Exploring the Potential of Multinuclear Solid-state 1H, 13C, and 35Cl Magnetic Resonance To Characterize Static and Dynamic Disorder in Pharmaceutical Hydrochlorides

Crystallographic disorder, whether static or dynamic, can be detrimental to the physical and chemical stability, ease of crystallization and dissolution rate of an active pharmaceutical ingredient. Disorder can result in a loss of manufacturing control leading to batch-to-batch variability and can lengthen the process of structural characterization. The range of NMR active nuclei makes solid-state NMR a unique technique for gaining nucleus-specific information about crystallographic disorder. Here, we explore the use of high-field Cl-35 solid-state NMR at 23.5 T to characterize both static and dynamic crystallographic disorder: specifically, dynamic disorder occurring in duloxetine hydrochloride (1), static disorder in promethazine hydrochloride (2), and trifluoperazine dihydrochloride (3). In all structures, the presence of crystallographic disorder was confirmed by C-13 cross-polarization magic-angle spinning (CPMAS) NMR and supported by GIPAW-DFT calculations, and in the case of 3, H-1 solid-state NMR provided additional confirmation. Applying Cl-35 solid-state NMR to these compounds, we show that higher magnetic fields are beneficial for resolving the crystallographic disorder in 1 and 3, while broad spectral features were observed in 2 even at higher fields. Combining the data obtained from H-1, C-13, and Cl-35 NMR, we show that 3 exhibits a unique case of disorder involving the N+-H hydrogen positions of the piperazinium ring, driving the chloride anions to occupy three distinct sites.

Automated summary

Crystallographic disorder can have negative effects on the stability and manufacturing control of active pharmaceutical ingredients. Solid-state NMR is a useful technique for studying crystallographic disorder. This study used high-field Cl-35 solid-state NMR to characterize the disorder in duloxetine hydrochloride, promethazine hydrochloride, and trifluoperazine dihydrochloride. The results showed that higher magnetic fields were beneficial for resolving the disorder in some compounds.