(M1230-08-45) Comparing the Stability-Indicating Parameters for 4 New Salts of Bedaquiline

Purpose: New salts of bedaquiline have been developed and communicated within the past years (1); however, the stability of these salts has been omitted. The ability of salts to remain unchanged under elevated conditions of temperature and relative humidity is one of the important criteria for choosing a lead compound. This study evaluated the impact of storing 4 new bedaquiline salts under ICH-recommended accelerated stability conditions.

Methods: Replicate bedaquiline salt samples were exposed to accelerated conditions in a 75% RH chamber placed inside an incubator maintained at 40^oC, with an external verifiable temperature readout device. The samples were withdrawn and assessed at 0, 3, and 6-months intervals. The samples were analyzed as per the stability protocol for powder X-ray diffraction [PXRD] and Rietveld measurements. Other tests conducted were the potencies of the salts using the HPLC and thermal analysis with DSC and TGA. Finally, the stability of replicate suspensions of the benzoate and fumarate salts were compared over 4-hours for a dog PK study.

Results: The chemical structure for benzoate, nicotinate, and malonate were not significantly altered at 3, and 6-months. The salts refined against their single crystals when examined with Rietveld refinements. However, the hydrochloride salt lost its crystallinity after 3 months. The potency for benzoate declined from 90.4% at the initial time to 86.1% in the 6^th month, malonate from 95.6% to 71.3%, nicotinate from 84.7% to 64.1%, and hydrochloride from 101.9% to 77.3%. The suspensions of the benzoate and fumarate salts indicated no loss in crystallinity after 4hours. The DSC and TGA analysis of the hydrated benzoate and nicotinate salts after 6 months of accelerated stability conditions suggested that the salts did not become anhydrous. The Rietveld analysis of the benzoate and fumarate indicated the salts were both stable up to 4 hours in suspension used for the dog PK study.

Conclusion: The benzoate, nicotinate, and malonate salts maintained their crystalline structure, while the hydrochloride did not. The benzoate and nicotinate salts maintained their hydrate status under accelerated stability conditions. And, though all salts lost their chemical potencies, the lowest decline was observed in the benzoate salt. In the PK dog study, the benzoate, just like the fumarate salt was stable for up to 4 hours in a liquid vehicle.

References: (1) Okezue, M., Bogdanowich-Knipp, S., Smith, D. et al. Salts and Polymorph Screens for Bedaquiline. AAPS PharmSciTech 22, 228 (2021)


Presence of additional peaks in HPLC chromatographs of salts after accelerated stability at 3 and 6 months


Chemical potencies of salts declined after accelerated stability at 3 and 6 months


Salts suspensions were stable after 4-hour in dog PK studies