Abstract
Purpose. The application of solid-state nuclear magnetic resonance (NMR) characterization of three crystalline forms (VIII, XI, XII) and the amorphous form V of delavirdine mesylate (DLV-M) is presented.
Methods. Conventional 13C CP (cross-polarization)/MAS (magic angle spinning) NMR and related spectral editing methods were employed. NMR relaxation times (T1pH, T1H, and T1C) were also measured.
Results. Distinctly different spectral features among the four solid forms were observed, indicating high sensitivity of 13C NMR to the variations in solid structure. Assessment based on NMR data suggests that both anhydrous forms VIII and XI may contain one molecule per asymmetric unit. DLV may adopt a similar molecular conformation in the two forms. In contrast, form XII is found to consist of two molecules per asymmetric unit. Molecule conformation of DLV in forms VIII, XI, and XII is altered from the dominant conformer in solution. The amorphous form V may contain DLV molecules of a variety of conformations. NMR relaxation times (TlpH, T1H, and T1C) provide valuable information about the motional characteristics in these solids. Values and the rank order of TlpH, T1H, and T1C also reveal significant differences in local environments and the short range order among the four forms.
Conclusions. Four solid forms of DLV-M (V, VIII, XI. and XII) can be distinctly differentiated by 13C CP/MAS NMR spectroscopy and their structural difference can be partially revealed without obtaining single crystal data. NMR relaxation times reveal motion dynamics and aid structural elucidation for these forms.
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REFERENCES
I. W. Althaus, J. J. Chou, A. J. Gonzales, M. R. Deibel, K-C. Chou, F. J. Kezdy, D. L. Romero, R. C. Thomas, P. A. Aristoff, W. G. Tarpley, and F. Reusser. Kinetic studies with the nonnucleoside human immunodeficiency virus type-1 reverse transcriptase inhibitor U-90152E. Biochemical Pharmacology 47:2017–2028 (1994).
M. S. Bergren, R. S. Chao, P. A. Meulman, R. W. Sarver, M. A. Lyster, J. L. Havens, and M. Hawley. Solid phase diversity of delavirdine mesylate. J. Pharm. Sci. 85:830–837 (1996).
H. Martinez, S. R. Byrn, and R. R. Pfeiffer. Solid state chemistry and crystal structure of cefactlor dihydrate. Pharm. Res. 7:147–153 (1990).
S. R. Byrn, P. A. Sutton, B. Tobias, J. Frye, and P. Main. The crystal structure, solid-state NMR spectra and oxygen reactivity of five crystal forms of prednisolone tert-butylacetate. J.A.C.S. 110:1609–1614 (1988).
G. A. Jeffrey, R. A. Wood, P. E. Pfeffer, and K. B. Hicks. Crystal structure and solid-state NMR analysis of lactulose. J.A.C.S. 105:2128–2133 (1983).
R. K. Harris, A. M. Kenwright, B. J. Say, and R. R. Yeung. Cross-polarization/magic angle spinning NMR studies of polymorphism: cortisone acetate. Spectrochim. Acta. 46A:927–935 (1990).
R. A. Fletton, R. W. Lancaster, R. K. Harris, K. J. Packer, D. N. Waters, and A. Yeadon. A comparative spectroscopic investigation of two polymorphs of 4′-methyl-2′-nitroacetanilide using solid-state infrared and high resolution solid-state nuclear magnetic resonance spectroscopy. J. Chem. Soc. Perkin. Trans. II 1705–1709 (1986).
N. J. Clayden, C. M. Dobson, L. Y. Lian, and J. M. Twyman. A solid-state 13C nuclear magnetic resonance study of the conformational states of penicillins. J. Chem. Soc. Perkin. Trans. II 1933–1940 (1986).
D. L. VanderHart. Influence of molecular packing on solid-state 13C chemical shifts. The n-alkanes. J. Mag. Res. 44:117–125 (1981).
L. E. Diaz, F. Morin, C. L. Mayne, D. M. Grant, and C. Chang. Conformational analysis of DL-, L-, and D-methionine by solid-state 13C NMR spectroscopy. Mag. Res. Chem. 24:167–170 (1986).
F. G. Morin, W. J. Horton, D. M. Grant, D. K. Dalling, and R. J. Pugmire. Carbon-13 magnetic resonance of hydroaromatics. 2. Conformation of tetralin and tetrahydroanthracene and their methyl derivations. J.A.C.S. 105:3992–3998 (1983).
D. K. Dalling, K. W. Zilm, D. M. Grant, W. A. Heeschan, W. J. Horton, and R. J. Pugmire. A solution and solid carbon-13 magnetic resonance study of the conformation of 9,10-dihydronthracene and methylated derivatives. J.A.C.S. 103:4817–4824 (1981).
C. E. Brown, S. C. Roerig, V. T. Burger, R. B. Cody, Jr., and J. M. Fujimoto. Analgesic potencies of morphine 3-and 6-sulfates after intracerebroventricular administration in mice: Relationship to structural characterization defined by mass spectrometry and nuclear magnetic resonance. J. Pharm. Sci. 74:821–824 (1985).
M. Bardet, A. Rousseau, and M. Vincedon. High resolution solid-state 13C CP/MAS NMR study of scleroglucan hydration. Mag. Res. Chem. 5:886–892 (1993).
M. H. Frey and S. J. Opella. Observation of conformationally distinct proline residues in two cyclic peptides by solid-state nuclear magnetic resonance. J.A.C.S. 103:467–468 (1981).
P. Gao. Determination of the composition of delavirdine mesylate polymorph and pseudopolymorph mixtures using 13C CP/MAS NMR. Pharm. Res. 13:1095–1104 (1996).
C. A. Fyfe. Solid State NMR for Chemists. CFC Press, Guelph, Canada, 1983. Chapter 8.
X. Wu and K. W. Zilm. Complete spectral editing CPMAS NMR. J. Mag. Res. A. 102:205–213 (1993).
J. S. Fyre and G. E. Maciel. Setting the magic angle using a quadrupolar nuclide. J. Mag. Res. 48:125–131 (1982).
L. W. Jelinski and M. T. Melchior. High-resolution NMR of solids. in C. Dybowski and R. L. Lichter (eds.), NMR Spectroscopy Techniques. Marcel Dekker, Inc., New York, 1985.
K. A. Farley, G. S. Walker, R. H. Robins, J. E. Kupstas-Guido, W. K. Dulholke, D. L. Romero, R. A. Morge, P. A. Meulman, R. S. Chao, J. L. Havens, J. R. Gage, M. A. Lyster, P. E. Fagerness, and G. E. Martin. Spectroscopic studies of delavirdine mesylate (U-90152T) a bis(heteroary)piperazine (BHAP) HIV reverse transcriptase inhibitor. J. Heterocyclic. Chem. 33:493–497 (1996).
J. L. Koenig. Spectroscopy of Polymers. ACS, Washington D.C., 1992, pg 267–277.
A. Naito, S. Ganapathy, K. Akasaka, and C. A. McDowell. Spinlattice relaxation of 13C in solid aminoacids using the CP/MAS technique. J. Mag. Res. 54:226–235–5856 (1983).
R. K. Harris. Nuclear Magnetic Resonance Spectroscopy. Pitman Publishing, Inc., Marshfield, MA, 1983. Chapter 6.
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Gaou, P. Characterization of Three Crystalline Forms (VIII, XI, and XII) and the Amorphous Form (V) of Delavirdine Mesylate Using 13C CP/MAS NMR. Pharm Res 15, 1425–1433 (1998). https://doi.org/10.1023/A:1011909907031
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DOI: https://doi.org/10.1023/A:1011909907031