Impurities, degradation

Normally, degradants are chemical breakdown compounds of the drug substance formed during storage. In rare cases, degradants are formed when the drug 

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When a plant was taken out of use, the cooling water lines were left full of water. Dismantling started nearly 20 years later. When a mechanic cut a cooling water line open with a torch, there was a small fire. Bacteria had degraded impurities in the water, forming hydrogen and methane [20]. 

CEC using a binary solvent composition containing ACN and tetrahydrofuran provided rapid and reliable separation of norgestimate and its four degradation impurities within... 

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. 

Boccardi, G., Deleuze, C, Gachon, M., Palmisano, G, and Vergnaud, J. P. (1992), Autoxi-dation of tetrazepam in tablets Prediction of degradation impurities from oxidative behavior in solution, J. Pharm. Sci., 81,183-185. 

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. 

Boccardi G. Autoxidation of drugs prediction of degradation impurities from results of reaction with radical chain initiators. II Farmaco 1994 49(16) 431-435. 

Alsante KM, Snyder KD, Swartz M, Parks C. Application development using out-of-the-box-software a structure searchable degradation/impurity database. Sci Comp Instrument 2002 30-37. 

B. The Fate of the Unstable Peroxy Species The Origin of the Stable 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. 

At least two systems can be cited as catalysts of peroxide oxidation the first are the iron (III) porphyrins (44) and the second are the Gif reagents (45,46), based on iron salt catalysis in a pyridine/acetic acid solvent with peroxide reagents and other oxidants. The author s opinion is that more than systems for stress testing these are tools useful for the synthesis of impurities, especially epoxides. From another point of view, they are often considered as potential biomimetic systems, predicting drug metabolism. Metabolites are sometimes also degradation impurities, but this is not a general rule, because enzymes and free radicals have different reactivity an example is the metabolic synthesis of arene oxides that never can be obtained by radical oxidation. 

V-Formylkynurenine is one of the 16 autoxidation products of tryptophan (51) (Fig. 8). The dye-sensitized photo-oxygenation of tryptophan in sodium carbonate - acetic acid buffer (pH 7) gave TV-for my Iky n urenine as the major product (52). This is also the oxidation product of tryptophan with hydrogen peroxide (53) and with ozone (54). This is an interesting case the same degradation impurity can be obtained in different ways, probably... 

The first step of the design of stress experiments should be to examine the molecular formula of the test compound. Does the structure resemble substances for which a degradation pattern is already known Does it contain easy oxidizable functional groups Do tautomers exist, that can be more sensitive to oxidants Can pH affect the sensitivity, because prototropic equilibria can generate easily oxidizable species Are potential degradation impurities available Time spent in answering these questions and in collecting literature data is never lost. 

Hydrogen peroxide is a good test to produce selected degradation impurities, but also has some predictive value. Sensitivity to hydrogen peroxide can predict interaction with peroxide generating excipients. Moreover, a positive result of both AIBN and hydrogen peroxide is a strong evidence that the test substance is susceptible to oxidation. 

Boccardi G, Deleuze C, Gachon M, Palmisano G, Vergnaud JP. Autoxidation of tetrazepam prediction of degradation impurities from the oxidative behaviour in solution. J Pharm Sci 1992 81 183-185. 

Levels of three individual degradation products and the total amount of degradation impurities were monitored at timepoints of 1, 2, 4, 8, 12, and 24 weeks. Statistical software was used to analyze the data and derive models for the rates of degradation as a function of the temperature and sample water content. The analysis showed that temperature and water content were both significant in their effect on degradation rate (Table 4). The... 

The content of the principal degradation impurity, 3-methylenecarboxyl-6-benzyl-2,5-diketopiperazine (also called 5-benzyl-3,6-dioxo-2-piperazine-acetic acid), is controlled at not more than 1.5% [19, 20]. Other controlled impurities are moisture (i.e., loss on drying, < 4.5%), residue on ignition (< 0.2%), arsenic (< 3 ppm), heavy metals (< 0.001%), and related substances (< 2%) [19]. 

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. 

Specificity Analyte + placebo, synthesis intermediates, exdpients, degradation impurities versus pure analyte. Peak purity and resolution assessed. Resolution >1.5... 

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