Pseudoracemate

Certain pairs of enantiomers, such as 25°C solutions of camphor in aqueous ethanol (Fig. 26a), 2,2,5,5-tetramethyl-l-pyrrolidinoxy-3-carboxylic acid in chloroform (Fig. 26b), or carvoxime in hexane (Fig. 26c), cocrystallize throughout the entire range of mole fractions. The crystals that are in equilibrium with the saturated liquid solution are solid solutions (mixed crystals), since they constitute a single phase. The racemic solid solution is termed a pseudoracemate [141]. 

Figure 26 shows the ternary phase diagrams (solubility isotherms) for three types of solid solution. The solubilities of the pure enantiomers are equal to SA, and the solid-liquid equilibria are represented by the curves ArA. The point r represents the equilibrium for the pseudoracemate, R, whose solubility is equal to 2Sd. In Fig. 26a the pseudoracemate has the same solubility as the enantiomers, that is, 2Sd = SA, and the solubility curve AA is a straight line parallel to the base of the triangle. In Figs. 26b and c, the solid solutions including the pseudoracemate are, respectively, more and less soluble than the enantiomers. 

Fig. 26 Isothermal solubility diagrams of the three types of pseudoracemates (see text). The appearance of the tie lines is shown in the right half of the triangles. (Reproduced with permission of the copyright owner, John Wiley and Sons, Inc., New York, from Ref. 141, p. 197.)...

The racemic compound forms crystals containing a 1 1 ratio of d- and /-molecules in a regular array. The pseudoracemate, eventually, forms crystals with both d- and /-molecules in an irregular arrangement and in any ratio. The corresponding phase diagrams are shown in Figure 13. 

The conglomerate shows a lower melting point (and hence, a higher solubility) than the individual enantiomers. From a melt or a solution with an enantiomeric ratio +1 1, the excess enantiomer crystallizes in pure form. The racemic compound may have a lower (curve 1) or a higher (curve 2) melting point (or solubility) than the corresponding enantiomers the eutectic mixture (E), however, always lies at a minimum. Finally, crystallization of pseudoracemates always yields enantiomerically impure samples. 

Takacs, J.M., Hrvatin, P.M., Atkins, J.M., Reddy, D.S. and Clark, J.L. (2005) The selective formation of neutral, heteroleptic zinc(ll) complexes via self-discrimination of chiral bisoxazoline racemates and pseudoracemates. New J. Chem., 29, 263—265 Atkins, J.M., Moteki, S.A., DiMagno, S.G. and Takacs, J.M. (2006) Single enantiomer, chiral donor—acceptor metal complexes from bisoxazoline pseudoracemates. Org. Lett., 8 (13), 2759-2762. 

Table 2 Pharmacokinetic Parameters for Propranolol Enantiomers in Dog and Man after i.v. Administration of a Deuterium-Labeled Pseudoracemate and Their Bioavailability and Urinary Excretion upon Oral Administration...

Walle, T. (1985). Stereochemistry of the in vivo disposition and metabolism of propranolol in dog and man using deuterium-labeled pseudoracemates. Drug Metab. Disp., 13 279-282. 

M. E. Jones, B. C. Sallustio, Y. Purdie, and E J. Meffin, Enantioselective disposition of 2-arylpropionic acid non-steroidal anti-inflammatory drugs. II. 2-Phenylpropionic acid binding, /. Pharmacol. Exp Ther., 238 288 (1986). R. A. O Reilly, W. E Trager, C. H. Motley, and W. Howald, Stereoselective interaction of phenylbutazone with (12C/13C) warfarin pseudoracemates in man, /. Cfm. Invest., 65 746 (1980). 

R. A. O Reilly, W, E Trager, C. H. Motley, and W. Howald, Interaction of secobarbital with warfarin pseudoracemates, Clin. Pharmacol. Then, 28 187 (1980). 

Enantiomers are stereoisomers, which are mirror images of eath another. An equimolecular mixture of two enantiomers is called a racemate. Crystalline race-mates occur in three different types. The first is termed a conglomerate, that is, a mechanical mixture of crystals of pure enantiomers that is formed from two solid phases. The most common type is the racemic compound, which consists only of one crystalline phase in which the two enantiomers are present in equal quantities. The third type is the pseudoracemate in which a solid solution of the two enantiomers is present. 

D. Determination of Differences in Pharmacokinetic Parameters of Enantiomers and Drug-Interaction Studies—Pseudoracemate Approach... 

A pseudoracemate approach, wherein one of the isomers of the race-mate is stable labeled and acts as a stereochemical marker, circumvents the issues related to derivatization methods and use of chiral columns for analysis of race-mates. Separation and detection by mass spectrometry, using another stable-labeled variant as the internal standard when possible, allows quantitation of the... 

T Walle, MJ Wilson, UK Walle, SA Bai. Stereochemical composition of propranolol metabolites in the dog using stable isotope labelled pseudoracemates. DrugMetab Disp 11 544—549, 1983. 

RA O Reilly, WF Trager, CH Motley, WN Howald. Stereoselective interaction of phenylbutazone with (12C/13 Qwarfarin pseudoracemates in man. J Clin Invest 65 746—753, 1980. 

UG Eriksson, K-J Hoffman, R Simonsson, CG Regardh. Pharmacokinetics of the enantiomers of felodipine in the dog after oral and intravenous administration of a pseudoracemic mixture. Xenobiotica 21 75, 1991. 

Alternatively, they can form a solid solution (a pseudoracemate) in which one enantiomer replaces the other at random in the packing arrangement. This situation, extremely rare in practice, would be characterized by either a maximum or a minimum in the melting point diagram and by the same X-ray powder diffraction pattern over the entire range of concentrations [15]. 

There is a third form of solid state organization of racemic compounds, called the sohd solution or pseudoracemic compound. This is a rare form in which the arrangement of the enantiomers in the crystal is variable and not defined. The significance of this is that, while the stoechiometry of the two enantiomers in the whole crystal may well be 1 1, it is possible to find homochiral unit cell structures, one enantiomer being substituted for the other. Such disorder arises from the strong similarity of the two enantiomers, particularly in the case of quasispherical molecules. This arrangement is also called a racemic solid solution of the two enantiomers. 

Mitchell, A. G. Racemic Drugs Racemic Mixture, Racemic Compound, or Pseudoracemate J. Pharm. Pharm. Sci. 1998, I, 8-12. 

A crystalline racemate may exist as a conglomerate, a racemic compound, or a pseudoracemate (Fig. 1). A racemic conglomerate is an equimolar eutectic mixture consisting of crystals of the two opposite enantiomers. 

Figure 1 Schematic representation of the molecular arrangements in three t) es of racemates (a) enantiomeric or homochiral crystal (same chirality) (b) racemic or heterochiral crystal (paired enantiomers) (c) pseudoracemate or solid solution (randomly arranged enantiomers). (Adapted from Ref. 11.)...

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