Solid state NMR Princple and application .

SSNM is more precise, effective, and sensitive. It is one of the most powerful techniques for structural elucidating solids and other compounds. Whereas in the solution NMR, there are limitations for some solids. So SSNMR is in high demand in various areas.

1. EVALUATORY SEMINAR-I SUBJECT CODE: PQA-MQA106S Presented by : Mr. Sonawane Tejas Sanjay Reg. No : 220609018 Specialization: Pharmaceutical Quality Assurance Guided by : Dr. Muddukrishna B.S. Associate Professor Department of Pharmaceutical Quality Assurance, MCOPS, Manipal . Solid State NMR : Principle And Application

2. Introduction Solid-state nuclear magnetic resonance (NMR) spectroscopy is an atomic level method used to determine the chemical structure, three-dimensional structure, and dynamics of solids and semi-solids. NMR experiments, and data analysis approaches for investigating biological macromolecules, organic materials, and inorganic solids. Continuing development of sensitivity-enhancement approaches . Properties are the active pharmaceutical ingredient (API) physical state, which can be amorphous or crystalline, and, in the latter case, possibly in different polymorphic forms; the physical and/or chemical interactions between API and excipients in a drug formulation. 1

3. Evolution of solid-state NMR in pharmaceutical analysis Between 1995 to 1998, the traditional ‘fingerprint’ role was expanded with applications to a variety of different drug systems that displayed polymorphism, hydration and solvation as well as different salt formation behaviour . While the development of probes was interest to the ssnmr community and highly impact pharmaceuticals and modern medicinal chemistry, under high-power conditions also occurred between 1998 and 2005.  2

4. Evolution of solid-state NMR in pharmaceutical analysis 3

5. Principle of SSNMR It provides element specific atomic resolution insight into solids by exploiting atomic nuclei with magnetic dipole and electric quadrupole moments as tiny probe for the detection of the local magnetic and electric field through the detection of these field solid state NMR offers insight into the local structures , processes and dynamic in solid . When a sample containing a large ensamble of atomic nuclei is placed into magnetic field the energy of some nuclei rises and of some nuclei it falls the energy difference between the two energy level depend on the strength of the magnetic field which is a sum of external magnetic field generated by the strong magnet of the NMR spectrometer and of the local magnetic field produced by nearby electron and atomic nuclei in the solid . 4

6. Some of the most important aspects that have been tackled by SSNMR in the pharmaceutical field are Identification of different solid forms of an API in bulky samples, solid dispersions with excipient . Structural properties of API forms, involving conformational behavior , number of crystallographically inequivalent molecules in the unit cell, intra- and intermolecular interactions, internuclear distances . Stability of API forms . Structural behavior of the crystalline or amorphous forms . Dynamic behavior of API usually related to interconformational motions cross-linking degree in polymeric systems . Physical or chemical interactions between APIs and excipients in solid dispersions . Identification of impurities or degradation products . 5

7. Instrumentation 6

8. Gyrotron Oscillators The gyrotron oscillator of a DNP-NMR system generates high-power microwave radiation. An annular cathode launches the electron beam and advances it through a superconducting magnet. Transmission Line The transmission line links the gyrotron to the NMR probe, an essential instrument component of DNP-NMR spectrometer systems .  Probe The probe excites the nuclear spins and detects the NMR signal. The NMR probe is placed into the magnetic field at its center , and the sample is then inserted in the probe to conduct the study. 7

9. Roter RF coil Superconducting magnet Preamplifier Rf amplifier Rf pulse generator Roter Probe NMR spectrometer 8

10. Interpretation of SSNMR 9

11. Commonly studied nuclei in solid state NMR spectroscopy 10

12. Solid state NMR has been applied to. • ceramics • bones • semiconductors • metals and alloys • archaeological specimens • resins • minerals • biological molecules • cements aluminosilicates /phosphate • organic complexes • inorganic complexes • zeolites • polymers • mesoporous solids • microporous solids • glasses • food products • wood/cellulose/lignin 11

13. Solid-state NMR line shapes powder pattern A powder pattern arise in powdered samples where crystallites. In presence of a chemical shift anisotropy interaction, each orientation with respect to the magnetic field gives a different resonance frequency. If enough crystallites are present, all the different contributions overlap continuously and lead to a smooth spectrum. Dipolar pattern The dipolar powder pattern (also Pake pattern) has a very characteristic shape that arises when two nuclear spins are coupled together within a crystallite. The splitting between the maxima (the "horns") of the pattern is equal to the dipolar coupling constant          12

14. Nuclear spin interactions The  resonance frequency  of a  nuclear spin  depends on the strength of the  magnetic field  at the  nucleus , which can be modified by isotropic (e.g.  chemical shift , isotropic J- coupling ) and anisotropic interactions ( e.g. chemical shift anisotropy , dipolar interactions) RF Field -under experimental control for spin rotations Chemical shift interaction - Reports on local electronic environment Magnetic Dipole Dipole Interaction -Reports on the distance between two coupled spin Scalar J-coupling -Reports on chemical bonds between two spins Quadrapole coupling - Reports on the electric field gradient around the nucleus Zeeman Effect - the effect of splitting of a spectral line into several components in the presence of a static magnetic field. 13

15. Limitations SSNMR Sensitivity and resolutions the main challenge of NMR spectroscopy is its low sensitivity . A common limitation of SSNMR spectroscopy is insufficiently concentrated samples, owing to the low sensitivity of the technique and depending on the application. Magnetic field drift, which is highly detrimental to SSNMR spectra. SSNMR spectroscopy and imaging compared with other modalities is the intrinsic insensitivity of the methods . Poor resolution   Technique is nonroutine and requires a highly trained operator. 14

16. Developments and Emerging Trends in Solid State NMR of Pharmaceuticals The development and application of solid-state NMR spectroscopy (SSNMR) in pharmaceutical analysis continues to progress through research in both academic and industrial settings, particularly as laboratories continue to implement and extend recent accomplishments in the wider field of SSNMR . High Field 1H SSNMR and Homonuclear Dipolar Decoupling The use of high static fields for 1 H SSNMR enables detailed observation of effects such as hydrogen bonding in pharmaceutical materials of interest. This is particularly relevant in studies of pharmaceutical cocrystals, which generally involve a molecular complex of two or more components that when separate are also solid phases. 15

17. Dynamic Nuclear Polarization High spin polarization , typically derived from a bath of free radical electrons, is transferred to a nuclear spin bath, enhancing the difference between the nuclear energy levels and thereby producing dramatically enhanced NMR signals for detection. 16

18. Advanced solid-state NMR spectroscopy Rotational Echo Double Resonance (REDOR) To determine the dipolar interaction strength between two dilute heteronuclear spins.  Ultra Fast MAS for  1 H NMR Suppresses 1 H- 1 H homonuclear dipolar interaction and elongates 1 H - T2 relaxation time leading to enhancement of both resolution and sensitivity in 1D and multidimensional 1 H NMR 17

19. Solid state NMR spectroscopy is a powerful method in many research areas . Batteries In semi-ordered or ordered materials, such as batteries, important transport processes can be measured. Measuring the charge transport in batteries can help understand the reason for its conductivity. Polymers For polymers, order, cross-linking and other local connectivity characteristics can be observed and correlated to material properties, enabling improved control for the chemical design process. Crystallography Together with mathematical chemistry, solid state NMR has become a key supplementary tool for crystallography. 18

20. Applications It is an analytical chemistry It is used in research for determining the content and purity of a sample as well as its molecular structure. SSNMR spectroscopy is routinely used by chemists to study chemical structure using simple one-dimensional techniques. Two-dimensional techniques are used to determine the structure of more complicated molecules. These techniques are replacing x-ray crystallography for the determination of protein structure. Other scientists have developed NMR methods-of measuring diffusion coefficients. 19

21. New Horizon : NMR spectroscopy to play an increasing role in discovering new materials, in addition to characterizing materials . Pharmaceuticals assisting in the understanding of chemical properties and therapeutic efficacy during drug development and further advancing the overall practice of medicine. In chemical biology, increasing interest in mapping brain functions invites the application of solid-state NMR . studying protein–RNA interactions; the structurally poorly understood y disease-significant glycan layers of pathogens and cancer cells . Drug discovery and development relies on the understanding of the intricate structures of chemical compounds. 20

22. Conclusion 21 . SSNM is more precise, effective, and sensitive. It is one of the most powerful techniques for structural elucidating solids and other compounds. Whereas in the solution NMR, there are limitations for some solids. So SSNMR is in high demand in various areas.

23. References 22 Charpentier -CEA Saclay T. An introduction to Solid State NMR and its Interactions. 2009. 2. Reif B, Ashbrook SE, Emsley L, Hong M. Solid-state NMR spectroscopy. Vol. 1, Nature Reviews Methods Primers. Springer Nature; 2021. 3. Xu J, Wang Q, Li S, Deng F. Solid-State NMR Principles and Techniques. In 2019. p. 1– 55. 4. Reif B, Ashbrook SE, Emsley L, Hong M. Solid-state NMR spectroscopy. Vol. 1, Nature Reviews Methods Primers. Springer Nature; 2021. 6. Gerhard Wider: Technical aspects of NMR spectroscopy with biological macromolecules Layout of a high resolution NMR spectrometer. 7. Innovation with Integrity. 8. Ashbrook SE, Griffin JM, Johnston KE. Recent Advances in Solid-State NMR Spectroscopy.