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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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/2/257 |
| _version_ | 1827756023860953088 |
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| author | Mercy A. Okezue Stephen R. Byrn |
| author_facet | Mercy A. Okezue Stephen R. Byrn |
| author_sort | Mercy A. Okezue |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T08:18:20Z |
| format | Article |
| id | doaj.art-cca1d8c153804efda75ebe00f762cc9f |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T08:18:20Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-cca1d8c153804efda75ebe00f762cc9f2023-11-16T22:37:09ZengMDPI AGPharmaceuticals1424-82472023-02-0116225710.3390/ph16020257Synthesis, Characterization, and Stability Assessment for the Benzoate, Hydrochloride, Malonate, and Nicotinate Salts of BedaquilineMercy A. Okezue0Stephen R. Byrn1Industrial and Physical Pharmacy Department, Purdue University, West Lafayette, IN 47907, USAIndustrial and Physical Pharmacy Department, Purdue University, West Lafayette, IN 47907, USABedaquiline 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.https://www.mdpi.com/1424-8247/16/2/257lead candidatesolubilityX-ray diffractionRietveld refinementbioavailabilityNMEs |
| spellingShingle | Mercy A. Okezue Stephen R. Byrn Synthesis, Characterization, and Stability Assessment for the Benzoate, Hydrochloride, Malonate, and Nicotinate Salts of Bedaquiline Pharmaceuticals lead candidate solubility X-ray diffraction Rietveld refinement bioavailability NMEs |
| 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 | lead candidate solubility X-ray diffraction Rietveld refinement bioavailability NMEs |
| url | https://www.mdpi.com/1424-8247/16/2/257 |
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