Related Impurities

Another point is related to the high acidity level of the final solution, which leads to certain limitations in the subsequent technological steps. Specifically, the high acidity of the initial solution eliminates any possibility for selective extraction, i.e. sequential separation of tantalum and then of niobium. Due to the high concentration of acids, only collective extraction (of tantalum and niobium together) can be performed, at least at the first step. In addition, extraction from a highly acidic solution might cause additional contamination of the final products with antimony and other related impurities. In order to reduce the level of contaminants in the initial solution, some special additives are applied prior to the liquid-liquid extraction. For instance, some mineral acids and base metals are added to the solution at certain temperatures to cause the precipitation of antimony [455 - 457]. 

Litowski, J. R., Semchuk, P. D., Mant, C. T., and Hodges, R. S., Hydrophilic interaction/cation-exchange chromatography for the purification of synthetic peptides from closely related impurities Serine side-chain acetylated peptides, /. Peptide Res., 54, 1, 1999. 

D acquarica, I., Gasparrini, F., Giannoli, B., Badaloni, E., Galletti, B., Giorgi, F., Tinti, M.O., Vigevani, A. (2004). Enantio- and chemo-selective HPLC separations hy chiral-achiral tandem-columns approach the combination of CHIROBIOTIC TAG and SCX for the analysis of propionyl carnitine and related impurities. J. Chromatogr. A 1061, 167-173. 

Figure 13.17 gives an example of some process-related impurities that can be resolved by TLC. 

High pressure liquid chromatography is the standard method used to quantify the API and related impurities. It is often used to measure solubility. 

A primary role of crystallization is to purify the desired product and exclude impurities. Such impurities are frequently related in chemical structure to the desired product, through the mechanisms of competitive reaction and decomposition. Where the impurities are similar in structure it is likely that their interactions with the solvent in the liquid phase will also be similar. In this instance the selectivity of crystallization is mainly attributed to the difference between the respective pure solid phases. The ideal solubility equation can be applied to such systems [5, 8] on a solvent free basis to predict the eutectic composition of the product and its related impurities. The eutectic point is a crystallization boundary and fixes the available yield for a single crystallization step. 

Product-related impurities are molecular variants of the desired product (e.g., precursors, certain degradation products arising during manufacture and storage) which do not have properties comparable to those of the desired product with respect to activity, efficacy, and safety.2 Variants may exert different biological effects (potentially uncontrolled or hazardous) and specifically lead to antibody formation in the patient.3... 

Process-related impurities Impurities that are derived from the manufacturing process. They may be derived from cell substrates (e.g., HCPs, host cell DNA), cell culture (e.g., inducers, antibiotics, or media components), or downstream processing (e.g., processing reagents or column leachables). 

FIGURE 13 (a) Overlay chromatograms of an API and its related impurities on five HPLC... 

As mentioned previously, process related impurities are typically starting materials, by-products of side reactions, intermediates, or reagents. Starting materials are easy to identify as their structure is known, and their retention times can be quickly compared to known standards during method development. Reagents that are organic in nature could fall into... 

A recent review on CE of small-molecule pharmaceuticals dedicates one part to the determination of drug-related impurities. ... 

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