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J Pharm Sci. 1983 Nov;72(11):1294-8.

Prodrugs as drug delivery systems XXV: Hydrolysis of oxazolidines--a potential new prodrug type.


The hydrolysis kinetics of several oxazolidines derived from (-)-ephedrine and various aldehydes and ketones were studied to assess their suitability as prodrug forms for beta-amino alcohols and/or carbonyl-containing compounds. The oxazolidines were found to undergo a facile and complete hydrolysis in the pH range of 1-11 at 37 degrees. The hydrolysis rates were subject to general acid-base catalysis by buffer substances and depended strongly on pH. Most oxazolidines showed sigmoidal pH-rate profiles with maximum rates at pH greater than 7-7.5. At pH 7.40 and 37 degrees the following half-lives of hydrolysis for the various ephedrine oxazolidines were found: 5 sec (formaldehyde), 18 sec (propionaldehyde), 5 min (benzaldehyde), 5 sec (salicylaldehyde), 30 min (pivalaldehyde), 4 min (acetone), and 6 min (cyclohexanone). The reaction rates in neutral and basic solutions were shown to decrease with increasing steric effects of the substituents derived from the carbonyl component and to decrease with increasing basicity of the oxazolidines. The oxazolidines are weaker bases (pKa 5.2-6.9) than the parent beta-amino alcohol and more lipophilic at physiological pH. It is suggested that oxazolidines can be considered as potentially useful prodrug candidates for drugs containing a beta-amino alcohol moiety or carbonyl groups.

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