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  • Use of NMR in Impurity Profiling for Pharmaceutical Products

    Nuclear Magnetic Resonance Spectrometry (NMR) is the best instrument technique in the pharmaceutical for the identification and characterization of impurities.

    NMR is also called proton NMR since it gives structural clarification based on the number of proton pairs present in the structure. The key use of NMR spectroscopy is that it gives identification and molecular structure elucidation of compounds of interest. It also offers indications about the exact bonding of molecules in the structural evidence, configuration, atomic integration, and stereochemistry. Hydrogen is the very easy, reactive, and most regularly detected nucleus.

    Principle:

    The principle is based on nuclei having spins and all atomic nuclei are electrostatically charged. The interaction spin of nuclei with magnetic field subsequently absorption of radio frequency. Magnetic measurement depends upon the spin of unpaired electrons whereas NMR measures magnetic moment caused by the spin of protons and neutrons.

    Uses of NMR:

    NMR spectroscopy has numerous uses in pharmaceuticals. Method development and sample preparation are very easy also it’s a non-destructive nature technique. NMR spectroscopy is a rugged and quasi-universal detector that is sensitive to low molecular weight organic compounds.

    NMR spectroscopy sensitivity improved by the following advancements in the technology:

    1. Increase in sample concentration and processing with higher sample quantity,
    2. Excessive magnetic field power i.e. shielded and progressively sturdier high-field magnets,
    3. Latest sensors such as cryogenic probes,
    4. Improved sensitivity to the nanomolar range,
    5. Solvent suppression techniques,
    6. Small volume or microtubes and micro coil capillary assembly,
    7. Use of NMR crystallography
    8. Use of fluorine NMR and Nitrogen NMR spectroscopy,
    9. Nanoparticle (Monolayer-protected gold nanoparticles) assisted NMR spectroscopy,
    10. Maximum number of scans with advanced data processing,
    11. Methyl TROSY-spectroscopy is useful for higher molecular weight complexes and complicated biological structures.

    The utmost advantageous trials for a spectral assignment are COSY and TOCSY (homo nuclear correlation), NOESY and ROESY (nuclear Over Hauser effect), HSQC, HMBC, and HMQC (heteronuclear single or multiple quantum coherence spectroscopy).

    The main applications of NMR are structural clarification of small organic molecules. Quantitative HNMR spectroscopy is very much useful in the purity calculation of small organic molecules also enhancing the identification of potential impurities. It is also a powerful tool for the identification and elucidation of the chiral compound and for the discrimination of diastereomers.

    NMR spectroscopy is found to be the most popular technique for the identification of unknown impurities in pharmaceutical products. NMR spectroscopy is generally used to acquire structural information. NMR is a very useful technique to get evidence about the structure of the compound in a combination of impurities. The main application of NMR is the quantitative determination of the low level of impurities.

    References:

    1. Nuclear Magnetic Resonance Spectrometry, An Introduction to Principles, Applications and Experimental Methods, Joseph B. Lambert, Eugene P. Mazzola,
    2. Structure Elucidation by NMR in Organic Chemistry, A Practical Guide, Eberhard Breitmaier,
    3. Various Aspects of the Estimation of Impurities in Drugs, Sandor Gorog,
    4. G.F. Pauli, T. Gödecke, B.U. Jaki, D.C. Lankin, Quantitative1H NMR. Development and potential of an analytical method: an update,
    5. U. Holzgrabe, Quantitative NMR spectroscopy in pharmaceutical applications,
    6. T.J. Wenzel, C.D. Chisholm, Using NMR spectroscopic methods to determine enantiomeric purity and assign absolute stereochemistry,
    7. Principles of NMR By John C. Edwards, Ph.D.,
    8. Malz, F. Quantitative NMR in the solution state NMR. In NMR Spectroscopy in Pharmaceutical Analysis; Holzgrabe, U., Wawer, I., Diehl,
    9. Ahuja S (1998) Impurities Evaluation of Pharmaceuticals. Marcel Dekker, New York,