Salts and Polymorph Screens for Bedaquiline.
Salts and Polymorph Screens for Bedaquiline.
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DOI：
10.1208/s12249-021-02106-7
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发表时间：
2021-08-25
影响因子：
3.3
通讯作者：
Clase K
中科院分区：
文献类型：
--
作者：
Okezue M;Bogdanowich-Knipp S;Smith D;Zeller M;Byrn S;Smith P;Purcell DK;Clase K
贝达奎林用于治疗成人的多重耐药结核病。富马酸盐在商业上可以买到，并用于产品Sirturo。为了在化学物质的专利到期后提供对贝达奎兰分子的开放访问，筛选了新的盐。这项工作提供了关于贝达奎兰系统的更多信息，因为新的盐可能表现出更好的药代动力学特性。目前的研究集中在贝达奎林的醋酸盐、苯甲酸盐、苯磺酸盐、氢溴酸盐、琥珀酸、盐酸盐、酒石酸盐、乳酸盐、马来酸盐、苹果酸盐和甲磺酸盐的分离。使用常规筛选和小规模实验以及结晶学分析和红外显微光谱分析的独特组合来筛选潜在的盐。将各成盐剂和甜菜碱碱(30 mg，0.055 mg)按1：1的比例溶解在不同的溶剂中，使溶液蒸发或结晶，制备了更大规模的盐。用X射线衍射仪(XRD)、光谱分析和热分析对盐进行了表征。在审查了初步表征数据后，选择了苯甲酸盐和马来酸盐作为铅候选物。为了确定最稳定的引线形式，使用不同极性的溶剂进行了多形筛选。这些盐筛成功地产生了五种新的贝达奎林盐，即苯甲酸盐、马来酸盐、盐酸盐、苯磺酸盐和甲磺酸盐。粉末X射线衍射、质子核磁共振和红外光谱证实了这些盐的存在。用TGA、DSC热分析和热台光学显微镜进一步对盐进行了表征。对盐类进行的多态筛选表明，在1微克的范围内没有额外的多态。网上版载有补充材料，可在10.1208/s12249-021-02106-7查阅。
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. The online version contains supplementary material available at 10.1208/s12249-021-02106-7.
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影响因子：
6.1
作者：
Krause L;Herbst-Irmer R;Sheldrick GM;Stalke D
通讯作者：
Stalke D
影响因子：
6.1
作者：
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通讯作者：
Dittrich B
影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
3.8
作者：
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通讯作者：
Zaworotko, Michael J.