Evaluation of N- Hydroxymethyl Chlorphensin Carbamate and Ethionamide as Potential Prodrugs

ABSTRACT Chlorphensin carbamate is a centrally acting muscle relaxant, insoluble in water, readily absorbed from the gastro-inteatinal tract, when administered orally and highly metabolished. The mechanism of action is by depressing spinal polysynaptic reflexes. Neuronal conduction, neuromuscular transmission and muscle excitability are not depressed except after nearly lethal doses. This action led to its characterisation as inter-neuronal blocking agent and therefore used to relief symptomatic muscular spasm, treat osteoarithritis of hand or hip and t,rigeminnl neuralgia. Ethion:midt> 1:; a drug thaL is readily absorbed from the gastro-intest inall tract and is extensivcb l y metabolised, so that less than one percent of it is excreted as active form in urine. The drug is anti-tubercular against ~ycobacteriwn balnei; and its action is bacteriostatic and in high concentrvation, it becomes bactericidal and therefore used to trc!at pulmonary tuberculosis, peritonitis tuberculosis and leprosy. In the present study, N-hydroxymet,hyl chlor~hensin carbamate and ethiomamide were synthesised and evaluated as potential prodrugs. This was do~~e by studing their aqueous solubilities, intrinsic dissolution rates, apparent partition co- efficients and their kinetics of decnmpositiorl in buffer systems. The results obtained showed the N-hydroxymethyl derivatives to possess higher water solubilities, higher intrinsic dissolution rates and lower lipophilicity than the parent compounds. The rate of decomposition to formaldehyde and the parent compound followed firstiorder kinetics and it is suggested that N-hydroxymethylation may be a potential useful means of obtaining prodrug forms of chlorphensin carbamate and ethionamide.