Okezue Mercy, Bogdanowich-Knipp Susan, Smith Daniel, Zeller Matthias, Byrn Stephen, Smith Pamela, Purcell Dale K, Clase Kari
Biotechnology Innovation and Regulatory Science Center, ABE, Purdue University, 225 S. University Street, Indiana, 47906, West Lafayette, USA.
Ravine Pharmaceuticals, LLC, 3425 DuBois St., Indiana, West Lafayette, USA.
AAPS PharmSciTech. 2021 Aug 25;22(7):228. doi: 10.1208/s12249-021-02106-7.
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.
贝达喹啉用于治疗成人多重耐药结核病。富马酸盐有商业供应，用于产品斯耐瑞（Sirturo）。为了在化学物质专利到期后能公开获取贝达喹啉分子，对新盐进行了筛选。这项工作提供了关于贝达喹啉体系的更多信息，因为新盐可能具有更好的药代动力学性质。当前的研究集中于尝试分离贝达喹啉的醋酸盐、苯甲酸盐、苯磺酸盐、氢溴酸盐、琥珀酸盐、盐酸盐、酒石酸盐、乳酸盐、马来酸盐、苹果酸盐和甲磺酸盐。使用传统筛选与小规模实验相结合的独特方法，并辅以晶体学分析和红外显微光谱法对潜在的盐进行筛选。通过将各成盐剂与贝达喹啉碱（30毫克，0.055毫摩尔）按1:1比例溶解在不同溶剂中，然后让溶液蒸发或结晶，大规模制备盐。采用X射线衍射（XRD）技术以及光谱和热分析对盐进行表征。在审查初步表征数据后，选择苯甲酸盐和马来酸盐作为主要候选物。为了确定主要候选物的最稳定形式，使用各种极性的溶剂进行了多晶型筛选。这些盐筛选成功产生了贝达喹啉的五种新盐，即苯甲酸盐、马来酸盐、盐酸盐、苯磺酸盐和甲磺酸盐。通过粉末XRD、质子NMR和红外光谱证实了这些盐的存在。进一步使用热重分析（TGA）和差示扫描量热法（DSC）以及热台光学显微镜对盐进行表征。对盐进行的多晶型筛选表明，在1克规模下不存在其他多晶型物。
