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

Abstract

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.

Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers

“…Indeed, rapid conversion of the cocrystals into pure drug was demonstrated by PXRD analysis of the solids recovered after the dissolution tests in short time periods (~1-5 min, Figure 3). A similar behavior has been documented for other cocrystal phases in the literature [24,25,30,36,37,[55][56][57]. For example, exemestane-maleic-acid cocrystals did not increase solubilization of the drug due to rapid phase transformation [55].…”

“…The use of excipients such as polymers and surfactants constitutes an efficient strategy to prolong drug supersaturation achieved from pharmaceutical cocrystals [23][24][25]36,57]. An addition of a cellulosic polymer into the dissolution medium for powder dissolution studies under non-sink conditions revealed that these can induce a supersaturation effect starting from NTZ-SUC and NTZ-GLU cocrystals.…”

“…Cellulosic polymers are the most common hydrophilic polymers used for the development of formulations with cocrystals [24,26,28,29,33,36,37]. They can inhibit or at least delay phase transformations of cocrystals [29,30], by establishing drug-polymer interactions [37] and maintaining the solubilization state of APIs.…”

“…Previous formulations with cocrystals were based on polymer matrix tablets [29,30] and pre-dissolved polymers [24,36]. However, there are few studies which have tested the effect of a polymer incorporated in the powder solid-state form on the dissolution profiles of cocrystals [23].…”

“…In this line, there are several recent reports on the effect of polymers and surfactants in increasing solubility and dissolution rates of poorly soluble drugs, starting from a cocrystalline solid phase. Some representative APIs and nutraceutical compounds studied under this approach are celecoxib [23], danazol [24], indomethacin [25], carbamazepine [26][27][28][29][30][31], flufenamic acid [32], cilostazol [33], resveratrol [34], dihydromyricetin [35], tadalafil [36], exemestane [37] and posaconazole [38].…”