Three Candesartan Salts with Enhanced Oral Bioavailability

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.