Enhancing Skin Permeation of Biphenylacetic Acid (BPA) Using Salt Formation with Organic and Alkali Metal Bases

Abstract

In the present study, a series of organic and alkali metal salts of biphenylacetic acid (BPA) have been prepared and evaluated in vitro for percutaneous drug delivery. The physicochemical properties of BPA salts were determined using solubility measurements, DSC, and IR. The DSC thermogram and FTIR spectra confirmed the salt formation with organic and alkali metal bases. Among the series, salts with organic amines (ethanolamine, diethanolamine, triethanolamine, and diethylamine) had lowered melting points while the alkali metal salt (sodium) had a higher melting point than BPA. The in vitro study showed that salt formation improves the physicochemical properties of BPA, leading to improved permeability through the skin. Amongst all the prepared salts, ethanolamine salt (1b) showed 7.2- and 5.4-fold higher skin permeation than the parent drug at pH 7.4 and 5.0, respectively, using rat skin.

Keywords: BPA; Lipophilicity; NSAID; Salt; Skin permeation.

Fig. 1

The structures of BPA (1) and its salts (1a–e)

Fig. 2

FTIR Spectra of BPA (1) and its salts (1a–e)

Fig. 3

Scanning electron microscope images of compounds (1, 1a, 1b, 1d)

Fig. 4

DSC thermograms of BPA (1) and its salts (1b, 1d)

Fig. 5

Aqueous solubility of BPA (1) and its salts (1a–e)

Fig. 6

Partition coefficient (Log P_app) values of BPA (1) and its salts (1a–e)

Fig. 7

Steady-state flux (J_ss) of 6-MNA (1) and the salts (1a–e) through rat skin in vitro at 37°C

Fig. 8

Permeation profile of BPA (1) and its salt (1b) (mean±SEM, n=3-6) at pH 5.0 and 7.4