Stereoselective chromatography of cardiovascular drugs: an update

J. Biochem. Biophys. Methods 54 (2002) 197 – 220 www.elsevier.com/locate/jbbm

Stereoselective chromatography of cardiovascular drugs: an update Jacek Bojarski * Department of Organic Chemistry, Medical College, Faculty of Pharmacy, Jagiellonian University, Medyczna 9, 30-688 Cracow, Poland

Abstract This review reports the latest achievements in chromatographic enantioseparations of various classes of cardiovascular drugs and selected applications of these methods in pharmaceutical and clinical analysis. The use of these drugs as test compounds for new chiral stationary phases and different parameters of chromatographic processes is also presented. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Enantiomer separation; Cardiovascular drugs; h-Blockers; Adrenoceptor agonists; Antiarrhythmic drugs; Calcium channel blockers

1. Introduction Cardiovascular disease is responsible for about 50% of premature deaths in Western industrialized countries [1], and therefore, an extensive search for new and better therapeutic agent is continued in different pharmaceutical laboratories. Many cardiovascular drugs of different classes and therapeutic utility have chiral center(s) in the molecules, and their enantiomers (and/or diastereomers) differ in biological activity [2]. Investigations of the stereospecific fate of drugs in the body and requirements of optical purity determinations of chiral drugs before their introduction into the market and during industrial manufacture call for efficient analytical methods of separation of enantiomers. Methods of stereoselective chromatography have long been the methods of choice in this respect and have proven to be very useful for both clinical and pharmaceutical analysis.

* Tel.: +48-12-657-0374; fax: +48-12-657-0262. E-mail address: [email protected] (J. Bojarski). 0165-022X/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 5 - 0 2 2 X ( 0 2 ) 0 0 1 4 3 - 4

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Stereoselective chromatography of cardiovascular drugs has been reported in many research papers and several reviews of a more general nature, dealing with enantioseparations of drugs and summarizing the earlier results [3– 7]. One of the latest reviews devoted solely to the separation of enantiomers of cardiovascular drugs appeared in 1999 and covered the literature up to 1997 [8]. The present review supplements and updates the information contained therein and reports the latest achievements in enantioseparations of different classes of cardiovascular drugs and selected applications of these methods.

2. Bioanalytical enantioseparations 2.1. b-adrenoreceptor blocking drugs (b-blockers) These drugs (Fig. 1) are effective in the treatment of hypertension, prevention of anginal attacks, suppression of cardiac arrhythmia, prevention of myocardial infarction and possibly, amelioration of congestive heart failure [1]. The HPLC enantioseparations of h-adrenergic antagonists in both indirect and direct modes are the most common methods of resolution of enantiomers of these drugs. Earlier literature on this subject was excellently reviewed in 1993 [9,10]. Later years brought further development of these methods and their applications. 2.1.1. Indirect mode This mode has some advantages over the direct one, such as wide applicability, inexpensive achiral column packings and enhancement of detection, due to the possibility of introducing additional chromophores or fluorophores. On the other hand, some disadvantages of this approach include requirements of high optical purity of derivatizing reagents, equal reaction rate for derivatization of enantiomers and the same detector response for the resulting diastereomeric products. Last but not least, the method may be sometimes laborious and time-consuming. Applications of both modes to biological samples may create additional problems with isolation and/or recovery of analytes from the matrix. A new chiral derivatizing agent (1S, 2S) N-[(2-isothiocyanato)-cyclohexyl]-pivalinoyl amide (PDITC) was used for indirect enantioseparations of racemic propranolol, carvedilol, metoprolol, normetoprolol and mexiletine, and its advantages, compared to those of 2,3,4,6-tetra-O-acetyl-h-D-glucopyranosyl isothiocyanate (GITC), were demonstrated [11]. Toyo’oka et al. used (R)-( )-4-(3-isothiocyanatopyrrolidin-1-yl)-7-(N,N-dimethylaminosulfonyl)-2,1,3-benzoxadiazole (DBD-PyNCS) for the derivatization of several hblockers. The derivatized enantiomers were separated on a reversed-phase column with an aqueous acetonitrile mobile phase, containing 0.1% of trifluoroacetic acid (TFA), and using isocratic [12] or linear gradient elution [13]. It was found that the method is particularly suitable for compounds with an isopropylamino moiety but not for those with a tert-butylamino group. The method was successfully applied to the determination of concentrations of propranolol enantiomers in rat plasma and saliva [12]. Eight h-blockers were derivatized with ( )-methyl chloroformate and then the diastereomeric products were separated in reversed phase with an acetonitrile/methanol water system. Different

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Fig. 1. Structures of h-blockers.

optimal conditions were found for the derivatization reaction, and was not completed quantitatively for arotinolol and celiprolol [14]. This procedure was found useful for the determination of the chiral purity of metoprolol enantiomers, yielding a detection limit of 0.03% for each antipode. The enantioseparation of these enantiomers was also achieved in direct mode on a Chiralcel OD column (chiral selector: cellulose tris(3,5-dimethylphenylcarbamate) with n-hexane/ethanol/2-propanol/diethylamine (90:5:5:0.25 v/v) as the

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mobile phase. [15]. Beal and Tett [16] used (S)-( )-a-methylbenzyl isocyanate for the derivatization of pindolol enantiomers and the determination of their concentration in human plasma and urine. The authors claimed that the method was easier and less expensive than the methods reported earlier. The GITC reagent was used for the derivatization of atenolol enantiomers, and the method was applied to in vitro metabolic studies [17]. The applicability of other chiral isocyanate reagents for the derivatization of h-blockers was recently studied for 11 drugs of this class. The results proved that the method is simple, effective, and readily available [18]. A proper selection of internal standard after derivatization of h-blockers was also a matter of discussion [19]. 2.1.2. Direct mode Several papers have recently reported direct analytical HPLC enantioseparation methods for h-blockers in biological fluids. The acebutolol enantiomers and those of its metabolite, diacetolol, where an N-butanoyl substituent is changed to an N-acetyl substituent, were separated on a Chiralpak AD column [chiral selector: amylose tris(3,5-dimethylphenylcarbamate)] using hexane/ethanol/diethylamine (85:15:0.1, v/v/v) as the mobile, phase and were determined in human serum [20]. The results obtained were compared and found similar to those of an indirect chromatographic assay of these enantiomers after derivatization with GITC reagent. The enantiomers of atenolol were assayed in blood and brain extracellular fluid of rats, using one-column (A) and coupled column (B) systems with cellobiohydrolase I as a chiral stationary phase [21]. The mobile phases were 5% 2-propanol in sodium phosphate buffer of pH 6.8, and 50 AM sodiumEDTA for both systems (for System A 50 AM cellobiose was added, to regulate selectively the retention of the internal standard, (S)-metoprolol. Additionally, for System B, a mobile phase with 7.5% acetonitrile in sodium phosphate buffer of pH 6.8 was also used. Enantiomers of the same drug were also analyzed in urine with a column-switching system, teicoplanin as the chiral selector (Chirobiotic T column) and acetonitrile/methanol/ acetic acid/triethylamine (55:45:0.3:0.2, v/v/v/v) as eluent [22]. The methods used fluorescence detection and were validated. A similar technique of column-switching was used for the determination of propranolol enantiomers in rat microdialysate. Both teicoplanin and ovomucoid served as chiral selectors, and 20 mmol/l phosphate buffer (pH 6.9) and acetonitrile was a mobile phase system for an Ultron ES-OVM column [23]. Earlier, propranolol enantiomers and those of a series of its analogs were separated on commercial cellulose [chiral selectors: cellulose tris(4-chlorphenylcarbamate) and cellulose tris(phenylcarbamate) for Chiralcel OF and OC, respectively] and amylose carbamate columns [24]. An enantioselective assay of propranolol, pindolol and oxprenolol was performed on a Chiral-AGP column (chiral selector: a1-acid glycoprotein) and the method was used for studying the enantioselective release of the drugs from the dosage form. [25]. The application of the LC/MS system for the resolution of metoprolol, oxprenolol and pindolol enantiomers on the same column was also briefly described [26]. The enantiomers of metoprolol were also determined in human urine with a coupled column system, and enantioseparation was accomplished on a Chiralcel OD column with nhexane/ethanol/2-propanol/diethylamine (85:7.5:7.5:0.05, v/v/v/v) as the mobile phase. The method was applied to assess the excretion rates of metoprolol enantiomers in healthy human volunteer [27]. The enantioseparations of the same drug and its metabolites were

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investigated on different chiral columns [Chiralcel-OD, Chiral-AGP, Cyclobond I (chiral selector: h-cyclodextrin) and Sumichiral OA-4900 (chiral selector: combined (S)-indoline2-carboxylic acid and (R)-1-(1-naphthyl)ethylamine)] [28]. Chiral chromatography was also used to assess the enantiomeric excess of synthesized metoprolol and its metabolites [29]. The enantiomers of the same drug were determined in plasma in both direct (on Chiralpak AD and Chiralcel OD-H columns) and indirect mode (derivatization with (S)( )-menthyl chloroformate) [30]. The enantiomers of metoprolol and one of its metabolites were also determined in plasma with teicoplanin as chiral selector and a mobile phase consisting of acetonitrile/methanol/methylene chloride/glacial acetic acid/ triethylamine (56:30:14:2:2, v/v/v/v/v) [31]. The method proved useful for bioavailability studies. An interesting method of chromatographic determination of bufuralol enantiomers and its metabolites implies the use of specific antibodies with different affinities to the antipodes and a subsequent chromatographic separation of enantiomers on an Ultron ESOVM column with linear gradient elution from 14:1 to 2:1 0.3% ammonium acetate buffer (pH 6.7) and acetonitrile [32]. To lower the detection limit, three racemic h-blockers were first derivatized with fluorogenic reagent and then the resulting enantiomers were separated on Chiralcel OJ-R [chiral selector-cellulose tris(4-methylbenzoate)-for atenolol and metoprolol] and Chiralcel OD-R (for propranolol) columns [33]. Labetalol (21, Fig. 1) is an antihypertensive drug with both a- and h-adrenoceptor blocking properties and has two chiral centers in the molecule. Its four stereoisomers were assayed in plasma and urine using a Chirex 3022 column with (S)-indoline-2-carboxylic acid (R)-1-(a-naphthyl) ethylamine as chiral selector, hexane/1,2-dichloroethane/ethanol/TFA (55.75:35:9:0.25) as mobile phase and fluorescence detection [34]. Similar results with shorter retention times and other elution pattern were obtained with a different mobile phase {hexane/1,2dichloroethane/[ethanol + TFA (20:1) premixed]/methanol (58:35:7:0.7)} [35]. The use of double-helical nickel chelate as a chiral mobile phase additive for the enantioseparation of labetalol stereoisomers was also reported [36]. A new drug with h-receptor blocking properties as well as anxiolytic-like effects—isamoltane-{1-[2-(1-pyrrolyl)-phenoxy]-3isopropylamino-2-propanol hydrochloride)—was directly resolved on a Chiralcel OD column using n-hexane/ethanol/diethylamine (98:2:0.5, v/v/v) as the mobile phase and UV for detection [37]. Recently, some studies were published on the mechanism of enantioseparations of alprenolol, metoprolol, and propranolol on protein chiral stationary phases [38 – 40]. Although HPLC is the most frequently used method for enantioseparations of hblockers, other techniques are also occasionally reported for that purpose. Thus, application of supercritical-fluid chromatography was explored for enantioseparations of several h-blockers (among other drugs) on different columns and with different mobile phases [41,42]. TLC served for enantioseparation of atenolol, pindolol, propranolol, and propafenone, an antiarrhythmic drug (23, Fig. 2), using (1R)-( )-ammonium-10-camphorsulfonate and N-benzoxycarbonyl-glycyl-L-proline as chiral counter-ion reagents, added to the mobile phase (methanol/dichloromethane in various ratios). It was found that low temperature (5 jC) is required for effective separation [43]. Atenolol, propranolol, and metoprolol enantiomers were separated by TLC after impregnation of the plate with Llysine and L-arginine as chiral selectors. Acetonitrile/methanol solvent systems of different ratios were used as the mobile phases [44]. Finally, the separation of enantiomers of 3-tert-

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Fig. 2. Structures of h-adrenoceptor agonists and antiarrhythmic drugs.

butylamino-1,2-propanediol, an intermediate in the synthesis of (S)-timolol, on a Chiralpak column [chiral selector: amylose (S)-a-methyl benzyl carbamate] may also be mentioned here [45,46].

2.2. b2-adrenoceptor agonists These drugs are mainly used as bronchodilators in the treatment of asthma. The enantiomers of salmeterol (24, Fig. 2) were resolved using a coupled achiral/chiral HPLC system with a Sumichiral-OA 4700 column (with N-[(R)-1-(a-naphthyl)ethylamino-carbonyl]-L-tert-leucine) and determined in human urine [47]. An indirect mode and derivatization with GITC were applied for the resolution of salbutamol enantiomers (25, Fig. 2) in the same body fluid [48], whereas the direct mode on a Chirex 3022 column with a mobile phase of hexane/dichloromethane/methanol/TFA (250:218:31:1, v/v/v/v) was used for the same purpose [49]. Salbutamol enantiomers were also determined directly in plasma, using teicoplanin as a chiral selector and a mobile phase of methanol/acetonitrile/glacial acetic

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acid/diethylamine (50:50:03:0.2 and 40:60:0.3:0.2, v/v/v/v) [50]. Carbuterol (26, Fig. 2) and clenbuterol (27, Fig. 2) enantiomers were separated by RP-HPLC, using nickel(II) chelate in the mobile phase [51,52], whereas the enantiomers of this last drug were determined in animal tissues after derivatization with phosgene and separation by gas chromatography in chiral column of dimethyl h-cyclodextrin [53]. Clenbuterol enantiomers were also resolved on a teicoplanin chiral stationary phase known as Chirobiotic T [54], and the method was applied to the determination of these enantiomers in plasma [55]. Both indirect and direct mode enantioseparations were investigated for terbutaline (28, Fig. 2). In the former, GITC [56] and a-methylbenzyl isocyanate [57] reagents served for derivatizations, whereas in the latter a Sumichiral OA-4900 chiral column and a mobile phase n-hexane/ethyl acetate/ methanol/TFA (240:250:25:1, v/v/v/v) [58] and n-hexane/ethyl acetate/1,2-dichloroethane/ methanol-TFA (240:220:160:35:1, v/v/v/v/v) [59] were applied. 2.3. Antiarrhythmic drugs The enantiomers of metabolites of the antiarrhythmic drug mexiletine (29, Fig. 2) were assayed in human plasma after derivatization with o-phthaldialdehyde and N-acetyl-Lcysteine by RP-HPLC on a Lichrospher RP-18 column with 2-propanolacetonitrile and 0.05 M acetate buffer of pH 5.5 (22:10:68 or 25:10:65, v/v/v) [60]. Diprafenone (30, Fig. 2) was enantioseparated after derivatization with (R)-( )-1-(1-naphthyl)ethyl isocyanate on Nucleosil RP C18 column with methanol/acetonitrile/water/orthophosphoric acid (50:11:20:0.1, v/v/v/v) [61] Both methods were applied to pharmacokinetic studies. Besides, the above-mentioned indirect enantioseparation of propafenone (21, Fig. 2), this drug was also derivatized with GITC reagent [62] and, together with its metabolites, was directly separated on different chiral phases, such as, Chiralcel OD-R with a mobile phase of 0.25 M sodium perchlorate/acetonitrile (60:40, v/v) [63], Chiral-AGP with mobile phase of 10 mM ammonium acetate buffer (pH 5.96)/1-propanol (100:9, v/v) [64], Chiralpak AD with a mobile phase of hexane/ethanol (88:12, v/v) and 0.1% of diethylamine [65], and Chiralcel OD-H, OD-R Chiral-AGP, and Ultron ES-OVM with different mobile phases [66]. The enantiomers of disopyramide (31, Fig. 2) and its dealkylated metabolite were assayed in body fluids by chromatography on a Chiralpak AD column, using hexane/ ethanol (91:9, v/v) with 0.1% diethylamine as the mobile phase [67]. Earlier, the resolution of these analytes was studied also on the Chiralcel OD-H column [68]. The enantiomers of disopyramide and another antiarrhythmic drug, flecainide (32, Fig. 2), as well as those of verapamil (33, Fig. 3)—a calcium channel blocker—were assayed in rat plasma and tissues (on Chiralpak AD column for flecainide and on verapamil and Chiralcel OF for disopyramide, using as mobile phases hexane/2-propanol/diethylamine (82:18:0.1, 96:4:0.1, and 94:6:0.1, v/v/v) for disopyramide, flecainide, and verapamil, respectively [69]. 2.4. Calcium channel blockers Recently published papers on the chiral chromatography of verapamil (33, Fig. 3) report its enantioseparation (and that of its methoxy derivative, gallopamil) on a Chiral-

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Fig. 3. Structures of calcium channel blockers.

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AGP column with a mobile phase of ammonium acetate (pH 6.8)/acetonitrile (89:1, v/v), using UV and MS for detection [70]. The enantiomers of verapamil and its demethylated metabolite were resolved on the same phase, and optimisation studies took into account: buffer pH, content of organic modifier, and column temperature [71]. These enantiomers were also assayed in human urine (on a Chiralcel OD-R phase) [72], serum (also with metabolites on an AGP column with a1-acid glycoprotein as the chiral selector) [73], and plasma (Chiralcel OD-RH column) [74]. The enantiomers of norverapamil and its metabolites were separated in microsomal samples on Chiralcel OD-R and a1-AGP columns [75]. Application of column-switching techniques for verapamil (and other drugs) was discussed in the review [76]. 4-Aryl-dihydropyridines constitute a group of calcium channel blockers used mainly as antihypertensive drugs. Their enantiomers differ in biological activity and their chromatographic enantioseparations are of continuing interest. The earlier methods were reviewed in 1995 [77]. Updating the review [8], one should mention separations of enantiomers of nicardipine (34, Fig. 3) in human plasma, using a Sumichiral OA-4500 column [chiral selector: combined (S)-proline and (R)-1-(1-naphthyl)ethylamine], mobile phase, n-hexane/1,2-dichloroethane/methanol/TFA (250:40:10:1, v/v/v/v/) and UV detection. The method was applied in pharmacokinetic studies [78]. The same authors investigated the resolution of the enantiomers of manidipine (35, Fig. 3) under similar conditions [79]. The effect of different cyclodextrins as chiral selectors in the mobile phase on the HPLC enantioseparation of amlodipine (36, Fig. 3) was investigated and the enantioselectivity was found for anionic but not for the neutral cyclodextrins studied [80]. The enantiomers of amlodipine were semi-preparatively separated on a Chiral-AGP column, and the method was adopted for analytical determinations in plasma [81] and for pharmacokinetic studies [82]. Enantioselective pharmacokinetics of clevidipine (37, Fig. 3)—a new ultrashort-acting drug—was studied using enantioseparation on Chiralcel ODH column [83], whereas the drug and the enantiomers of its primary metabolite (the respective acid without the CH2OOCCH2CH2CH3 moiety) were resolved by supercritical-fluid ion-pair chromatography on porous graphitic carbon with N-benzoyloxy-Larginine as the chiral ion-pair reagent [84] and on a Chiral-AGP column [85]. The nisoldipine (38, Fig. 3) enantiomers were separated on a Chiralcel OD-H column with the mobile phase n-hexane/ethanol (97.5:2.5, v/v) and determined in human plasma for pilot pharmacokinetic study [86]. Isradipine (42, Fig. 3) enantiomers were resolved on a Chiralcel OJ column at 39 jC, using 9.5% 2-propanol in hexane as the mobile phase [87]. Recently, the TLC resolution of felodipine (39, Fig. 3) enantiomers was accomplished on the Chiralplate (a Macherey-Nagel plate coated with a reversed-phase silica gel and impregnated with a chiral selector, being a proline derivative, and copper(II) ions) according to the ligand-exchange principle, using two mobile phase systems: chloroform/ 25% ammonia (10:0.2) and acetonitrile/triethylamine (5:3), modified with different amounts of methanol [88]. Two asymmetric carbon atoms are present in the molecule of diltiazem (43, Fig. 3), yielding two pairs of enantiomers, which were separated on Chiralcel columns (OD, OC and OF) by supercritical-fluid chromatography. The best results (base-line resolution within 8 min) were obtained for the first column; the second one did not give complete enantioseparation, whereas for the last one, the retention times were too long. The results

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were compared with those obtained by HPLC, and higher efficiency was found in SFC, especially on the Chiralcel OD column [89,90]. Stereoselective chromatography on protein columns (human and bovine serum albumin and human a1-acid glycoprotein) also assisted in an assessment of protein binding of semotiadil (44, Fig. 3) and its enantiomer [91]. Chromatographic enantiomeric separations were also applied to some drug candidates of this class [92,93].

2.5. Other cardiovascular drugs Warfarin (45, Fig. 4) is a widely used oral anticoagulant, and its enantiomers were determined in plasma using different stereoselective chromatography systems, like a Chiralcel OD column with a mobile phase of 2-propanol/acetic acid/hexane (18:0.5:81, v/ v/v) [94], a (R,R) Whelk-O 1 column, (chiral selector, 1,2,3,4-tetrahydrophenantrene with 3,5-dinitrobenzamide moieties) with a mobile phase of acetonitrile/0.5% glacial acetic acid (40:60, v/v) [95], a Hypercarb column and dimethyl-h-cyclodextrin at a concentration of 20 mM in the mobile phase of acetonitrile/water/acetic acid/triethylamine (850:150:3:2.5, v/v/v/v) [96], and a h-cyclodextrin column with a mobile phase of acetonitrile/acetic acid/

Fig. 4. Structures of other cardiovascular drugs.

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triethylamine (1000:3:2.5, v/v/v) [97,98]. The enantiomeric purity of warfarin was also checked on a Chiralcel OD column by using 2-propanol with 0.2% acetic acid as the mobile phase [99]. Other anticoagulants—acenocoumarol (46, Fig. 4) and phenprocoumon (47, Fig. 4)—were resolved on a (S,S) Whelk-O 1 column using gradient elution with nhexane/ethanol as the mobile phase [100]. The angiotensin-converting enzyme (ACE) inhibitors are drugs used as antihypertensives. They have two chiral centers in the molecule, and chromatographic separations of their stereoisomers reported recently deal with benazepril (48, Fig. 4) [101], idrapril (49, Fig. 4) [102] and captopril (50, Fig. 4) [103]. Different buffers and organic modifiers were investigated to find the optimal chromatographic conditions. Chlorthalidone (51, Fig. 4) is a diuretic drug used in therapy of hypertension and edema. Chromatographic separations of its enantiomers by cyclodextrin chiral selectors added to the mobile phase, were studied recently, and satisfactory results were reported for underivatized h-cyclodextrin, comparable to those for 2-hydroxypropyl and methyl derivatives. The method may be adapted to the enantioselective determination of the drug in biological samples [104]. Chlorthalidone and warfarin enantiomers were also resolved on Hypercarb column with dimethyl-h-cyclodextrin in the mobile phase by supercriticalfluid chromatography [105]. Synephrine (52, Fig. 4) is a sympathomimetic drug, its main metabolite is phydroxymandelic acid. The enantiomers of this last compound were assayed in urine after resolution on a chiral ligand-exchange column [Sumichiral OA-6000 (chiral selector: combined (L)-tartaric acid and (R)-1-(1-naphthyl) ethylamine)]. The mobile phase was water with 1 nM copper(II) acetate and 20 nM ammonium acetate/methanol (99:1, v/v) [106]. Another sympathomimetic drug, metyrosine (53, Fig. 4), used for the control of hypertension, was resolved in an indirect mode on an octadecylsilane column in the form of methyl esters of the enantiomers, derivatized with GITC reagent [107]. Metaraminol [(1R,2S)-m-hydroxyphenylpropanolamine], a clinically used vasopressor, and its stereoisomers were separated on a Crownpak CR column (with crown ether as a chiral selector) using 113 mM aqueous perchloric acid as the mobile phase [108]. Debrisoquine, an antihypertensive drug (54, Fig. 4), is not chiral but its hydroxylated metabolite (4hydroxydebrisoquine) has a chiral center in the molecule. Its enantiomers were resolved on a Chiralcel OD-R column using the mobile phase: 0.125 M sodium perchlorate (pH 5.0)/acetonitrile/methanol (85:12:3, v/v/v), and the method was applied to metabolic studies [109]. A vast majority of the methods mentioned above was designed for and applied to the analytical determination of cardiovascular drugs in body fluids. These methods were optimized and validated, the resolutions were performed on commercial chiral stationary phases and their applications to pharmacokinetic or metabolic studies were often reported. There are also many papers devoted mainly to such studies where enantioselective chromatographic methods are only briefly described. Therefore, only their citations are presented here in chronological order [110 – 130]. Other papers deal with pharmaceutical analysis topics [131 – 133] and applications of stereoselective chromatography in the synthesis of cardiovascular drugs [134 – 136]. Some preparative enantioseparations of chiral drugs were also reported. They dealt with the enantiomers of h-blockers (2, 16, and 18) resolved by flash chromatography on cellulose tris(3,5-

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dimethylphenylcarbamate) column [137], the antiasthmatic drug formoterol (55, Fig. 4) resolved on a Chiralcel OJ column [138], and the enantiomers of propranolol hydrochloride separated on a Chiralpak column [139].

3. Cardiovascular drugs as chromatographic test compounds There is another broad field of stereoselective chromatography where enantioseparations of cardiovascular drugs are explored. Many of these drugs, among other compounds, are used as test substances in studies of the resolving power of novel chiral stationary phases of different kinds and of the effects of different parameters of the chromatographic process (temperature, amount of modifier, etc.) on the quality of enantioseparation. The drugs used for such studies are summarized in Table 1 for polysaccharide and antibiotic phases, whereas in Table 2, for protein chiral stationary phases used in HPLC. Other chiral stationary phases, tested with cardiovascular drugs, comprise chitosan derivatives (45)— [192], cholic acid (2,4,15,17,18,22) [193], molecularly imprinted polymers (nine different h-blockers and four propranolol metabolites [194], 15,18 [195]) and others (45 [196]). Quite recently, the enantioseparation of a number of h-blockers was studied on normal and reversed-phase Chiralcel columns (OD and OD-RH, respectively), where the latter was used in normal and narrow-bore versions. Hexane/2-propanol/diethylamine mixtures were used as mobile phase in the normal-phase mode, and sodium perchlorate buffer, containing different amounts of acetonitrile, in the reversed-phase mode. Sixteen and eleven compounds were resolved under normal-phase and reversed-phase conditions, respectively

Table 1 Cardiovascular drugs used as test compounds for enantioseparations by HPLC on polysaccharide and antibiotic chiral stationary phases Polysaccharide phases a

Drug no.

b

1,2,4,15 – 19,21,22 15,17,18,45 15,18,45,51 10,15,17,18, 22,45 17,18,22,34 17,18,45 4,18 5,15,17,18 16,18,19,31 18 1,2,4,15 – 19,21,25,27,33,34d 45 a b c d

Numbers refer to Figs. 1 – 4. Additionally: isoproterenol and nadolol. Additionally: coumachlor. Additionally: nadolol.

Antibiotic phases Reference

Drug no.a

Reference

[140] [141 – 143] [144] [145] [146] [147] [148] [149] [150] [151] [152] [153]

15,45,51 33c 18,45 45c 4,17,45 15 4,17,33,45

[154] [155] [156] [157] [158] [159] [160]

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Table 2 Cardiovascular drugs used as test compounds for enantioseparations by HPLC on protein chiral stationary phases Drug no.a

Reference

Drug no.a

Reference

37 45 18,33 – 36,40,42,45b 15,17,18,51 18,31,33 – 36,40,42,45c 15,16,45,51 32,51 56d 2,16,18,45 2,18,31 2,18

[161] [162 – 171] [172] [173] [174] [175] [176] [177] [178] [179] [180]

2,16,18 2,15,18 19 2,16,18 15,18,29,45,51 18 36,45 2,16,18 38 – 42 2,15,18 2,4,15,16,18,28,29,45

[181] [182] [183] [184] [185] [186] [187] [188] [189] [190] [191]

a b c d

Numbers refer to Figs. 1 – 4. Additionally: practolol, gallopamil, lercanidipine, bepridil. Additionally: practolol, gallopamil, bepridil. Additionally: deglymidodrine.

[197]. In another study, it was found that, for the resolution of the same class of drugs, a Pirkle phase [chiral selector—N-(3,5-dinitrobenzoyl)-3-amino-4-phenylazetidin-2-one] gives satisfactory results [198]. Selected cumulative data on the separation of cardiovascular drugs on different chiral stationary phases can be also found in review articles [199 – 202]. Several papers report the stereoselective chromatography of compounds closely related to actually used cardiovascular drugs, which may be considered as drug candidates. They are exemplified by a series of reports of enantioseparation under different conditions of several amino alcohols synthesized at the Astra Ha¨sle laboratories [203 –209] Another paper describes comparative studies of enantioseparations on eight commercially available chiral stationary phases of a set of 29 aza-analogs of nifedipine-type dihydropyridine calcium channel modulators with different substituents in the heterocyclic ring [210]. The performance of a vancomycin chiral stationary phase was checked for a set of compounds with h-blocking activity [211] and the structure/enantioselectivity relationships were studied for that class of compounds on this and teicoplanin phases [212]. The enantioseparation of a new h-blocker, nebivolol, was studied on Chiralpak AD and AD-RH columns [213], whereas resolution of verapamil and its metabolites was tested on Chiralpak AD and on Chiralcel OJ and OD-R columns [214]. Drugs like nos. 17, 18, 52, and isoproterenol, among other compounds, converted to pentafluoropropionyl and heptafluorobutyryl derivatives have served for testing chiral stationary phases of polydimethylsiloxane, anchored with (S)-( )-tert-leucine derivatives for capillary gas chromatography [215].

4. Conclusion The enantioseparations presented above clearly demonstrate that stereoselective chromatography of cardiovascular drugs is an active research field with prospects for further

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development. The results are very important not only for a better therapeutical use of these drugs, but also for expansion of our knowledge about their stereochemical fate in the body and for still on-going discussions about their applications in pure enantiomeric forms [216 – 218].

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