Overview & Determination of Enantiomeric Impurities

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Overview and Determination of Enantiomeric Impurities
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Structures of a) ofloxacin (R-form)

b) levofloxacin.



Introduction

Most of the drugs substance single enantiomer is active. In such cases the inactive enantiomer is considered as an impurity, e. g. If Dextro form is active then in this case levo form is considered as an impurity.

An enantiomer can be named by the direction in which it rotates the plane of polarized light. An optical isomer can be named by the spatial configuration of its atoms. Clockwise rotation of the light traveling toward the viewer is labelled (+) or R (in Latin Rectus for right) also termed as d-isomer i.e. dextrorotatory enantiomer. Its mirror-image is labelled (−) or S (in Latin Sinister for left) also termed as l-isomer i.e. levorotatory enantiomer. 

The R / S system is an important nomenclature system for representing enantiomers. This method labels each chiral centre R or S according to a system by which its substituents are each assigned a priority, according to the Cahn–Ingold–Prelog priority rules (CIP), based on atomic number.

Enantiomeric Impurities

Chiral molecules are normally called enantiomers. Chiral separation plays a very important role in the modern pharmaceutical analysis. Separation and identification of chiral impurities is very crucial. As per ICH guidelines, only active enantiomer of the drug has to be marketed, so there is attention on separation of the inactive enantiomer which acts as a chiral impurity. The impurities present in the enantiomers having similar chemical structure but different spatial orientation and pose various toxic adverse effects on bioavailability and efficacy. Hence it is essential to separate these impurities.

Presently there are more than 50% of the drug substances were chiral compounds. The enantiomers of chiral drugs can differ in their interactions with enzymes, proteins, receptors, and other chiral molecules, which result in differences in biological activity. The effect on biological activity can be further extended to variations in pharmacology, pharmacokinetics, metabolism, and toxicity. The body may metabolize each enantiomer by separate pathways to generate differing pharmacological activity. Therefore, one isomer may produce the desired therapeutic effect while another may be inactive or produce adverse effects.

Analytical Methods for Determination of Enantiomeric Impurities:

To ensure that chiral impurities are adequately controlled, suitable analytical methods are required. Several analytical techniques have been used for the determination of chiral impurities. Physicochemical methods that can be used to provide information about chiral drugs are listed below.

  • High-Performance Liquid Chromatography (HPLC)

Chiral HPLC method has recognized to be one of the finest methods for chiral separation, and quantification of enantiomers of chiral drugs. Chiral HPLC may be used to separate mixtures of enantiomers directly without forming diastereoisomeric derivatives. Separations can be achieved through the use of chiral stationary phases, or chiral mobile phase in combination with achiral columns.

  • Gas Chromatography

Stationary phases altered with chiral agents are available for the separation of enantiomers.

  • Nuclear Magnetic Resonance (NMR)

NMR is a suitable instrument for the determination of enantiomeric composition. This is achieved by making the NMR signals for the protons of the enantiomers non-equivalent by the use of chiral lanthanide shift reagents, chiral solvating or derivatizing agents.

  • Capillary electrophoresis (CE)

Capillary electrophoresis is fast method uses cyclodextrins and substituted cyclodextrins as the most common chiral selectors.

  • Polarimeter

This method can be used to distinguish between enantiomers because they rotate the plane of polarized light in opposite directions but in equal amounts.

  • X-ray Diffractometer

X-Ray diffractometer in the solid state could be used for the estimation of complete conformation of molecules and to differentiate conglomerates from racemic compounds.

  • Melting Point

The melting points may be used in characteristic, specific enantiomers from the race-mate.

Conclusion

Maximum drug substances are chiral in nature hence it is necessary to develop a suitable enantiomeric method. Enantiomerically only active enantiomer drug compounds will be one of the standards for drug substances to be accepted by the US Food and Drug Administration and as per ICH guideline. Chiral analyses play an important role in the pharmaceutical business and there is growing requirement for a significant means of chiral analysis for quality control and detection of trace enantiomeric impurities particularly when it is verified to be toxic.

References:

  1. ICH, Q3A(R2) Impurities in New Drug Substances,
  2. ICH, Q3B(R2) Impurities in New Drug Products,
  3. ICH, Q2(R1) Validation of Analytical Procedures: Text and Methodology,
  4. Relationship between physical properties and crystal structures of chiral drug’’ Z.jane Li and David J.W.Grant,
  5. Encyclopedia of pharmaceutical technology,
  6. Tsukamoto M, Kagan HB (2002) Recent Advances in the Measurement of Enantiomeric Excesses,
  7. https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents, Guidance for Industry: Stereochemical Issues in Chiral Drug Development A.J.Romero and C.T.Rhodes,

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