Abstract
A number of N-Mannich bases of various NH-acidic compounds (benzamide, phthalimide, chlorzoxazone, phenytoin, barbital, p-toluenesulfonamide, acetazolamide, chlorothiazide and hydrochlorothiazide) with morpholine or piperidine as the amine component were evaluated as potential pro-drugs with the purpose of enhancing the aqueous solubility and dissolution rate. The N-Mannich bases were shown to decompose very rapidly in aqueous solution with formation of formaldehyde, amine and parent compound in stoichiometric amounts. Dissolution rate studies showed that the derivatives, especially as hydrochloride salts, possessed markedly greater intrinsic dissolution rates in 0.1 M hydrochloric acid in comparison with the parent compounds, the largest rate acceleration observed being a factor of 2,000. It is concluded that N-Mannich bases of various NH-acidic drug substances of poor aqueous solubility may be of potential usefulness as pro-drugs with the aim of increasing the dissolution rate in an effort to improve the oral bioavailability.
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