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

FANDIÑO, OCTAVIO E.; F. P. BRUNO; G. A. MONTI; N. R. SPERANDEO

pharmaceutical science

TUOMS PRESS

Año: 2021

1735-403X

Background: Nitazoxanide (NTZ) is a broad spectrum antimicrobial agent with poor aqueoussolubility and low bioavailability. Thus, the generation of new solid forms of NTZ is relevant toimprove its unfavorable properties. The present study deals with the application ofmechanochemistry 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) andcharacterized using differential scanning calorimetry (DSC), hot stage microscopy (HSM), X-rayPowder Diffraction (XRPD),13C Solid-state Nuclear Magnetic Resonance (SSNMR) and DiffuseReflectance Infrared Fourier Transform (DRIFT) spectroscopy. Powder dissolution (PD) profileswere 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 releasewas 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, amelting temperature lower than those of NTZ and SAC. PD data indicated that the 1:1 NTZ-SACsample obtained by LAG exhibited a slightly higher DE than pure NTZ in the two assayedmedia.Conclusion: NTZ and SAC formed a eutectic, the first reported for this drug, which improvedits dissolution rate and opened the pathway for studies searching for new eutectics with betterbiopharmaceutical attributes than NTZ and the NTZ-SAC eutectic reported herein.