**5. Conclusions**

The results presented herein have shown that NTZ cocrystals can induce a superior dissolution behavior in the presence of hydroxypropyl methylcellulose (HMPC) and methylcellulose (Methocel ® 60 HG) in comparison to pure NTZ. Although rapid transformation to the less soluble drug form is observed, the inclusion of polymer in the formulations with NTZ-SUC cocrystals in amounts of 2.5 and 5.0% ( *w*/*w*) enabled significantly increasing the dissolution rate of NTZ when compared to pure NTZ and the commercially available drug formulation. The comparative analysis of di fferent powder formulations showed that the amount of polymer in the formulation is an important parameter to consider during cocrystal formulation development for accessing a good solubilization potential for poorly soluble APIs in aqueous solutions.

In conclusion, the use of cocrystals combined with an appropriate selection of pharmaceutical excipients as drug precipitation inhibitors or retardants for crystal growth, such as cellulosic polymers, is a feasible approach to modify the dissolution environment and conditions starting from cocrystals. As a result, the development of a polymer–cocrystal powder formulation is a true alternative to enhance the solubilization of poorly water soluble NTZ and to generate solid dosage forms with better bioavailability and e fficacy in the treatment of parasitic and viral diseases, among others.

**Supplementary Materials:** The following data are available online at http://www.mdpi.com/1999-4923/12/1/23/s1: Table S1. General characteristics of polymers used. Figure S1. Scheme of the solvent-shift methodology employed to select polymers that delay nucleation and/or API crystallization. Figure S2. The UV-vis quantification method was specific for NTZ at 435 nm. At 2.97 μg/mL of pure NTZ and both cocrystals, there is no interference by coformers in the quantification method used herein. At other concentration levels of NTZ and coformers, the observation was the same, there was no interference in NTZ quantitation by the coformers presence. Figure S3. UV-vis spectra of samples from powders dissolution of NTZ (left) and NTZ-SUC cocrystal (right) formulated at di fferent concentrations of Methocel ® 60 HG. NTZ spectrum did not change in presence of polymer. Figure S4. Comparison of PXRD patterns: A. (a) Nitazoxanide, (b) glutaric acid, (c) NTZ-GLU simulated from SCXRD data, (d–m) Batches No. 1–10 of NTZ-GLU cocrystals prepared in l gram scale by SDG with acetone as solvent. B. (a) Nitazoxanide, (b) succinic acid, (c) NTZ-SUC simulated from SCXRD data, (d–m) Batches No. 1–10 of NTZ-SUC cocrystals prepared in l gram scale by SDG with acetone as solvent. Figure S5. SEM images of the solid starting materials used for the powder dissolution tests: (a) NTZ, (b) physical mixture of NTZ and SUC; and solid residues recovered after the dissolution tests of the solids formulated with Methocel ® 60 HG: (c) NTZ with 1.0% *<sup>w</sup>*/*<sup>w</sup>*, (d) physical mixture of NTZ and SUC with 1.0% *<sup>w</sup>*/*<sup>w</sup>*, (e) NTZ with 5.0% *<sup>w</sup>*/*<sup>w</sup>*, (f) physical mixture of NTZ and SUC with 5.0% *<sup>w</sup>*/*<sup>w</sup>*. Note: The SEM images of the starting materials are presented at higher resolution than the remaining images (see scale in each image).

**Author Contributions:** Conceptualization, H.H. (solid-state), H.M.-R. (physical organic) and D.H.-R. (pharmaceutics); methodology, R.S.-Z., C.R.-R., and P.R.-C.; formal analysis and investigation, R.S.-Z.; resources, H.H. and D.H.-R.; writing—original draft preparation, R.S.-Z., H.H., and D.H.-R.; writing—review and editing, H.M.-R.; supervision, O.S.-G.; project administration, D.H.-R., and funding acquisition, H.M.-R. and D.H.-R. All authors approved the final version of this article. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work received support from Consejo Nacional de Ciencia y Tecnología (CONACyT) and Secretaría de Educación Pública (SEP-PRODEP) in form of postgraduate fellowships for R.S.-Z and C.R.-R. and a postdoctoral fellowship for O.S.-G. Financial support through CONACYT grants No. 404178, INF-2015-251898 and CB-2013-221451 is gratefully acknowledged.

**Conflicts of Interest:** The authors declare no conflict of interest.
