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Esmolol hydrochloride, an important anti-hypertensive and anti-arrhythmic agent, is administered as intravenous infusion only. The objective of the present work is to screen the feasibility of this drug for transdermal delivery. To enhance the lipophilicity, a pro-drug approach was adopted. Four pro-drugs, esmolol acetate, propionate, butyrate, and valerate, were synthesized and characterized by IR, NMR, Mass spectroscopy, and elemental analysis. Physicochemical parameters were ascertained and in vitro skin permeability study was carried out using excised porcine skin. Drug and pro-drugs were assessed for anti-hypertensive effect on male Sprague Dawley rats and data was statistically analyzed by one-way ANOVA. The results indicate that esters had much higher lipophilicity ( p < 0.001) than the parent drug. All the esters had recorded significantly higher ( p < 0.001) skin permeability than the parent moiety, with esmolol valerate showing the highest steady state flux (1.899 ± 0.035 µmol/cm2/h). Esters showed greater reduction of blood pressure than the parent drug, with esmolol propionate showing the highest efficacy. The findings suggest that esterification can be a promising tool for enhancing the skin permeability of esmolol, which is an essential requirement for transdermal development. [ABSTRACT FROM AUTHOR]