**Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers**

**Reynaldo Salas-Zúñiga 1,2, Christian Rodríguez-Ruiz 1,2, Herbert Höpfl 2,\*, Hugo Morales-Rojas 2,\*, Obdulia Sánchez-Guadarrama 2, Patricia Rodríguez-Cuamatzi 3 and Dea Herrera-Ruiz 1,\***


Received: 22 November 2019; Accepted: 22 December 2019; Published: 25 December 2019

**Abstract:** The effect of hydroxypropyl methylcellulose (HPMC) and methylcellulose (Methocel® 60 HG) on the dissolution behavior of two cocrystals derived from nitazoxanide (NTZ), viz., nitazoxanide-glutaric acid (NTZ-GLU, 1:1) and nitazoxanide-succinic acid (NTZ-SUC, 2:1), was explored. Powder dissolution experiments under non-sink conditions showed similar dissolution profiles for the cocrystals and pure NTZ. However, pre-dissolved cellulosic polymer in the phosphate dissolution medium (pH 7.5) modified the dissolution profile of NTZ when starting from the cocrystals, achieving transient drug supersaturation. Subsequent dissolution studies under sink conditions of polymer-based pharmaceutical powder formulations with NTZ-SUC cocrystals gave a significant improvement of the apparent solubility of NTZ when compared with analogous formulations of pure NTZ and the physical mixture of NTZ and SUC. Scanning electron microscopy and powder X-ray diffraction analysis of samples recovered after the powder dissolution studies showed that the cocrystals undergo fast dissolution, drug supersaturation and precipitation both in the absence and presence of polymer, suggesting that the solubilization enhancement is due to polymer-induced delay of nucleation and crystal growth of the less soluble NTZ form. The study demonstrates that the incorporation of an appropriate excipient in adequate concentration can be a key factor for inducing and maintaining the solubilization of poorly soluble drugs starting from co-crystallized solid forms. In such a way, cocrystals can be suitable for the development of solid dosage forms with improved bioavailability and efficacy in the treatment of important parasitic and viral diseases, among others.

**Keywords:** nitazoxanide; cocrystals; multicomponent crystals; dissolution behavior; supersaturated formulations; crystallization inhibitors; drug-polymer interactions
