Crystallization of isoniazid in choline-based ionic liquids: Physicochemical properties and anti-tuberculosis activity

Abstract

Isoniazid is a drug commonly employed in the treatment of tuberculosis. One major barrier to its widespread use is that it can undergo hydrolysis when stored inadequately, resulting in the formation of hydrazine, a toxic and carcinogenic compound. Therefore, there is a clear need for further research aimed at improving the stability of isoniazid while still maintaining its therapeutic efficiency and solubility. To this end, five choline ionic liquids (ILs) were used for synthesizing improved forms of isoniazid: (2-hydroxyethyl)-trimethylammonium hydroxide [ChOH], (2-hydroxyethyl)-trimethylammonium hydrogen sulfate [ChBis], (2-hydroxyethyl)-trimethylammonium acetate [ChAc], (2-hydroxyethyl)-trimethylammonium citrate [ChCit], and (2-hydroxyethyl)-trimethylammonium benzoate [ChBenz]. The INH:[ChOH] and INH:[ChCit] forms were obtained in powder form, and presented low solubility and a minimum inhibitory concentration for Mycobacterium tuberculosis of 100 μg/mL and 12.5 μg/mL, respectively. The INH:[ChBenz], INH:[ChBis], and INH:[ChAc] forms showed a minimum inhibitory concentration value lower than 6.2 µg/mL. In the process using [ChBis], 2-(4-pyridiniumcarbonyl)-hydrazine sulfate with a water solubility of 155.9 mg/mL at 25 °C was produced, which showed to be more soluble than isoniazid (137.9 mg/mL). Therefore, the IL used had a direct influence on the solubility, conformational structure, and stability of isoniazid. This research is highly relevant and innovative for the use of new solvents in the crystallization of drugs, especially when aiming at the improvement of their properties.