Achiral purity methods

MS compatibility is not a must, but preferred. For achiral purity methods an alternative MS compatible, supportive method is available to support identification... 

Chiral or achiral assay and purity determinations are done according to an external calibration calculation procedure, either with or without internal standardization. The calibration is performed against a 10% w/w (compared to the nominal concentration of the sample solution at 100% w/w) reference standard solution. The sample solution for the purity determination remains at the 100% w/w level, while that of the assay determination is diluted 10 times. The reason for the difference in concentration levels is similar to the purity method. A suggested sample injection sequence can be... 

For compounds with one or more stereocenters, it is prudent to screen the key samples (10-20% degradation timepoint) with the current chiral purity method to determine if the degradation pathway is stereospecific. From the achiral method development perspective, stereospecific degradation pathways will not affect the outcome of the method development process, but this information can affect the impurity control strategy for the compound. 

In principle, separation of resonances of diastereomeric compounds (such as dl and meso isomers) may be increased simply through use of an appropriate achiral solvent. Chiral solvents may in some cases be especially effective in producing a separation, particularly if the diastereomers differ in configuration about a center that is amenable to analysis by the CSA method. Kaehler and Rehse (89) give a detailed account of conditions necessary for measurement of the ratio of meso- and dZ-tartaric acid employing A,N-dimethyl PEA. Bomyl acetate used as solvent for l,2-difluoro-l,2-dichloroethane (90) allows measurement of the diastereomeric composition. Paquette and co-workers (91,92), using TFAE, were able to determine the diastereomeric purity of the recrystallized adducts 47 of... 

Progress of the reaction was monitored using a GC equipped with a FID on an achiral CP 1301 capillary column (30 m x 0.25 mm x 0.25 m film) and N2 as carrier gas. Enantiomeric purity of 2-octanol was analysed after derivatization with acetic anhydride (see below) using a CP-Chirasil Dex-CB column (25 m x 0.32 mm x 0.25 pm film, column B) and H2 as carrier gas. Enantioselectivities (expressed as the enantiomeric ratio E) were calculated from enantiomeric excess of the product and conversion as previously reported. Retention times and methods are listed in Table 3.1. 

PLATE I Determination of the enantiomeric purity of active pharmaceutical ingredient (main compound = MC, peak I is the enantiomeric impurity). Conditions lOOmM sodium phosphate buffer pH = 3.0, lOmM trimethyl -cyclodextrin, 60 cm fused silica capillary (effective length 50 cm) X 75 pm I.D., injection 10 s at 35 mbar, 25°C, 20 kV (positive polarity) resulting in a current of approximately lOOpA, detection UV 230 nm. The sample solution is dissolved in a mixture of 55% (v/v) ethanol in water. (A) Typical electropherogram of an API batch spiked with all chiral impurities, (B) overlay electropherograms showing the selectivity of method toward chiral and achiral impurities, a = blank, b = selectivity solution mixture containing all known chiral and achiral compounds, c = API batch, d = racemic mixture of the main compound and the enantiomeric impurity. 

The determination of enantiomeric purity (ee) by NMR spectroscopy is usually carried out with the help of a nonracemic chiral auxiliary compound. NMR methods not requiring a chiral auxiliary compound are also known and are based on self-association of the enantiomers or on their reaction with a bifunctional achiral compound (see Section 3.1.4.7.). 

A highly versatile method for enantiomer analysis is based on the direct separation of enantiomeric mixtures on nonraceinic chiral stationary phases by gas chromatography (GC)6 123-12s. When a linearly responding achiral detection system is employed, comparison of the relative peak areas provides a precise measurement of the enantiomeric ratio from which the enantiomeric purity ee can be calculated. The enantiomeric ratio measured is independent of the enantiomeric purity of the chiral stationary phase. A low enantiomeric purity of the resolving agent, however, results in small separation factors a, while a racemic auxiliary will obviously not be able to distinguish enantiomers. 

Actually, it is very hard to determine whether the crystals (or solid) are doped in chiral or achiral. The space group can be determined by only X-ray crystallographic analysis. Now, we can conveniently survey the crystal from the measurement of CD spectra (KBr or nujor method)[8] or activity of SHG (Second Harmonic Generation). [9] However, sense of high accuracy is required for the use of both methods. When we could observe a Cotton effect from the CD spectra, the crystal system should be chiral. On the other hand, there are many examples of chiral crystals that exhibit quite a little Cotton effect. As a matter of course, it is also difficult to recognize chiral crystals when the enantiomeric purity is poor. 

There are several alternative methods for the synthesis of optically active polymers from achiral or racemic monomers that do not involve polymerization catalysts. Optically active polymers have been formed from achiral dienes immobilized in a chiral host lattices [ 106]. In these reactions, the chiral matrix serves as a catalyst and can be recovered following the reaction. For example, 1,3-penta-dienes have been polymerized in perhydrotriphenylene and apochoUc acid hosts, where asymmetric induction occurs via through-space interactions between the chiral host and the monomer [107,108]. The resultant polymers are optically active, and the optical purities of the ozonolysis products are as high as 36%. In addition, achiral monomers have been found to pack in chiral crystals with the orientations necessary for topochemical soHd-state polymerization [109]. In these reactions, the scientist is the enantioselective catalyst who separates the enantiomeric crystals. The oligomers, formed by a [27H-27i] asymmetric photopolymerization, can be obtained in the enantiomeric pure form [110]. 

Dienes (80) and (81) were synthesized by previously described methods. The inherent facial selecti-vities of these dienes in their reactions with benzaldehyde under achiral [Eu(fod)3] catalysis were determined (Scheme 29). In line with previous precedents, these reactions are highly endo specific, thus giving rise to a two-component mixture of (82) and (83). The extent and sense of the facial inductions were ascertained by conversion of this mixture to (68) and (69). The optical purities of compounds (68) and (69) were determined by NMR methods using chiral shift reagents. The data shown in Scheme... 

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