Abstract:

Chiral chromatography has recently become a preferred method for rapidly separation of enantiopure compounds in the pharmaceutical industry. Chiral chromatographic enantioseparation has been practiced for a decade by researchers. In the current context there has been considerable interest in the synthesis and separation of enantiomers of organic compounds especially because of their importance in the biochemistry and pharmaceutical industry. Pharmaceutical industry is looking for advances in equipment and stationary phases, but more importantly, to an increasingly widespread realization of the cost-effectiveness of this technique. In many instances, developing and executing a chromatographic enantioseparation is faster and less labour-intensive than more traditional approaches for enantiopurity. Consequently, chiral chromatography is increasingly used in place of, or in conjunction with, the more traditional methods of organic synthesis. We herein present a general discussion that focuses on some of the current areas of interest in the field of chromatographic enantioseparation, which we hope will be useful to chromatographer and pharmaceutical industries.

Keywords: chiral drugs; analysis; chiral compounds; chiral separation; chiral terms; enantioselective; detectors; application

1. Introduction:

There are several ways that a molecule can display "handedness" (chirality).Firstly if an atom such as carbon, silicon, nitrogen, phosphorus or sulphur forms a tetrahedral structure with four different groups attached then two non-superimposable mirror images will be formed. The most common and simplest example of this is with carbon. If you look at the diagram below you will see that there is no way that you can put the two molecules on top of one another and have all the groups lined up. One molecule is the mirror image of the other one. This is an example of a molecule with a chiral centre.

2. Some terms and definitions are used in chiral chemistry and chromatography:

Chirality: The word "chiral" comes from the ancient Greek "cheir" which means "hand".  The definition of chirality is something which has a mirror image, but cannot be superimposed.  These two mirror images are known as "enantiomers".  They are, unsurprisingly, left and right "handed".  A mixture of these enantiomers in equal proportions is known as "racemic", but of course they can be separated in other word if the compound is superposable on its mirror image the object said to be as a chiral.

Diastereoisomers (Diastereomers): Diastereoisomers are stereoisomers with a different relative configuration and are not related as mirror images. They have different chemical and physical properties. Molecules possessing more than one stereogenic centre also exhibit diastereoisomerism because inverting one or more (but not all) of the centres leads to structures which do not have a mirror image relationship with the original. Inversion of a single stereogenic centre gives an epimer of the original structure. Inversion of all stereogenic centres gives the enantiomer. A molecule possessing n stereogenic centres has a maximum of: 2n stereoisomers, 2n–1 pairs of enantiomers and n epimers Molecular symmetry within the molecule may result in a reduction of the numbers of different isomers due to internal compensation. Example:2,3,4-Trihydroxybutanal (Fig.1)

Enantiomers: An enantiomer is one of a pair of stereoisomers that are related as non–superimposable mirror images. Enantiomerism commonly results from the presence of one or more stereogenic centres in a molecule but may also occur in orthogonal structures (allenes, hindered biaryls), helical structures (E–cyclic alkenes, helicenes) and extended tetrahedra (differentially substituted adamantanes). Such molecules are chiral and display identical chemical and physical properties in an achiral environment. However, opposite enantiomers will react at different rates with a single enantiomer of a reagent. A solution of a single enantiomer will rotate the plane of plane–polarised light and is referred to as optically active; although this physical property cannot be directly related to absolute configuration of the molecule. An enantiomer is given the prefix (+)– if the rotation is clockwise (dextrorotatory) and (–)– if the rotation is anticlockwise (levorotatory).

Fig.2  example of enantiomers dl –menthol (+): if the rotation is clockwise   (dextrorotatory) and (–): if the rotation is anticlockwise (levorotatory).

 Stereoisomers: Stereoisomers are molecules with identical connectivity but different spatial arrangements of their constituent atoms that cannot be interconverted by bond rotation.

Fig 3 example of Stereo isomers

3. Terms used in the chiral chromatography

Chiral stationary phase: A stationary phase which incorporates a chiral selector. If not a constituent of the stationary phase as a whole, the chiral selector can be chemically bonded to (chiral bonded stationary phase)or immobilized onto the surface of a solid support or column wall (chiral coated stationary phase),or simply dissolved in the liquid stationary phase.

Chiral selector: The chiral component of the separation system capable of interacting enantioselectively with the enantiomers to be separated.

Chiral additive: The chiral selector which has been added as a component of a mobile phase or electrophoretic medium.

Chiral mobile phase:A mobile phase containing a chiral selector.

4. Application of chirality to pharmaceutical industries:

Every living body contains amino acids, sugars, proteins and nucleic acids. All of these are important to living body is of chiral molecule. An interesting feature of these chiral biomolecules is that in nature they usually exist in only one of the two possible enantiomeric forms. When a chemist synthesizes a chiral molecule in an achiral environment using achiral starting materials, an equal mixture of the two possible enantiomers (i.e. a racemic mixture) is produced. In order to make just one enantiomer, some enantioenriched starting material, reagent, catalyst, or template must be present in the reaction medium. Oftentimes, only a single enantiomer of a chiral molecule is desired, as is the case when the target molecule is a chiral drug that will be used in living systems. Drug molecules can be likened to tiny keys that fit into locks in the body and elicit a particular biological response. Since the ‘locks’ in living organisms are chiral, and exist in only one of the two possible enantiomeric forms, only one enantiomers of the ‘key’ molecule should be used (the mirror image of our car key will not start our car).

In general, the use of both enantiomers in a racemic formulation of a chiral drug may be wasteful, and sometimes even introduces extraneous material that may lead to undesired side effects or adverse reactions. The importance of chirality has been appreciated and addressed by the pharmaceutical industry for decades. As technologies for measuring and making enantiopure materials have improved, the production of enantiopure pharmaceuticals has become commonplace, with many of the top selling drugs in the world now being sold in enantiopure form. Consequently, the subject of chirality and the pharmaceutical industry is a topic of considerable recent interest and importance.

Transformations of achiral compounds. If these reactions result in the formation of a chirality element in the molecule, the reaction product appears to be an equivalent mixture of a pair of enantiomers, a racemate, which is optically inactive. Racemates are also formed through racemisation of chiral compounds. Racemates crystallize in the form of a racemic compound or, less frequently, as a conglomerate. Separation of the enantiomers comprising the racemate, ie., the resolution of the racemate, is a common problem in stereochemical research as well as in the preparation of biologically active compounds, in particular, drugs. The problem is that in contrast to diastereomers and all other types of isomeric species, enantiomers, in an achiral environment, display identical physical and chemical properties.

One approach to separate enantiomers, sometimes refened to as indirect enantiomeric resolution, involves the coupling of the enantiomers with an auxiliary chiral reagent to convert them into diastereomers. The diastereomers can then be separated by any achiral separation technique.

Direct enantiomeric resolutions are only feasible in chromatographic systems which contain an appropriate chiral selector. The latter can be incorporated into the stationary phase that is chiral stationary phase or be permanently bonded to or coated onto the surface of the column packing material, chiral bonded and chiral coated stationary phases. In all these cases it is appropriate to refer to the chromatographic column as an enantioselective (chiral) column. Enantioselective chromatography can also be performed on achiral chromatographic columns using the required chiral selector as a chiral mobile phase or a chiral mobile phase additive. Combinations of several chiral selectors in the mobile phase  as well as mobile and stationary phases  are also feasible. In the case of chiral stationary phases, the enantiomer that forms the more stable association with the chiral selector will be the more strongly retained species of the racemate. The enantioselectivity of the chiral chromatographic system is then expressed as the ratio of the retention factors of the two enantiomers. This ratio may approach the value of the thermodynamic enantioselectivity of the association of the chiral selector with the enantiomers. This situation occurs when the association with the chiral selector governs the retention of the enantiomers in the chromatographic system and other, nonselective types of solute-sorbent interactions are negligible. On the other hand, a chiral mobile phase reduces the retention of the solute enantiomer which forms a stronger association with the chiral selector. Here again, the limit for the enantioselectivity of the chiral chromatographic system is set by the enantioselectivity of the selector-solute association in the mobile phase. However, in the majority of chiral mobile phase systems, the chiral selectors as well as its associates with the solute enantiomers are distributed between the mobile and stationary phases. The effective enantioselectivity of the chromatographic system will therefore be proportional to the ratio of the enantioselectivities of the association processes in the stationary and mobile phases. Interaction of the chiral selector of the system with the enantiomers of the solute results in the formation of two labile diastereomers. These differ in their thermodynamic stability, provided that at least three active points of the selector participate in the interaction with corresponding sites of the solute molecule. This three-point interaction rule is generally valid for enantioselective chromatography, with the extension to the rule, stating that one of the required interactions may be mediated by the adsorption of the two components of the interacting pair onto the sorbent surface .

Because of the multiplicity and complexity of the interactions of the enantiomers to be separated with the chiral selector, sorbent surface and other components of the chromatographic system, the total enantioselectivity can depend strongly on the composition, pH and temperature of the mobile phase. Therefore, in papers on enantioselective chromatography, it is important to define these parameters. Enantioselective chromatography and capillary electrophoresis are extensively employed in the analysis of the enantiomeric composition (enantiomeric excess, optical purity) of chiral compounds. Liquid and supercritical fluid chromatography are also used for the isolation of chiral compounds from racemic mixtures on a preparative scale. Enantioselective separations have been realised in all possible separation techniques, including gas chromatography, column liquid chromatography, thin-layer chromatography, supercritical fluid chromatography, as well as electromigration methods, counter current liquid chromatography and liquidliquid extractions. Numerous review papers and special monographs describe the technical details as well as the achievements and potential of these important modern separation techniques.

5. Chiral  stationary phases :

 The term chiral stationary phase does not necessarily mean that the stationary phase itself is chiral (although in practice it usually is) but that the stationary phase is used to separate chiral substances. Two substances can only be separated if their standard energy of distribution differ, which means that their standard enthalpies and/or their standard entropies of distribution also differ. In general, the standard enthalpy reflects the net difference in the interactive forces on the molecule in the two phases (polar, dispersive and ionic interactive forces) whereas the standard entropy reflects their spatial disposition and, thus, their probability and proximity of interaction. Thus, for any chiral separation the stationary phase is chosen such that the spatial arrangement of its composite atoms results in the probability or proximity of interaction differing significantly between the two enantiomers to be separated. In practice this usually mans that the stationary phase itself is also chiral and, in fact, the first chiral separations in gas chromatography were achieved by using and enantiomer of an amino acid as the stationary phase.

In the GC analysis of enantiomeric compounds on nonracemic or achiral stationary phases requires the use of enatiopure derivatization reagents. These reagents generally target one specific functional group to produce diastereomers of each of the enantiomeric analytes. From the resulting chromatograms, calculations are conducted to determine the enantiomeric concentration of the analyte.

GC determination of enantiomeric purity is facilitated by using enantiopure derivatization reagents. These derivatization reagents produce covalent diastereomers of the enantioenriched analytes. TPC (N-TFA-L-Propyl Chloride) and MCF (1R, 2S, 5R-L-7-Menthylchloroformate trifluoracetyl) are the most commonly used derivatization reagents

Separation of chiral compounds typically is performed using by capillary electrophoresis and chromatographic techniques such as HPLC, GC, and SFC. Scientists also might use a variety of methods to analyze stereoisomers such as polarimetry, NMR,  calorimetry, and LC/MS/MS.

In HPLC, there are five types of chiral stationary phases including macrocyclic glycopeptides, cyclodextrins, cellulose/amylose, small molecule, and proteins, which are typically bonded to silica. The elution order of chiral compounds depends upon the formation of transient diastereoisomers due to the interaction with the column packing. The compound that forms the less stable diastereoisomer will elute first.

Chiral chemists can use different solvents, additives, and alter parameters like pH to increase resolution. Temperature plays a key role in separation of chiral compounds. Generally, if the temperature is low enough, it will increase the chiral recognition. However, a temperature that is too low will affect the kinetics of the compound and cause peaks to broaden. Depending upon the class of compounds to be separated, there often is a temperature standard that scientists follow.

The market for HPLC chiral columns is about $30–50 million. The pharmaceutical industry is responsible for the majority of the market and is expected to drive future growth. Applications in agriculture and chemical markets also fuel demand.

6. Commonly detectors used in chiral chromatography:

Chiral chromatography is highly dependent on the column, which has seen many recent improvements, and the detector. However following types of commercial chiral detectors are available. Therefore only the concepts as there relate to liquid chromatography detectors are highlighted here.

Polarimeter-1 (PLR-1)

Normal light waves vibrate in many planes; however plane polarized light is generated when normal light is passed through an optical polarizing filter. This effect results in a light beam emerging that vibrates in a single plane (linearly polarized). A compound is optically active if linearly polarized light is rotated when passing through it.

The degree of rotation is dependent on both the concentration of a chiral compound and its molecular structure.

The specific rotation of the molecule, not the absorption characteristics, is what determines the signal strength using the polarimeter. The Polarimeter-1 uses a diode laser at 670 nm as the light source.

Polarimeter-2 (PLR-2)

The Polarimeter-2 detector is similar in design and function to the Polarimeter-1, with the exception of a light emitting diode (LED) at 426 nm being the light source and having a second polarizing filter present in-line after the sample. The choice of the blue wavelength is based on the plain curve, The normal behaviour of optical rotation dispersion (the dependence of rotational strength of optically active molecules on the wavelength of light used for the measurements) in the absence of chromophores or in spectral regions that are distant from absorption bands.

The angle of rotation, as a function of wavelength, is greatest at shorter wavelengths Therefore, to optimize the chiral response in a molecule, lower source wavelengths yield stronger responses.

Optical Rotary Dispersion (ORD) Detector:

The ORD detector is similar in design and function to the Polarimeter-1; however the light source for this detector is a Xe-Hg lamp, which is readily available and utilizes the strong line emissions of Hg at 365 nm, which can be tuned to cover a spectral range of 350 to 900 nm, if required. This detector utilizes the lowest wavelength of the polarimeters (365 nm vs. 426 and 670 nm) and therefore one would expect that this detector would give the strongest signal, based on Drude’s equation. However, the analog signals collected from these detectors were dependent on the gain set for each detector.

The Detectors: Circular Dichroism (CD)

When an optically active compound preferentially absorbs right or left circularly polarized light, the difference between the right and left absorbances [A(r) – A(l)] (often a very small value) is recorded as the CD signal. As with UV absorbance, the CD signal is wavelength dependent. A molecule should have a chromophore with absorption in the range of 200 to 420 nm to have strong CD signal.

7. Future trends:

With the move to green chemistry gaining more momentum every day, the "clean" technique of Chiral HPLC continues to grow in popularity. Once considered too costly to be practical in many laboratories, Chiral technologies are becoming cheaper and more effective than ever.

With pharmaceutical companies building up their drug candidate pipeline, the need for faster analysis and higher column resolving power led to the development of chiral columns packed with 3-µm particles. To address the need for robust and stable stationary phases to carry out challenging separations, immobilized chiral columns have also been developed.  People are buying more SFC and fewer chiral columns! Recent weakness in the chiral column business has been attributed to the benefits of SFC, which is far more gentle on the chiral stationary phase. More and more prep applications are being developed in SFC instead of HPLC. With the introduction of more and more sources of chiral phases, the costs are beginning to decline.

Recently, there has been a trend in having immobilized chiral stationary phases (CSPs). Previously, most chiral stationary phases were coated which meant that there were limitations in the types of solvents that could be used. With the newer immobilized phases, widely varying solvent polarities can be used to develop and optimize chiral methods. There has also been a trend in the use of smaller particles analogous to other modes of HPLC. Although sub-two micron CSPs are not yet widely available, 3-µm columns are and they allow faster separations with good resolution. Another trend has been in the use of supercritical fluid chromatography for the separations of chiral compounds. This trend does put some stress on CSPs because supercritical fluids can play havoc on some of the coated phases. Another trend is the development of newer wide-range phases that allow most enantiomeric separations to occur on just a few CSPs. Only a few years ago, users had to purchase a dozen or so expensive chiral columns in order to find one that might do the job.

8. Future of Chiral HPLC:

Although the market for biological drugs is growing rapidly, the traditional small-molecule drugs are entering clinical trials in much greater numbers than biologics. Clearly, use of chiral chromatography, especially for preparative separations, will continue to grow. Furthermore, chromatography, being the fastest route to market, will be viewed as part of drug production development in the future.

A recent poster by Dr. Ziqiang Wang at Merck presented at Pittcon 2008 showed chiral screening on four simultaneous chiral stationary phases on a 5 min gradient with a total run time of 9 min including column equilibrations. This could change chiral screening for the entire pharmaceutical industry because now there is a greater than 90% likelihood to get a separation using the main CSPs but with only one SFC instrument using three UV detectors and one Photo Diode Array detector.

Chiral HPLC will continue to grow at a good rate as it has done in the recent past. More and more applications will be incorporated into production of pharmaceuticals and chemicals such as herbicides, pesticide, and others.

Many compounds in the pharmaceutical discovery stage have chiral centers. Since the regulatory requirements demand proof of the enantiomeric purity of chiral drugs, there is a bright future for the use of HPLC and SFC for analytical purposes. In addition, chiral SFC has found a niche in the preparation and purification of chiral pharmaceuticals; preparative chiral HPLC should be around for a long time to come. I think an area for future development would be a single CSP that would suffice for 90-95% of all chiral compounds. Thus, users would have to purchase a single column instead of a half a dozen columns to perform method development.

Rational and timely selection of drug candidates for further development is of major concern for pharmaceutical companies. Use of chiral chromatography for rapid compound screening and compound purification, followed by biology analysis of the purified enantiomers, will allow customers to rapidly eliminate racemic compounds with undesirable (Table 1) characteristics. Preparative and semi-preparative separations for pre-clinical and early clinical development will continue to be the fast growing area.

More chiral compounds moving from development to production and from branded drugs to generics. This means more analysis in QA/QC. Pharmaceutical enantiomers of basic drugs for drug candidates and finished goods both for analytical and preparative purposes. The single biggest application would be the analytical separation and preparative purification of chiral pharmaceuticals.One of the major obstacles is lack of understanding of chromatography, in general, by synthetic chemists. Consequently, efforts have to be made to convince the researchers that chromatography is a highly scalable technique and as such can be a cost-effective commercially-visible drug production.

HPLC is an old-fashioned wasteful way to purify chiral compounds and the new word for all chemical processes is sustainability. SFC is a much more sustainable technology that is not only better in terms of productivity, but in a hydrocarbon-constrained and CO₂ neutral world facing water and food shortages and a surfeit of waste CO₂ - why not reuse the waste CO₂ for SFC use or even supercritical synthesis?

The lack of new and different stationary phases presents a limitation. The industry is in need of a different chiral approach. Currently it is expensive to do HPLC-Chiral especially for hard to separate compounds.

Although some strides have been made in CSP development, it is often a matter of "trial and error" in terns of choosing the optimum phase. Often, chiral method development consists of a bank of columns in a column selector valving system set up with various mobile phase combinations. The chiral compound(s) is repeatedly injected into each of the columns with different combinations of solvents until the best combo is found. This screening approach is rather archaic and it seems like a set of experiments more scientifically based could be developed.  The new generic phases that have come out onto the market are making it more affordable for scientists outside of Big Pharma to experiment with chiral separations. The introduction of lower cost stationary phases to compete with previously sole source suppliers. The development of the new immobilized phases that cover a very wide range of chiral compounds with only three stationary phases.

Conclusion:

Chiral chromatography has become a preferred method for rapidly separation enantiopure compounds in the pharmaceutical industry, largely owing to the speed with which a chromatographic method can be developed and executed as well as the comparatively small labor requirements of the chromatographic approach. The use of chiral chromatography within the field of organic synthesis can be expected to increase as the technique becomes more familiar to synthetic chemists. It is important today to develop fast, cost effective chiral chromatographic methods in discovery labs and stimulate chemists to take advantage of available chiral stationary phases for enantiomer or ligand screening.

Acknowledgment

The authors gratefully acknowledge the valuable insights provided by Mr. Anwer saeed and Mr. Anand Kondaguli of Jamjoom pharma in their review of this article. We also thank Fatima Fazil, Tahir Gazzali, Javed akmal, Mastan, and khalil pavne, of Jamjoom pharma for valuable discussions over the months on the subject of chiral hromatography

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Table 1. Example of racemic compounds with undesirable characteristics (l=levorotary, d=dextrorotary)

Note: This table is in the publication Lien Ai Nguyena, Hua Heb, Chuong Pham-Huyc, ref. 47.

About Authors:

Saleem Shaikh, M.S.Muneera , and O.A .Thusleem

Saleem Shaikh 

Department of Analytical Research & Development, Jamjoom Pharmaceuticals, P.O.Box- 6267, Jeddah-21442, Saudi Arabia.

M.S.Muneera

Department of Analytical Research & Development, Jamjoom Pharmaceuticals, P.O.Box- 6267, Jeddah-21442, Saudi Arabia.

O.A .Thusleem

Department of Analytical Research & Development, Jamjoom Pharmaceuticals, P.O.Box- 6267, Jeddah-21442, Saudi Arabia.