Probing the Molecular and Macroscopic Structure of Solid Solutions by Dynamic Nuclear Polarization (DNP) Enhanced ¹³C and ¹⁵N Solid-State NMR Spectroscopy

Abstract

Crystallization is a widely used purification technique in the manufacture of active pharmaceutical ingredients (APIs) and precursor molecules. However, when impurities and desired compounds have similar molecular structures, separation by crystallization may become challenging. In such cases, some impurities may form crystalline solid solutions with the desired product during recrystallization. Understanding the molecular structure of these recrystallized solid solutions is crucial to devise methods for effective purification. Unfortunately, there are limited analytical techniques that provide insights into the molecular structure or spatial distribution of impurities that are incorporated within recrystallized products. In this study, we investigated model solid solutions formed by recrystallizing salicylic acid (SA) in the presence of anthranilic acid (AA). These two molecules are known to form crystalline solid solutions due to their similar molecular structures. To overcome challenges associated with the long 1 H longitudinal relaxation times (T 1 ( 1 H)) of SA and AA, we employed dynamic nuclear polarization (DNP) and 15 N isotope enrichment to enable solid-state NMR experiments. Results of solid-state NMR experiments and DFT calculations revealed that SA and AA are homogeneously alloyed as a solid solution. Heteronuclear correlation (HETCOR) experiments and plane-wave DFT structural models provide further evidence of the molecular-level interactions between SA and AA. This research provides valuable insights into the molecular structure of recrystallized solid solutions, contributing to the development of effective purification strategies and an understanding of the physicochemical properties of solid solutions.

Thermodynamic Stability Transitions and Coexistence of Two Polymorphs via Crystalline Solid Solutions: The T-X Phase Diagram of Salicylic Acid and 2,3-Dihydroxybenzoic Acid

“…23DHBA only differs from SA in one additional hydroxyl group and thus exhibits sufficient molecular similarity to be partially miscible in the solid state. Based on structural analysis for a related system (salicylic acid–anthranilic acid) via SSNMR, it can expected that the guest molecules are most likely located within the host lattice as single molecules distributed homogeneously throughout the crystal lattice . This is equivalent to so-called substitutional CSS.…”