Evaluation of experimental strategies for the development of chiral chromatographic methods based on diastereomer formation

Abstract

The past two decades has seen explosive growth in the field of chirality as illustrated by the rapid progress in the various facets of this intriguing field. Firstly, it is the basic understanding of the importance of chirality and, secondly, the awareness of the therapeutic pitfalls due to failure to recognize chirality that have paved the way for a rejuvenated interest in the field. Needless to say that the impetus for chiral separation advancement and enhancement has been found to be the highest in the past decade and still continues to be an area of high focus. In this regard, both direct and indirect separation approaches have been instrumental in placing into literature stereoselective pharmacokinetic and pharmacodynamic data of plethora of drug racemates. Also, today, the cloud of uncertainty associated with the development of a chiral molecule is a thing of the past because the field is so evolved and numerous options are available for stereoselective analysis. However, the decision to advance either a single enantiomer or a racemate for development has to be made by a rational approach with adequate justification. Although indirect method of chiral separation has been well established with numerous examples of well-documented cases of stereoselective pharmacokinetic data, there is a growing need for a review that provides a strategic overview of considerations and key issues for developing chromatographic methods based on diastereomer formation. This review provides a general framework for the exploratory planning and a definitive game plan for the establishment of chiral methods based on diastereomer formation. Also, it provides an exhaustive list of applications of numerous chiral derivatization reagents that have been used in the generation of stereoselective pharmacokinetic data.

Sensitive, rapid and validated gas chromatography/negative ion chemical ionization-mass spectrometry assay including derivatisation with a novel chiral agent for the enantioselective quantification of amphetamine-type stimulants in hair☆

“…The presence of the two stereogenic centers separated by two bonds in the tagging molecule may enhance the relative differences in the chromatographic properties of their diasteromeric derivatives [25,26]. In addition, the use of heptafluorobutyryl-chains as functional groups at the chiral centers may provide a certain structural stability and conformational rigidity [25,26].…”

“…In addition, the use of heptafluorobutyryl-chains as functional groups at the chiral centers may provide a certain structural stability and conformational rigidity [25,26]. Finally, the attachment of a great number of electronegative atoms on the molecule may enhance the volatility of these derivatives and elicit a strong detector response [26,29].…”

“…As the separation of diastereoisomers on a non-chiral phase is based on the differences of the physico-chemical properties of the diastereoisomers, the choice of a chiral derivatisation reagent is of great importance for the indirect chromatographic resolution of chiral molecules [25,26].…”

Drug disposition in three dimensions: an update on stereoselectivity in pharmacokinetics

“…The merit of using a nonstereoselective assay is questionable. There are a variety of approaches available to separate and measure drug enantiomers, including chiral stationary phases or derivatization with a single enantiomer of a chiral reagent [103,104].…”

Purification, Stereoisomeric Analysis and Quantification of Sex Pheromone Precursors in Female Whole Body Extracts from Pine Sawfly Species

“…Diastereomers, such as (2S,3R,7R)-and (2S,3S,7S)-3,7-dimethylpentadecan-2-ol, have very small differences in their physical properties, and separating them directly by using standard GC chiral columns is difficult. Enantiomers, such as (2R,3R,7R)-and (2S,3S,7S)-3,7-dimethylpentadecan-2-ol, can either be separated directly on a chiral column, or indirectly by using a chiral derivatizing reagent (Gübitz and Schmid, 2001;Srinivas, 2004) to form diastereomers. Stereoisomeric analysis of secondary alcohols has been accomplished via derivatization with chiral acid chlorides, benzoyl chloride, or isopropyl isocyanate, sometimes in combination with chiral columns (Brooks et al, 1973;Doolittle and Heath, 1984;Högberg et al, 1990;Wassgren and Bergström, 1995).…”