Impurities/degradants process

Injecting solutions of known process impurities, degradation products, intermediates, homologues, dimers, etc. further challenges the specificity of a method. Identification of these compounds may require an extensive search in order to identify all possible species that may be... 

Impurities generally fall into three main categories process impurities, degradation impurities, and contaminant impurities. Additionally, enantiomers and polymorphs may be considered impurities under some circumstances. 

Selectivity is often referred to as the specificity of an analytical method and is a measure of the discriminating ability of the technique. The general requirement for specificity is that the method should be capable of unambiguously determining the compounds of interest in the presence of impurities, degradation products and other sample matrix components. A specificity study often involves accelerated degradation studies to ensure all degradation products will not interfere and the collection of likely process impurities. Often a placebo sample is assayed to check for interference fi om the sample matrix. 

Determine feasibility for related compounds Analyze all related compounds available (process impurities, degradation products, etc.) and perform purposeful degradation on the API. Determine interferences. 

Analytical procedures have to be developed for the active ingredient as well as for starting materials and the excipients used in the final formulation. These tests should be able to specify and confirm the identity, purity, potency, stability and consistency of these materials. If significant impurities, degradation products or critical metabolites occur, analytical methods for these will also be required. In-process control methods must be devised and developed to observe all relevant steps of the manufacturing process in order to have adequate control over the inherent variants and to detect potentially harmful contaminants at a stage where they may be easier to trace. 

Terephthalic acid is a useful source material of PET, as well as benzoic acid and benzoates. However, in order to recycle the terephthalic acid, produced further purification is required, because other organic compounds are also produced as impurities in the degradation process of waste plastic mixtures, e.g. PE and PET mixtures described in Section 2.3. 

Since pure PP does not Incorporate chromophorlc groups, it is clear that photolnltlatlon of radical degradation processes must Involve chromophorlc impurities. There has been a great deal of discussion of this in the past and hydroperoxides or carbonyl structures formed by oxidation of the parent polymer and transition metal residues from the polymerization catalyst seem to be the most likely candidates. It is not appropriate to discuss this aspect in the present paper, suffice it to say that the association of methane with photolnltlatlon, but not thermal Initiation, suggests that photolnltlatlon Involves C-CH3 bond scission to form chain side radicals in contrast to thermal Initiation which involves scission of the C-C bond In the main chains. 

The last two processes are undesirable chlorophenols have a very strong taste and some of the aliphatic chlorohydrocarbons (e.g. chloroform) are also suspected of being carcinogenic. It is therefore usual to perform the chlorination only up to the chloramine stage and to carry out the further elimination of impurities, e.g. microbiological degradation processes, on activated charcoal. 

Process-related impurities Degradation-related impurities... 

This impurity isolation process (TLC —> HPLC) is commonly utilized in our laboratory. However, the process is tedious and lengthy for extraction from the silica plates, and timing must be coordinated such that the sample is immediately analyzed by the HPLC system to rule out any potential degradation. Sometimes, the band in question is very close to the drug substance or another band, making it difficult to extract for TLC —> HPLC. An alternative is to correlate an impurity by collecting the impurity from HPLC and reapplying it to the TLC system (HPLC — TLC). 

FIGURE I Impurity/degradant isolation and Identification process flowchart (RRT relative retention time PRI = process-related impurity). 

FIGURE 2 Impurity/degradant isolation and identification process flowchart. 

The process of characterization of impurities described in this chapter uses a designed approach for the isolation of unknown impurities and degradants in pharmaceutical drug substances. This approach focuses on efficiency, so that the success of data collection is maximized. The isolation of pure material is crucial when trying to identify the structure of an unknown impurity/degradant. Once the unknown has been isolated, it can be submitted for structure elucidation using mass spectrometry and NMR spectroscopy. 

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