Synthesis of Organic HCl Salts via Mechanochemical Salification and their Characterization with 35/37Cl Solid-State NMR Spectroscopy

Abstract

Hydrochloride (HCl) salts are among the most common solid forms of active pharmaceutical ingredients (APIs) because of their favorable physicochemical properties, including enhanced solubility and stability. However, their syntheses via conventional solution-based methods are often complicated by challenges related to solvent use, stoichiometric control, phase selectivity, and environmental waste. This work presents a novel mechanochemical salification protocol that enables rapid and quantitative syntheses of a variety of organic HCl salts using precise, stoichiometric amounts of HCl. Seventeen salts were prepared from eight organic free base molecules, primarily through mechanochemistry, encompassing hydrates, anhydrous forms, and rare hemihydrochloride phases. Careful consideration is given to a variety of factors affecting these reactions, including the quantity of HCl, solvents of HCl solutions, duration and frequency of milling, the relevance of pK_a and material stability, and upward reaction scalability. Structural characterization was carried out using ^35/37Cl solid-state NMR (SSNMR) spectroscopy and powder X-ray diffraction, which provide detailed insights into the local chloride ion environments and phase purities. Dispersion-corrected density functional theory (DFT-D2*) methods were used to geometry-optimize structural models based on known crystal structures and to establish correlations between ^35/37Cl electric field gradient (EFG) tensors and hydrogen bonding networks essential for stabilization of crystal structures. These results demonstrate the efficiency and precision of mechanochemical salification for generating a diverse array of solid forms, as well as the utility of advanced SSNMR techniques and DFT methods for uncovering subtle structural features that govern the structures and behaviors of salts of APIs.