes of an oxazolidine prodrug of (-)-ephedrine, cis-2-(4-methoxyphenyl)-3,4-dimethyl-5-phenyloxazolidine, with alpha-, beta-, dimethyl-beta- (DM-beta-) and hydroxypropl-beta- (HP-beta-) cyclodextrins (CDs) were examined using ionspray mass spectrometry. The results suggest, under our experimental conditions, a 1:1 stoichiometric complex between the prodrug and all CDs. Apart from the putative inclusion complexation, the stabilization effect of CDs on the prodrug in an aqueous solution was studied. beta-, DM-beta- and HP-beta-CD exhibited a retardation effect on the rate of hydrolysis of the prodrug. Conversely, alpha-CD did not alter the rate of hydrolysis even at excess concentrations. Presumably, the larger cavity diameter of beta-CDs may permit a greater depth of penetration of the prodrug, resulting in its shielding from hydrolysis. The observations in this work indicate that mass spectrometry could be a rapid and informative analytical method to aid in the preliminary evaluation of the potential utility of CDs in enhancement of drug stability.
Bakhtiar
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R
Merck Research Laboratories, Rahway, NJ 07065-0900, USA.
Hop
C E
CE
Walker
R B
RB
D003505:Cyclodextrins / Q000737:chemistry*; D004809:Ephedrine / Q000031:analogs & derivatives* / Q000737:chemistry; D006868:Hydrolysis; D007700:Kinetics; D013058:Mass Spectrometry; D010080:Oxazoles / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*
C106249:2-(4-methoxyphenyl)-3,4-dimethyl-5-phenyloxazolidine; D003505:Cyclodextrins; D010080:Oxazoles; D011355:Prodrugs; C064210:oxazolidine; D004809:Ephedrine