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

Abstract

Antiprotozoal tinidazole (TNZ) exhibits low aqueous solubility (Sw) and poor photochemical stability. In this work, TNZ was used to form cocrystals and eutectics with the aim of enhancing its solubility and physical stability. The choice of coformers was based on a crystal engineering strategy focused on the success rate of supramolecular heterosynthon formation between azoles and carboxylic acids. By liquid-assisted grinding, three cocrystals [with p-aminobenzoic acid (PABA), citric acid (CA), and salicylic acid (SA)] and two eutectics [with nicotinamide and succinic acid] were obtained and characterized using powder X-ray diffraction, 13 C solid-state nuclear magnetic resonance, infrared spectroscopy, differential scanning calorimetry, thermogravimetry, and hot-stage microscopy. The crystal structures of TNZ-PABA and TNZ-SA were resolved by means of single-crystal X-ray diffraction, which revealed that they are a solvated and an unsolvated cocrystal, respectively. The Sw values of the obtained samples were determined at 37 °C, with the outcome that only the TNZ-CA cocrystal had a slightly higher Sw than pure TNZ. A physical stability study was also performed under UV−visible irradiation, and it was found that the three cocrystals showed better photostability when compared to TNZ, the two eutectics, and each respective physical mixture, a finding that could be relevant from the pharmacotechnical point of view.

Tribochemistry, Mechanical Alloying, Mechanochemistry: What is in a Name?

“…Generally, the origin of this fluid phase can be classified as being intrinsic or extrinsic to the reacting system itself. Intrinsic origins include melting (or contact melting) (Saratovkin and Savintcev, 1941;Gerasimov and Boldyrev, 1996;Urakaev and Boldyrev, 2000a;Boldyrev and Tkáčová, 2000;Chadwick et al, 2007;Michalchuk et al, 2014;Humphry-Baker et al, 2016;Fandiño et al, 2020;Haneef and Chadha, 2020), sublimation of solids (Kuroda et al, 2004;Mikhailenko et al, 2004), or dehydration/desolvation (Losev and Boldyreva, 2014) which result from the excess heating of mechanical impacts or bulk heating during mechanical treatment. Where a solids' glass transition temperature is above the milling temperature, one can consider also the formation of transient amorphous phases (Descamps and Willart, 2016a).…”

Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications

“… API Coformer Ref. Furosemide Caffeine Nicotinamide 115 Brexpiprazole Catechol 108 Nifedipine Isonicotinamide 116 Progesterone Phloroglucinol 85 Antiprotozoal tinidazole p -Aminobenzoic acid 117 Salicylic acid 117 Levofloxacin Metacetamol 95 Epalrestat Betaine 104 Linagliptin Ferulic acid 118 Vitamin K3 1-Hydroxy-2-naphthoic acid 114 6-Hydroxy-2-naphthoic acid 114 Sulfamerazine 114 Tranilast Urea 119 Nicotinamide 119 Nitrofurantoin 4-Hydroxybenzoic acid 120 Vitamin D3 Vitamin D2 106

Figure 11 Diagram of the mechanisms by which cocrystals improve the chemical stability of APIs.

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

“…The HSM images of the 1:1 NTZ-SAC samples obtained by NG and LAG (taken as representative of NTZ-SAC products), together with those of NTZ and SAC, are depicted in Figures S2-S5. Thus, taking into account that XRPD is a diagnostic way of differentiating cocrystalline phases from physical mixtures/eutectics, 28 the XRPD patterns of the prepared samples were recorded. Figure 2 exhibits the powder patterns of NTZ, SAC, their 1:1 physical mixture (1:1 PM) and three NTZ-SAC products.…”

“…The DRIFT spectra of the 1:1 NTZ-SACNG, 1:1 NTZ-SACLAG; 1:2 NTZ-SACNG and 1:2 NTZ-SACLAG samples (Figure S6) were also the superposition of those of the respective starting materials, like their 1:1 PM (Figure S6), indicating that all samples represent physical mixtures or eutectics, in accordance with the XRPD and SSNMR evidence. Hence, since DSC works as a bench diagnostic technique for a eutectic and cocrystals, 28,29 the behavior on heating of the obtained samples was assessed by DSC.…”

“…Interestingly, the Te of these endotherms was lower than those of NTZ (Figure 4a) and SAC (Figure 4b), supporting the interpretation that these peaks corresponded to eutectic endotherms as for binary mixtures a lower DSC melting endotherm compared to the parent materials is an indicator of eutectic formation. 15,17,28,29,31 No distinctive depressed DSC melting peaks of excess NTZ or SAC were visualized in Figure 4. However, the shapes of the eutectic endotherms of Figure 4d,e,g looked as they comprised overlapping effects since endothermic shoulders are distinguishable on the right sides of these endotherms (typical of the superposition of two peaks into one peak), and this may be attributed to superposition of solidus (eutectic melting) and liquidus (melting of the excess of starting material particles) events, as it was observed for other eutectic mixtures.…”