Chiral purity properties

Molecules which exhibit optical activity are molecules which have a handedness in their structure. They are chiral . Chemists often have reasons to obtain chemical pure aliquots of particular molecules. Since the chirality of molecules can influence biological effect in pharmaceuticals, the chiral purity of a drug substance can pose a challenge both in terms of obtaining the molecules and in assaying the chiral purity by instrumental methods. While diastereomers can have different physical properties including solubility, enantiomers have the same physical properties and the same chemical composition. How then to separate optically active molecules ... 

Numerous methods are required to characterize drug substances and drug products (Chapter 10). Specifications may include description identification assay (of composite sample) tests for organic synthetic process impurities, inorganic impurities, degradation products, residual solvents, and container extractables tests of various physicochemical properties, chiral purity, water content, content uniformity, and antioxidant and antimicrobial preservative content microbial tests dissolution/disintegration tests hardness/friability tests and tests for particle size and polymorphic form. Some of these tests may be precluded, or additional tests may be added as dictated by the chemistry of the pharmaceutical or the dosage form. 

Property data from pharmaceutical prohling is not exclusively for optimizing PK. It can be considered as part of the multivariate ensemble of data (e.g., MW, chirality, purity, IC50, LD50) that is available to research teams for application to any drug-discovery experiment. 

The oil possesses moderate antibacterial and strong antifungal properties. Thus the appHcation of the oil to the cmst of cheese could serve to prevent the formation of mycotoxia ia the cheese. The optical purity of the carvone ia caraway has been determined usiag a chiral gc column (72). It was found to be (i )(+) = 97.64% and (5 )(—) = 2.36%. 

What happens for a nonracemic mixture of enantiomers Is it possible to calculate the values of the chiral properties of the solution from knowledge of the properties of the enantiopure compound In principle, yes, on the condition that there is no autoassociation or aggregation in solution. Then, the observed properties will be simply the weighted combination of the properties of two enantiomers. A nice example of where this normal law may be broken was discovered by Horeau in 1967 it is the nonequivalence between enantiomeric excess (ee) and optical purity (op, with op = [a]exi/[ ]max) for 2,2-methylethyl-succinic acid. In chloroform op is inferior to ee, while in methanol op = ee. This was explained by the formation of diastereomeric aggregates in chloroform, while the solvation by methanol suppresses the autoassociation. 

From other approaches to optically active [2.2]metacyclophanes the following are noteworthy as just mentioned for 64 (medium pressure) liquid chromatography on microcrystalline triacetylcellulose (cf. Ref. 82 ) in ethanol or ether (practicable also at lower temperatures) is a very efficient and successful method for the optical resolution of many axial and planar chiral (aromatic) compounds 83). In many cases baseline-separations can be achieved and thereby both enantiomers obtained with known enantiomeric purity and in amounts sufficient for further investigations, especially for studying their chiroptical properties (see also 3.2 and 3.3). The disub-stituted [2.2]metacyclophanes 57 and 59 (which had been previously correlated to many other derivatives) 78- 79) were first resolved by this method83). 

For [2.2]paracyclophane-4-carboxylic acid (25) as (—)(R) This result has been mentioned in a footnote in Ref. 1011 but seems never to have been published (see also Ref. 61). The chirality of this acid was correlated via its ( )-aldehyde with a levo-rotatory hexahelicene derivative which, according to the paracyclophane moiety at the terminal, had to adopt (A/)-helicity. Its chiroptical properties are comparable to those of hexahelicene itself101. For the (—)-bromoderivative of the latter the (A/)-helicity was established by the Bijvoet-method 102). In a later study, (—)para-cyclophane-hexahelicene prepared from (—)-l,4-dimethylhexahelicene with known chirality (which in turn was obtained with approximately 12% enantiomeric purity by asymmetric chromatography) confirmed these results. It should be mentioned that [2.2]paracyclophane-4-carboxylic acid (25) was the first planar chiral cyclophane whose chirality was determined 1041 (see also Ref.54 ). The results justmentioned confirmed the assignment (+)( ). 

Resolution Methods. Chiral pharmaceuticals of high enantiomeric purity may be produced by resolution methodologies, asymmetric synthesis, or the use of commercially available optically pure starting materials. Resolution refers to the separation of a racemic mixture. Classical resolutions involve the construction of a diastcrcomcr by reaction of the racemic substrate with an enantiomerically pure compound. The two diastereomers formed possess different physical properties and may be separated by crystallization, chromatography, or distillation. A disadvantage of the use of resolutions is that the best yield obtainable is. 50%, which is rarely approached. However, the yield may he improved by repeated raccmization of the undcsired enantiomer and subsequent resolution of the racemate. Resolutions are commonly used in industrial preparations of homochiral compounds. 

The measurement of the optical rotatory power of chiral substances has been of major importance in the characterization of the enantiomeric purity. A number of computational techniques have been developed in the last year to evaluate this property. A recent review [142] shows in detail the advances in this field. Application of the new implementation of the evaluation of the optical rotatory power has allowed to the study of the conformational [143-146] and solvent effects [147,148] on the magnitude and sign of the optical rotation power. 

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