**1. Introduction**

Nitazoxanide (NTZ), 2-acetyloxy-*N*-(5-nitro-2-thiazolyl)benzamide, is a synthetic nitrothiazole derivative (Scheme 1) with a broad spectrum of applications as an antiparasitic, antibacterial and antiviral agent, being effective against protozoal infections, helminths, gram negative and gram positive bacteria, and diverse viruses (respiratory viruses, rotavirus, norovirus, coronavirus, hepatitis B and C, dengue-2, yellow fever, Japanese encephalitis, and human immunodeficiency viruses) [1–3]. Moreover, NTZ has shown anticancer activity [4], suppresses the production of interleukins (IL) such as IL-6 [5], and is a promising compound for the treatment of neuropathic pain and the Ebola virus disease [6,7]. However, due to poor aqueous solubility (0.0075 mg/mL), NTZ has low bioavailability and requires

high doses for treatment [8]. Considering its high permeability across intestinal epithelium [9], NTZ is a class II drug according to the criteria established by the Biopharmaceutical Classification System (BCS). To take advantage of the broad therapeutic spectrum of NTZ, the implementation of strategies to modify its solubility are necessary. A general strategy to overcome the limited solubility of drugs is the generation of novel solid phases, such as metastable amorphous, polymorphs, salts and, more recently, cocrystals [10–12].

**Scheme 1.** Molecular structures of nitazoxanide (NTZ), coformers and cellulosic polymers used herein to achieve a polymer-based pharmaceutical powder formulation.

A cocrystal constitutes a solid single-phase crystalline material composed of two or more molecular and/or ionic compounds in a stoichiometric ratio, which is neither a solvate nor a simple salt. If at least one of the components is an active pharmaceutical ingredient (API) and if the coformer is pharmaceutically acceptable, then the substance is recognized as pharmaceutical cocrystal. A pharmaceutical cocrystal can offer multiple benefits for physicochemical and biopharmaceutical properties of APIs, such as increased solubility and dissolution rates, improvement of mechanical properties, and stability [13–15]. Particularly, cocrystals have exhibited higher, similar or lower solubility compared to the parent API, depending on the nature of the coformer and the solution conditions [16,17]. Solubility advantages of cocrystals over parent drugs can be higher by orders of magnitude, however, this also represents a risk due to precipitation to the less soluble form of the drug at supersaturated concentrations reached during the dissolution process [18,19].

Due to this former behavior, cocrystals are potential candidates for the development of supersaturating drug delivery systems [20,21]. A strategy to control cocrystal dissolution, drug supersaturation and precipitation is the use of supersaturated formulations, which incorporates additives and excipients such as cyclodextrins, surfactants and polymers [22]. In such systems, the supersaturation state must be maintained over a reasonable time period in order to promote adequate absorption for increased bioavailability. 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 [26–31], flufenamic acid [32], cilostazol [33], resveratrol [34], dihydromyricetin [35], tadalafil [36], exemestane [37] and posaconazole [38].

Dissolution methods under non-sink conditions are commonly used for evaluating the ability of poorly soluble APIs to generate and to maintain a supersaturation state in solution [24,39]. Additionally, powder dissolution experiments are a good alternative to intrinsic dissolution tests for cocrystals

undergoing rapid transformation to a less soluble phase of the drug [24], as recently found in the biopharmaceutical characterization of cocrystals with meloxicam, indomethacin, apixaban and myricetin [40–43].

Recently, the synthesis and characterization of NTZ cocrystals using succinic, glutaric, 2,5-dihydroxybenzoic, *p*-aminobenzoic and *p*-aminosalicylic acid as coformers were reported [8,44]. In both publications, improved intrinsic dissolution rates were documented, showing that NTZ cocrystals can improve the solubilization of NTZ in physiologically relevant media [8], thus being good candidates for the future development of novel dosage forms. Herein, two cocrystals, viz., NTZ-GLU and NTZ-SUC (GLU = glutaric acid; SUC = succinic acid), were chosen to evaluate the e ffect of two cellulosic polymers, namely hydroxypropyl methylcellulose (HPMC) and methylcellulose (Methocel ® 60 HG) (Scheme 1), on the dissolution performance of the API, in comparison with pure NTZ, a commercially available NTZ medicine and the respective physical mixtures of NTZ and the coformer. Our study includes an API widely used in treatments concerning tropical neglected diseases, even though scarcely studied [45]. The purpose of this work was to study the behavior of NTZ cocrystals in solution and the conditions to sustain supersaturation levels since these conditions cannot be apparent and must be studied case-by-case. Given its therapeutic relevance, approaches to formulate nitazoxanide cocrystals will be of benefit to improve its e fficacy, considering that its low solubility impacts its bioavailability. Importantly, nitazoxanide has been proposed as a potential agen<sup>t</sup> for public health control [46].
