Stereochemical identity specifications

Certain identity tests intended to establish the stereochemical identity of a drug are known. Their applicability to a specific drug substance may vary depending upon the magnitude of differences between the values to be determined. These are discussed below in the following order (which does not suggest the suitability of the technique for regulatory purposes) ... 

Some chiral drug substances either occur naturally or are synthetic derivatives of natural products. In these cases, the controls on the raw materials are often assumed to guarantee the stereochemical identity of the finished bulk drug substance product without the use of a specific stereochemically sensitive test. Such an assertion is of little significance for regulatory purposes. First, determination of the source species for an... 

For any chiral drug, establishment of its stereochemical identity is not an insurmountable technical problem, even for enantiopure material. The techniques of X-ray crystallography and NMR spectroscopy will, in general, lead to conclusions of high certainty, at least for the material studied. However, for enantiopure material, it is critical that the relevance of conclusions based on these techniques be correlated to larger batches of material through chiral properties, such as optical rotation. Of the thousands of published determinations of absolute configuration based on X-ray studies, most are unsupported by such data on solutions of the specific crop of crystals from which a few were selected for study. 

As Z-lelobanidine II also yields Z-lelobanine on oxidation the difference between the I and II forms must be stereochemical and lie in one of the side-chains, in spite of the quantitative identity of their specific rotations. The four asymmetric centres might have the following individual directional effects I. I. d. d. and d. 1. d. 1. in the two forms, but the total effect might be identical. 

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]. 

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. 

In reality, NMR spectroscopy has broadened the scope and absolute possibility for performing more extensive as well as intensive studies with regard to recording the spectrum of isolated and synthesized organic molecules in addition to their mechanistic and stereochemical details hitherto inaccessible. Therefore, NMR spectroscopy finds its applications for compound identification, by means of a fingerprint technique very much identical to that used in lR-spectroscopy. Besides, it is invariably utilized as a specific method of assay for the individual constituents of a mixture. A few typical examples of drug assays will be dealt separately at the end of this chapter to justify its efficacy and usefulness. 

Mineral series Minerals that have an identical basic chemical and structural unit in which small amounts of chemical substitution of similar elements (cations of similar size, stereochemical, and bonding character) in the same site in the crystal structure are usual and predictable. Mineral series are usually defined by the end member species, that is, those compounds that contain only one of the possible cations. Intermediate members may have specific names or be identified by the ratio of the cations (see chapter 2). 

Because diastereomeric impurities and degradation products, as well as geometric isomers, present an analytical challenge that is substantially similar to that of other impurities, the FDA policy statement specifically excludes these stereochemical problems. The considerations here are limited to those that are the direct consequence of the analytical problem of simultaneously quantitating molecules that are identical in their physical (except for the rotation of the plane of polarization of light) and most chemical properties. 

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. 

Many chiral compounds are known by the chemist to be racemic because of the lack of stereoselective influences on the synthesis or to be enantiopure because of natural origin. Such knowledge, while based on a sound technical foundation, may not be suitable for regulatory purposes. For example, the commercial availability of a racemate or the "opposite" enantiomer may make its substitution for the approved component conceivable. Therefore, it may be necessary to bring other factors (e.g synthetic feasibility or commercial sources) into consideration to establish whether a stereochemically specific identity test is necessary. 

A relatively common use of optical rotation is as an identity test for a racemate with specification limits that are symmetrical around zero. Such a specification has Little if any regulatory significance. Its validation necessarily depends upon knowledge of the specific rotation and thus requires the resolution of the racemate on a laboratory scale. Furthermore, even with such supporting data, the method is dependent upon the accuracy of the sample preparation, since a solvent blank would also show a rotation of zero. Other analytical methods are far more appropriate for the stereochemically specific identification of racemates. 

Few drugs make use of X-ray powder diffraction as a regulatory test. However, this method has a unique advantage as a stereochemically specific identity test for chiral drugs. The crystal structure, and therefore the powder diffraction pattern, are necessarily different between the racemate and the enantiomer, except in the case of a racemic conglomerate. Furthermore, published reference data are readily available. In combination with the invariance of the d-spadng measurements, this msy make X-ray diffraction more attractive to the regulatory scientist. 

Stereochemical specificity of drugs, when it occurs, was considered some of the early evidence for the existence of receptors. Since enantiomers have identical chemical and physical properties11 but are nonsuperimposable mirror images of each other, it can be rationally assumed that the three-dimensional shape of the drug is decisive in determining its action. A logical extension of this idea is that at least part of the molecule must be a structure complementary to it. 

The main difficulties associated with constructing the biaryl moiety as a single atropisomer early in the synthesis lies within the arene substitution pattern. The thermal isomerization barrier for a steganone precursor that carries only three ortho substituents is extremely sensitive to the exact identity of those substituents. Specifically, when one of the three groups (e.g., a formyl moiety) adds only a small amount to the inversion barrier and a second substituent (e.g., a methoxy group) is also relatively small, the barrier to inversion renders the biaryl stereochemically labile even at 0 For example, at least one of... 

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