Limiting impurity

Although in several cases complex multicomponent mixtures are purified, the optimization problem can usually be reduced to the investigation of a binary mixture because there always exists a limiting impurity that elutes closest to the major component. The limiting impurity sets the constraint for the throughput, production rate, recovery yield, and other parameters. 

The maximum production rate, however, often results in nnacceptable recovery yields. Low recovery yield requires further processing by recycling the mixed fractions. The recovery yield at the maximum production rate strongly depends on the separation factor. In the cases of difficnlt separations, when the separation factor under linear conditions is aronnd or lower than a= 1.1, the recovery yield is not higher than 40%-60%. Even in the case of a=1.8, the recovery yield at the maximum production rate is only about 70%-80%. The situation is still less favorable in displacement chromatography, particularly if the component to be purified is more retained than the limiting impurity. In this case, from one side the impurity, whereas from the other side the displacer, contaminates the product. 

Which performance criteria have to be evaluated depends also on the purpose of the method. Different ICFI/USP guidelines are set up for (1) identification tests, (2) impurity tests, and (3) assay tests. An identification test ensures the identity of an analyte in a sample by comparison to a known reference material. An impurity test is intended to confirm the identity of (limit impurity test) or to accurately quantify (quantitative impurity test) an impurity, defined as an entity which may normally not be present. An assay test finally implies the major component or active ingredient in a sample and quantifies the drug substance as such as a whole or the drug substance in a drug product. 

Method Performance Parameter Identification Test Impurity Test Limit Impurity Quantitative Test Impurity Test Assay Test... 

For impurity tests (limit impurity test, quantitative impurity test) and assay tests, the accent lies on the ability to determine or discriminate for the analyte in the presence of other interferants. Selectivity can be assessed by spiking samples with possible interferants (e.g., degradation products) [55,56,72]. 

Identify possible limiting impurities (may be revised as process development prtKceds). 

Identify mobile-phase c-omposition. stationary phase, temperature and particle size which give the greatest separation factor of the product and the expected limiting impurity. 

Based on touching bands between the product and the limiting impurity, the loading factor for the second component is estimated in Eq. (7.11). 

Improving product quality by limiting impurity incorporation requires an understanding of all major incorporation mechanisms as well as their root causes. In determining the primary causes of impurity retention, it is necessary to identify the location and type of impurities in the crystalline phase surface trapped, surface adsorbed, bulk phase, or lattice substituted. A few useful experimental techniques for making these determinations are mentioned below. 

The API must possess appropriate chemical and physical attributes to assure that it delivers the intended pharmacological effect. The chemical attributes describe the appropriate purity and impurity limits. Impurity specifications are established from clinical toxicological studies and are also based on reasonable minimums expected from regulatory authorities and consumers. The physical attributes describe the necessary characteristics for reliable pharmaceutical processing into final dosage forms. These attributes are determined by empirical evidence from formulation trials to produce uniform and stable dosage forms of adequate bioavailability. 

In conclusion, specifications to limit impurities in pharmaceuticals can only be based on proper validated quantitation limits in order to avoid rejecting batches that are maybe of acceptable quality. 

The concentration polarization is a result of decreasing surface concentration of reactant. The restriction can be a result of gas-phase transport limits, impurity absorption at the catalyst surface, liquid blockage in low-temperature fuel cells, or other reasons. The thermodynamic (Nernst) and kinetic concentration polarization at an electrode can be written as... 

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