Impurities chiral

Ferretti et al. (1988) used an amino column coupled to a derivatized amylose column (Chiralpak AS) operated in the reverse-phase mode to separate the enantiomers of the antifungal agent voriconazole from several chiral impurities and one achiral impurity. Three of the chiral impurities are the other enantiomer and corresponding diastereomers of voriconazole. More chiral impurities result from a chlorinated voriconazole. Additionally, this multidimensional method could baseline separate all but two of the chiral impurities into their respective enantiomers. These separations are shown in Figure 14.5. 

Newly used chiral surfactants often have a low critical micellar concentration, are highly soluble and can be synthesized both in L- and D-forms. This last feature makes it possible to easily change the migration order of the optical isomers, which is very interesting for the determination of the optical pnrity of drugs, where for quantification purposes it is favorable that the chiral impurity migrates before the main component. 

By complexation, compounds with low solubility in aqueous media can be solubilized. Chiral selectors can also enhance the separation of non-chiral impurities from the drug... 

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. 

Huang et al. [96] developed a method for the enantiomeric purity determination of (6 )-ornidazole in raw material and injection solution that was used in an preclinical study. In this publication, a mobile phase of n-hexane, MeOH, and 2-PrOH (95 4 1) was used with a Chiralcel OB-H column. No chiral impurity (/ )-ornidazole was detected above the LOD (0.05%) in either the raw material or the injection solution (see Figure 17.4D and E). The separation of the racemate is presented in Figure 17.4A, and the minor peak in Figure 17.4B corresponds to an enantiomeric impurity of 0.5%. 

The precision and accuracy of polarimetry critically depends on temperature, solvent, and traces of achiral and chiral impurities. 

The guidance recommends treating chiral impurities as though they were achiral impurities with the caveat that the ICH identification and... 

Since the enantiomeric distribution, i.e., the incidence of generating the R or S product, did not appear clearly as random but seemed to be correlated to the specific set-up used and to the order in which the experiments were carried out, the authors interpreted these results as possibly caused by chiral impurities in the starting mixture [34]. However, attempts to detect these impurities failed. In essence, the experiments of Singleton and Vo showed that... 

Subsequent attempts by Singleton and Vo supported these results [36]. Also in this case, a clear random distribution of the R and S enantiomers in a number of the 54 experiments was observed, indicating that a systematic effect coming from chiral impurities may be excluded. Each experimental rim afforded a clearly detectable prevalence of either the R or the S enantiomer, giving rise to a total of 27 events in which the R enantiomer dominated and 27 events in which the S enantiomer was found in excess (no quantification of the particular ee was given). 

For example, the sergeants and soldiers experiment features a preferential screw-sense helical amplification in optical active copolymers with racemic helical structures named by Green et al. [17,18], This effect means that a small portion of enantiopure chiral side groups determines the overall screw sense (P or M) of the helical main chain bearing a majority of achiral side groups, and a population of helicity with one preferential screw-sense is nonlinearly amplified as a function of the chiral impurity. Since the first report of this phenomenon in poly-a-olefin copolymers by Pino et al. [21],... 

Although catalytic transformations gained increasing importance after the First World War, asymmetric reactions were considered at the time to be an academic curiosity. Of note, the determination of enantioselectivity was hampered by a lack of methods to achieve not only efficient purification but also reliable analyses. Hence, the presence of a chiral impurity - which often arose from the catalyst -spoiled the determination of the correct, optical rotation-based ee-values. 

Singleton and Vo [157] demonstrated that an excess of 60000 D molecules of the alcohol in the starting solution yields an induced asymmetric induction of the same alcohol after several catalytic cycles. On the other hand, when they performed the same reaction with racemates 54 times, the reaction was driven towards the formation of the D- 27 times and towards the formation of the L-alcohol 27 times. These reference experiments suggest that the reaction is not affected by unforeseen chiral impurities present in the environment. Based on these results, the authors suggested that their observations are more consistent with an asymmetric synthesis originating from the chance ee present in the racemic mixture. 

Whereas the Soai system does not develop intrinsic spontaneous asymmetry (the ee in an undoped Soai system, which pretends to do so, is not statistical, and therefore the appearance of asymmetry is attributed to the action of a chiral impurity [15]), Asakura et al. report random variations of ee values (up to 4- or — 25-30%) in the creation of asymmetry by chiral autocatalysis in the reaction of a trinuclear Co complex with ammonium bromide [142]. The authors propose a stochastic model. The reactions quickly reach a state of supersaturation of the racemic chiral product, and enantiopure autocatalytic clusters of 10 and more product molecules are formed, which tips the reaction to one enantiomeric side. 

A theoretical explanation has been developed to explain the effect of chiral impurities on the crystallization rates of the enantiomorphic components of a conglomerate system [31]. The theory provides the time required to complete the crystallization of the separated enantiomers, suggests that one might be able to obtain an enantiomerically pure product even if the chiral impurity was less than enantiomerically pure, and even provides information regarding the particle size distribution. The model was tested on the crystallization of (D,L)-glutamic acid that was carried out in the presence of a resolved (L)-lysine impurity. 

D.K. Kondepudi, K.E. Crook, Theory of conglomerate crystallization in the presence of chiral impurities, Cryst. Growth Des. 5 (2005) 2173-2179. 

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. 

Several chiral substituted a-phenyl-alkyl alcohols, which were partially enantio-merically enriched, were successfully purified by this method after esterification with 9-anthroic acid optical purities higher than 95% were obtained.Fluorescence studies of racemic compounds show a characteristic a-type excimer emission, whereas the chiral enantiomer exhibits a typical y-type monomer emission. Figure 7 shows the spectra of l-(2-chlorophenyl)ethyl 9-anthroate for a crystalline sample of enantiomeric (1) and racemic (2) at 77 K. It has been demonstrated that in the absence of configurational disorder chiral impurities in the range of 1 % can be detected by this method. ... 

It should be noted that none of the terminologies given above adequately highlights polymorphic, solvatomorphic, and chiral impurities (see Section III). 

Chiral molecules are frequently called enantiomers. Enantiomers are optical isomers that have the same chemical structure but different spatial arrangement, which leads to different optical rotation. It is important not to overlook them because the d-isomer of a compound can have different pharmacologic or toxicologic activity from that of the 1-isomer.11 Therefore, the undesired optical isomer is considered a chiral impurity of the API. Furthermore, it is important to remember that the number of chiral impurities increases with the increasing number of asymmetric carbon atoms in a molecule. 

In addition to the residual solvents, polymorphic, solvatomorphic, and chiral impurities mentioned previously, impurities in a pharmaceutical compound or a new chemical entity (NCE) can originate during the synthetic process from raw materials, intermediates, and/or by-products. Raw materials are usually produced to lesser purity requirements than a drug substance. Therefore, it is easy to understand why they could include a number of components that in turn could have an impact on the purity of the drug substance. 

Figure 13.14 Identification of chiral impurities in pharmaceutical /evo-thyroxine sodium salt [78].

Chiral impurities present a particularly difficult problem however, the specification guidelines require the following conditions ... 

Tests for New Drug Substances That Are Optically Active. Chiral impurities had been excluded from ICH guidelines on impurities because of the practical difficulties of measuring them. However, in Q6A, a decision tree describes if, and when, chiral identity tests, impurity tests, and assays may be needed for both new drug substances and products, according to criteria such as the following ... 

The cannabinergic ligand library includes a number of key enantiomeric pairs that have found substantial use in laboratories engaged in cannabinoid research. A careful examination of the literature reveals striking discrepancies in reported bioenantioselectivities. These are generally attributable to inadequate chiral resolution leading to a chirally impure enantiomer. Variation in enantioselectivity can... 

For optical purity to accurately reflect enantiomeric purity, it is obvious that the sample must be free of any chiral impurities. It may not be as obvious that achiral... 

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