Ketorolac Ester Enhancer-prodrugs: Preparation and Evaluation of Their Physicochemical Properties

Six ester analogues of Ketorolac were synthesized as potential enhancer prodrugs for transdermal delivery. Solubility of these esters was determined in 10% propylene glycol (PG)/isotonic phosphate buffer (IPB) at room temperature while lipophilicity was obtained as partition coefficients (log P) and capacity factors (k') using HPLC. Stability of the prodrugs in skin extract and in plasma was investigated at $37^{\circ}C$. The lipophilicity of the potential prodrugs increased in proportion to their alkyl chain length. Good linear relationship between partition coefficients (log P) and capacity factors (log k') was observed ($R^2=0.9961$). All of the analogues were fairly stable but slowly degraded in IPB over a 12 hour period. However, their stability in skin extract and in plasma varied with most compounds gradually decomposing over a 12 hour period. Although unsaturation of the alkyl ester chain did not alter the over all lipophilicity of the compound, the half-life was significantly affected. In plasma, degradation of the esters was slower than in the skin extract, which is a desirable trait for enhancer-prodrugs. However, the overall hydrolysis in the skin extract needs to be facilitated for the development of an effective enhancer prodrug. The analogue with the shortest half life in the skin extract was the unsaturated C-12 analogue of 0.96 hr.