Solid-state nuclear magnetic resonance polymorphism

In the following, some examples of applications of Fourier transform infrared (FTIR) Spectroscopy and of solid-state nuclear magnetic resonance (NMR) to the study of polymorphism in polymers are described. 

The two structurally similar polymorphs of (R,S)-ethambutol dihydrochloride have been shown to bear an enantiotropic relationship, and can reversibly interconvert in a single crystal transformation mode [27]. It was reported that despite the identity in space group type and similarity in unit cell constants, the two forms could be distinguished on the basis of their X-ray powder diffraction and solid-state nuclear magnetic resonance properties. Interestingly, while the (polymorphic forms, the (R,S)-diastereomer was only obtained in two different polymorphs. 

In terms of the structural features that are probed with various analytical methods, solid state nuclear magnetic resonance (SSNMR) may be looked upon as representing a middle ground between IR spectroscopy and X-ray powder diffraction methods. The former provides a measure of essentially molecular parameters, mainly the strengths of bonds as represented by characteristic frequencies, while the latter reflect the periodic nature of the structure of the solid. For polymorphs differences in molecular environment and/or molecular conformation may be reflected in changes in the IR spectrum. The differences in crystal structure that define a polymorphic system are clearly reflected in changes in the X-ray powder diffraction. Details on changes in molecular conformation or in molecular environment can only be determined from full crystal structure analyses as discussed in Section 4.4. 

Solid state nuclear magnetic resonance spectroscopy provides information on the environment of individual atoms. In essence, the change in environment of any atom can arise from two factors, which usually are not separable in the interpretation of the SSNMR spectra, but are conceptually independent. Since different polymorphs are different crystal structures, it is expected that the crystal environment of at least some atoms will differ from polymorph to polymorph (Section 2.4.2). In addition, since the molecular conformation may also vary among polymorphs (Section 5.6), the change in the environment of an atom due to conformational differences will also be reflected in the SSNMR (Levy et al. 1980 Bugay 2001 Strohmeier et al. 2001). 

Fletton, R. A., Lancaster, R. W., Harris, R. K., Kenwright, A. M., Packer, K. J., Waters, D. N. and Yeadon, A. (1986). 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. 2,1705-9. [224]... 

One technique that is becoming increasingly important for the characterization of materials is that of solid-state nuclear magnetic resonance (NMR) spectroscopy, and the application of this methodology to topics of pharmaceutical interest has been amply demonstrated.The NMR spectra of polymorphs or solvatomorphs often contains non-equivalent resonance peaks for analogous nuclei since the intimate details of the molecular environments associated with differing crystal structures can lead to perturbations in nuclear resonance energies. 

Detection and characterization of polymorphs and/or solvates rely on various experimental techniques. X-ray powder diffraction (XRPD), solid state nuclear magnetic resonance (NMR), solid state infrared (IR) and solid state Raman are useful in demonstrating differences in the solid state. Thermal analytical techniques, including differential thermal analysis (DTA), differential scanning calorimetry (DSC), and thermogravimetry (TG), are also... 

Solid-state nuclear magnetic resonance (ssNMR) spectroscopy has emerged over the years as a powerful analytical method in solid-state chemistry, especially with the advancements in techniques that allow the acquisition of high-resolution spectra [47]. In the broadest sense, ssNMR is mostly applied in characterization of crystalline materials as a means to support PXRD structural analyses by providing information on the number of molecules in the asymmetric unit or the symmetry of the occupied positions within the unit cell. Another major field of application is the structural characterization of amorphous and disordered solids where standard X-ray diffraction-based techniques fail to give detailed structural information. When discussing ssNMR in the context of API polymorphism and synthesis of co-crystals,... 

In the present paper, differences between isotactic PMEPL and the stereocomplex are examined by solid state nuclear magnetic resonance (NMR) spectroscopy. These studies reveal new polymorphic behaviour of the isotactic polymer and differences in crystal structure which depend on tacticity. Crystal structures of the various polymorphs were also determined by electron and x-ray diffraction studies. 

Solid-state nuclear magnetic resonance (NMR) is nowadays an established technique in the pharmaceutical industry, used mainly as a tool to distinguish different polymorphs. Its advantages are high versatility and resolution, which allow for studies of aU the materials in a formulation. Compared to, for example, powder XRPD and Raman scattering, spectral overlap is most often much less of a problem in NMR. Also, the primary parameter, the resonance frequency or the chemical shift, is very sensitive not only to the intramolecular structure but also to intermolecular interactions and spatial arrangement, which is the basis for polymorph selectivity. A range of nuclei can be studied for complementary information, for example, H, N, and T. 

Solid-state nuclear magnetic resonance (SSNMR) spectroscopy is a more advanced method for differentiating the polymorphs of a material. The substance is placed in a strong magnetic field and subjected to radiofrequency radiation. The individual nuclei experience different magnetic environments and thus show different changes in resonant frequency characterized by chemical shift. SSNMR spectra show sharp resonance at chemical shifts characteristic of the molecular and crystal structure. The polymorphs are differentiated by their characteristic spectra. 

Raman spectroscopy with variable temperature accessories has been valuable for probing phase transitions within solid-state pharmaceutical samples. In combination with other techniques [x-ray diffractometry, solid-state nuclear magnetic resonance (NMR), FTIR spectroscopy, and thermal analysis], the molecular basis for thermal transitions between dihydrates of carbamazepine prepared from different polymorphs of the drug were re-... 

Brittain, H. G., Morris, K. R., Bugay, D. E., Thakur, A. B. and Serajuddin, A. T. M. Solid state characterization of fosinopril sodium polymorphs. J. Pharm. Biomed. Anal. 11 1063, 1993. Geppi, M., Guccione, S., Mollica, G., Pignatello, R. and Veracini, C. A. Molecular properties of ibuprofen and its solid dispersions with Eudragit RLIOO studied by solid-state nuclear magnetic resonance. Pharm. Res. 22 1544-1555, 2005. 

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