Pharmaceutical salts to improve diffusion permeability of a BCS class III β-blocker drug atenolol†

Abstract

Atenolol (ATL) is a cardioselective β1-receptor antagonist used to treat cardiovascular disorders such as hypertension and angina. It belongs to the biopharmaceutical classification system (BCS) class III, for which permeation across the intestinal membrane is the rate-limiting step. This study aims to screen biologically acceptable salts of ATL to improve its diffusion properties using six dicarboxylic acids such as oxalic acid (OXA), fumaric acid (FUM), malic acid (MAL), glutaric acid (GLU), adipic acid (ADP) and pimelic acid (PIM). The organic salts were subjected to solid-state characterization such as powder XRD, single crystal XRD, DSC/TGA, and FT-IR spectroscopy. The crystal structures confirm the proton transfer from the carboxylic acid to the isopropyl amine fraction of ATL. Among the multicomponent salts, ATL forms anhydrous salts with GLU/MAL, whereas ATL–OXA/FUM/ADP/PIM are confirmed to be salt hydrates. Similar to the native drug, all the salts maintained stability for more than 1 month during exposure to 35 ± 5 °C/75 ± 5% relative humidity conditions. In addition, the salts were thermally stable at 50 °C for an hour. The aqueous solubility and diffusion study of the ATL salts (ATL–ADP/FUM/PIM/GLU/MAL/OXA) in pH 6.8 phosphate buffer indicated improved solubility (up to 33-fold) and flux (up to 2.8-fold) compared to the native drug due to ionic interactions between the drug and the counterion. Improved diffusion properties of the ATL salts are partially correlated with their enhanced solubility distribution coefficients and log P of the salt former.