Determining the solubilities for benzoate, nicotinate, hydrochloride, and malonate salts of bedaquiline

Okezue, Mercy; Byrn, Stephen J.; Clase, Kari

doi:10.1016/j.ijpharm.2022.122229

Cited by 3 publications

(8 citation statements)

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“…The experimental details for elucidating the structures of the single crystals for bedaquiline nicotinate and malonate are found in Appendix Table A2 and Table A3 ; others were published in our earlier communication ( Crystal structures of salts of bedaquiline ). The new structures were deposited with the CCDC and allocated the following numbers: nicotinate (Deposition #2179234), hydrochloride (2179235), benzoate (2036004), and malonate (2179236) [ 10 ].…”

Section: Resultsmentioning

confidence: 99%

“…These showed improved aqueous solubility over the free base. Extensive details of the results were published in our communication for the solubilities of the four new salts of bedaquiline [ 10 ].…”

Section: Resultsmentioning

confidence: 99%

“…These assumptions were based on earlier experiments that described the principles of salt formation and the interrelationships of pH a solubility [ 16 ]. Alternatively, the disproportionation of the hydrochloride salt may be related to its higher aqueous solubility (0.6437 mg/mL) [ 10 ], which would lower the pHmax value and make it more prone to conversion to the free base with increased environmental pH [ 17 ]. If the goal was to pursue the hydrochloride salt, it would have been necessary to conduct further studies to fully understand the physical and chemical properties of the salt, relating its pHmax and solubility to its tendency to disproportionate.…”

Section: Discussionmentioning

confidence: 99%

“…A low value of 0.0000193 mg/mL was reported in the DrugBank database for the bedaquiline molecule. However, the malonate (0.0268 mg/mL), nicotinate (0.0024 mg/mL), HCl (0.6437 mg/mL), and benzoate (0.0004 mg/mL) salts showed higher aqueous solubilities [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…Solubility plays an important role in determining the best formulation for a drug molecule, the selection excipients, and in predicting the drug’s bioavailability. The aqueous, ideal, and non-ideal solubilities of the new benzoate salts were extensively described in one of our earlier publications [ 10 ]. In the study presented here, we focused on generating data for bedaquiline salts that are critical to their quality attributes, namely, their identification, assay results, melting points, particle sizes, polymorphic forms, and water content.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Okezue

Byrn

2023

Pharmaceuticals

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Characterization of stress degradation products of bedaquiline fumarate and bedaquiline by LC-PDA and LC-MS

Guo,

Wang,

2023

Journal of Pharmaceutical and Biomedical Analysis

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Preparation Strategies of the Anti-Mycobacterial Drug Bedaquiline for Intrapulmonary Routes of Administration

et al. 2023

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Mycobacterium tuberculosis (M.tb) has infected one-quarter of the world’s population and led to the deaths of 1.6 million individuals in 2021 according to estimates from the World Health Organization. The rise in prevalence of multidrug-resistant and extensively drug-resistant M.tb strains coupled with insufficient therapies to treat such strains has motivated the development of more effective treatments and/or delivery modalities. Bedaquiline, a diarylquinoline antimycobacterial agent, effectively targets mycobacterial ATP synthase but may lead to systemic complications upon oral delivery. Targeted delivery of bedaquiline to the lungs represents an alternative strategy to harness the sterilizing benefits of the drug against M.tb while mitigating off-target side effects. Two pulmonary delivery modalities were developed herein, including dry powder inhalation and liquid instillation. Despite bedaquiline’s poor water solubility, spray drying was performed in predominantly aqueous conditions (≥80%) to avoid a closed-loop, inert system. Aerosols of spray-dried bedaquiline with L-leucine excipient outperformed spray-dried bedaquiline alone, demonstrating superior fine particle fraction metrics (~89% of the emitted dose below <5 µm), suitable for inhalation therapies. Furthermore, the use of a 2-hydroxypropyl-β-cyclodextrin excipient allowed a molecular dispersion of bedaquiline in an aqueous solution for liquid instillation. Both delivery modalities were successfully administered to Hartley guinea pigs for pharmacokinetic analysis and were well-tolerated by the animals. Intrapulmonary liquid delivery of bedaquiline led to adequate serum absorption and appropriate peak serum concentrations of the drug. The liquid formulation was superior in systemic uptake compared to the powder formulation. The predominant route via which M.tb bacilli enter the body is aerosol droplets that are deposited onto airway surfaces. For this reason, we believe that further studies should focus on inhalation or intrapulmonary therapies that target the site of entry and primary site of infection for M.tb.

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Determining the solubilities for benzoate, nicotinate, hydrochloride, and malonate salts of bedaquiline

Cited by 3 publications

References 26 publications

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

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

Characterization of stress degradation products of bedaquiline fumarate and bedaquiline by LC-PDA and LC-MS

Preparation Strategies of the Anti-Mycobacterial Drug Bedaquiline for Intrapulmonary Routes of Administration

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