Tadalafil–Malonic Acid Cocrystal: Physicochemical Characterization, pH-Solubility, and Supersaturation Studies

The purpose of this study was to enhance the solubility and dissolution of a poorly water-soluble drug, tadalafil (TDF), by cocrystal formation with malonic acid (MOA), to characterize the cocrystal structure and to quantify the cocrystal solution behavior. The crystal structure revealed a 1:1 stoichiometry, wherein the TDF molecules form a double layered structure through N–H···OC interactions linked to a catemeric chain of MOA molecules via O–H···O hydrogen bonds. Cocrystal solubility advantage (SA defined as S cocrystal/S drug) or supersaturation index was determined from eutectic point measurements to be 102 to 129 in the pH range of 1 to 3. Cocrystal dissolution generated supersaturation levels (C max/S drug) of 30 in buffer and 120 in the presence of a nucleation inhibitor, HPMC. The amorphous form of TDF generated supersaturation three times lower than cocrystal in buffer, and not significantly different from cocrystal in the presence of HPMC. Thus, supersaturation index is a valuable metric for assessing the risk of cocrystal conversion during kinetic studies and for predicting conditions when the usage of a precipitation inhibitor may significantly increase cocrystal exposure levels.