Effect of drug lipophilicity on in vitro release rate from oil vehicles using nicotinic acid esters as model prodrug derivatives

The rate constants For transfer of a homologous series of nicotinic acid es ters from oil vehicles to aqueous buffer phases were determined using a rot ating dialysis cell. The chemical stability of butyl nicotinate has been in vestigated at 60 degreesC over pH range 0.5-10. Maximum stability occurs at pH 4-5 and an inflection point was seen around the pK(a). For the nicotini c acid esters. a linear correlation was established between the first-order rate constant related to attainment of equilibrium. k(obs) and the apparen t partition coefficient. P-app: log k(obs) = - 0.83 log P-app + 0.26 (k(obs ) in h(-1) n = 9). For hexyl nicotinate with a true partition coefficient o f 4 it was possible to determine k(obs) by decreasing pH in the aqueous rel ease medium to 2.05. Thus. under the latter experimental conditions estimat ion of the relative release rates for the esters were performed. The ratio between the specific rate constant k(ow), related to the transport from oil vehicle to aqueous phase. for ethyl and hexyl nicolinate was 139. The hydr ophobic substituent constant for a methylene group. pi (CH2). was determine d for nicotinic acid esters in different oil-buffer partitioning systems to 0.54-0.58. Addition of hydroxypropyl-beta -cyclodextrin to the aqueous rel ease medium did not enhance the transport rate of the esters From the oil p hase. (C) 2001 Published by Elsevier Science B.V.