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) andDiffuse 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% TweenÒ 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 DSCand 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 NTZSACsample 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.

Keywords

• differential scanning calorimetry
• dissolution efficiency
• liquid-assisted grinding
• powder dissolution
• saccharine
• x-ray powder diffraction