The free hydralazine anti-hypertensive drug and new salts with improved solubility

Abstract

Although long used as an antihypertensive drug because of its vasodilator properties, Hydralazine (HDZ) has received renewed attention in the last few years due to its secondary therapeutic effects, which has led to its repurposing for its antioxidative, anti-apoptotic, and anti-inflammatory abilities, especially in cardiovascular and renal diseases. Given the worldwide prevalence of these diseases and that only the hydrochloride salt form of this drug has been reported and commercialized until now, in this paper we describe the synthesis, crystalline structure and physicochemical properties of the free hydralazine and its two new salts, a bromide (HDZ-Br) and a nitrate (HDZ-NO3), aiming to provide new candidates of HDZ solid forms that can be potentially used as an alternative to the pattern antihypertensive treatment, with better properties than the commercial one and can also be used in new applications addressed to this drug. Herein we investigated the three new multicomponent solid forms using single crystal X-ray diffraction (SCXRD), X-ray powder diffraction (XRPD), Differential Scanning Calorimetry (DSC), Thermogravimetric analysis (TGA), Infrared/Raman spectroscopies, and relative solubility studies. Interestingly, all structures showed the formation of HDZ columns intercalated with ions columns as well as a strong tendency to develop π···π stacking interactions among HDZ molecules which can be useful for future design of new potential multicomponent forms of HDZ. The new reported salts show a relative solubility higher than the commercially hydralazine hydrochloride form, suggesting that they can be potentially useful in new pharmaceutical formulations.