Three Candesartan Salts with Enhanced Oral Bioavailability

Abstract

Three new salts, [H3N(CH2)2NH3][can]·2H2O (1), [H3N(CH2)3NH3][can]·2H2O (2), and [NH4][Hcan] (3), of the minimally soluble antihypertensive drug, Candesartan (H2can), have been prepared by solvent-assisted grinding. Salts 1–3 also have been thoroughly characterized by single-crystal X-ray diffraction, powder X-ray diffraction, Fourier transform infrared spectroscopy, 1H nuclear magnetic resonance, thermogravimetry, and differential scanning calorimetry. In the case of 1 and 2, two protons of carboxyl and tetrazole groups of Candesartan transfer to the diamine, resulting in salts where both hydrogen bonding and electrostatic interactions that link the Candesartan and diamine (diammonium) units into a one-dimensional supramolecular ribbon. However, unlike the case in 1 and 2, only one proton from the carboxyl group of Candesartan transfers to ammonia in 3 and ionic components now assemble into a three-dimensional supramolecular network. Dissolution studies indicate that both the apparent solubility and dissolution rate of salts 2 and 3 in phosphate buffer are dramatically improved compared to those of the original active pharmaceutical ingredient (API). Furthermore, to evaluate the absorption effect of salts 1–3 in vivo, pharmacokinetic studies were performed in rats. It is notable that the oral bioavailability of salts 1–3 is enhanced by 1.3, 2.5, and 3.1 times, respectively, compared to that of the API.