Polymorphs of Theophylline Characterized by DNP Enhanced Solid-State NMR

Overview

Journal Mol Pharm

Publisher American Chemical Society

Specialty Pharmacology

Date 2015 Sep 23

PMID 26393368

Citations 17

Authors

Arthur C Pinon

Aaron J Rossini

Cory M Widdifield

David Gajan

Lyndon Emsley

Affiliations

Soon will be listed here.

Abstract

We show how dynamic nuclear polarization (DNP) enhanced solid-state NMR spectroscopy can be used to characterize polymorphs and solvates of organic solids. We applied DNP to three polymorphs and one hydrated form of the asthma drug molecule theophylline. For some forms of theophylline, sample grinding and impregnation with the radical-containing solution, which are necessary to prepare the samples for DNP, were found to induce polymorphic transitions or desolvation between some forms. We present protocols for sample preparation for solid-state magic-angle spinning (MAS) DNP experiments that avoid the polymorphic phase transitions in theophylline. These protocols include cryogrinding, grinding under inert atmosphere, and the appropriate choice of the impregnating liquid. By applying these procedures, we subsequently demonstrate that two-dimensional correlation experiments, such as (1)H-(13)C and (1)H-(15)N HETCOR or (13)C-(13)C INADEQUATE, can be obtained at natural isotopic abundance in reasonable times, thus enabling more advanced structural characterization of polymorphs.

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References

Potrzebowski M, Tekely P, Dusausoy Y . Comment to 13C-NMR studies of alpha and gamma polymorphs of glycine. Solid State Nucl Magn Reson. 1998; 11(3-4):253-7. DOI: 10.1016/s0926-2040(98)00028-9. View

Matsuki Y, Maly T, Ouari O, Karoui H, Le Moigne F, Rizzato E . Dynamic nuclear polarization with a rigid biradical. Angew Chem Int Ed Engl. 2009; 48(27):4996-5000. PMC: 2980755. DOI: 10.1002/anie.200805940. View

Rossini A, Schlagnitweit J, Lesage A, Emsley L . High-resolution NMR of hydrogen in organic solids by DNP enhanced natural abundance deuterium spectroscopy. J Magn Reson. 2015; 259:192-8. DOI: 10.1016/j.jmr.2015.08.020. View

Mifsud N, Elena B, Pickard C, Lesage A, Emsley L . Assigning powders to crystal structures by high-resolution (1)H-(1)H double quantum and (1)H-(13)C J-INEPT solid-state NMR spectroscopy and first principles computation. A case study of penicillin G. Phys Chem Chem Phys. 2006; 8(29):3418-22. DOI: 10.1039/b605227d. View

Webber A, Masiero S, Pieraccini S, Burley J, Tatton A, Iuga D . Identifying guanosine self assembly at natural isotopic abundance by high-resolution 1H and 13C solid-state NMR spectroscopy. J Am Chem Soc. 2011; 133(49):19777-95. DOI: 10.1021/ja206516u. View

Zagdoun A, Casano G, Ouari O, Schwarzwalder M, Rossini A, Aussenac F . Large molecular weight nitroxide biradicals providing efficient dynamic nuclear polarization at temperatures up to 200 K. J Am Chem Soc. 2013; 135(34):12790-7. DOI: 10.1021/ja405813t. View

Ong T, Mak-Jurkauskas M, Walish J, Michaelis V, Corzilius B, Smith A . Solvent-free dynamic nuclear polarization of amorphous and crystalline ortho-terphenyl. J Phys Chem B. 2013; 117(10):3040-6. PMC: 3936015. DOI: 10.1021/jp311237d. View

Perras F, Kobayashi T, Pruski M . Natural Abundance (17)O DNP Two-Dimensional and Surface-Enhanced NMR Spectroscopy. J Am Chem Soc. 2015; 137(26):8336-9. DOI: 10.1021/jacs.5b03905. View

Kubicki D, Rossini A, Purea A, Zagdoun A, Ouari O, Tordo P . Amplifying dynamic nuclear polarization of frozen solutions by incorporating dielectric particles. J Am Chem Soc. 2014; 136(44):15711-8. PMC: 4671102. DOI: 10.1021/ja5088453. View

10.

Ochsenfeld C, Brown S, Schnell I, Gauss J, Spiess H . Structure assignment in the solid state by the coupling of quantum chemical calculations with NMR experiments: a columnar hexabenzocoronene derivative. J Am Chem Soc. 2001; 123(11):2597-606. DOI: 10.1021/ja0021823. View

11.

Blanc F, Chong S, McDonald T, Adams D, Pawsey S, Caporini M . Dynamic nuclear polarization NMR spectroscopy allows high-throughput characterization of microporous organic polymers. J Am Chem Soc. 2013; 135(41):15290-3. DOI: 10.1021/ja408074v. View

12.

Takahashi H, Viverge B, Lee D, Rannou P, De Paepe G . Towards structure determination of self-assembled peptides using dynamic nuclear polarization enhanced solid-state NMR spectroscopy. Angew Chem Int Ed Engl. 2013; 52(27):6979-82. DOI: 10.1002/anie.201210093. View

13.

Harris R, Hodgkinson P, Zorin V, Dumez J, Elena-Herrmann B, Emsley L . Computation and NMR crystallography of terbutaline sulfate. Magn Reson Chem. 2010; 48 Suppl 1:S103-12. DOI: 10.1002/mrc.2636. View

14.

Mollica G, Dekhil M, Ziarelli F, Thureau P, Viel S . Quantitative structural constraints for organic powders at natural isotopic abundance using dynamic nuclear polarization solid-state NMR spectroscopy. Angew Chem Int Ed Engl. 2015; 54(20):6028-31. DOI: 10.1002/anie.201501172. View

15.

Grillo D, Polla G, Vega D . Conformational polymorphism on imatinib mesylate: grinding effects. J Pharm Sci. 2011; 101(2):541-51. DOI: 10.1002/jps.22772. View

16.

Trask A, Shan N, Motherwell W, Jones W, Feng S, Tan R . Selective polymorph transformation via solvent-drop grinding. Chem Commun (Camb). 2005; (7):880-2. DOI: 10.1039/b416980h. View

17.

Ni Q, Daviso E, Can T, Markhasin E, Jawla S, Swager T . High frequency dynamic nuclear polarization. Acc Chem Res. 2013; 46(9):1933-41. PMC: 3778063. DOI: 10.1021/ar300348n. View

18.

Qiu J, Li G, Sheng Y, Zhu M . Quantification of febuxostat polymorphs using powder X-ray diffraction technique. J Pharm Biomed Anal. 2015; 107:298-303. DOI: 10.1016/j.jpba.2015.01.005. View

19.

Fernandez-de-Alba C, Takahashi H, Richard A, Chenavier Y, Dubois L, Maurel V . Matrix-free DNP-enhanced NMR spectroscopy of liposomes using a lipid-anchored biradical. Chemistry. 2015; 21(12):4512-7. DOI: 10.1002/chem.201404588. View

20.

Althaus S, Mao K, Stringer J, Kobayashi T, Pruski M . Indirectly detected heteronuclear correlation solid-state NMR spectroscopy of naturally abundant 15N nuclei. Solid State Nucl Magn Reson. 2013; 57-58:17-21. DOI: 10.1016/j.ssnmr.2013.11.001. View