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Synthesis, Characterization, and Stability Assessment for the Benzoate, Hydrochloride, Malonate, and Nicotinate Salts of Bedaquiline

Bedaquiline has been approved as a combination therapy to treat multi-drug-resistant tuberculosis in adults ≥ 18 years old. The citrate, fumarate, phosphate, and tartrate salts have obtained patents, but the structures for these moieties have not been extensively described in the literature; only th...

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Autores principales: Okezue, Mercy A., Byrn, Stephen R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9963305/
https://www.ncbi.nlm.nih.gov/pubmed/37259402
http://dx.doi.org/10.3390/ph16020257
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author Okezue, Mercy A.
Byrn, Stephen R.
author_facet Okezue, Mercy A.
Byrn, Stephen R.
author_sort Okezue, Mercy A.
collection PubMed
description Bedaquiline has been approved as a combination therapy to treat multi-drug-resistant tuberculosis in adults ≥ 18 years old. The citrate, fumarate, phosphate, and tartrate salts have obtained patents, but the structures for these moieties have not been extensively described in the literature; only the powder X-ray patterns have been published. To expand the knowledge of the bedaquiline structure, this study provides detailed information for the synthesis, elucidation, characterization, and stability of four additional new potential molecular entities, namely, benzoate, hydrochloride (HCl), nicotinate, and malonate salts. The salts were formed using a 1:1 ratio of the counter ions (acids) to a 30 mg equivalent of the bedaquiline free base. The principles of the International Conference on Harmonization Q6 were used to characterize the new salts and their stability-indicating parameters were evaluated at 0, 3, and 6 months under accelerated conditions of 40 °C and 75% relative humidity. The benzoate salt exhibited the lowest tendency to lose its chemical potency. Aside from the HCl salt, the others retained their chemical structure, displaying long-term stability. All salts were non-hygroscopic and the hydrated benzoate and nicotinate salts were stable to dehydration. Regarding their chemical potencies, thermal analysis, chemical stability, and water sorption potential, the salts were ranked as follows: benzoate > malonate > nicotinate > HCl.
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spelling pubmed-99633052023-02-26 Synthesis, Characterization, and Stability Assessment for the Benzoate, Hydrochloride, Malonate, and Nicotinate Salts of Bedaquiline Okezue, Mercy A. Byrn, Stephen R. Pharmaceuticals (Basel) Article Bedaquiline has been approved as a combination therapy to treat multi-drug-resistant tuberculosis in adults ≥ 18 years old. The citrate, fumarate, phosphate, and tartrate salts have obtained patents, but the structures for these moieties have not been extensively described in the literature; only the powder X-ray patterns have been published. To expand the knowledge of the bedaquiline structure, this study provides detailed information for the synthesis, elucidation, characterization, and stability of four additional new potential molecular entities, namely, benzoate, hydrochloride (HCl), nicotinate, and malonate salts. The salts were formed using a 1:1 ratio of the counter ions (acids) to a 30 mg equivalent of the bedaquiline free base. The principles of the International Conference on Harmonization Q6 were used to characterize the new salts and their stability-indicating parameters were evaluated at 0, 3, and 6 months under accelerated conditions of 40 °C and 75% relative humidity. The benzoate salt exhibited the lowest tendency to lose its chemical potency. Aside from the HCl salt, the others retained their chemical structure, displaying long-term stability. All salts were non-hygroscopic and the hydrated benzoate and nicotinate salts were stable to dehydration. Regarding their chemical potencies, thermal analysis, chemical stability, and water sorption potential, the salts were ranked as follows: benzoate > malonate > nicotinate > HCl. MDPI 2023-02-08 /pmc/articles/PMC9963305/ /pubmed/37259402 http://dx.doi.org/10.3390/ph16020257 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Okezue, Mercy A.
Byrn, Stephen R.
Synthesis, Characterization, and Stability Assessment for the Benzoate, Hydrochloride, Malonate, and Nicotinate Salts of Bedaquiline
title Synthesis, Characterization, and Stability Assessment for the Benzoate, Hydrochloride, Malonate, and Nicotinate Salts of Bedaquiline
title_full Synthesis, Characterization, and Stability Assessment for the Benzoate, Hydrochloride, Malonate, and Nicotinate Salts of Bedaquiline
title_fullStr Synthesis, Characterization, and Stability Assessment for the Benzoate, Hydrochloride, Malonate, and Nicotinate Salts of Bedaquiline
title_full_unstemmed Synthesis, Characterization, and Stability Assessment for the Benzoate, Hydrochloride, Malonate, and Nicotinate Salts of Bedaquiline
title_short Synthesis, Characterization, and Stability Assessment for the Benzoate, Hydrochloride, Malonate, and Nicotinate Salts of Bedaquiline
title_sort synthesis, characterization, and stability assessment for the benzoate, hydrochloride, malonate, and nicotinate salts of bedaquiline
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9963305/
https://www.ncbi.nlm.nih.gov/pubmed/37259402
http://dx.doi.org/10.3390/ph16020257
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