Novel Salt of Tinidazole with Improved Solubility and Antibacterial Activity

Abstract

The present study describes the preparation of novel salt of Tinidazole (TN) with p-Toluenesulfonic acid (PTSA) that display enhanced solubility and antibacterial activity in Bacillus. The salt was prepared by solvent-drop grinding and characterised by powdered X-Ray diffraction, thermal analysis, Fourier transformation infrared spectroscopy (FT-IR) and polarized microscopy. FT-IR data confirms Tinidazole salt with p-Toluenesulfonic acid (TN-PTSA). Powdered X-ray diffraction and thermal analysis data reveals that both TN and TN-PTSA are crystalline nature. From microscopic photographs of polarized microscopy, crystals of TN-PTSA are rod shape whereas crystals of TN are plate shape. Solubility measurement of TN-PTSA on UV spectrophotometer showed solubility improvement compared with TN by 49.7 times in water. Antibacterial test showed higher activity in TN-PTSA to the Gram-positive bacillus bacteria as compared to the TN. This study demonstrates that TN-PTSA can be a potential substitute to the TN in the treatment of infection with Gram-positive bacillus bacteria.

Novel Cocrystals and Eutectics of the Antiprotozoal Tinidazole: Mechanochemical Synthesis, Cocrystallization, and Characterization

“…The 13 C CP/MAS spectra of TNZ-SA LAG (Figure 8g) and TNZ-SA CRYS-ETOH (Figure 8h) matched one another, indicating that the same cocrystalline phase was obtained by LAG and crystallization, in accordance with the PXRD data. The spectra exhibit, like those of the TNZ-PABA cocrystal (Figure 8e,f), noticeable upfield shifts for C-1 and the carboxylic carbon from the SA component (C-22).…”

“…In contrast, the DSC and TG curves of TNZ-SUC LAG (Figure S12) and TNZ-NA LAG (Figure S13) showed, in the 25−160 °C temperature range, single endotherms at 105.5 (T e ) and 102.6 °C (T e ) respectively, which were not accompanied by TG mass losses, and corresponded to melting processes as indicated by HSM. Taking into account that these endotherms occurred at temperatures below the observed DSC melting points (T e ) of TNZ and each coformer (SUC: 187.5 °C, and NA: 128.0 °C) and that PXRD, FTIR, and SS 13 C NMR indicated no interaction between the API and either coformer, these samples represented eutectic mixtures. Interestingly, the DSC curve of the TNZ-SUC PM (Figure S12) exhibited a single endotherm with a T e identical to that of the respective LAG sample, a result, which is also in accordance with Yamashita et al, 31 who observed only a single DSC endotherm, associated with eutectic melting, for binary physical mixtures incapable of cocrystal formation.…”

“…SS NMR. High-resolution solid-state 13 C cross-polarization/magic angle spinning (CP/MAS) spectra were recorded using a Bruker Avance II spectrometer (Bruker) operating at 300.13 MHz for protons and at 75.46 MHz for carbon, equipped with a 4 mm MAS probe. The 13 C experiments were performed at a spinning rate of 10 kHz employing a variable amplitude CP pulse (2 ms contact time).…”

“…The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.cgd.9b01435. Microscopic images of TNZ samples; X-ray crystallographic information files for TNZ-PABA and TNZ-SA; 13 C CP-MAS chemical shifts for TNZ-PABA, TNZ-SA and TNZ-CA; 13 C CP-MAS spectra for TNZ-SUC, TNZ-NA, and their 1:1 physical mixtures; DSC and TG curves for TNZ-SUC, TNZ-NA, and their 1:1 physical mixtures, and images of samples before and after to be exposed to UV−visible light (PDF)…”

“…Tinidazole, 1-(2-ethylsulfonylethyl)-2-methyl-5-nitro-imidazole (TNZ, Figure ), is an antiprotozoal agent synthesized in 1969, which has been used widely throughout Europe and developing countries for the treatment of amebic and parasitic infections, and it has been approved by the United States Food and Drug Administration (U.S. FDA) for the treatment of trichomoniasis, giardiasis, amebiasis, and amebic liver abscess since 2004 . An inherent drawback of TNZ is its low aqueous solubility (pH 2: 0.0324 M = 8.01 mg/mL; pH 6: 0.0301 M = 7.44 mg/mL, at 37 °C); therefore, several formulation strategies have been applied to improve its solubility, including the preparation of polymorphs, , cyclodextrin complexes, solid dispersions, , microcrystals, nanofibers, salts, , and cocrystals. , Regarding the most recent open literature, to the best of our knowledge four products cited as cocrystals of TNZ have been reported, specifically, one with lactose as coformer and three with the coformers tartaric acid (TA), oxalic acid (OA), and glutaric acid (GA) . However, the experimental data presented did not prove the existence of a noncovalent interaction between TNZ and the four coformers employed.…”