Solid-State NMR in Drug Analysis

NMR spectra cannot be measured in solids in the same way in which they are routinely obtained in solutions because NMR lines from solids are too broad. In solution all interactions apart from chemical shift and indirect coupling are averaged to zero by thermal motions of molecules. Magnetic interactions in the solid state are described by a Hamiltonian H [1], which is a sum of several contributions Zeeman interaction (the same as in solution), direct dipole-dipole interaction, magnetic shielding (giving chemical shifts), scalar spin-spin coupling to other nucleus, and for nuclei with / 1/2 also quadrupolar interactions. 

H eeman H(jjpolai+ Hohemical shift Hspjn coupling Hquadrupolai 

The most important is the dipole-dipole interaction with neighboring nuclei. Magnetic fields of nuclei i ( H) in the neighborhood of the nucleus j (for example C, ) under observation generate local fields  

5ioc fit (3cos 6ij- 1), which depend on the magnetic moment // of the nuclei and the mutual orientation of the nuclei (3cos //-l), where Gy is an angle between intemuclear vector and the direction of static magnetic field. 

The Se is a A spin nucleus of 7.7% abundance and the recording time for the experiment is as for C NMR. For slow spinning (3530 Hz), one observes a set of lines spaced at the rotation frequency at the left and right side (upper trace) the lines decrease in intensity and move away fi om the center resonance as the spinning rate increases to 6367 Hz (lower trace). 

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K. Paradowska, I. Wawer, Solid-state NMR in the analysis of drugs and naturally occurring materials, J. Pharm. Biomed. Anal. 93 (2014) 27—42. 

The solid-state properties like crystallinity, polymorphism (crystal structure), shape (morphology), and particle size of drugs are important in the stability, dissolution, and processibility of drugs. Some commonly used methods in solid-state studies include microscopy, hot stage microscopy with polarized light, x-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infrared FTIR/Raman, and solid-state NMR. 

Solid-state NMR has emerged as a powerful tool in the analysis of polymorphic drug forms. CP-MAS spectroscopy can be used to identify the number of crystallographically inequivalent sites in a unit cell and to understand the molecular structure on the basis of the chemical shifts. Fig. 14 shows the solid-state spectra of two forms of lamivudine. Form II shows a relatively simple spectrum in which there is only one molecule in the crystallographic asymmetric unit. 

Nuclei that are typically analyzed with this technique include those of 13C, 31P, 1SN, 2SMg, and 23Na. Different crystal structures of a compound can result in perturbation of the chemical environment of each nucleus, resulting in a unique spectrum for each form. Once resonances have been assigned to specific atoms of the molecule, information on the nature of the polymorphic variations can be obtained. This can be useful early in drug development, when the single-crystal structure may not be available. Long data acquisition times are common with solid-state NMR, so it is often not considered for routine analysis of samples. However, it is usually a very sensitive technique, and sample preparation is minimal. NMR spectroscopy can be used either qualitatively or quantitatively, and can provide structural data, such as the identity of solvents bound in a crystal. 

F.G. Vogt, M. Strohmeier, 2D solid-state NMR analysis of inclusion in drug-cyclodextrin complexes, Mol. Pharm. 9 (11) (2012) 3357-3374. 

I. Wawer, Solid-State Measurements of Drugs and Drug Formulations , in NMR Spectroscopy in Pharmaceutical Analysis, eds. U. Holzgrabe, I. Wawer and B. Diehl, Elsevier Ltd., Oxford, UK, 2008, p. 201. 

Our goal is to show the utility of NMR spectroscopy for the study of low molecular structures in solution and its application as a tool for a routine analysis. Some solid-state NMR studies are also included. Our interest will focus mostly on bioactive compounds, such as drugs and pharmaceutical formulations, and potential drugs, as well as on natural products, such as small-molecular-weight secondary metabolites produced by plants. A vital problem for chemists remains chiral discrimination, which can be assessed using NMR." ... 

Identification and characterization of the structures of unknown substances are an important part of organic chemistry. It is often, of necessity, a micro process, e.g., in drug analyses. It is sometimes possible to establish the structure of a compound on the basis of spectra alone (ir, uv, and nmr), but these spectra must usually be supplemented with other information about the unknown physical state, elementary analysis, solubility, and confirmatory tests for functional groups. Conversion of the unknown to a solid derivative of known melting point will often provide final confirmation of structure. 

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