Disproportionation of a crystalline citrate salt of a developmental pharmaceutical compound: Characterization of the kinetics using pH monitoring and online Raman spectroscopy plus quantitation of the crystalline free base form in binary physical mixtures

• Citrate salt disproportionates rapidly in solution, monitored by pH and online Raman.
• Salt dissolution obeys first-order (Noyes–Whitney) kinetics.
• Free base recrystallization exhibits nucleation-and-growth type kinetics.
• XRPD, Raman and DSC allow calibration curves to be constructed for binary mixtures.
• Limits of detection are max. 7 wt% for XRPD, Raman and DSC.

The crystalline citrate salt (CS) of a developmental pharmaceutical compound, MK-Q, was investigated in this work from two different, but related, perspectives. In the first part of the paper, the apparent disproportionation kinetics were surveyed using two different slurry systems, one containing water and the other a pH 6.9 phosphate buffer, using time-dependent measurements of the solution pH or by acquiring online Raman spectra of the solids. While the CS is generally stable when stored as a solid under ambient conditions of temperature and humidity, its low pHmax (<3) facilitates rapid disproportionation in aqueous solution, particularly at higher pH values. The rate of disappearance of the CS was found to obey first-order (Noyes–Whitney/dissolution rate-limited) kinetics, however, the formation of the crystalline product form in the slurry system was observed to exhibit kinetics consistent with a heterogeneous nucleation-and-growth mechanism. In the second part of this paper, more sensitive offline measurements made using XRPD, DSC and FT-Raman spectroscopy were applied to the characterization of binary physical mixtures of the CS and free base (FB) crystalline forms of MK-Q to obtain a calibration curve for each technique. It was found that all calibration plots exhibited good linearity of response, with the limit of detection (LOD) for each technique estimated to be ≤7 wt% FB. While additional calibration curves would need to be constructed to allow for accurate quantitation in various slurry systems, the general feasibility of these techniques is demonstrated for detecting low levels of CS disproportionation.

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