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A Review on Chiral Chromatography and Its Application to the Pharmaceutical Industry

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A Review on Chiral Chromatography and Its Application to the Pharmaceutical Industry Chemsearch Journal 2(1): 8 - 11 Publication of Chemical Society of Nigeria, Kano Chapter CHIRAL CHROMATOGRAPHY AND ITS APPLICATION TO THE PHARMACEUTICAL INDUSTRY: A REVIEW Mudi, S. Y. and *Muhammad, A. Department of Pure and Industrial Chemistry, Bayero University, PMB 3011, Kano. *Correspondence author: [email protected] ABSTRACT Chiral chromatographic enantioseparation has been in practice by researchers. There has been a considerable interest in the synthesis and separation of enantiomers of organic compounds especially because of their importance in the biochemical and pharmaceutical industries. Often, these compounds are purified rather than being produced by chiral-specific synthesis. We herein present a general discussion that focuses on the chromatographic enantioseparation, which we hope will be useful to chromatographic and pharmaceutical industries. Keywords: Chiral chromatography, enantioseparation, pharmaceutical industry. INTRODUCTION giving differing affinities between the analytes Chromatography is the collective term for a set of (Schreier et al., 1995). laboratory techniques for the separation of mixtures. It The main goal of this review is to provide a brief involves passing a mixture dissolved in a "mobile overview of chiral separations to researchers who phase" through a “stationary phase”, which separates are versed in the area of analytical separations but the analyte from other compounds in the mixture unfamiliar with chiral separations. This review based on differential partitioning between the mobile highlights significant issues of the chiral and stationary phases. Subtle differences in a separations and provides salient examples from compound's partition coefficient result in differential specific classes of chiral selectors where retention on the stationary phase and thus effecting appropriate. the separation (Laurence and Christopher, 1989; Pascal et al., 2000). Terms and Definitions Chromatography may be preparative or analytical. The General Terms Related to Chirality Chirality; The word "chiral" comes from the ancient purpose of preparative chromatography is to separate Greek "cheir" which means "hand". The definition of the components of a mixture for further use and is chirality is something which has an object to mirror thus a form of purification technique. Analytical image relationship like a pair of hands which cannot chromatography is done normally with smaller be superimposed. These two mirror images are amounts of material and is for measuring the relative known as "enantiomers". A mixture of these proportions of analytes in a mixture (Laurence and enantiomers in equal proportions is said to be Christopher, 1989; Pascal et al., 2000). "racemate or racemic mixture" (Eliel, et al., 1994; Chiral chromatography involves the separation of Moss, 1996). stereoisomers. In the case of enantiomers, these have Isomers that possess identical no chemical or physical differences apart from being Stereoisomers: constitution but which differ in the arrangement of their three-dimensional mirror images. Conventional atoms in space, i.e. enantiomers, diastereomers, cis- chromatography or other separation processes are trans-isomers (Eliel, et al., 1994; Moss, 1996). incapable of separating them. To enable chiral One of a pair of molecular entities which separations to take place, either the mobile phase or Enantiomer: are mirror images of each other and non-superposable the stationary phase must themselves be made chiral, (Eliel, et al., 1994; Moss, 1996). Example, 2,3- dihydroxypropanal. CHO CHO H C OH OH C H CH2OH CH2OH S-Enantiomer R-Enantiomer Diastereoisomers (Diastereomers): Are a single stereogenic centre gives an epimer of the stereoisomers with a different relative configuration original structure. Inversion of all stereogenic centres and not related as mirror images. They have different gives the enantiomer. chemical and physical properties (Schreier et al., A molecule possessing n stereogenic centres 1995). has a maximum of: 2n stereoisomers, 2n–1 pairs of Molecules possessing more than one stereogenic enantiomers and n epimers. Molecular symmetry centre also exhibit diastereoisomerism because within the molecule may result in a reduction of the inverting one or more (but not all) of the centres leads numbers of different isomers due to internal to structures which do not have an object to mirror compensation (Eliel, et al., 1994; Moss, 1996). image relationship (Schreier et al., 1995). Inversion of 8 Chemsearch Journal 2(1): 8 - 11 Mudi and Muhammad Example: 2,3,4-Trihydroxybutanal; CHO CHO H OH H OH C C Enantiomer C C HO H HO H CH2OH CH2OH D 2R,3S 2S,3R ia st er eo m e r r r e e m m o r o e e e r m r e o e t e t s er s a t a i s i ia D D D CHO CHO H OH H OH C Enantiomer C C HO H C HO H CH2OH CH2OH 2S,3S 2R,3R Diastereoisomerism; Stereoisomerism other than Enantioselective chromaItography enantiomerism and cis-trans isomerism. (electrophoresis): The separation of enantiomeric Diastereoisomers (or diastereomers) are species due to the enantioselectivity of their stereoisomers not related as an object to mirror interaction with the chiral selector(s) of a images. Diastereoisomers are characterised by chromatographic (electrophoretic) system. The term is differences in physical properties, and by differences also sometimes referred to as Chiral chromatography in chemical behaviour towards achiral as well as chiral (electrophoresis) (Eliel, et al., 1994; Moss, 1996). reagents (Eliel, et al., 1994; Moss, 1996). Enantioselective column; A chromatographic column containing a chiral stationary phase is also Terms Related to the Separation Process called a chiral column (Eliel, et al., 1994; Moss, 1996). Chiral additive: This is a chiral selector which has Enantioselectivity (in chiral separations): The been added as a component of a mobile phase or preferential interaction with the chiral selector of one electrophoretic medium that change it to chiral mobile enantiomer over the other (Eliel, et al., 1994; Moss, phase (Eliel, et al., 1994; Moss, 1996). 1996). Chiral selector: The chiral component of the Enantioselectivity of a chromatographic separation system capable of interacting (electrophoretic) system: the ratio of the retention enantioselectively with the enantiomers to be factors of two solute enantiomers in a chiral separated (Eliel, et al., 1994; Moss, 1996). chromatographic (electrophoretic) system (Eliel, et al., Chiral stationary phase: A stationary phase which 1994; Moss, 1996). incorporates a chiral selector. If not a constituent of the stationary phase as a whole, then chiral selector Terms Related to the Chiral Purity of the Sample Enantiomer excess/Enantiomeric excess; for a mixture can be chemically bonded to (chiral bonded stationary of (+) and (-) enantiomers, with composition given as phase) or immobilised onto the surface of a solid the mole or weight fractions; F(+) and F(-); Where, support or column wall (chiral coated stationary F(+) + F(-) = 1. phase), or simply dissolved in the liquid stationary Thus, the enantiomeric excess (frequently this term is phase (Eliel, et al., 1994; Moss, 1996). abbreviated as e.e. (Cox, 2001)) is defined as: Enantiomeric purity see Enantiomer excess. enantiomers to the optical rotation of one pure Optical purity: the ratio of the observed optical enantiomer: See enantiomeric excess (Cox, 2001). rotation of a sample consisting of a mixture of 9 Chemsearch Journal 2(1): 8 - 11 Mudi and Muhammad Diastereoisomer excess/Diastereoisomeric In general, the use of both enantiomers in a racemic excess; this is defined by analogy with enantiomer formulation of a chiral drug may be wasteful, and excess, as D1 - D2; and the percent diastereoisomer sometimes even introduces extraneous material that excess as 100 (D1 - D2), where the mole fractions of may lead to undesired side effects or adverse the two diastereoisomers in a mixture or the fractional reactions. The importance of chirality has been yields of two diastereoisomers formed in a reaction appreciated and addressed by the pharmaceutical are D1 and D2 (D1 + D2 = 1). The term is not industry for decades. As technologies for measuring applicable if more than two diastereoisomers are and making enantiopure materials have improved, the present. Frequently this term is abbreviated to d.e. production of enantiopure pharmaceuticals has (Cox, 2001). become commonplace, with many of the top selling drugs in the world now being sold in enantiopure form. Chiral Separations Consequently, the subject of chirality and the There are series of technique used in separating pharmaceutical industry is a topic of considerable racemate below some of these methods listed recent interest and importance (Lien et al., 2006). (Timothy, 2006) . • Capillary Electrophoresis, CE. Transformations of achiral compounds • Thin-Layer Chromatography, TLC. If these reactions result in the formation of a chirality • Supercritical Fluid Chromatography, SFC. element in the molecule, the reaction product appears • Gas Chromatography, GC. to be an equivalent mixture of a pair of enantiomers, a • High-Performance Liquid Chromatography, racemate, which is optically inactive. Racemates are HPLC. also formed through racemisation of chiral • Capillary Electrochromatography, CEC. compounds. Racemates crystallize in the form of a racemic compound or, less frequently, as a Thin-layer chromatography conglomerate. Separation of the enantiomers Though TLC is used less often than other separation comprising the racemate, i.e., the resolution
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