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.
Highlights
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 [1,2,3]
NTZ-SUC and NTZ-GLU cocrystals were prepared in scales of 1.0 g, and in all cases a homogeneous single phase was obtained, for which the experimental powder X-ray diffraction (PXRD) pattern agreed with the pattern simulated from the crystal structure determined by single-crystal X-ray diffraction analysis
In order to evaluate the effect of Methocel® 60 HG on the dissolution process of NTZ-SUC cocrystals starting from a solid polymer–cocrystal formulation, we examined a series of pharmaceutical powder-based formulations containing different amounts of Methocel® 60 HG (0.0, 1.0, 2.5 and 5.0% w/w) in comparison to analogous forms with pure NTZ and the physical mixture of NTZ and SUC
Summary
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) [1,2,3]. 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 P(BhaCrmS)a.ceTuotictsa2k0e20a, d12v, axntage of the broad therapeutic spectrum of NTZ, the implementation of stra3teogfie18s to modify its solubility are necessary.
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