Salts and Polymorph Screens for Bedaquiline
Open Access
- 25 August 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in AAPS PharmSciTech
- Vol. 22 (7), 1-16
- https://doi.org/10.1208/s12249-021-02106-7
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.Keywords
This publication has 36 references indexed in Scilit:
- Polymorphs, Salts, and Cocrystals: What’s in a Name?Crystal Growth & Design, 2012
- Polymorphism and Solvatomorphism 2010Journal of Pharmaceutical Sciences, 2012
- ShelXle: a Qt graphical user interface forSHELXLJournal of Applied Crystallography, 2011
- Strategies at the Interface of Drug Discovery and Development: Early Optimization of the Solid State Phase and Preclinical Toxicology Formulation for Potential Drug CandidatesJournal of Medicinal Chemistry, 2010
- Kinetic parameter estimation from TGA: Optimal design of TGA experimentsChemical Engineering Research and Design, 2008
- A short history of SHELXActa Crystallographica Section A Foundations of Crystallography, 2007
- DSC studies on organic melting point temperature standardsThermochimica Acta, 2006
- Identifying the Stable Polymorph Early in the Drug Discovery-Development ProcessPharmaceutical Development and Technology, 2005
- Identifying the Stable Polymorph Early in the Drug Discovery–Development ProcessPharmaceutical Development and Technology, 2005
- Humidity fixed points of binary saturated aqueous solutionsJournal of Research of the National Bureau of Standards Section A: Physics and Chemistry, 1977