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

Abstract

The rate constants for transfer of a homologous series of nicotinic acid esters from oil vehicles to aqueous buffer phases were determined using a rotating dialysis cell. The chemical stability of butyl nicotinate has been investigated at 60°C over pH range 0.5–10. Maximum stability occurs at pH 4–5 and an inflection point was seen around the p K a. For the nicotinic acid esters, a linear correlation was established between the first-order rate constant related to attainment of equilibrium , k obs and the apparent 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 of 4 it was possible to determine k obs by decreasing pH in the aqueous release medium to 2.05. Thus, under the latter experimental conditions estimation 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 nicotinate was 139. The hydrophobic substituent constant for a methylene group, π(CH 2), was determined for nicotinic acid esters in different oil/buffer partitioning systems to 0.54–0.58. Addition of hydroxypropyl- β-cyclodextrin to the aqueous release medium did not enhance the transport rate of the esters from the oil phase.