Component Quantification in Solids with the Mixture Analysis Using References Method

Quantifying components in solid mixtures composed of the same chemical species exhibiting different physical forms represents a difficult challenge in many areas of chemistry. The development of small-molecule active pharmaceutical ingredients (APIs) is a classic example. APIs predominantly exhibit polymorphism and the propensity to form solvates and hydrates. The various API phases typically display different physical properties affecting chemical stability, processability, and bioperformance. Accordingly, API development critically relies on characterizing and quantifying the relevant API forms in complex mixtures in the presence of each other and in the presence of excipients. Presented here is a new solid-state-NMR-based quantification method for components in solid mixtures: mixture analysis using references (MAR). The method utilizes weighted pure component reference spectra in a linear combination fitting procedure to reproduce the corresponding mixture spectrum. The results yield the respective component contributions to the mixture composition. Using several model systems of varying complexity, the applicability and performance of the MAR analysis utilizing ¹³C and ¹⁹F cross-polarization magic-angle-spinning data are evaluated. Finally, the MAR method is compared to one of the most commonly applied traditional quantification methods. The results demonstrate that MAR performs with the same high accuracy as conventional methods. However, MAR exhibits clear efficiency advantages over conventional methods by requiring significantly less overall time (experimental and computational) and displaying remarkable robustness and general applicability. The MAR quantification protocol as presented here can easily be applied to nonpharmaceutical molecular systems in other branches of chemistry.