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More than 50% of active pharmaceutical ingredients (APIs) are crystallized as simple salts, and of these, over 50% are HCl salts. In many instances, APIs can crystallize into pseudopolymorphic forms, such as hydrates or solvates, which have structures and molecular properties distinct from the non-hydrated or non-solvated solid phases. The polymorphic form of an API can influence its physicochemical properties, including bioavailability, shelf life, toxicity, and solubility. Additionally, each unique hydrate or solvate of an API represents unique intellectual property, and may be separately patented. As such, it is very important to precisely structurally characterize all solid forms of APIs. Numerous methods, such as single crystal X-ray diffraction (scXRD), powder X-ray diffraction (pXRD), and 13C NMR are often employed to accurately elucidate these structures. Previous work in our group has shown that 35Cl SSNMR can be extremely valuable in the study of APIs in both bulk and dosage forms. In particular, we have shown that 35Cl powder patterns are extremely sensitive to slight modifications in the molecular structure of an API, and serve as unique spectral fingerprints for each compound.1,2 The focus of this project is to use 35Cl SSNMR, pXRD, as well as quantum-chemical calculations, to systematically study hydrates and anhydrous forms of HCl APIs. By analyzing their 35Cl SSNMR spectra, we hope to study the hydrogen bonding interactions between chloride anions and water molecules, and the influence of water molecules on the molecular structures of the APIs. It is our hope that these proof of concept findings will be of interest to the pharmaceutical industry, for potential use in high throughput analysis of APIs, hydrate identification, and detection of impurities and disproportionation. 1. Hildebrand, M. et al. CrystEngComm 2014, 16, 7334. 2. Hamaed, H. et al. J. Am. Chem. Soc. 2008, 130, 11056.

In this work, we show how to obtain efficient dynamic nuclear polarization (DNP) enhanced Cl-35 solid-state NMR (SSNMR) spectra at 9.4 T and demonstrate how they can be used to characterize the molecular-level structure of hydrochloride salts of active pharmaceutical ingredients (APIs) in both bulk and low wt% API dosage forms. Cl-35 SSNMR central-transition powder patterns of chloride ions are typically tens to hundreds of kHz in breadth, and most cannot be excited uniformly with high-power rectangular pulses or acquired under conditions of magic-angle spinning (MAS). Herein, we demonstrate the combination of DNP and H-1-Cl-35 broadband adiabatic inversion cross polarization (BRAIN-CP) experiments for the acquisition of high quality wideline spectra of APIs under static sample conditions, and obtain signals up to 50 times greater than in spectra acquired without the use of DNP at 100 K. We report a new protocol, called spinning-on spinning-off (SOSO) acquisition, where MAS is applied during part of the polarization delay to increase the DNP enhancements and then the MAS rotation is stopped so that a wideline Cl-35 NMR powder pattern free from the effects of spinning sidebands can be acquired under static conditions. This method provides an additional two-fold signal enhancement compared to DNP-enhanced SSNMR spectra acquired under purely static conditions. DNP-enhanced Cl-35 experiments are used to characterize APIs in bulk and dosage forms with Cl contents as low as 0.45 wt%. These results are compared to DNP-enhanced H-1-C-13 CP/MAS spectra of APIs in dosage forms, which are often hindered by interfering signals arising from the binders, fillers and other excipient materials.