LAUSR

Abstract 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 35Cl 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 13C cross‐polarization magic‐angle spinning (CPMAS) NMR and supported by GIPAW‐DFT calculations, and in the case of 3, 1H solid‐state NMR provided additional confirmation. Applying 35Cl 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 1H, 13C, and 35Cl 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.