Report_2011.pub

2010-2011 Annual Report
14N solid-state NMR spectroscopy of pharmaceuticals and their
polymorphs
Stanislav L. Veinberg,a Christopher R. Mireault,a Kristopher J. Harris,a Luke A. O’Dellb and (a) Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario (b) Steacie Institute for Molecular Sciences, National Research Council, Ottawa, Ontario In a previous publication by our group [1], we demonstrated that 35Cl solid-state NMR (SSNMR) spectroscopy is a powerful complimentary technique to powder X-ray diffraction (XRD) and 13C SSNMR for the study of pharmaceutical polymorphs. It provides clear information on the number of chlorine sites and shows great utility for identifying sites in non-crystalline, disordered or even impurity phases, or in cases where the solid-state 13C NMR spectra or powder XRD data are unable to differentiate polymorphs. However, there are many pharmaceuticals and associated polymorphs that are not crystallized as hydrochloride (HCl) salts; hence, there is a need for additional probe nuclei. Nitrogen is present in many pharmaceuticals and may serve as an attractive probe nucleus. Nitrogen has two NMR active nuclei (14N and 15N) which are 99.63 % and 0.37 % naturally abundant, respectively. Recent optimization of the WURST-QCPMG pulse sequence [2,3] and availability of high magnetic fields (21.1 T) nucleus possible. Nitrogen-14 is a spin-1 nucleus, has a non-zero electric quadrupole moment (eQ = 20.44 mb) and a low gyromagnetic ratio (γ = 1.93 × 107 rad T−1 s−1). Previous studies have demonstrated the sensitivity of the 14N solid-state NMR spectra to local nitrogen environments [2,4]; thus, we would like to explore the possibility of using 14N SSNMR for pharmaceutical polymorph differentiation. In this study, a series of pharmaceuticals and Figure 1: 14N powder patterns of (a) bupiv I, CQ = 1.00 their associated polymorphs have been
MHz and ηQ = 0.31 and (b) bupiv II, CQ = 1.25 MHz and ηQ
= 0.22. The spectra taken at 21.1 T are composed of 2 and investigated by 14N SSNMR. The samples were
4 sub-spectra, respectively, and took ca. 8 and 16 hours, chosen such that they all contained nitrogen respectively, to collect. Dashed lines highlight discontinuities of bupiv I. atoms in pseudo-tetrahedral environments, 2010-2011 Annual Report
which have been previously demonstrated to be amenable to 14N SSNMR [2]. Results from two Bupivacaine HCl (bupiv) contains a nitrogen
atom bonded to three carbon atoms and one (a)
hydrogen atom. The two polymorphs, bupiv I and bupiv II, were prepared by recrystallization from a 50/50 mixture of water and acetone and by heating to 170°C, respectively. 14N SSNMR spectra for the two polymorphs show distinct (b)
discontinuities (horns, shoulders and feet) marked by the dashed lines (Figure 1).
Accordingly, the CQ and ηQ values are different
for each sample. The crystal structures of both
polymorph phases of bupiv are known; it is clear Figure 2: 14N powder patterns of (a) mexil I, CQ = 0.915
that the local environments of the nitrogen MHz and ηQ = 0.125 and (b) mexil III, CQ = 0.97 MHz and
atoms are distinct from one another due to ηQ = 0.13. The spectra recorded at 21.1 T are composed of
2 and 4 sub-spectra, respectively, and took ca. 2 and 5 variation in hydrogen bond lengths and hours, respectively, to collect. Dashed vertical lines positions. Mexiletine HCl (mexil) contains a nitrogen atom bonded to one carbon atom and three hydrogen atoms. Two polymorphs of mexil were studied; mexil I, which was recrystallized from water, and mexil III, which was produced by heating mexil I to 160 °C. Their 14N powder patterns appear different, although they yield similar quadrupolar parameters (Figure 2). The mexil III powder pattern displays significant broadening, which may arise from a number of possible scenarios, including decreased long-range order, local dynamic processes, and/or an increased number of longer-range 14N-1H dipolar couplings (some of which may alter the relaxation characteristics of the 14N nuclei in this sample). Although a crystal structure for mexil III is not available, based on the quadrupolar parameters of the two systems, it can be concluded that the nitrogen environment varies only slightly between the two polymorphs. We are currently continuing our investigation of pharmaceutical polymorph systems using 14N SSNMR. References [1] H. Hamaed, J.M. Pawlowski, B.F.T. Cooper, R. Fu, S.H. Eichhorn, and R.W. Schurko, J. Am. Chem. Soc. 130 (2008) 11056.
[2] L.A. O’Dell and R.W. Schurko, Chem. Phys. Lett. 464 (2008) 97.
[3] L.A. O’Dell and R.W. Schurko, J. Am. Chem. Soc. 131 (2009) 6658.
[4] L.A. O’Dell, R.W. Schurko, K.J. Harris, J. Autschbach, and C.I. Ratcliffe, J. Am. Chem. Soc. 133

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