Azilsartan-nicotinamide cocrystal: Preparation, characterization and in vitro / vivo evaluation

Azilsartan (AZL) is an angiotensin II receptor antagonist, which is mainly used for the treatment of hypertension. AZL has the advantages of high selectivity, hypotensive effect, protection of cardiovascular and cerebrovascular diseases. In order to improve the water solubility of AZL and its bioavailability, AZL -nicotinamide (NA) cocrystal was prepared by mechanical ball milling, and the effect of ball milling conditions on cocrystal preparation were studied. AZL-NA cocrystal was identified and characterized by powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, scanning electron microscopy and Fourier transform infrared spectrometry. The results showed that AZL-NA cocrystal with the molar ratio of 1:2 was successfully prepared. And the optimum ball milling condition was milling speed of 300 rpm, milling time of 50 min, the solvent was ethanol/acetonitrile (1:1, v/v), and the solvent dosage (η) was 0.8 μL/mg. The results of solubility tests showed that the solubility of AZL in the cocrystal was 3.39 times higher than the pure drug at 24 h. And the results of vitro dissolution tests showed that the cumulative dissolution of AZL in 2 h was about 10%. While distilled water, pH 1.2 and pH 4.5 acid or buffered solutions and pH 6.8 buffer phosphate salt solution was used as the dissolution medium, the cumulative dissolution of AZL in cocrystal reached 50%, 35%, 55% and 90%, respectively, showing obvious improvement of dissolution. In addition, the accelerated stability tests showed that the AZL-NA cocrystal had good chemical stability. And the pharmacokinetic results showed that AZL-NA cocrystal could significantly improve the bioavailability of AZL.