Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers

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.

Salt Cocrystal of Diclofenac Sodium-L-Proline: Structural, Pseudopolymorphism, and Pharmaceutics Performance Study

“…By increasing dissolution, NDP salt cocrystals can be expected to improve diclofenac bioavailability [ 6 , 59 ]. The dissolution profile of the salt cocrystals was better than the previous non-salt cocrystal of diclofenac–proline [ 20 ], as the sink dissolution conditions can lead to problems with the absorption step of the drug [ 47 , 60 ] did not exist. ND had a good dissolution profile in the buffered pH 6.8 medium, but the cocrystals were superior.…”

“…The decrease of melting point reflects hydrogen bond formation between the compounds with the water molecule, which contributed crucially. The new thermal profile can be expected to impact on other physicochemical properties such as solubility, dissolution rate, and stability [14,15,20,[47][48][49][50][51].…”

Mechanochemical synthesis of a novel eutectic of the antimicrobial nitazoxanide with improved dissolution performance

“…1 NTZ is also active against numerous other parasitic pathogens and viruses, including Trypanosoma cruzi (the causative agent of American trypanosomiasis), 2 Leishmania mexicana, 2 the ulcer-causing pathogen Helicobacter pylori, 3 multidrug resistant strains of Mycobacterium tuberculosis, 1 as well as respiratory viruses, rotavirus, norovirus, coronavirus, hepatitis B and C, dengue-2, yellow fever, Japanese encephalitis, and human immunodeficiency viruses. 4 Moreover, NTZ has shown anticancer activity, 4 and is a promising compound for the treatment of neuropathic pain, 4 the Ebola virus disease 4 and is also under investigation for potential use in COVID-19 treatment. 5 Although NTZ is an agent with diverse pharmacological activities and minimal toxicity, it has unfavorable physicochemical and biopharmaceutical properties, in particular very poor aqueous solubility 6 and low bioavailability, 4 and this provided the motivation for discovering new solid forms which may improve its solubility, dissolution rate, and bioavailability, and thus provide improved therapeutic options for patients.…”

“…4 Moreover, NTZ has shown anticancer activity, 4 and is a promising compound for the treatment of neuropathic pain, 4 the Ebola virus disease 4 and is also under investigation for potential use in COVID-19 treatment. 5 Although NTZ is an agent with diverse pharmacological activities and minimal toxicity, it has unfavorable physicochemical and biopharmaceutical properties, in particular very poor aqueous solubility 6 and low bioavailability, 4 and this provided the motivation for discovering new solid forms which may improve its solubility, dissolution rate, and bioavailability, and thus provide improved therapeutic options for patients. In fact, NTZ has been in the focus of pharmaceutical research to discover and prepare alternative solid forms such as cyclodextrin complexes, 7,8 solid dispersions, 9 cocrystals 10 and cocrystal alloys.…”

Cocrystal Applications in Drug Delivery

“…Salas-Zuniga et al studied the effect of hydroxypropyl methylcellulose and methylcellulose on the dissolution behaviour of two nitazoxanide cocrystals [ 11 ]. Using polymer-based powder formulations of nitazoxanide-succinic acid, they achieved a significant improvement of the apparent solubility of nitazoxanide compared to formulations of the pure API.…”