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

Abstract

Background: Nitazoxanide (NTZ) is a broad spectrum antimicrobial agent with poor aqueous solubility and low bioavailability. Thus, the generation of new solid forms of NTZ is relevant to improve its unfavorable properties. The present study deals with the application of mechanochemistry for the preparation of alternate solid forms of NTZ, using saccharine (SAC) as coformer. Methods: NTZ-SAC mixtures were prepared by neat and liquid-assisted grinding (LAG) and characterized using differential scanning calorimetry (DSC), hot stage microscopy (HSM), X-ray Powder Diffraction (XRPD), 13C Solid-state Nuclear Magnetic Resonance (SSNMR) and Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy. Powder dissolution (PD) profiles were obtained with USP apparatus 2 in buffer phosphate pH 6.5 with 0.25% Tween 80 - 0.25% triethanolamine and in 0.25% sodium lauryl sulfate, at 37 ºC ± 0.5 ºC and 75 rpm. Drug release was characterized in terms of dissolution efficiency (DE). Results: XRPD, SSNMR and DRIFT indicated that NTZ and SAC did not cocrystallize but DSC and HSM revealed that they formed a binary eutectic mixture which melted near 176 °C, a melting temperature lower than those of NTZ and SAC. PD data indicated that the 1:1 NTZ-SAC sample obtained by LAG exhibited a slightly higher DE than pure NTZ in the two assayed media. Conclusion: NTZ and SAC formed a eutectic, the first reported for this drug, which improved its dissolution rate and opened the pathway for studies searching for new eutectics with better biopharmaceutical attributes than NTZ and the NTZ-SAC eutectic reported herein.

Synthesis of active-site rich molybdenum-doped manganese tungstate nanocubes for effective electrochemical sensing of the antiviral drug (COVID-19) nitazoxanide

“…Owing to the above antiviral properties, severe rotavirus diarrhea, AIDS, or HIV in concurrent infections with HCV have been effectively treated with NTZ (Sharma et al; Jain et al, 2014 ). In addition, NTZ is a promising drug Reddy et al, 2012 for treating Ebola virus disease and has been investigated for potential use in the treatment of COVID -19 ( Fandino et al, 2021 ). However, using NTZ leads to various side effects, which are usually mild and may include diarrhea, gastrointestinal discomfort, headache, and hair loss ( Reddy et al, 2012 ).…”

Solution Stability of Pharmaceutical Cocrystals

“…Different strategies have been considered to increase the solubility and dissolution rate of drugs, such as salt formation, nanoparticulate strategy, cosolvency, micellar solubilization, eutectic mixture, etc. Among all the ways mentioned above, salt formation is one of the most popular and practical ways to increase drug solubility.…”

“…Solubility improvement, especially in the case of BCS II, could help to reach the therapeutic effect by using the lower dosage, which results in a reduction in adverse effects and costs. 1 Different strategies have been considered to increase the solubility and dissolution rate of drugs, such as salt formation, 2 nanoparticulate strategy, 3 cosolvency, 4 micellar solubilization, 5 eutectic mixture, 6 etc. Among all the ways mentioned above, salt formation is one of the most popular and practical ways to increase drug solubility.…”