Salts and Polymorph Screens for Bedaquiline

Abstract

Bedaquiline is used to treat multi-resistant tuberculosis in adults. The fumarate salt is commercially available and used in the product Sirturo. To provide open access to bedaquiline molecule once the patent on the chemical substance expires, new salts were screened. This work offers additional information on the bedaquiline system, as new salts may present better pharmacokinetic properties. The current studies focus on the attempted isolation of the acetate, benzoate, benzenesulfonate, hydrobromide, succinate, hydrochloride, tartrate, lactate, maleate, malate, and mesylate salts of bedaquiline. Potential salts were screened using a unique combination of conventional screening, and small-scale experiments supplemented by crystallographic analysis and infrared microspectroscopy. Salts were prepared on a larger scale by dissolving 1:1 ratios of the individual salt formers and bedaquiline base (30 mg, 0.055 mmol) in different solvents and allowing the solutions to evaporate or crystallize. X-ray diffraction (XRD) techniques and spectroscopic and thermal analyses were employed to characterize the salts. The benzoate and maleate salts were selected as lead candidates after reviewing preliminary characterization data. To determine the most stable forms for the leads, a polymorph screen was conducted using solvents of various polarities. These salt screens successfully generated five new salts of bedaquiline, namely, benzoate, maleate, hydrochloride, besylate, and mesylate. The existence of these salts was confirmed by powder XRD, proton NMR, and IR spectroscopies. TGA and DSC thermal analysis along with hot-stage optical microscopy were further used to characterize the salts. The polymorph screen conducted on the salts suggested the absence of additional polymorphs at 1 g scale.

New Case of Pharmaceutical Solid-State Forms: Several Novel Solvates/Polymorphs of Nilotinib and Their Phase Transformation Controls

“…This caused economic damage of more than 250 million dollars. , Therefore, it is strategic to take control of pharmaceutical solid-state forms by using different and effective crystallization process regulations. The preparation methods of the solid-state forms can be classified as thermal and solution methods, including melting method, − sublimation method, evaporation method, cooling method, reaction method, antisolvent method, and other novel methods, which indicate the complication of preparing different crystal forms, hence informing us the necessity for solid-state form screening. , …”

“…The preparation methods of the solid-state forms can be classified as thermal and solution methods, including melting method, 20−22 sublimation method, 23 evaporation method, 24 cooling method, 25 reaction method, 26 antisolvent method, 27 and other novel methods, 28 which indicate the complication of preparing different crystal forms, hence informing us the necessity for solid-state form screening. 29,30 The external conditions of the solution crystallization processes, such as the cooling method, antisolvent method, and slurry method, are decisive for obtaining solid-state forms. Song et al 31 reported the pyrazinamide polymorphism in different solvent systems, whereas Fondren et al 32 reported how the external conditions such as various temperatures or crystallization solvents affected the polymorphism development in 2,4,6-trinitrotoluene.…”

Synthesis, Characterization, and Stability Assessment for the Benzoate, Hydrochloride, Malonate, and Nicotinate Salts of Bedaquiline

“…This suggests that no new polymorph was formed at the 10 kg laboratory scale for the benzoate salt. The full details of the polymorph screening results for bedaquiline benzoate were published in an earlier communication [ 15 ].…”

“…Therefore, the salicylate salt was not characterized further. On the other hand, the benzoate salt had the highest probability for success because it was possible to synthesize it using several routes, which have been extensively discussed in two earlier publications [ 3 , 15 ] The malonate and nicotinate salts were successfully synthesized via the slow evaporation of a 1:1 mixture of acetone and 2-propanol.…”

Comparison of pharmacokinetics and bioavailability of bedaquiline fumarate, benzoate and maleate in dogs

“…New salts of BDQ have been developed and characterized. 2 – 4 These salts will encourage additional organizations to manufacture BDQ. BDQ benzoate and maleate have been identified as promising salts.…”