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Home , Chirality (chemistry), Enantiomeric excess, Optical rotation, Racemic mixture, Stereoisomerism

Chemsearch Journal 2(1): 8 - 11 Publication of Chemical Society of Nigeria, Kano Chapter

CHIRAL AND ITS APPLICATION TO THE PHARMACEUTICAL INDUSTRY: A REVIEW

Mudi, S. Y. and *Muhammad, A. Department of Pure and Industrial , 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 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; 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 " (Eliel, et al., 1994; Chiral chromatography involves the separation of Moss, 1996). stereoisomers. In the case of enantiomers, these have 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, , 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 : 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 possessing n stereogenic centres 1995). has a maximum of: 2n stereoisomers, 2n–1 pairs of possessing more than one stereogenic enantiomers and n epimers. Molecular 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

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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; 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/; 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 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

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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 of the techniques in enantioresolution methods, it remains a racemate, is a common problem in stereochemical reliable separation technique. Chiral separations of research as well as in the preparation of biologically and were reported on active compounds, in particular, drugs. The problem is commercially available TLC plates with detection by that in contrast to diastereomers and all other types of densitometry, and a TLC method for the isomeric species, enantiomers, in an achiral enantioseparation of ibuprofen was used in environment, display identical physical and chemical physicochemical studies of the oscillatory instability of properties (Cox, 2001; Duff et al., 1993). profens when stored for long periods in aqueous One approach to separate enantiomers, sometimes media (Cox, 2001). A method using silica gel plates referred to as indirect enantiomeric resolution, and (-)-brucine as a chiral selector was reported for involves the coupling of the enantiomers with an the enantioseparation of ibuprofen (Cox, 2001). The auxiliary chiral reagent to convert them into TLC enantioseparation of was also diastereomers. The diastereomers can then be achieved using the macrocyclic antibiotic vancomycin separated by any achiral separation technique (Cox, as the chiral selector impregnated on silica gel plates 2001; Duff et al., 1993). (Cox, 2001). Direct enantiomeric resolutions are only feasible in chromatographic systems which contain an Applications of Chirality to Pharmaceutical appropriate chiral selector. The latter can be Industries incorporated into the stationary phase that is, chiral Every living body contains amino , , stationary phase or be permanently bonded to or and nucleic acids. All of these are important coated onto the surface of the column packing to living body and are of chiral molecules. An material, chiral bonded and chiral coated stationary interesting feature of these chiral is that phases. In all these cases it is appropriate to refer to in nature they usually exist in only one of the two the chromatographic column as an enantioselective possible enantiomeric forms. When a chemist (chiral) column. Enantioselective chromatography can synthesizes a chiral molecule in an achiral also be performed on achiral chromatographic environment using achiral starting materials, an equal columns using the required chiral selector as a chiral mixture of the two possible enantiomers (i.e. a racemic mobile phase or a chiral mobile phase additive mixture) is produced. In order to make just one (Timothy, 2006). Combinations of several chiral enantiomer, some enantioenriched starting material, selectors in the mobile phase as well as mobile and reagent, catalyst, or template must be present in the stationary phases are also feasible. In the case of reaction medium. Oftentimes, only a single enantiomer chiral stationary phases, the enantiomer that forms the of a chiral molecule is desired, as is the case when the more stable association with the chiral selector will be target molecule is a chiral drug that will be used in the more strongly retained species of the racemate. living systems. Drug molecules can be likened to tiny The enantioselectivity of the chiral chromatographic keys that fit into locks in the body and elicit a particular system is then expressed as the ratio of the retention biological response. Since the ‘locks’ in living factors of the two enantiomers. This ratio may organisms are chiral, and exist in only one of the two approach the value of the thermodynamic possible enantiomeric forms, only one enantiomer of enantioselectivity of the association of the chiral the ‘key’ molecule should be used (the mirror image of selector with the enantiomers. our car key will not start our car) (Lien et al., 2006).

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This situation occurs when the association with the enantioselectivity can depend strongly on the chiral selector governs the retention of the composition, pH and temperature of the mobile phase. enantiomers in the chromatographic system and other Therefore, in papers on enantioselective nonselective types of solute-sorbent interactions are chromatography, it is important to define these negligible (Cox, 2001; Duff et al., 1993). On the other parameters. Enantioselective chromatography and hand, a chiral mobile phase reduces the retention of capillary electrophoresis are extensively employed in the solute enantiomer which forms a stronger the analysis of the enantiomeric composition association with the chiral selector. Here again, the (enantiomeric excess, optical purity) of chiral limit for the enantioselectivity of the chiral compounds. Liquid and supercritical fluid chromatographic system is set by the chromatography are also used for the isolation of enantioselectivity of the selector-solute association in chiral compounds from racemic mixtures on a the mobile phase (Timothy, 2006). However, in the preparative scale. Enantioselective separations have majority of chiral mobile phase systems, the chiral been realized in all possible separation techniques, selectors as well as its associates with the solute including gas chromatography, column liquid enantiomers are distributed between the mobile and chromatography, thin-layer chromatography, stationary phases. The effective enantioselectivity of supercritical fluid chromatography, as well as the chromatographic system will therefore be electromigration methods, counter current liquid proportional to the ratio of the enantioselectivities of chromatography and liquid-liquid extractions the association processes in the stationary and mobile (Krstulovic, 1989; Pirkle and Pochapsky 1989; Welch, phases. Interaction of the chiral selector of the system et al., 2004). with the enantiomers of the solute results in the formation of two labile diastereomers. These differ in CONCLUSION their thermodynamic stability, provided that at least Chiral chromatography has become a preferred three active points of the selector participate in the method for rapid separation of enantiopure interaction with corresponding sites of the solute compounds in the pharmaceutical industry, largely molecule. This three-point interaction rule is generally owing to the speed with which a chromatographic valid for enantioselective chromatography, with the method can be developed and executed as well as the extension to the rule, stating that one of the required comparatively small labor requirements of the interactions may be mediated by the adsorption of the chromatographic approach. The use of chiral two components of the interacting pair onto the chromatography within the field of sorbent surface (ACS Symposium Series, 1991; Cox, can be expected to increase as the technique 2001; Duff et al., 1993; Welch, et al., 2004) . becomes more familiar to synthetic chemists. It is Because of the multiplicity and complexity of the important today to develop fast, cost effective chiral interactions of the enantiomers to be separated with chromatographic methods in research labs and the chiral selector, sorbent surface and other stimulate chemists to take advantage of available components of the chromatographic system, the total chiral stationary phases for enantiomer screening.

REFERENCES Moss G.P.; (1996); Basic Terminology of ACS Symposium Series, (1991) Chiral Separations by (IUPAC Recommendations Liquid Chromatography, edited by S. Ahuja; 1996), Pure Appl. Chem., 68, J. Chromatogr. American Chemical Society, Washington, A, 666,565-601. 2193-2222 (1996). DC, No. 471: pp 239. Pascal B., George K. E., Wen-Jian F. and Wolfgang Cox, G.B.; (2001); “Chiral chromatography: given the B,; 2000; An Overview of Affinity new techniques currently in development, the Chromatography, Humana Press. ISBN 978- use of chiral chromatography in the large- 0-89603-694-9, ISBN 978-1-60327-261-2. scale separation of racemic compounds will Pirkle W.H. and Pochapsky T.C.; (1989); eventually become commonplace”, Innovat. Consideration of chiral recognition relevant to Pharm. Technol., 1, 131–137. the liquid chromatographic separation of Duff K.J., Gray H.L., Gray R.J. and Bahler C.C.; enantiomers, Chem. Rev., 89,347-362. (1993); Chiral stationary phases in concert Schreier P., Bernreuther A. and Huffer M.; (1995); with homologous chiral mobile phase Analysis of Chiral Organic Molecules, Walter additives: Pusldpull model, Chirality, 5,201- de Gruyter 8c Co. , 331 pp. 206. Timothy J. W.; 2006; Chiral Separations; Anal. Chem. Eliel, E.L., Wilen, S.H. and Maunder, L.N.; (1994); 78. 3947, Millsaps College, 1701 North State Stereochemistry of Organic Compounds, Street, Box 150306, Jackson, Mississippi John Wiley and Sons, New York. 3921. Krstulovic A.M.; (1989); Chiral Separations by HPLC, Welch, C.J., Fleitz, F., Antia, F., Yehl, P.,Waters, R., Applications to Pharmaceutical Compounds, Ikemoto, N., Armstrong, J.D. and Mathre, Ellis Horwood, pp 548. D.J., (2004), “Chromatography as an Laurence M. H., Christopher J. M.; (1989); enabling technology in pharmaceutical Experimental : Principles process development: expedited and Practice (Illustrated ed.). WileyBlackwell. multikilogram preparation of a candidate HIV pp. 180–185. ISBN 9780632020171. protease inhibitor”, Org. Proc. Res. Dev., Lien A. N., Hua He and Chuong P. H.; (2006); Chiral 8(2), 186–191. Drugs. An Overview; International Journal of Biomedical Science 2(2), 85-100. 11