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USE OF MAGNETIC RESONANCE SPECTROSCOPY IN PHARMACEUTICALS

Updated on February 24, 2015

THE USES OF NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY FOR POLYMORPH DETECTION IN PHARMACEUTICALS

Since drugs in clinical use are mostly natural or synthetic products, Nuclear Magnetic Resonance (NMR) spectroscopy is used to elucidation and confirmation of structures. Introduction of Nuclear Magnetic Resonance Spectroscopy for polymorph detection in pharmaceuticals, over the past years, helps in the determination of the impurity profile of a drug. Consequently, medical researchers can characterize the drug products. Further, the method helps in investigating drug metabolites in the body fluids. For the pharmaceutical technologists, solid-state measurement provides detailed information about polymorphism of drug powder and confirms drug in tablets (Geppi, Borsacchi, Mollica, & Veracini, 2009 p 1). Micro-imaging assists in studying tablet dissolution. Studies on whole body imaging create important tools in clinical diagnostics. The paper will look into the use of Nuclear Magnetic Resonance Spectroscopy for polymorph detection in pharmaceuticals.

Multiple applications

The main function of Nuclear Magnetic Resonance in pharmaceutical analysis is to elucidate and confirm the structures of substances that relate to drug (Kamienska-Trela, 2011). Nuclear Magnetic Resonance helps in the study drug contaminants and impurities including synthetic precursors, solvents, decomposition products and synthesis intermediates. In the natural product case, Nuclear Magnetic Resonance assists in determining the identity of co-extractives. The NMR plays a role in studying of drug metabolism where it works to identify and quantify of many metabolites.

In many of the cases, it is possible to deduce full chemical structures from Nuclear Magnetic Resonance data. The data includes 2D spectra where appropriate. FT-IR is another spectroscopic technique but applies for chemical structures confirmation where appropriate library spectrum exists. According to Shah, Kakumanu & Bansal, (2006 95), some pharmaceuticals exist in more than two polymorphs (crystal forms) that may have distinct FT-IR spectra. The spectrum of appropriate polymorph may be missing from the library. Polymorphs consist of the same chemical composition but differ in their geometrical and packaging arrangement. This may affect the pharmaceutically important physical and chemical properties such as the chemical reactivity, melting point, dissolution rate, solubility, powder flow and tableting behavior. Interactions occurring between nuclei in the molecule do not occur between molecules. The opening up of the potential use Nuclear Magnetic Resonance on mixtures as well as pure compounds means that NMR can become a rapid screening method. It helps in the fight against counterfeit pharmaceuticals.

Counterfeit pharmaceutical business is on the rise according to the European Commission. The less regulated economies such as China and India are leading in the rapid and expanding business. These economies, United Arab Emirate, China and India account for more than eighty percent of the counterfeit medicine in transit to Europe (WHO, 1999). Counterfeiting copies drug products with the actual ingredients but not in the correct amounts. They may contain toxic chemical endangering unsuspecting consumers. Counterfeit drugs never offer the intended medical benefit. There are techniques used to detect counterfeit drugs. Other than Nuclear Magnetic Resonance, techniques based on Raman or Infra-red spectroscopy are useful in examining paperwork, and packaging suspected to be counterfeit.

Initial screening

The Nuclear Magnetic Resonance is an essential tool in profiling suspected counterfeit products. Authorities can always compare genuine item and counterfeit. It is always worthwhile to have knowledge about the nature of the fake products. Counterfeits are easy to identify through naked eyes. However, the microscopic screening is vital perhaps to study parameters. This may include quality of intagliation on tablet, the packaging card thickness, printing on the package or the filler materials. Microscopic use is a powerful analytical analysis technique to look into the elements and drug coating composition. Further, microscopic screening investigates microstructure of powders to assist in differentiating genuine and counterfeit drugs in circulation (Chadha & Bhandari, 2014 p82)

Identifying the unknown contaminant starts with the creating high-resolution H-NMR spectrum. The chemical integration and shifts reveal the relative protons number (olefinic, aromatic, aliphatic). Coupling of the patterns suggests the protons relative proximity. Nuclear Magnetic Resonance and Distortionless Enhancement by Polarization Transfer (DEPT) spectra help in obtaining the different numbers of carbons and protons attached to each. Combination of carbon and proton data is adequate to solve the structures of the unknown (Geppi, Borsacchi, Mollica, & Veracini, 2009 p 89). Where this is not achieved, advanced Nuclear Magnetic Resonance experiments carried out can establish the proximity and connectivity of atoms in the molecule, thus defining the structure. Where Nuclear Magnetic Resonance invisible nuclei such as oxygen and chlorine be present, the IR data or the MS data will be helpful to complete the structure. However, the location of such heteroatom can be deduced from the Nuclear Magnetic Resonance chemical shift of the carbon and its associated protons attached to it.

It is very possible for unknown chemicals (appears as impurities) to be present in genuine products. A 1H- Nuclear Magnetic Resonance spectrum taken for a drug indicates impurities (Geppi, Borsacchi, Mollica, & Veracini, 2009 p 44). Additional, analysis peaks will indicate impurities and further examination often permits identification. Integration deduces impurity presence percentage or compares relative peak heights. So long as each impurity gives unique resonance peaks, a single spectrum can quantify great number of impurities. At times, it is hard to identify impurities without proper examination. However, it is possible to separate such impurities from the drug leading to the formation the required Nuclear Magnetic Resonance techniques to identify the foreign materials. Alternatively, when HPLC methods exist to separate the impurity, the Nuclear Magnetic Resonance may collect and analyze the eluted peak. The Nuclear Magnetic Resonance in conjunction with other analyzing techniques like the HPLC and MS proves to be helpful (GAO, 1996 p1095). The method will continuously ensure the purity and safety of newly developed and existing pharmaceuticals. It is necessary to verify the Polymorphism and detect the polymorphic changes in drugs.

Optimal purity

The absence or presence of optical isomers in drugs is very critical. The Nuclear Magnetic Resonance offers means to determine the optical purity for many drug products. Many of the earlier studies on optical isomers in drugs used the lower-field-strength instruments. The technique used the CLSRs (Chiral Lanthaniside Shift Reagents). According to Geppi, Mollica, Borsacchi, & Veracini, 2008 p 202 the quantification limit was 1-5%. Latest studies indicate that using the CLSRs, and the higher-field-strength instruments provide great sensitivity. The detection limits are less than 0.1% in some cases. These results make Nuclear Magnetic Resonance an attractive technique in determining whether the pharmaceutical products meet the required standards set by the different countries pharmacopoeias. The Food and Drug Administration in the United States, for instance, recognizes the essence of polymorphs. The FDA requires appropriate analytical procedures used in guiding drugs and detecting polymorphic, amorphous or hydrated forms of the drug.

Conclusion

Solid-state Nuclear Magnetic Resonance Spectroscopy is a powerful technique used in analyzing the structural, chemical and physical properties of pharmaceuticals solids. The technique is non-invasive and non-destructive (Tishmack, Bugay, & Byrn, 2003)pg 92. Additionally, the samples set for analysis requires no special preparation. In comparison to other solid-state characterization techniques, the Nuclear Magnetic Resonance Spectroscopy offers vital information about the local environment in crystal packing and mobility in pharmaceuticals solids.


References

CHADHA, R., & BHANDARI, S. (2014). Drug-excipient compatibility screening-Role of

thermoanalytical and spectroscopic techniques. Journal of Pharmaceutical and Biomedical Analysis. 87, 82-97.

GAO P. (1996). Determination of the composition of delavirdine mesylate polymorph and

pseudopolymorph mixtures using 13C CP/MAS NMR. Pharmaceutical Research.13, 1095-104.

GEPPI, M., BORSACCHI, S., MOLLICA, G., & VERACINI, C. A. (2009). Applications of

Solid-State NMR to the Study of Organic/Inorganic Multicomponent Materials. Applied Spectroscopy Reviews. 44, 1-89.

GEPPI, M., MOLLICA, G., BORSACCHI, S., & VERACINI, C. A. (2008). Solid-State NMR

Studies of Pharmaceutical Systems. Applied Spectroscopy Reviews. 43, 202-302.

KAMIENSKA-TRELA, K. (2011). Nuclear magnetic resonance. Volume 40 Volume 40.

London, Royal Society of Chemistry. http://dx.doi.org/10.1039/9781849732796.

SHAH, B., KAKUMANU, V. K., & BANSAL, A. K. (2006). Analytical techniques for

quantification of amorphous/crystalline phases in pharmaceutical solids. Journal of Pharmaceutical Sciences. 95, 1641-1665.

TISHMACK, P. A., BUGAY, D. E., & BYRN, S. R. (2003). Solid-state nuclear magnetic resonance spectroscopy—pharmaceutical applications. Journal of Pharmaceutical Sciences. 92, 441-474.

WORLD HEALTH ORGANIZATION. (1999). Counterfeit drugs: guidelines for the

development of measures to combat counterfeit drugs. Geneva, Switzerland, Dept. of Essential drugs and Other Medicines, World Health Organization.

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