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.
Highlights
The solid-state form of pharmaceuticals impacts physicochemical properties during drug development, so, it is important that a manufacturer understands the material properties of the API and the finished product
PXRD of all the salts showed identifiable diffraction patterns at 2-theta angles that differentiates them from the free base
The salts were formed from equimolar combinations of bedaquiline base and the counterions from the corresponding acids
Summary
The solid-state form of pharmaceuticals impacts physicochemical properties during drug development, so, it is important that a manufacturer understands the material properties of the API and the finished product. Time and material constraints may hinder a full analysis of the solid-state properties of an API in the early stages of drug development [2]. In such instances, a drug developer can conduct some simple screening and provide an abbreviated solid-state chemistry profile for the new material. During the screening process in early drug development, it is beneficial to identify the most stable drug form before scaling up production of the material, as the API form selection impacts solubility, bioavailability, stability, and other physicochemical properties. It is important to know the relative stabilities of the various polymorphic forms of the drug before scale-up of drug production, to reduce the risk of transformation that may occur during the non-clinical and clinical stages [3]
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