Cargando…

Salts and Polymorph Screens for Bedaquiline

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 inf...

Descripción completa

Detalles Bibliográficos
Autores principales: Okezue, Mercy, Bogdanowich-Knipp, Susan, Smith, Daniel, Zeller, Matthias, Byrn, Stephen, Smith, Pamela, Purcell, Dale K., Clase, Kari
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387259/
https://www.ncbi.nlm.nih.gov/pubmed/34435280
http://dx.doi.org/10.1208/s12249-021-02106-7
_version_ 1783742425710198784
author Okezue, Mercy
Bogdanowich-Knipp, Susan
Smith, Daniel
Zeller, Matthias
Byrn, Stephen
Smith, Pamela
Purcell, Dale K.
Clase, Kari
author_facet Okezue, Mercy
Bogdanowich-Knipp, Susan
Smith, Daniel
Zeller, Matthias
Byrn, Stephen
Smith, Pamela
Purcell, Dale K.
Clase, Kari
author_sort Okezue, Mercy
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1208/s12249-021-02106-7.
format Online
Article
Text
id pubmed-8387259
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Springer International Publishing
record_format MEDLINE/PubMed
spelling pubmed-83872592021-09-14 Salts and Polymorph Screens for Bedaquiline Okezue, Mercy Bogdanowich-Knipp, Susan Smith, Daniel Zeller, Matthias Byrn, Stephen Smith, Pamela Purcell, Dale K. Clase, Kari AAPS PharmSciTech Research Article 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1208/s12249-021-02106-7. Springer International Publishing 2021-08-25 /pmc/articles/PMC8387259/ /pubmed/34435280 http://dx.doi.org/10.1208/s12249-021-02106-7 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Okezue, Mercy
Bogdanowich-Knipp, Susan
Smith, Daniel
Zeller, Matthias
Byrn, Stephen
Smith, Pamela
Purcell, Dale K.
Clase, Kari
Salts and Polymorph Screens for Bedaquiline
title Salts and Polymorph Screens for Bedaquiline
title_full Salts and Polymorph Screens for Bedaquiline
title_fullStr Salts and Polymorph Screens for Bedaquiline
title_full_unstemmed Salts and Polymorph Screens for Bedaquiline
title_short Salts and Polymorph Screens for Bedaquiline
title_sort salts and polymorph screens for bedaquiline
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387259/
https://www.ncbi.nlm.nih.gov/pubmed/34435280
http://dx.doi.org/10.1208/s12249-021-02106-7
work_keys_str_mv AT okezuemercy saltsandpolymorphscreensforbedaquiline
AT bogdanowichknippsusan saltsandpolymorphscreensforbedaquiline
AT smithdaniel saltsandpolymorphscreensforbedaquiline
AT zellermatthias saltsandpolymorphscreensforbedaquiline
AT byrnstephen saltsandpolymorphscreensforbedaquiline
AT smithpamela saltsandpolymorphscreensforbedaquiline
AT purcelldalek saltsandpolymorphscreensforbedaquiline
AT clasekari saltsandpolymorphscreensforbedaquiline