Advances in chiral multidimensional liquid chromatography

Trends in Analytical Chemistry 120 (2019) 115634

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Advances in chiral multidimensional liquid chromatography Imran Ali a, b, **, Mohd. Suhail b, Hassan Y. Aboul-Enein c, * a

Department of Chemistry, College of Sciences, Taibah University, Al-Medina Al-Munawara, 41477, Saudi Arabia Department of Chemistry, Jamia Millia Islamia, Central University, New Delhi, 110025, India c Pharmaceutical and Medicinal Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Cairo, 12622, Egypt b

a r t i c l e i n f o

a b s t r a c t

Article history: Available online 29 August 2019

It is well known that the chiral separation is different but very important in separation science. Increase in number of chiral centers makes the chiral separations more difficult. In this respect multidimensional chromatography is gaining importance in chiral separations. There is a great demand of multidimensional chromatography in the chiral separations. The present article describes the separation and identification various racemates using multidimensional chromatography i.e. high performance liquid chromatography, gas chromatography, super critical fluid chromatography, thin layer chromatography. Besides, the efforts were made to discuss the importance of chiral separations, multidimensional chromatography, future perspectives and challenges. Certainly, this article will be useful for the researchers, academicians, government authorities and industrial persons. © 2019 Elsevier B.V. All rights reserved.

Keywords: Chiral separations Multidimensional chromatography Chromatographic modalities Future perspectives Challenges

1. Introduction It is interesting to mention here that the chiral drugs share about 40% production in the pharmaceutical industries with pharmaceutical potency of only one enantiomer while the other enantiomers lead to numerous serious side health effects [1e4]. In non-chiral environment, the racemic form of chiral drugs owes the same physiochemical properties. On the other hand, they behave as completely dissimilar molecules in chiral environment, which lead to speckled metabolism, distribution rate, excretion, toxicity, and pharmacological activities. On the chiral medicinal products, Japan, USA, and some other European countries reread the governing features with pharmaceutical industries [5,6]. Later on, Rauws and Groen (1994) and [7] pronounced four-point attachment model showing the interaction between protein CSP and the chiral drug. Though the developed countries (Canada, Europe, USA, and Japan) have completely expelled the marketing of the racemic drugs yet these are regularly prescribed and advertised in most of the Asian countries [8,9].

* Corresponding author. Fax:þ20233370931. ** Corresponding author. Department of Chemistry, Jamia Millia Islamia, Central University, New Delhi, 110025, India. E-mail addresses: [email protected] (I. Ali), [email protected] (H.Y. Aboul-Enein). https://doi.org/10.1016/j.trac.2019.115634 0165-9936/© 2019 Elsevier B.V. All rights reserved.

In the development of the drugs, economy plays an important role. The stereogenic synthetic methods are not as economical as the separation methods; especially in case of multi chiral centre molecules. Many pharmaceutical companies are now preparing single enantiomers using separation methods. Also, numerous techniques have been developed for the enantioseparation of enantiomeric forms, but chromatography is considered the best one due to several advantages [10e22]. Among various modalities of chromatography multidimensional chromatography (MDC) is an ideal type for the enantiomeric resolution. Multicomponent blends with extraordinary multifaceted nature need division methods offering expanded settling power, as complete partition of complex mixture are not fully performed by single-dimension chromatography. In two dimensional liquid chromatography achiral and chiral modes are operated simultaneously; giving extraordinary selectivity. The upsides of the multidimensional methodology are completely misused, since there is a limitation of the potential for co-eluting sample components in the two dimensions. The most important phenomena in MDC is the exchange of effluent from primary column to secondary column. This exchange of effluent also makes a difference between one dimensional chromatography and MDC chromatography. In MDC, the columns in the two dimensions are associated by means of a fitting interface. The fundamental contrast being the measure of the essential section effluent is exchanged. Therefore, MDC has a special place in chiral resolution and the pharmaceutical companies are demanding new

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List of abbreviations (±)IDRA21 (±)-7-Chloro-3-methyl-3,4-dihydro-2H-1,2,4benzothiadiazine 1,1-dioxide 2-APA 2-arylpropionic acids CSP Chiral Stationary Phase DAD Diode array detection DIPPCDN O-9-(2,6-Diisopropylphenylcarbamoyl)quinodine DIPPCQN O-9-(2,6-Diisopropylphenylcarbamoyl)quinine DNP-AAs Dinitrophenylated amino acids DOA D-Amino acid oxidase DZSM Denzhan Shenmai FDA Food and drugs administartion GABA b-Ala, g-aminobutyric acid GC  GCeECD Gas Chromatography with micro ElectronCapture Detection GCequadrupole-MS Gas Chromatography quadrupolewith mass pectrometry HPLC High performance liquid chromatography ICS/LABA In corticosteroid/long-acting b-agonist LC  LC-qTOF-MS Quadrupole time-of-flight mass spectrometry MCF Methyl chloroformate MDC Chromatography Multidimensional Chromatography

and novel MDC methods for the chiral resolution. Due to the importance of chiral separation and capabilities of MDC, the efforts are made to write a review article, which may be used for the researchers, academicians, government authorities and industrial persons. Therefore, the present article describes the application of MDC in direct enantio-separation. 2. Importance of chiral separations As effectively expressed that one of the enantiomeric structure is naturally significant and other might be dormant or dangerous or stabilizer, which demonstrated certain reactions, illnesses, and problems. This circumstance turns out to be more mind boggling for the medications having more than one chiral centers. Subsequently, it is progressively unsafe to give multichiral centers medication for public. It is additionally intriguing that some multichiral centers racemates show astounding therapeutic qualities and can't be stayed away in clinical practices and restorative science. There are two significant viewpoints, which require a quick consideration. One is the cognizance of stereoselective binding of the enantiomeric form of such chiral drugs and their catabolism and metabolism with their ramifications for the human body. Second, the enantio-separation of these chiral drugs is furthermore a critical requirement. Optically active chiral drugs have preference over their mixture of enantiomers as the previous ties with different enzymes, hormones, and different proteins stereoselectively, prompting great efficacies with no symptom [23e25]. The therapeutic properties of some significant multichiral racemates/drugs are condensed in the accompanying section. With two chiral centers, diltiazem has importance in the treatment of hypertension, angina pectoris, and some different kinds of arrhythmia. Diltiazem is additionally given for headache. Besides, during depolarization of the myocardium and vascular smooth muscles, diltiazem loosens up coronary vascular smooth muscles by repressing influx of calcium ion [26]. Formoterol with

MD-GC Multidimensional Gas Chromatography MD-HPLC Multidimensional High Performance Liquid Chromatography MD-LC Multidimensional-Liquid Chromatography MHC Multi Heart Cut MHC-qTOF-MS Multiple Heart-Cutting Two-dimensional liquid chromatography coupled with Quadrupole Time-Of-Flight Mass Spectrometry NBD-F 4-fluoro-7-nitro-2,1,3-benzoxadiazole NMA N-Methylaspartic acid NMDA N-Methyl-D-aspartic acid N-MeAla N-Methylalanine NMG N-Methylglutamic acid ODS Octa decyl silica QTOFMS Quadrupoleeaccurate mass time-of-flight mass spectrometry SBMP 3-Sec-butyl-2-methoxypyrazine SFC Supercritical Fluid Chromatography sf-MD-HPLC Soft flow Multidimensional HPLC sRPLC  SFC Reversed Phase Liquid Chromatography and Supercritical Fluid Chromatography t-BuCQN tert-Butylcarbamoylated TLC Thin layer chromatography

two chiral centers is a beta agonist for long acting b1-and b2particular adrenoceptor. Formoterol is the main mixture of breathed in corticosteroid/long-acting b-agonist (ICS/LABA). As a drug for brisk help of an asthma assault, this is the indication of great adequacy [27,28]. Likewise, nebivolol with four chiral centers is used in the hypertension treatment. Besides, nebivolol with nitric oxide potentiating vasodilatory effect is a b1-receptor blocker [29]. In like manner, enantiomers of labetalol (RR, SS, RS, and SR) display b2-opponent exercise with some 2-agonist and a 1-hostility action. Labetalol is successful in the overseeing of postoperative hypertension, hypertensive crises, pheochromocytoma related hypertension, and bounce back hypertension [30]. Nadolol has three chiral centers [31] and FDA has approved it for the treatment of angina pectoris and hypertension. Briefly, the chiral separation is the most important issue in drugs development, environmental studies and agriculture sector. The use of optically active molecules may save large amount of energy, manpower; strengthening the economy of a country. 3. Significance of multidimensional liquid chromatography The multi-dimensional chromatography has risen as a choice for analysis of complex samples in those circumstances in which onedimensional chromatography is unfit to get an acceptable division. Since chiral separations is a very difficult and needs specific requirements multidimensional chromatography is the best choice for this purpose. Multidimensional chromatography permits the mix of at least two autonomous or about free chromatographic partition steps, significantly expanding the separation power of the relating one-dimensional methods. First by any means, for a simpler comprehension of the multidimensional chromatography, some broad view points (for example execution, conventions and terminology) are clarified. Some of the users realized the specific qualities of MDC instrumentation. The various surveys and books have been distributed lately, managing various parts of multidimensional chromatography all in all [32e39].

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4. Multidimensional high performance liquid chromatography High performance liquid chromatography is the most suitable and feasible technique in chiral separations. For enantiomeric separation, HPLC can be utilized either by implication with chiral derivatization reagents or legitimately with CSPs or chiral mobile phase added substances. All in all, selectivity is demonstrated by the CSP rates for the partition of the enantiomers, however, it is less particular for sample having other achiral mixes. Therefore, multidimensional approach was used to solve these problems and the technique was termed as multidimensional high performance liquid chromatography (MD-HPLC). Because of the amazing properties of MD-HPLC like selectivity, affectability, reproducibility, speed, and the accessibility of an extensive scope of CSPs, MD-HPLC has accomplished an incredible notoriety in the chiral separations. Taking in perspective on the headways of this strategy, few authors used this technique for the enantio-separation of racemates. Cannazza et al. [40] created a noble halted flow multidimensional HPLC (sf-MD-HPLC) technique to explore the impact of the pH on the hydrolysis and enantio-stability of (±)-7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide [(±)IDRA21]. The determination of free vitality obstructions, hydrolysis rate constants and the rate constants of enantiomerization of (±)IDRA21 was very conceivable utilizing one achiral C18 column and two chiral stationary stages (CSPs). Woiwode et al. [41] described enantio-separation of amino acids after derivatization. In 1D-separation dimension, the O-9-(2,6-diisopro pylphenylcarbamoyl)quinine (DIPPCQN) CSP was used first followed by O-9-(2,6-diisopropylphenylcarbamoyl)quinodine (DIPPC DN) CSP. On the other hand, tert-butylcarbamoylated (t-BuCQN) CSP was constituted for 2D-separation. Besides, UV detection at 360 nm was used in 1D-separation with DAD detection at 360 nm in 2Dseparation. Methanol/acetic acid/ammonium acetate (98/2/0.5, v/v/ w) was used as mobile phase in both dimensions with flow rate 0.1 in 2 D and 2 mL/min in 2d (Fig. 1). Furthermore, Woiwode et al. [42] reported a different heart cut (MHC) 2D-UHPLC technique in a single run with UV detection for enantio-selective separation of a complex mixture of amino acids. The MHC technique depends on an achiral slope reversed phase

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liquid chromatography with 1.8 mm C18 column (100 mm  2.1 mm ID section) in 1D. In the second dimension (2D), a tert-butylcarbamoylquinine-based 2.7 mm Coreshell molecule column (50 mm  3 mm ID) was used for enantioselective isocratic separation. Sanger's reagent (2,4-dinitrofluorobenzene) was used in pre-column for derivatization yielding chromogenic 2,4-dinitrophenylated amino acids (DNP-AAs). Dugo et al. [43] investigated the enantiomeric distribution of chiral coumarins (epoxyaurapten and meranzin), and furocoumarins (byakangelicol, epoxybergamottin and oxypeucedanin) in various citrus oils (grapefruit, lemon, bitter orange and lime) by heart-cutting multidimensional-liquid chromatography (MD-LC) framework. In this MD-LC, the first dimension was a micro silica column, while second dimension was a column based on cellulose. This arrangement gave a decent pattern separation of the chiral coumarins (epoxyaurapten and meranzin) and furocoumarins (byakangelicol and epoxybergamottin); existing in cold pressed citrus important oils. The results demonstrated the chiral molecules separations in citrus essential oils. There was a clear prevalence of
n-Casla et al. [44] initially isoone of the two enantiomers. Guille lated D-and L-phenylalanine (Phe), D-and L-tryptophan (Trp), Dand L-tyrosine (Tyr) (Fig. 2), and their deterioration products using a primary column (C18) and ammonium acetate buffer (20 mM, pH 6) (94%) and MeOH (6%) as the mobile phase. At that point, a part of every peak at 260 nm UV detection was exchanged by heart cutting through a changing valve to a teicoplanin chiral column. Utilization of MeOH-H2O (90:10) as the mobile phase played an important role. Yang et al. [45] described the enantiomeric separation of atenolol, salmeterol and salbutamol in urine utilizing a heart-cut 2D-LC strategy. It included the utilization of two achiral and chiral liquid chromatography in coupling. In an essential column (Kinetex™ HILIC, 2.6 mm, 150  2.1 mm I.D.) the mobile used was MeOH:ACN:ammonium acetate buffer (5 mM, pH 6) 90:5:5 (v/v/v) with 0.40 mL min1 flow rate. Peak exchanging of each compound through a changing valve to a vancomycin chiral column (Chirobiotic™ V, 2.6 mm, 150  2.1 mm I.D.) played an important role in enantioseparation. Besides, utilization of MeOH:ammonium acetate buffer (2 mM, pH 4) 97:3 (v/v) as mobile phase with flow rate of 0.50 mL min1 also played an important role at UV detection of

Fig. 1. Chiral separation of derivatized amino acids in 2D-HPLC [41].

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Fig. 2. Chromatogram of Chiral separation of 1. D-and L-phenylalanine (Phe), 2. D-and L-tryptophan (Trp), 3. D-and L-tyrosine (Tyr) [44].

227 nm. A validated two-dimensional HPLC system combining a microbore monolithic ODS column and a narrow bore-enantioselective column was established by Hamase et al. [46] for a simultaneous and sensitive analysis of hydrophilic enantiomers of amino acid (Asn, His, Gln, Ser, Arg, allo-Thr, Asp, Thr and Glu) and the non-chiral amino acid (Gly) in biological samples. For accomplishing this work, 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) was used to tag the amino acids. In the first dimension, these amino acids were separated by a micro-reversed-phase column. In second dimension (Pirkle type enantio-selective column), the automatically collected fractions of the target peaks were then transferred where factors were higher than 1.13 for all the enantiomeric target analytes (Fig. 3). The D-isomers of all the investigated nine amino acids were found in rat urine but at various enantiomeric ratios. A validated and fully automatic chiral 2D-HPLC system was developed by Koga et al. [47] for the simultaneous determination of N-methyl-D-aspartic acid (NMDA). In this system a long microboremonolithic ODS column (0.53 mm i.d.  1000 mm) and narrowbore-enantioselective columns (1.5 mm i.d.  150 or 250 mm) were used. Besides, the derivatization of enantiomers of N-methylaspartic acid (NMA) and N-methylglutamic acid (NMG) with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) was done in

precolumn condition. The obtained results (Fig. 4) were confirmed using a 2D-HPLC-MS/MS system. Hamase et al. [48] established a two-dimensional chiral highperformance liquid chromatographic (2D-HPLC) system for a simultaneous and sensitive analysis of 8 chiral amino acids [alanine (Ala), valine (Val), 2-aminobutyric acid (2AB), norvaline (nVal), Nmethylalanine (N-MeAla), isovaline (iVal), 3AB and 3aminoisobutyric acid (3AIB) and 5 non-chiral amino acids (glycine (Gly), b-Ala, g-aminobutyric acid (GABA), sarcosine (Sar) and 2AIB] and the non-chiral amino acid Gly. For accomplishing this work, 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) was used to tag the amino acids. In the first dimension, these amino acids were separated by a capillary monolithic ODS column. In second dimension (Pirkle type enantio-selective column), the automatically collected fractions of the target peaks were then transferred where factors were higher. The impacts of the probable factors controlling the enantiomers of D-Ala, D-amino acid oxidase (DAO) and intestinal bacteria were investigated by Karakawa et al. [49] (Fig. 5). It was achieved by using 2D-HPLC system having two dimension in which 1D was a reversed-phase column and 2D was an enantioselective column. The circadian rhythm was not changed under fasting conditions. In the mice lacking D-amino acid oxidase

Fig. 3. 2D-HPLC separation of hydrophilic amino acid enantiomers [46].

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Fig. 4. 2D-HPLC separation of N-methyl-d-aspartic acid (NMDA) [47].

Fig. 5. 2D-HPLC separation of D-amino acid [49].

activity, clear day-night changes were observed, suggesting that the factors controlling D-Ala rhythm were not their food and DAO activity. A fully automated 2D-HPLC system was established by Han et al. [50] using ACN-CF3COOH-H2O (9:0.05:92, V/V) as the mobile phase for 1D i.e., monolithic ODS column: 10 mmol/L citric acid in MeOHACN (50: 50, v/v) as the mobile phase for 2D i.e., micro Chiralpak QD-1-AX column. 4-Fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) was used as the derivatizing agent. An excellent peak shape, selectivity, and repeatability were achieved by Barhate et al. [51]. They joined achiral and chiral narrow bore columns (2.1 mm  100 mm and 2.1 mm  150 mm, sub- 2 and 3 mm) in the first dimension with 4.6 mm  30 mm and 4.6 mm  50 mm columns packed with highly efficient chiral selectors (sub-2 mm fully porous and 2.7 mm fused-core particles) in the second dimension.

Besides, 0.1% phosphoric acid/acetonitrile was used as mobile phase in both dimensions. Multiple achiral  chiral and chiral  chiral 2D-LC samples (single and multiple heart-cutting, high-resolution sampling, and comprehensive); using ultrafast chiral chromatography in the second dimension; were successfully applied to the analysis and separation of complex mixtures of closely related pharmaceuticals. A feasible strategy was developed by Sheng et al. [52] for characterization and identification of complex chemical constituents in Denzhan Shenmai (DZSM) using 2DHPLC coupled with quadrupole time-of-flight mass spectrometry (LC  LC-qTOF-MS) with multiple heart-cutting two-dimensional liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (MHC-qTOF-MS). DZSM was separated using C8  C18 HPLC column system for comprehensive 2D-LC system, and 283 compounds (Fig. 6) most of which belonged to saponin,

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Fig. 6. The MHC chromatograms at 280 nm (A: 1D chromatogram; B: 2D chromatographic overlay chart of four time columns) [52].

flavonoid, phenolic acid and lignan families were characterized and identified within 75 minutes. Analysis of some isomers and compounds at low level was done on C8  Chiral HPLC column system for multiple heart-cutting 2D-LC system with 1D and 2D optimized gradient elution program. A two-dimensional (2D) HPLC-MS/MS system was developed by Ishii et al. [53] for the analysis of simple and chiral amino acids proteins (Fig. 7) under various conditions. They selected 5 major Damino acid residues (Ala, Asp, Glu, Pro and Ser) for analysis. For the reversed phase separation, a capillary monolithic ODS column, ML-

1000 (0.53 mm i.d.  1000 mm, designed by the collaboration with Shiseido), was used at 40 C. By using this column, the NBD-D- and L-amino acids were isolated and manually fractionated as mixtures of the D- and L-forms using the gradient elution of aqueous 5e18% MeCN solutions; containing TFA (isocratic elution with 5% MeCN for 35 min and linear gradient from 5% to 18% MeCN for 20 min and additional isocratic elution with 18% MeCN for 45 min, 25 mL/min. For the chiral separation, an enantio-selective column, KSAACSP001S (1.5 mm i.d.  250 mm, original column produced by the collaboration with Shiseido) was used at 25 C.

Fig. 7. Separation of the NBD-amino acids derived from the model peptide by the monolithic ODS column (A) and enantiomer separations of racemic mixtures (B) by the enantioselective column (KSAACSP-001S) [53].

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5. Multidimensional gas-chromatography Due to its applicability in various ranges, multidimensional gas chromatography (MD-GC) is well-established method for many applications. Enantio-selective MD-GC (enantio-MD-GC) has been suggested as the method of preference for the separation of extremely overlapping enantiomers. Fig. 8 shows the schematic diagram of heart-cutting enantio-MD-GC [54]. A new method for the enantio-selective analysis of essential oils was described by Shellie et al. [55] by 2D-GC. 1D as first dimension consisted of a cyclodextrin derivative, and 2D as secondary column consisted of a polyethylene glycol. The enantiomeric compositions of a number of oxygenated monoterpenes and monoterpene hydrocarbons in Australian tea tree (Melaleuca alternifolia), including sabi-nene, a-thujene, a-phellandrene, b-pinene, limonene, cissabinene hydrate, trans-sabinene hydrate, terpinen-4-ol, linalool, and a -terpineol were described (Fig. 9). A fast chiral analysis in comprehensive 2D-GC was developed by Shellie et al. [56] in which a route to precise measurement of chiral ratios of enantiomers was provided by 2D (enantioselective capillary column). On the second column, fast elution was achieved sufficiently using GC/MS in which the sub ambient pressure (vacuum outlet) conditions promoted increased diffusion coefficients and higher component volatility. The separation of ephedrine-type alkaloids and their enantiomers in commercial herbal and raw herbs products was investigated by Wang et al. [57] by carrying out enantio-selective separation in the 1D column (consisting of bcyclodextrin as the chiral selector) of a comprehensive 2D-GC system. On the other hand, in 2D a polar polyethylene glycol capillary column was used in secondary column for separation (Fig. 10). The commercial herbal products tested contained mostly ()-ephedrine, (þ)-pseudoephedrine, ()-N-methylephedrine and ()-norephedrine, with concentrations in the range of 40e2100, 0e1300, 15e300 and 0e30 g/g of the product, respectively, and repeatability of analysis was generally in the range of 1e5%.

Fig. 8. Schematic diagram of heart-cutting enantioselective multidimensional gas chromatograph [54].

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Three commercially available chiral capillary columns were evaluated by Bordajandi et al. [58] for the separation into enantiomers of the 19 chiral polychlorinated biphenyls (PCB) congeners stable at room temperature (Fig. 11). These three chiral capillary columns were BGB-176SE, Chirasil-Dex and BGB-172. The enantiomers of 15 chiral PCBs were separated using these b-cyclodextrin based columns. A comprehensive two-dimensional gas chromatography with micro electron-capture detection (GC  GCeECD) was evaluated by Bordajandi et al. [59] for the enantio-separation of five chiral toxaphenes. From the two enantio-selective b-cyclodextrin-based columns evaluated as first dimension column (BGB-176SE and BGB172) and the later provided the best results and was further combined with three non-enantioselective columns in the second dimension (HT-8, BPX-50 and Supelcowax-10). The combination BGB-172  BPX50 was finally selected because it provided a complete separation among all enantiomers (Fig. 12). The feasibility of the method developed for real life analyses was illustrated by the determination of the enantiomeric ratios and concentration levels of the test compounds in four commercial fish oil samples. Chin et al. [60] reported enantio-separation of chiral PCBs by 2 comprehensive D-GC with electron-capture detection (GC  GCeECD) (Fig. 13). In 1D column, three commercially available enantio-selective b-cyclodextrin-based capillary columns (Chirasil-Dex, BGB-172 and BGB-176SE) were tested. Three nonenantio-selective stationary phases (HT-8, BPX-50 and Supelcowax-10) were combined with the enantio-selective columns to allow the unambiguous determination of the enantiomers of the target chiral PCBs. The Chirasil-Dex  Supelcowax-10 columns combination allowed the determination of the enantiomeric fraction (EF) of PCBs 84, 91, 95, 132, 136, 149, 174 and 176 in the working standard solution, while that of congener 135 was hindered. The BGB172  Supelcowax-10 column set allowed a proper EF determination of congeners 45, 84, 131, 132, 135, 171, 174 and 183, while that of PCB 91 was interfered with co-elutants. The column combination of BGB-176SE  Supelcowax-10 allowed the determination of all congeners that this enantio-selective stationary phase was able to separate into enantiomers, i.e. PCBs 45, 91, 95, 136, 149 and 176. The development of fast chiral analysis for use in comprehensive two-dimensional gas chromatography was described by Shellie et al. [56] in which a short second dimension enantio-selective capillary column provided a route to precise measurement of chiral ratios of enantiomers (Fig. 14). Retention times as short as 8 seconds was reported for (±)-limonene, with adequate enantioseparation (Rs ~ 1.0) on a cyclodextrin derivative-coated capillary column (1 meter). The enantiomeric distribution of several monoterpene compounds in bergamot essential oil was reported as a demonstration of the method. A chiral comprehensive 2D-GC (eGC  GC) coupled to quadrupoleeaccurate mass time-of-flight mass spectrometry (QTOFMS) was evaluated by Chin et al. [61] for its capability to report the chiral composition of several monoterpenes, namely, apinene, b-pinene, and limonene in cardamom oil (Fig. 15). Enantiomers in a standard mixture were fully resolved by direct enantiomeric-GC analysis with a 2,3-di-O-methyl-6-t-butylsilyl derivatized b-cyclodextrin phase; however, the (þ)-(R)-limonene enantiomer in cardamom oil was overlapped with other background components including cymene and cineole. Column phases SUPELCOWAX, SLB-IL111, HP-88, and SLB-IL59, were incorporated as the second dimension column (2D) in chiral GC  GC analysis; the SLB-IL59 offered the best resolution for the tested monoterpene enantiomers from the matrix background. The enantiomeric distribution of the potent aroma compound 3sec-butyl-2-methoxypyrazine (SBMP) in various species was

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Fig. 9. Enantioselective analysis of essential oils in 2D mode [55].

Fig. 10. (A) One dimensional GC separation of seven ephedrine-type alkaloid standards using a b-CD chiral column; (B) Portion of a GC  GC chromatogram of four ephedrine standards using Cyclodex-B as the first dimension (chiral) separation column and a short, narrow BP20 column. Peaks: 1, (þ)-ephedrine; 2, ()-ephedrine; 3, (þ)-pseudoephedrine; 4, (þ)-N-methylephedrine; 5, ()-N-methylephedrine; 6, (þ)-norephedrine; 7, ()-norephedrine [57].

determined by Legrum et al. [62] using heart-cut multidimensional gas chromatography (H/C MD-GC) or comprehensive 2D-GC (GC  GC). Complementary to an earlier described separation on octakis-(6-O-methyl-2,3-di-Opentyl)-g-cyclodextrin used as chiral

stationary phase, they found a reversal of the elution order of SBMP enantiomers on heptakis-(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-b-cyclodextrin; providing further confirmation options for that type of analysis (Fig. 16). In various vegetables, lady beetles

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Fig. 11. 2D chiral separation of 19 chiral polychlorinated biphenyls (PCB) [58].

and Vitis vinifera species analysed, only (S)-SBMP was detected, supporting the hypothesis of natural amino acids serving as starting material for the biosynthesis of alkyl-methoxypyrazines. An improved analytical procedure for the resolution and quantification of amino acid enantiomers was presented by

Myrgorodska et al. [63] (Fig. 17) using MD-GC. The procedure contains a derivatization step, by which amino acids were transformed into N(O,S)-ethoxy carbonyl hepta-fluoro butyl esters. It was optimized for the resolution of non-proteinogenic amino acids in the matrix of complex non terrestrial samples. The developed

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Fig. 12. Enantiomer resolution of the five toxaphenes analysed in (a) BGB-176SE and (b) BGB-172 (insert: detail showing the coelution of the first eluted enantiomer of Parlar 32 and Parlar 50) [59].

procedure was tested on a sample of the Murchison meteorite, for which obtained chromatograms showed excellent peak resolution, minimal co-elution and peak overlap. The potential of comprehensive 2D-GCetime-of-flight mass spectrometry (GC  GCeTOFMS) was investigated by Waldhier et al. [64] in the quantitative analysis of amino acid enantiomers (AAEs) as their methyl chloroformate (MCF) derivatives in physiological fluids. Of the two column sets tested, the combination of an Rt-DEXsa chiral column with a polar ZB-AAA column provided superior selectivity. Twenty AAEs were baseline resolved including L-Leu and D-Ile, which had failed separation by one-dimensional chiral GCequadrupole-MS (GCeqMS). The method was applied to the comparison of AAE serum levels in patients suffering from liver cirrhosis to a control group. 6. Multidimensional sub- and super critical fluid chromatography Supercritical liquid chromatography (SFC) strategy showed the focal points over different kinds of chromatography [65]. The reason behind of calling supercritical liquid chromatography is the use of supercritical liquids as mobile phase. In SFC, critical nature point is the point where the fluid exceeds the critical parameters of temperature and pressure. Now, the properties of both gas and liquid are contained by the fluid. This property has played an

important role in SFC strategy for enantio-separation. Trifluoromethane, nitrous oxide and carbon dioxide are the supercritical fluid, which are used in SFC as mobile phase [66]. CO2 has a great importance in supercritical fluid of choice among these fluids because of different properties including the compatibility with most identifiers, low critical pressure and temperature, low ecological burden, low critical quality, and low expenses. First dimension with RPLC and second dimension with SFC were used by Bernal et al. [67] for the accomplishment of synchronous. They created online two-dimensional chromatographic framework achiral and chiral analysis of pharmaceutical compounds. The interface comprises of an eight-port, double position exchanging valve with little volume C-18 catching column. Sharp concentration pulses of the peaks of interest which were eluting from the first RPLC dimension column around little volume C18 catching column were viably centered, and afterward inserted onto the second dimension SFC column. The achiral purity results were obtained by the primary column RPLC separation, while the chiral purity result (enantiomeric abundance) was given by the second dimension SFC separation (Fig. 18). The outcomes were quantitative enabling synchronous achiral, chiral analysis of mixes. Moreover, similar examinations to customary SFC and contextual analyses of the uses of 2D LC-SFC in pharmaceutical investigation were exhibited. A two-dimension liquid chromatography SFC-MS system to assess “in-vivo” inter-

I. Ali et al. / Trends in Analytical Chemistry 120 (2019) 115634

11

Fig. 13. 2D enantioseparation of chiral PCBs [60].

conversion of chiral drug molecules was optimized by Goel et al. [68]. At 40 C temperature and 130 bar pressure, a Chiralpak AD-3 section was used with 50  4.6 mm, 3 mm specification from Chiral Technologies (West Chester, PA, USA) using 75:25 scCO2 (MPA)/ EtOH containing 0.1% ammonium hydroxide (MPB) as mobile phase with the flow rate of 4.0 mL/min. The chromatographic conditions in 2D depended on SFC column screening with racemates (Fig. 19). On-line selective comprehensive two-dimensional chromatography was investigated by Iguiniz et al. [69] combining reversed phase liquid chromatography and supercritical fluid chromatography (sRPLC  SFC) for the analysis of chiral pharmaceutical

compounds. The preliminary studies were carried out with the aim of overcoming instrumental constraints which are related to such 2 D coupling. The resulting on-line sRPLC  SFC system was applied to the achiral  chiral analysis of a pharmaceutical sample. Using an Acquity BEH C18 column in the first dimension and a Chiralpak IC column in the second one, both chemical (achiral) and enantiomeric (chiral) purities could be evaluated in less than 50 min within a single run. Under such conditions, a detection limit of about 0.5% for R-enantiomer could be obtained with UV detection. The results obtained in sRPLC  SFC were compared to those obtained in conventional chiral 1D-SFC.

Fig. 14. 2D separation space for the GC  enantio-GC/MS analysis (SIM m/z 93 ion) of bergamot essential oil monoterpene region shown [56].

Fig. 15. GC  GC modulated chromatogram for standard mixture of limonene and cineole using 2 m length of different 2D columns. Arrows indicate the location of (þ)-(R)-limonene [61].

12

I. Ali et al. / Trends in Analytical Chemistry 120 (2019) 115634

Fig. 16. Influence of modulation time in enantio-GC  GC on SBMP separation: (a) modulation time; (b) raw chromatogram, the dashed line indicates allocation to (R)- or (S)-SBMP for peak integration; (c) ratio of the sum of peak areas of (R)- and (S)-SBMP calculated from the raw chromatogram; (d) 2D color plots.

Fig. 17. Close-up view of the two-dimensional and reconstructed one dimensional enantioselective gas chromatogram depicting standard amino acids identified in a sample of the Murchison meteorite [63].

I. Ali et al. / Trends in Analytical Chemistry 120 (2019) 115634

13

Fig. 18. Proof of concept demonstrating the application of heart-cutting 2D LC-SFC in simultaneous achiral-chiral separation of drug substance [67].

Fig. 19. 2D LC-SFC-UV analysis of compound A. The chromatogram at the top is the RPLC separation and the one at the bottom is the secondary SFC separation demonstrating the resolution of the enantiomers [68].

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I. Ali et al. / Trends in Analytical Chemistry 120 (2019) 115634

7. Multidimensional thin layer chromatography TLC has been utilized less as often as possible for enantioseparation. Although TLC can not be compared to GC and HPLC in regards to detachment productivity yet it demonstrates a few favorable circumstances. TLC is an extremely straightforward, reasonable, quick and adaptable system; numerous samples can be spotted analogous on one plate and exceptionally specific discovery can be completed by utilizing spray reagents. For enantioseparation, chiral mobile phase or chiral stationary phase can be utilized. While just one kind of TLC plate having a CSP depending on the LEC rule is industrially accessible. Insights regarding utilizations of chiral TLC to various compound classes can be found in specific surveys [70]. The separate plates were run for one- and twodimensional modes. The unique possibility of this technique to be used with successive elutions with different mobile phases and in the two-dimensional mode, thus, increasing the separation capabilities of the stationary phase, should also be underlined [71,72]. The efficiencies of those layers were evaluated by Schoenmakers et al. [66] using two-dimensional TLC with polyaromatic hydrocarbons as test compounds. The polarity of layers composed of C18/ cyano mixed silica-based bonded phase (and the resultant resolution capability) was controlled by varying the ratio of the two sorbents mechanically blended together during preparation. This procedure made it possible to modulate the polarity of the stationary phase in TLC. The layers were tested on mixtures of polyaromatic hydrocarbons and aza-arenes. Bhushan et al. [73] applied the spots of (±)-ibuprofen and the (þ)-isomer side-by-side on the same plate; in the two-dimensional mode first the spot of (±)-ibuprofen was applied to the L-arginine-impregnated plate and then the spot of the (þ)-isomer was applied after the first run at the side of the former spot. Spots of ()- and (þ)-ibuprofen were also applied separately on two different plates and both were developed under identical conditions in the two-dimensional mode side-byside. The chromatograms were developed at 32 ± 2 C for 30 min in acetonitrile-methanol-water (5:1:1, v/v/v) in a paper-lined rectangular glass chamber, pre-equilibrated with the solvent system for 10e15 min. Bhushan et al. [74] achieved direct enantioseparation of (±)-ibuprofen and (±)-flurbiprofen by two-dimensional thin-layer chromatography on silica gel plates impregnated with optically pure ()-brucine as chiral selector (Fig. 20). The solvent systems that were successful in resolving both the compounds were acetonitrile-methanol (16:3 v/v) for the first dimension and acetonitrileemethanolewater (16:3:0.4, v/v) for the second dimension. Chiral separation of S-(þ)- and R-(-)-ibuprofen was reported by Sajewicz et al. [75] using TLC. The original procedure was

performed with laboratory coated glass plates and resolution of the two enantiomers in one dimensional mode was incomplete. In an attempt to enhance the resolution, the authors made use of less convenient and considerably more time-consuming two-dimensional TLC and the final result was not very impressive (DRF ¼ 0.03). These chromatograms were visualized by exposure of the developed plates to iodine vapor and no direct confirmation of the identity of the two chromatographic bands was produced. The same group [76] had previously discussed in detail thin-layer chromatographic studies of the retention of the 2-arylpropionic acids (2-APA) S -(þ)-and S, R -(±)-ibuprofen, S -(þ)-naproxen, and S, R -(±)-2-phenylpropionic acid. Chiral TLC was performed on commercial silica gel layers impregnated with L-arginine in the cationic form as chiral ion-pairing reagent. Retention and separation of the species was checked by densitometry. Scanning of the chromatographic plates at 1 mm intervals revealed that the tracks of the S-(þ) and the R-() APA could deviate markedly from the vertical in mutually opposite directions. This striking effect in the two-dimensional separation of the enantiomers was most probably caused by stereo-specific intermolecular interactions which occur during ion-pair formation between L-arginine in the cationic form, deposited on the silica gel layer as chiral selector, and each individual 2-APA in the anionic form. For the convenience of the readers, the resolved racemates by multidimensional liquid chromatography are summarized in Table 1. 8. Future perspectives and challenges It is well established that the future of optically active pure drug is a key issue for human health. It is essential to develop sensitive, selective and reproducible enantio-resolution methods. Therefore, the continuous need and demand of chiral drug development is increasing day by day. It was observed that chiral separation of racemates having single asymmetric centre is well documented but the enantiomeric resolution of multiple chiral centre racemates is not developed. About four hundred chiral molecules as new drug candidates are entering into preclinical stage every year. Therefore, there is a great need to develop chiral-HPLC methodologies for racemates of more than one chiral centre. By keeping these facts into consideration, multidimensional chromatography is being used for this purpose. MDC is gaining importance in chiral resolution but has certain challenges. The main challenges are fast methods within a realistic time, which may be tackled by smart algorithms. Besides, the reproducibility of MDC systems is other problem in complex molecules analysis, which may be in chiral separations. All sorts of physical and phenomenon should be allowed to take place, permitting a wide diversity of experiments to

Fig. 20. Diagramatic illustration of the chromatograms obtained by two-dimensional TLC of (±)-ibuprofen or (±)-flurbiprofen, showing enantiomeric resolution. (A) Chromatogram obtained after first dimension run of either (±)-ibuprofen or (±)-flurbiprofen. (B) Chromatogram turned by 90 after first run: 1 ¼ pure (þ) isomer spotted after development; 2 ¼ eight-shaped spot obtained after first run. (C) After second-dimensional run: 1 ¼ pure (þ) isomer at equal Rf with the spot separated from the mixture; 2 ¼ resolved into (þ) and () isomers [74].

Table 1 The resolved racemates by multidimensional liquid chromatography. Racemates

Columns 2

D

Mobile Phases

Techniques

Results

Refs.

Kinetic rate constant for 1st enantiomer: 1.17 ± 0.57  103 s1 and for the second one 1.11 ± 0.12  103 s1. Rt ranged from 8.34 to 110.27 in 1 D Rt ranged from 0.607 to 0.685 to 1.193e1.385 in 2D

[40]

MD-HPLC

Chiral separtaion within 20 e130 min

[43]

MD-HPLC

Selectivity ranged from 1.91 to 1.95 in 1D selectivity ranged from 1.19 to 1.92 in 2D Rs ranged from 0.80 to 0.92 for salbutamol, 0.53e0.66 for Salmeterol and 0.80e0.75 for atenolol with increase in organic modifier Resolution of NBD-Glu and NBD-Thr increased with the increasing column temperature

[44]

MD-HPLC

Retention times of the enantiomers were reversed by using Sumichiral OA-2500S

[47]

MD-HPLC

Derivatization of amino acid improved the retention on reversed phase column

[48]

MD-HPLC

Chiral separtaion within 5 e50 min

[49]

2

D

Chiral OD-R column

C18 column

0.05 M NaClO4 buffer (pH 2):ACN (70:30, v/v) or H2O:ACN (60:40, v/v)

MD-HPLC

Complex amino acids

C18 column

t-BuCQN

MD-HPLC

Chiral coumarins & furocoumarins

A micro silica column

Cellulose

D-and L-Phenylalanine (Phe), Dand L-tryptophan (Trp), Dand L-tyrosine (Tyr)

C18 column

Teicoplanin

(1A) water þ 0.05% formic acid (v/v) (1B) acetonitrile þ 0.05% formic acid (v/v) for 1D; (2A) methanol/water (98/2, v/v) with 100 mM formic acid and 100 mM ammonium formate, (2B) methanol/water (98/2, v/v) for 2D Water/methanol/THF (85:10:5) (solvent A) and methanol/THF (95:5) (solvent B) for 1D; 98% of n-Hexane and 2% propanol Ammonium acetate buffer (20 mM, pH 6) (94%) and MeOH (6%)

Atenolol, salmeterol and salbutamol

Kinetex™ HILIC

Chirobiotic™ V

MeOH:ACN:ammonium acetate buffer (5 mM, pH 6) 90:5:5 (v/v/ v)

MD-HPLC

Amino acids

Microbore-monolithic ODS column

Pirkle type enantio-selective column

MD-HPLC

N-Methyl-d-aspartic acid (NMDA)

Microbore-monolithic ODS column

Narrowbore-enantioselective columns

8 Chiral amino acids

Capillary monolithic ODS column

Pirkle type enantio-selective column

D-Ala, D-amino acid oxidase (DAO)

Reversed-phase column

Enantioselective column

6% (v/v) MeCN and 0.06% (v/v) TFA for 1D. 2.5 mM Citric acid in the mixed solution of MeOHeMeCN (25:75 v/v) for Glu and Asp; 0.5 mM Citric acid in MeOH for His; pure MeOH for Arg in 2D MeCNeTFAewater (6:0.05:94, v/v/v) for 1D 1.5 mM citric acid mixed in MeOHeMeCN (50:50, v/v) or 0.8% formic acid mixed MeOH eMeCN (20:80,v/v) for OA; 6 mM citric acid mixed in MeOHeMeCN (20:80, v/v) for QN-2 (A) 7% MeCN 0.05% TFA in water and (B) 20% MeCN 0.05% TFA in water for 1D. MeOH-MeCN (90/10) with 0.375% formic acid or with 0.02% formic acid for 2D THFeTFAeMeCNewater (1:0.02:10:89, v/v/v/v) for 1D; 5 mM citric acid in MeOH for 2D

[42]

[45]

[46]

I. Ali et al. / Trends in Analytical Chemistry 120 (2019) 115634

(±)-7-Chloro-3-methyl-3,4dihydro-2H-1,2,4benzothiadiazine 1,1-dioxide [(±)IDRA21]

(continued on next page) 15

Racemates

16

Table 1 (continued ) Columns

Mobile Phases

Techniques

Results

Refs.

Vancomycin

0.1% Phosphoric acid/ acetonitrile

MD-HPLC

[51]

C8  C18

Chiral HPLC

MD-HPLC

Essential oils

A capillary monolithic ODS column Cyclodextrin derivative

An enantioselective column, KSAACSP-001S Polyethylene glycol

0.1% HCOOH (A) and MeOH containing 0.1% HCOOH (B). 5e18% MeCN solutions containing TFA Hydrogen

MD-GC

(±)-Limonene

Cyclodextrin

Enantioselective capillary column

CO2

MD-GC

Chiral ephedrine-type alkaloids

Cyclodextrin

Hydrogen

MD-GC

19 chiral polychlorinated biphenyls chiral toxaphenes

b-Cyclodextrin

Polar polyethylene glycol capillary column Polar stationary phase

Chiral separtaion within 2.5 e11.0 min Rs ¼ 0.60e1.88 Chiral separtaion within 1.0 e90.0 min Chiral separtaion within 10.0 e100.0 min Chiral separtaion within 25.0 e130.0 min; Rs values more than 1.0 Chiral separtaion within 3.0 e9.0 min; Rs values approximately 1.0 e

Nitrogen

MD-GC

[58]

n-Hexane

MD-GC

chiral PCBs

b-cyclodextrin

Helium

MD-GC

Monoterpenes

GCQTOFMS

Helium

MD-GC

3-sec-butyl-2methoxypyrazine (SBMP)

Octakis-(6-O-methyl-2,3-diOpentyl)-g-cyclodextrin

Chiral separtaion within 35.0 e200.0 min Chiral separtaion within 50.0 e110.0 min Chiral separtaion within 50.0 e110.0 min Chiral separtaion within 10.0 e40.0 min Chiral separtaion within 21.3 e22.3 and 34.0e35.0 mins.

Amino acid enantiomers

2

2

Warfarin and hydroxywarfarin

ZORBAX RRHD Eclipse Plus C18

Chemical constituents in DZSM Chiral amino acids

D

MD-HPLC

Helium

MD-GC

Chirasil-l-Val columns

HT-8, BPX-50 and Supelcowax10 HT-8, BPX-50 and Supelcowax10 SUPELCOWAX, SLB-IL111, HP88, and SLB-IL59 Heptakis-(2,3-di-O-methyl-6O-tert-butyldimethylsilyl)-bcyclodextrin DB Wax

Helium

MD-GC

Amino acid enantiomers

Rt-DEXsa

ZB-AAA column

Helium

MD-GC

Trans-stilbene oxide

C-18 Column

SFC column

CO2

MD-SFC

Chiral drugs

Chiralpak AD-3 section

SFC column

CO2

MD-SFC

Chiral pharmaceutical compounds (±)-Ibuprofen and (±)-Flurbiprofen

Acquity BEH C18 column

Chiralpak IC column

CO2

() -brucine

()-brucine

MD-SFC 1

ACN-MeOH (16:3 v/v) for D; ACN-MeOHeH2O (16:3:0.4, v/ v) 2D

MD-TLC

Chiral separtaion e60.0 min Chiral separtaion e86.0 min Chiral separtaion e4.0 min Chiral separtaion e4.0 min Chiral separtaion e2.0 min hRf values 86-96

[52] [53] [55]

[56]

[57]

[59] [60] [61] [62]

within 10.0

[63]

within 35.0

[64]

within 1.0

[67]

within 2.5

[68]

within 1.5

[69] [74]

I. Ali et al. / Trends in Analytical Chemistry 120 (2019) 115634

b-Cyclodextrin

D

I. Ali et al. / Trends in Analytical Chemistry 120 (2019) 115634

be carried out within solitary, competent and automated separations. Not much problems have been faced in MDC for enantioseparations because much work has not been done. The future will decide the challenges of this technique in chiral separations. During the write up of this article, it was realized that MDC has bright future in chiral separations due to several advantages of high repeatability, efficient, and low maintenance of the instrument. Besides, the accurate information, instrumental control, easy data processing and optimization made MDC ideal technique in chiral resolutions. However, a compact instrument may be useful for routine analytical and clinical laboratories. 9. Conclusion Chiral separation of drugs and pharmaceutical is gaining importance; especially with two or more chiral centre racemates. Due to the complex nature of enantio-resolution multidimensional chromatography is gaining importance in this area. During the write up it was observed that much work has not been carried out on chiral resolution using multidimensional chromatography. However, some publications are available on chiral resolution using multidimensional chromatography. The used modalities of chromatography are high performance liquid chromatography, gas chromatography, super critical fluid chromatography, thin layer chromatography. In this article, the efforts were made to discuss the importance of chiral separations, multidimensional chromatography, future perspectives and challenges. It was also observed that there is a great demand to develop more advance and novel methods for the enantio-resolution of complex racemates. Briefly, this article will be useful for researchers, academicians, government authorities and industrial persons. References [1] B. Testa, Chiral aspects of drug metabolism, Trends Pharmacol. Sci. 7 (1986) 60e64. [2] M. Simonyi, I. Fitos, J. Visy, Chirality of bioactive agents in protein binding storage and transport processes, Trends Pharmacol. Sci. 7 (1986) 112e116. [3] J.G. Cannon, S.T. Moe, J.P. Long, Enantiomers of 11-hydroxy-10methylaporphine having opposing pharmacological effects at 5-HT1A receptors, Chirality 3 (1991) 19e23. [4] W.J. Lough, Chromatographic enantioseparation: Methods and applications, in: second ed.Stig Allenmark. Ellis Horwood Series in Analytical Chemistry, Ellis Horwood, 1991, p. 282. pp, ISBN 0-13-132978-2, J. High Resolut. Chromatogr. 16 (1993) 120e120. [5] D.T. Witte, K. Ensing, J.-P. Franke, R.A. Zeeuw, Development and registration of chiral drugs, Pharm. World Sci. 15 (1993) 10e16. [6] A.G. Rauws, K. Groen, Current regulatory (draft) guidance on chiral medicinal products: Canada, EEC, Japan, United States, Chirality 6 (1994) 72e75. [7] A.D. Mesecar, D.E. Koshland, Sites of binding and orientation in a four-location model for protein stereospecificity, IUBMB Life 49 (2000) 457e466. [8] I. Ali, V.D. Gaitonde, H.Y. Aboul-Enein, A. Hussain, Chiral separation of betaadrenergic blockers on CelluCoat column by HPLC, Talanta 78 (2009) 458e463. [9] I. Ali, H.Y. Aboul-Enein, V.D. Gaitonde, P. Singh, M.S.M. Rawat, B. Sharma, Chiral separations of imidazole antifungal drugs on AmyCoat RP column in HPLC, Chromatographia 70 (2009) 223e227. [10] I. Ali, M. Suhail, M.M. Sanagi, H.Y. Aboul-Enein, Ionic liquids in HPLC and CE: a hope for future, Crit. Rev. Anal. Chem. 47 (2017) 332e339. [11] I. Ali, M. Suhail, Z.A. AL-Othman, A. Alwarthan, H.Y. Aboul-Enein, Enantiomeric resolution of multiple chiral centres racemates by capillary electrophoresis, Biomed. Chromatogr. 30 (2016) 683e694. [12] I. Ali, M. Suhail, M.N. Lone, Z.A. Alothman, A. Alwarthan, Chiral resolution of multichiral center racemates by different modalities of chromatography, J. Liq. Chromatogr. Relat. Technol. 39 (2016) 435e444. [13] I. Ali, M.N. Lone, M. Suhail, Z.A. AL-Othman, A. Alwarthan, Enantiomeric resolution and simulation studies of four enantiomers of 5-bromo-3-ethyl-3-(4nitrophenyl)-piperidine-2,6-dione on a Chiralpak IA column, RSC Adv. 6 (2016) 14372e14380. [14] I. Ali, M. Suhail, L. Asnin, Chiral separation of quinolones by liquid chromatography and capillary electrophoresis, J. Sep. Sci. 40 (2017) 2863e2882. [15] I. Ali, M. Suhail, Z.A. Alothman, A. Alwarthan, Chiral separation and modeling of baclofen, bupropion, and etodolac profens on amylose reversed phase chiral column, Chirality 29 (2017) 386e397.

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