Degradation-impurity process

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. 

Analytical potency method development should be performed to the extent that it is sufficient for its intended purpose. It is important to understand and know the molecular structure of the analyte during the method development process, as this will facilitate the identification of potential degradation impurities. For example, an impurity of M + 16 in the mass spectrum of a sample may indicate the probability of a nitrogen oxide formation. Upon successful completion of method development, the potency method will then be validated to show proof that it is suitable for its intended purpose. Finally, the method validated will be transferred to the quality control laboratory in preparation for the launch of the drug substance or drug product. 

Diazotization in the presence of boron trifluoride enables diazonium tetrafluoroborates to be isolated from the reaction mixture and purified. Subsequent controlled decomposition produces the required fluoroaromatic. Although explosion hazards and the toxicity of the isolated salts are significant concerns with this process, known as the Balz-Schiemann process, 4,4 -di-fluorobenzophenone (BDF. 6) has been prepared by this route as a monomer for the production of the engineering plastic poly(ether ether ketone) , or PEEK , by condensation with 1,4-dihydroxybenzene in the presence of potassium carbonate. BDF 6 is superior to its chlorine analog because in aromatic systems the nucleophilic displacement of fluorine is more facile than that of chlorine, leading to a shorter polymerization time and a better quality product containing less degradation impurities. 

Hydroperoxides are the early products of autoxidation and can be found as degradation impurities, but the most stable products develop in side reactions involving hydroperoxides and peroxy radicals. Some of these processes surrounding the formation and decomposition of hydroperoxides will be summarized here. 

Level III is applied during clinical phase III and for the submission, as well as for important intermediates, and corresponds to the ICH requirements. At this stage of development, the commercial synthetic process for drug substance is established, and important process and degradation impurities have been identified and synthesized. The final formulations and dosages have also been established. 

Actual case studies using these isolation and syntheses as well as mass spectral and NMR approaches are outlined in the remainder of this chapter. This collaborative multidisciplinary strategy is applied to the structure elucidation of all the impurity and degradant case studies presented. The successful elucidation of these structures was essential to predict potential toxicity, set threshold limits, and identify ways to prevent or greatly reduce their formation. The case studies have been organized into degradation and process-related impurities examples. 

The key degradation-impurity sample set for a given compound is equal to the degradation key sample set plus the process-related impurity sam-... 

An HPLC method for the estimation of potency and determination of degradation products is an integral part of release testing. The analytical method should be stability indicating and capable of separating the active ingredient peak from degradation product, process impurity, and excipient-related peaks (Fig. 1). 

Some organic molecules are able to absorb optical irradiation and pass on the increased energy to other molecules, which then degrade these processes are called photosensitized or secondary photochemical reactions. The absorbing molecules, which are denoted photosensitizers, are not decomposed in the photochemical reactions. Excipients, solvents, or small amounts of impurities may act as photosensitizers that initiate the photochemical reaction in the formulation. The photosensitizers may be present in concentrations not detectable by conventional analytical methods, such as UV-visible absorption spectroscopy or HPLC with UV detection. 

Some tramp impurities ate products of degradation of process ingredients. The presence of tramp impurities can frustrate and tax technical support organizations because it is a Imost never clear whether or not their effects are a curiosity or a determinant of significant outcomes. While risky and often painful to experience, a fruitful strategy for management of technical resources is to ignore tramp impurities. 

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