Enantiomer and racemate

For drug substances and drug products, applications for enantiomers and racemates should include a stereochemically specific identity test and/or a stereochemically selective assay. The choice of control tests should be based on the method of manufacture and stability characteristics and, in the case of the finished product, its composition. 

The solubility behavior of enantiomers and racemates has been reviewed by Jacques et al. [141]. Other solid state properties of chiral drugs have been reviewed by Brittain [142]. 

Vlhen the chiral methylation is carried out with 30% aqueous NaOH the indanone is deprotonated at the interface but does not precipitate as the sodium enolate (Figure 11). In this system there are 3 to 4 molecules of H2O per molecule of catalyst available while in the 50% NaOH reactions the toluene is very dry with only 1 molecule of H2O available per catalyst molecule thus forcing the formation of tight ion pairs. Solvation of the ion pairs in the toluene/30% NaOH system should decrease the ee which we indeed observe with an optimum 78% versus 94% in the 50% NaOH reaction. In the 30% NaOH reactions the ee decreases from 78% to 55% as the catalyst concentration increases from 1 mM to 16 mM (80 mM 5, 560 mM CH3CI, 20 C). Based on these ee s rates of formation of (-h)-enantiomer and racemic product can be calculated. When the log of these rates are plotted versus the log of catalyst concentrations (Figure 13) we find an order of about 0.5 in the catalyst for the chiral process similar to that found using 50% NaOH consistent with a dimer-monomer pre-equilibrium. The order in catalyst for the... 

Salom SM, Billings RE, Upton WW, Dalusky MJ, Grosman DM, Payne TI, Berisford GW, Shaver TN, Effect of verbenone enantiomers and racemic endo-brevicomin on response of Dendroctonus frontalis (Coleoptera Scolitidae) to attractant-baited traps, Can JForRes22 S2 i—3 i, 1992. 

Table 1-1 Dissociation Constants (Kd) of the Enantiomers and Racemate of Carvedilol. ...

Dicarboxy-2,2, 5,5 -tetraalkyl-3,3 -bithienyls (128a,b) were resolved into enantiomers and racemization experiments were carried out in 0.1 N sodium hydroxide solution (67AK115). The racemization of the tetramethyl derivative 128a was 80 times faster than that of the tetraethyl derivative 128b at 120°C. By comparison, biphenyl analogue 129 shows no racemization after 4 hr at 150°C. 

TABLE 9.2 Solubilities of separated enantiomers and racemic mixtures of conglomerate materials... 

In Section IV the computer simulation is extended to describe the effects of excitation in chiral molecules and racemic mixtures of enantiomers. The modification of the dynamical properties brought about by mixing two enantiomers in equimolar proportion may be explained in terms of rotation-translation coupling. The application of an external field in this context ai iplifies the difference between the field-on acf s and cross-correlation of enantiomer and racemic mixture and provides a method of studying experimentally the fundamental phenomenon of rotation-translation coupling in the molecular liquid state of matter. 

Specifically in this section we investigate laboratory and moving-frame differences between the molecular dynamics of the rec-butyl chloride enantiomers and racemic mixture, both at equilibrium in the supercooled condition and in their response to an extemd electric field. 

The effect of chiral discrimination at equilibrium is illustrated in Fig. 6 for the angular velocity acf of both enantiomers and racemic mixture at... 

SO K, in the supercooled liquid condition of the 2-chlorobutanes. There is little difference among the three cases, and this is buried in the statistical noise generated by the computer run. In the case of the center-of-mass velocity acf s in the same, equilibrium, condition (Fig. la) the difference between enantiomers and racemic mixture does, however, fall outside the noise, and this is an indication that the mixture of right and left stereoisomers has dynamical properties different from those of each component. 

The real enantiomers of the iluorochloroacetonitrile molecule have been synthesized recently and are available for >ectral investigation of then-molecular dynamics. The first results on the simulation of liquid fiuoro-chloroacetonitrile at 133 K, 1 bar, are reported in this section in the form of rise and fall transients for the enantiomers and racemic mixture. The site-site parameters for this simulation are given in Table II. The site symmetry in fiuorochloroacetonitrile is such that the net dipole moment reverses in direction from RioS enantiomer. In the R and S enantiomers the transients are mirror images, and transient averages of the type vanish for all... 

From physicochemical viewpoints, enantiomers and racemates are often very different from one another. For example, it has been shown that individual enantiomers of ibuprofen have greater water solubility and faster dissolution than their racemates (30). A formulation of S-ibuprofen, therefore, may have more rapid absorption and consequently a shorter onset of analgesia. This is important, as evidence exists in the literature in support of a meaningful relationship between ibuprofen serum concentrations and its analgesic effects (31). Hence, a more rapidly absorbed formulation may provide shorter onset of action, Therefore, as a pain reliever, stereochemically pure NSAIDs may be preferable to their respective race-mates. Furthermore, one may take advantage of the single enantiomer s greater solubility to prepare various soluble formulations of NSAIDs and products with an accelerated dissolution rate. 

Early studies on monolayers of chiral molecules like 2-hydroxyalkanes, amphiphilic amino acids, 2-methylhexacosanoic acid esters, and hydroxy-hexadecanoic acid and its esters have been reviewed. The interesting question about monolayers of chiral molecules is whether the parameters which can be determined and the phase transitions are different for pure enantiomers and racemates. For components of biomembranes like phosphatidylcholines 10 this appears not to be the case," but for synthetic compounds like iV-(a-methylbenzyl-stearamide) 11 specific interactions between the molecules of the enantiomers are observed (Chart 2). ° In recent years, advanced techniques have been developed to probe the order in monolayers at the air-water interface, including surface X-ray diffraction, and microscopic techniques, viz. fluorescence microscopy, and Brewster angle microscopy (BAM). The X-ray diffraction technique has been used to identify homochiral and heterochiral two-dimensional domains in mono-layers of racemic amphiphilic amino acids on subphases containing glycine. Fluorescence microscopy requires the introduction in the monolayer of a small... 

A. Chiral Carbon Atoms, Enantiomers, and Racemic Mixtures... 

An interesting method for distinguishing enantiomers and racemates has been proposed by Tekely and coworkers [47] for the determination of enantiomers in P-chiral oxazaphosphorine derivatives (Fig. 3.2.18). 

We prepared the enantiomers and racemates of these compounds both as hydrochlorides and methiodides and so, effectively, we studied the enantiomers and race-mate of 4 compounds (Fig. 2). 

Fig. 2. Molecular structure of the hydrochlorides and methiodides of the enantiomers and racemates of the dimethylaminoethyl N-methylpiperidin-4-yl 2-cyclohexyl-2-hydroxy 2-phenylacetates.

We examined the enantiomers and racemates of I and II by 4 tests for anticholinergic potency. 

RESULTS OF TESTING THE ENANTIOMERS AND RACEMATES OF COMPOUNDS I AND II FOR ANTICHOLINERGIC... 

Weissbuch, I., Berfeld, M., Bouwman, W., Kjaer, K., Als-Nielsen, J., Lahav, M., Leiserowitz, L. Separation of enantiomers and racemate formation in two-dimensional crystals at the water surface from racemic - amino acid amphiphiles design and structure, J. Amer. Chem. Soc. 119 (1997) 933-942. 

It should be possible to distinguish the crystals of pure optical isomers and racemic mixtures by solid-state NMR because intermolecular interactions render them diastereomeric whereas solute-solute interactions are generally so weak in solution that enantiomers and racemates have identical spectra. Hill, Zens and Jacobus [169] used solid-state C-NMR to determine the (+ )(R,R), ( ) and mejo-forms of tartaric acid. Each gave separate chemical shifts for the two carbonyl and two a-carbons in the molecule and the four chemical shifts were different for each form. Thus, the classical diastereoisom-ers could be distinguished and solid-state NMR forms the basis of a method of determination of optical purity. 

The next chemical modification was an attempt to bury the isosteric modification more deeply within the molecule in order to lessen its effect on overall molecular shape, viz. (3a) and (3b) with -heptyl groups in place of methyl. Comparison of the powder patterns in Figures 7(a)-7(d) clearly indicates four different crystal structures for enantiomers and racemates of (3a)... 

Table 1 Solubilities of Separated Enantiomers and Racemic Mixtures of Conglomerate Materials...

In general, the vibrational spectra of enantiomers and racemic mixtures will be identical. Exceptions arise where there are differences in the hydrogen bonding pattern between the two enantiomers which may cause differences in the spectra, or where a racemate crystallises as a racemic crystal (i.e. each unit cell contains one molecule of each enantiomer, rather than a two-phase mixture of the components). 

SOLID-STATE PROPERTIES OF CRYSTALLINE ENANTIOMERS AND RACEMATES... 

---