Stereochemical purity specifications

The guideline on chiral active substances states that particular attention should be paid to identity and stereochemical purity. It states that specifications for a racemate should include a test to show that the substance is indeed a racemate and this is a position supported by the requirements of the European Pharmacopoeia for drug substance monographs [16]. 

The basic point of the chemical approach to proof of structure of a naturally occurring phosphatidylcholine was to illustrate the type of information that can be gathered by rather simple, straightforward techniques. The proof of structure is not complete, since the stereochemical purity of the compound and the positioning of the fatty acyl chains—whether saturated and unsaturated are equally distributed between C-l and C-2 or specifically located on one or the other of the carbons (1 and 2)—remain to be elucidated. 

Optical rotation has the dual advantages of historical use and widespread recognition in the compendia. For an enantiopure material, it defines its configuration when used in conjunction with other valid chemical tests. However, optical rotation has been used ineffectively when the primary analytical goal is the determination of stereochemical purity. The limits selected for the specification seem to be unrelated to the purity required by other methods. For example, the compendial monograph for naproxen requires that the drug substance meet a specification of "between -f-63.0 and -1-68.5"" in a chloroform solution. Based on the published specific rotation, this corresponds to a stereochemical purity of 95.5 to 103.7%, compared to the assay limits of 98.5 to 100,5%, determined by titration with sodium hydroxide (5). 

A major disadvantage of optical rotation as a measure of stereochemical purity is that interpretation of the single value lacks significance if any impurities are chiral. To insure the validity of an optical rotation specification, it should be supported by specific rotation measurements on any known chiral impurity or degradation product. This is, of course, in addition to the usual studies of the effects of solvent, concentration, and temperature on the specific rotation of the principal analyte. 

A lactide synthesis reactor invariably produces a crude lactide stream that contains lactic acid, lactic acid oligomers, water, mc50-lactide, and further impurities. The specifications for lactide are stringent mainly for free acid content, water, and stereochemical purity. Basically, two main separation methods, distillation and crystallization, are currently employed for lactide purification ... 

In conclusion, the most important quality specifications for lactide monomers are those of free acidity, water, metal ion content, and stereochemical purity. 

Despite the convenience of handling and separation in heterogeneous catalysis, many other parameters have a strong influence on the stereochemical outcome pressure temperature modifier purity of substrates high substrate specificity catalyst preparation, which includes type, texture, and porosity of the support dispersion impregnation reduction and pretreatment of the metal.22 Reproducibility of catalyst activities and enantioselectivities can often be a problem attributed to variations in catalyst preparations and purity of the substrate.5-22... 

Application of natural products to pest control is subject to similar considerations to those that affect synthetic compounds. Elucidation of structure may be a relatively routine matter, but synthesis may present difficulties, particularly where there are several stereochemical possibilities. There are often great differences in biological activity among different stereoisomers and the presence of Inactive Isomers in a product may be undesirable. However, such technical problems can be overcome as in the case of the synthetic pyrethroids where specific stereoisomers of high purity are now produced on a commercial scale. 

The specifications for both enantiopure and racemic chiral drug substances should be sufficient to establish both chemical and stereochemical aspects of identity, strength, quality and purity. This implies both that the identity test use a stereochemically specific method and that the assay method be stereochemically selective. 

An attempt to obtain evidence for this hypothesis was made. Reduction of l-hydroxyl-4-pentanone might proceed via a stereochemically less favorable, seven-membered ring intermediate, and the product (1,4-pentanediol) of much less than 30% optically purity might result. Although optically active diol was obtained, no assignment of optical purity could be made since the diol could not be transformed stereo-specifically, despite several attempts, into 2-methyl-tetrahydrothiophene-1-dioxide, whose maximum rotation is known (18). The validity of the above hypothesis thus remains moot. 

In considering the potency ratios quoted above, it should be remembered that it is difficult to obtain the optical isomers of these alkaloids in a state of high purity, that their solutions racemize with great ease, and that the pharmacological measurements are not very accurate. Nevertheless, the stereochemical specificity of hyoscyamine and scopolamine is of great interest. The usual explanation of such specificity is that the drug forms a three-point attachment to some asymmetrical structure in the living cell on which it acts and consequently that only one of the optical isomers has... 

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