Maleate salts of bedaquiline

Zeller, Mat­thias; Bogdanowich-Knipp, Susan; Smith, Pamela; Purcell, Dale K.; Okezue, Mercy; Smith, Daniel T.; Byrn, Stephen R.; Clase, Kari

doi:10.1107/s2056989021002991

Cited by 3 publications

(3 citation statements)

References 18 publications

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“…The asymmetric unit of compound 1 consists of one hydrogen maleate anion, one cyclohexylammonium cation, and an {OH} entity from the lattice water molecule (Figure 1). The interconnection of two hydrogen maleate anions, two water molecules, and two cyclohexylammonium cations through simple (N1-H1A 19 , the lengths of intramolecular hydrogen bonds are similar. This dimer (motif) symbolized by a ring containing a total of twenty-two atoms, including six donors and six acceptors, is designated by this graphic notation R6 6 (22) 20 where R alludes to "ring" (Figure 2).…”

Section: Structure Descriptionmentioning

confidence: 94%

Crystal structure of cyclohexylammonium hydrogen maleate salt hemi-hydrated

et al. 2023

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The compound CyNH3[HOOC(CH)2COO]·H2O has been obtained using one pot-synthesis process by mixing, in methanol, HOOC(CH)2COOH, CyNH2 and SnPh3Cl in a 1:1:1 molar ratio. X-ray diffraction analysis of the compound reveals that in the crystal structure, hydrogen maleate [HOOC(CH)2COO]- in cis configuration interacts with [CyNH3]+ cations and water molecules to generate an R66(22) ring. The interconnections of the rings via simple (N–H··O and O–H··O) and bifurcated (N–H···(O, O)) hydrogen bonds give rise to a 2D supramolecular structure.

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Section: Structure Descriptionmentioning

confidence: 94%

Crystal structure of cyclohexylammonium hydrogen maleate salt hemi-hydrated

et al. 2023

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“…The citrate, phosphate, and tartrate salts have obtained patents, but the structures for these moieties were not extensively described in the literature; only the powder X-ray patterns have been published. However, our research laboratory generated single crystals, which were solved, for the fumarate, benzoate, and maleate salts [ 3 , 4 ]. The published data fostered a better understanding of the physicochemical properties of bedaquiline, which is critical for developing formulations for TB treatment in animal and clinical studies.…”

Section: Introductionmentioning

confidence: 99%

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

Okezue

Byrn

2023

Pharmaceuticals

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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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“…New salts of BDQ have been developed and characterized. 2 – 4 These salts will encourage additional organizations to manufacture BDQ. BDQ benzoate and maleate have been identified as promising salts.…”

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confidence: 99%

Comparison of pharmacokinetics and bioavailability of bedaquiline fumarate, benzoate and maleate in dogs

Jaw-Tsai¹,

Barry

Pande

et al. 2023

int j tuberc lung dis

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BACKGROUND: Bedaquiline (BDQ) as a fumarate salt is indicated as part of a regimen to treat multidrug-resistant TB (MDR-TB). BDQ benzoate and maleate have been identified as promising alternatives that will encourage generic pharmaceutical houses to manufacture this drug. Our study compared the pharmacokinetics (PK) of BDQ fumarate vs. the maleate and benzoate salts in dogs.METHODS: The PK of BDQ and its active N-desmethyl metabolite M2 following intravenous administration of 1 mg/kg BDQ (as fumarate) and oral administration of 10 mg/kg BDQ as fumarate, benzoate, or maleate salts in suspension to fasted male beagle dogs was evaluated in a parallel-group and crossover study with N = 4 per group. BDQ and M2 plasma concentrations were determined up to 168 h post-dose. T-tests were conducted to compare the area under the curve, AUC0–t among groups.RESULTS: Orally administered fumarate, benzoate, and maleate salts, in parallel-group design, resulted in mean BDQ AUC0–t of 9,267 ± SD 10,182, 19,258 ± SD 11,803, and 15,396 ± SD 9,170 ng.h/ml, respectively; and in a crossover design of 9,267 ± SD 10,182, 17,441 ± SD 24,049, and 18,087 ± SD 19,758 ng.h/ml, respectively. P values were >0.05.CONCLUSION: There was no statistically significant difference in BDQ and M2 AUC0–t following oral administration of fumarate, benzoate and maleate salts in dogs.

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Maleate salts of bedaquiline

Cited by 3 publications

References 18 publications

Crystal structure of cyclohexylammonium hydrogen maleate salt hemi-hydrated

Crystal structure of cyclohexylammonium hydrogen maleate salt hemi-hydrated

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

Comparison of pharmacokinetics and bioavailability of bedaquiline fumarate, benzoate and maleate in dogs

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