Moving towards fast characterization of polymorphic drugs by solid-state NMR spectroscopy

摘要

Graphical abstract Display Omitted Highlights ? Paramagnetic reagents were added to polymorphic drugs to decrease T 1 relaxation times. ? ICP-OES confirmed inverse relationship between concentration and T 1 relaxation time. ? SS-NMR and PXRD reveal that crystal structure is preserved after experimentation. ? Adding a paramagnetic agent does not alter the crystal structure nor transform the polymorph. ? Nickel and chromium ions have different effects on the T 1 relaxation times. Abstract Solid-state nuclear magnetic resonance (SS-NMR) spectroscopy has become a common technique to study polymorphism in pharmaceutical solids at high-resolution. However, high-throughput application of high resolution SS-NMR spectroscopy is severely limited by the long 1 H spin-lattice relaxation (T 1 ) that is common to solid phase compounds. Here, we demonstrate the use of paramagnetic relaxation reagents such as chromium (III) acetylacetonate (Cr(acac) 3 ) and nickel (II) acetylacetonate (Ni(acac) 2 ) for fast data acquisition by significantly reducing the T 1 value for carbamazepine Forms I, II, III, and dihydrate, cimetidine Forms A and B, nabumetone Form I, and acetaminophen Form I polymorphs. High resolution 13 C cross-polarization and magic angle spinning were used to measure T 1 values for each polymorph. In order to confirm the absence of polymorphic transitions during SS-NMR experiments, powder x-ray diffraction was implemented. The amount of chromium ions incorporated by the recrystallization process was quantified by using inductively coupled plasma optical emission spectroscopy. Our results suggest that the paramagnetic ions added to the polymorphs do not affect the polymorphic transformation or the quality of NMR spectra. We believe that this successful demonstration of fast data collection will enable high-throughput utilization of SS-NMR techniques to study polymorphic solids and could set the groundwork for NMR crystallography studies.