A pharmaceutical cocrystal of apigenin with piperazine: Preparation, structural characterization, and dissolution performance

As a natural flavonoid, apigenin (APG) has garnered considerable attention for its broad pharmacological properties. Unfortunately, the extremely poor aqueous solubility greatly restricts its clinical efficacy. Cocrystallization has been taken as an important approach to modulate physicochemical properties of parent drug. In this paper, piperazine (PIP) has been selected to assembly with APG and APG–PIP cocrystal has been successfully fabricated and characterized by single crystal X-ray diffraction and various analytical methods. Single-crystal X-ray diffraction analysis indicates APG–PIP crystallizes in the P21/c space group of monoclinic system and comprises neutral APG and PIP with the ratio of 1:1. APG and PIP are linked via O–H···N/N–H···O hydrogen bonds with a resulting 2D fes network. The 2D networks are further extended via π···π stacking interactions to afford its 3D architecture. The APG illustrates highly enhanced solubility and dissolving rate in APG–PIP cocrystal comparing with parent APG. It is notable that APG–PIP presents different equilibrium concentrations of APG along with insoluble residue when different dosages of APG–PIP are introduced. We speculate that APG and PIP may not be released equally within APG–PIP in aqueous medium due to their neutral nature and huge difference in solubility, and the existence of PIP can facilitate the dissolving of APG. This speculation has been further confirmed by investigation of relationship between equilibrium concentrations of APG and dosage of APG–PIP as well as powder dissolution experiment. The equilibrium concentrations are 0.118, 0.382, 0.556, 0.767, and 0.904 mg/mL when 5, 10, 15, 20, and 25 mg APG–PIP was put into 5 mL H2O and reveals good linear relation. The "spring and parachute" phenomenon and final similar solubility with parent APG in powder dissolution profile can be ascribed to the synergetic effect of metastable supersaturation and decreased PIP concentration due to withdrawing-replenishing operation.