Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers

Salas-Zúñiga, Reynaldo; Rodríguez-Ruiz, Christian; Höpfl, Herbert; Morales-Rojas, Hugo; Sánchez-Guadarrama, Obdulia; Rodríguez-Cuamatzi, Patricia; Herrera-Ruiz, Dea

Based on the large solubility difference between NTZ and aliphatic dicarboxylic acids as coformers [8] , we expected that cocrystal forms of NTZ with GLU and SUC increase the aqueous solubility of NTZ. Figure 2a shows that NTZ-GLU and NTZ-SUC cocrystals have dissolution profiles similar to NTZ in pH 7.5 phosphate buffer solution, and a higher solubilization of NTZ is not observed under these conditions. 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] . In a recent publication this cocrystal was reinvestigated observing that transformation into the parent drug occurred in less than 1 min in fasted state simulated intestinal fluid (FaSSIF) [37] . The critical role of the coformer physicochemical properties on the solubility and dissolution advantages of cocrystals it is now accepted, even though the exact mechanism by which this enhancement occurs is not fully understood. In NTZ cocrystals studied here, the coformers GLU and SUC are ionizable compounds (pK a values of 4.3 for GLU and 4.2 for SUC) and exhibit favorable water solubilities of 540 mg/mL and 71 mg/mL at 25 • C, respectively [12, 58] . The fast dissolution-supersaturation phenomenon induced for the NTZ cocrystals under the experimental conditions used herein (pH 7.5 PBS), is attributed to the favorable solubilization of these coformers. This rapid cocrystal dissolution produces drug supersaturation levels that are difficult to control in absence of suitable excipients at adequate concentrations, and therefore NTZ solubilization advantage was not observed.