Developing In Situ Chemometric Models with Raman Spectroscopy for Monitoring an API Disproportionation with a Complex Polymorphic Landscape

Abstract

An in situ Raman method was developed to characterize the disproportionation of two salts involving a complex polymorphic landscape comprising up to two metastable and one stable freebase forms. Few precedents exist for Raman calibration procedures for solid form quantitation involving more than two polymorphs, while no literature examples were found for cases with multiple metastable forms. Therefore, a new Raman calibration procedure was proposed by directly using disproportionation experiments to generate multiple calibration samples encompassing a range of polymorph ratios through in-line Raman measurements complemented by off-line reference X-ray diffraction measurements. The developed Raman methods were capable of accurately quantitating each solid form in situ when solid concentration variation was incorporated into the calibration dataset. The kinetic understanding of the thermodynamically driven polymorphic conversions gained from this Raman method guided the selection of the salt best suited for the delivery of the active ingredient in the drug product. This work provided a spectroscopic and mathematical approach for simultaneously quantitating multiple polymorphs from a complex mixture of solids with the objective of real-time monitoring.

Integrative Salt Selection and Formulation Optimization: Perspectives of Disproportionation and Microenvironmental pH Modulation

“…We used offline X-ray measurements as a reference during model development. The concept of using a single disproportionation run to generate quantitative Raman models has been reported previously . We used this approach to characterize the disproportionation kinetics for the HCl salt and maleate to verify X-ray diffraction measurements further and to enhance our mechanistic understanding of salt behaviors.…”

“…This relatively higher error can be attributed to the narrower weight fraction range of Form V used in model development from a partial disproportionation run. A more comprehensive assessment of concentration and solid form effects on quantitative Raman model development for this system is highlighted in our previous work …”

“…A more comprehensive assessment of concentration and solid form effects on quantitative Raman model development for this system is highlighted in our previous work. 48 Similar to the HCl salt disproportionation, the Raman models generated on maleate disproportionation had high correlation coefficients and low errors. The R 2 values were again 0.95 or greater, showing a good fit with Raman predictions and X-ray quantitation values.…”

“…To develop the maleate into a feasible product despite disproportionation liability, we resorted to a differentiating stress test, which further confirmed the maleate's superior robustness (vs HCl salt). An improved chemometric model originating from a previous publication 48 and an orthogonal X-ray analysis were utilized for the quantitation and kinetic assessment of the disproportionation event, further enhancing the understanding of the process. We took a strategic approach to select fumaric acid as the pH modulator to include in the drug product.…”

“…Its chemical structure and properties have been reported as API 2 in a recent publication. 47 The neutral form of the molecule (a weak base) is known to exist in many polymorphs (Forms I, II, III, IV, V), 48 all solvent-free with distinct melting points. Despite being early in development, the synthetic route has consistently produced high-purity (>99.5%) drug substances for pharmaceutical development.…”