Chiral resolution, drugs

CARBON-13 NMR SPECTRA SMALL PEPTIDES DIHYDROFOLATE REDUCTASE ANTIBIOTICS CHIRAL RESOLUTION DRUG METABOLISM... 

The first partial chiral resolution reported in CCC dates from 1982 [120], The separation of the two enantiomers of norephedrine was partially achieved, in almost 4 days, using (R,R )-di-5-ric my I tartrate as a chiral selector in the organic stationary phase. In 1984, the complete resolution of d,1-isoleucine was described, with N-dodecyl-L-proline as a selector in a two-phase buffered n-butanol/water system containing a copper (II) salt, in approximately 2 days [121], A few partial resolutions of amino acids and drug enantiomers with proteic selectors were also published [122, 123],... 

In another study, the authors reported a comparative study of the enantiomeric resolution of miconazole and the other two chiral drugs by high performance liquid chromatography on various cellulose chiral columns in the normal phase mode [79], The chiral resolution of the three drugs on the columns containing different cellulose derivatives namely Chiralcel OD, OJ, OB, OK, OC, and OE in normal phase mode was described. The mobile phase used was hexane-isopropanol-diethylamine (425 74 1). The flow rates of the mobile phase used were 0.5, 1, and 1.5 mL/min. The values of the separation factor (a) of the resolved enantiomers of econazole, miconazole, and sulconazole on chiral phases were ranged from 1.07 to 2.5 while the values of resolution factors (Rs) varied from 0.17 to 3.9. The chiral recognition mechanisms between the analytes and the chiral selectors are discussed. 

These polysaccharide-based stationary phases appear to be the most useful in organic, bio-organic and pharmaceutical analysis. Of the above-mentioned derivatives three of them, namely cellulose tris-(3,5-dimethylphenylcarbamate), amylose tris-(3,5-dimethylphenylcarbamate) and cellulose tris-(4-methylbenzoate), have very complementary properties and numerous publications have demonstrated that they have been able to achieve the chiral resolution of more than 80% of the drugs currently available on the market. " These CSPs are known under the commercial names, Chiralcel OD-H , Chiralpak AD and Chiralcel OJ , respectively (Figure 4). Their very broad enantiorecognition range is also the... 

The selection of the mobile phase is the key aspect in chiral resolution. The mobile phase is selected according to the solubility and the structure of the drugs to be resolved. In the normal phase mode, the use of pure ethanol or 2-propanol is recommended. To decrease the polarity of the mobile phase and increase the retention times of the enantiomers, investigators use hexane, cyclohexane, pentane, or heptane as one of the main constituents of the mobile phase. However, other solvents (e.g., alcohols, acetonitrile) are also used in the mobile phase. Normally, if pure ethanol or 2-propanol is not well suited for the mobile phase, pure ethanol and hexane, 2-propanol, or ethanol in the ratio of 80 20 is used as... 

Attempts have also been made to compile the results of chiral resolutions by SFC using polysaccharide-based CSPs, as summarized in Table 11. To show the nature of the SFC chromatograms, Figure 28 represents the SFC chiral resolution of ibuprofen on a Chiralpak AD CSP. Stringham et al. [144] resolved the enantiomers of four intermediates encountered in the process of developing synthetic antiviral drugs on a Chiralcel OD CSP. In another report, Blackwell... 

The effect of various SFC parameters on chiral resolution were also studied. Modifiers can provide control over both retention and selectivity and, therefore, certain modifiers were used to optimize the separation in sub-FC and SFC. The effect of the enantioselectivity of carbon dioxide on acidic drugs (benzoxaprofen, temazepam, and mephobarbital), profen, and barbiturate derivatives was carried out on Chiralcel OJ, with acetonitrile or methanol as organic modifier [140]. Acetonitrile proved to be a good alternative to methanol, especially for the profen compounds that were not well resolved when methanol was used. Wilson [143] studied the effects of methanol, ethanol, and 2-propanol as organic modifiers on the chiral resolution of ibuprofen on Chiralpak AD CSPs. Methanol was found to be the best organic modifier. 

Armstrong et al. [54] resolved the enantiomers of some amino acids and their derivatives on x-CD-based CSPs using 1% aqueous triethylammonium acetate (pH 5.1). The same authors also tested a /LCD CSP for the chiral resolution of amino acids [55]. In addition, they evaluated a y-CD phase for the enantiomeric resolution of some dansyl amino acids and other drugs. The mobile phase was 38% methanol with 1% triethylammonium acetate [58]. In another study, the same authors reported the chiral resolution of 25 pairs of amino acids in less than 30 min [63]. The enantiomers of some /i-adrcncrgic blockers were resolved on a /LCD stationary phase, with 1% aqueous triethylammonium acetate, containing methanol, as the mobile phase [9,48]. 

Major advances have been made in recent years in the development and optimization of chiral resolutions of derivatized CD-based CSPs [68]. It has been reported that CSPs based on CD derivatives were more enantioselective than CSPs obtained from native CDs [68]. An acetyl /CCD column exhibited enhanced separation for scopolamine in comparison to the native / -CD CSP in the reversed-phase mode [69]. The enantiomeric resolution of some drugs was compared on the native [l-CD and on CSPs based on (S)- and (i )-2-hydroxy-propyl /I-CD, and the best resolution was reported on the derivatized CSPs [44]. Five types of natural and chemically modified [>- or y-C D stationary phases were developed and used for the chiral resolution of dansyl amino acids. The best resolution of dansyl amino acids was provided by y-CD CSPs [70]. 

Sometimes, the use of high-concentration buffers in the reversed-phase mode decreases column life and efficiency. Therefore, the use of an alternative mobile phase (i.e., normal phase) is an advantage in chiral resolution with these buffers. The most commonly used solvents in the normal phase mode are hexane, cyclohexane, and heptane. However, dichloromethane, acetone, propanol, ethyl-acetate, ethanol, and chloroform also have been used as mobile phase solvents. Hargitai and Okamoto [110] used hexane-2-propanol (in different ratios) as the mobile phase in the chiral resolution of several drugs. These authors also studied... 

TABLE 8 Chiral Resolutions of Some Drugs on 4-Chloro-3-methylphenylcarbamate Derivatives of a-, /J-, and y-CDsa... 

TABLE 9 Chiral Resolutions of Some Drugs on Phenylcarbamate Derivatives of /1-CDs with Variations in the Nature and Position of the Substituents on the Phenyl Ring... 

TABLE 10 Chiral Resolutions of Some Drugs on 3-Chloro-4-methyl (CSPs 8 and 15, Bonded to Silica via the Narrow Opening of CD) and 3-Chloro-2-methyl (CSPs 13 and 16, Bonded to Silica via the Wider Opening of CD) Phenylcarbamate Derivatives of... 

Stalcup et al. [44] reported an interesting effect of spacers on the chiral resolution of some drugs, namely, there was no chiral resolution without a spacer between the CD and the silica gel. Chankvetadze et al. [49] studied the effects of such spacers on the chiral resolution of certain drugs. Two types of spacer, 4,4 -diphenylmethane diisocyanate and hexamethylene diisocyanate, were used to... 

The Pirkle-type chiral stationary phases are quite stable and exhibit good chiral selectivities to a wide range of solute types. These CSPs are also popular for the separation of many drug enantiomers and for amino acid analysis. Primarily, direct chiral resolution of racemic compounds were achieved on these CSPs. However, in some cases, prederivatization of racemic compounds with achiral reagents is required. The applications of these phases are discussed considering re-acidic, re-basic, and re-acidic-basic types of CSP. These CSPs have also been found effective for the chiral resolution on a preparative scale. Generally, the normal phase mode was used for the chiral resolution on these phases. However, with the development of new and more stable phases, the reversed phase mode became popular. 

In 1973, Stewart and Doherty [9] resolved enantiomers of tryptophan on a column packed with BSA-succinoylaminoethyl-agarose in a discontinuous elution procedure. The mobile phase used was 0.1 M borate buffer (pH 9.2). The chromatograms of this classical research are shown in Figure 2. Several years later, this technique was applied for the chiral resolution of warfarin enantiomers [10]. In 1981, the enantiomers of tryptophan and warfarin racemates were resolved on various serum albumin CSPs [11,21,22]. The same method was used for the resolution of other drugs [12-14]. Allenmark et al. [23] studied the resolution of a series of active racemic sulfoxides on a BSA column using 0.08 M phosphate buffer (pH 5.8) as the eluting solvent. 

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