Drug substance oxidation

Note in the above reaction scheme that molecular oxygen is involved in the propagation step of the reaction and is integral to the catalytic cycle responsible for the generation of drug substance oxidative degradation in pharmaceutical formulations. 

Stability of a drug substance and product is monitored throughout the development and clinical phases. This monitoring requires stability-indicating assay methodology, and this is a subject that is separate from performulation per se. In most instances, the major, feasible decomposition products are identified early [51], and as such it is known if the pathways are hydrolytic, oxidative, or photochemical. 

Calcitriol drug substance may be analyzed polaro-graphically, using a glassy carbon working electrode. The limiting current of the observed oxidation wave (E =... 

Chemical instability of medicinal agents may take many forms, because the drugs in use today are of such diverse chemical constitution. Chemically, drug substances are alcohols, phenols, aldehydes, ketones, esters, ethers, acids, salts, alkaloids, glycosides, and others, each with reactive chemical groups having different stability characteristics. Chemically, the most frequently encountered destructive processes involve hydrolysis and oxidation. 

In drug product formulation work, steps are taken to reduce or prevent the occurrence of drug substance deterioration due to hydrolysis, oxidation, and other processes. 

The drug substance in qnestion was known to degrade via an oxidative pathway that in solntion is enhanced by low pH and levels of heavy metals in the presence of oxygen. Two specific impurities 3,5-dihydroxybenzaldhyde and l-tert-bntyl 4,6,8-trihydroxytetrahydroiso-quinoline were known to increase nnder these conditions (Figure 5) and these were the same two that cansed the validation to fail. 

Oxidation. Oxidative studies are designed to reveal the primary oxidative degradation products due to oxidation. Oxidative degradants in drug substances and drug products normally are the result of reaction with molecular oxygen. As in the case of acid/base hydrolysis, appropriate controls are necessary. 

For sterile drug substances, an understanding of the drug substance and the sterilization process will help in avoiding potential impurities, for example, compounds formed by the appropriate functional groups of the drug substance reacting with residual ethylene oxide from the sterilization process. 

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. 

It is common practice to utilize forced degradation studies to accelerate degradation of the drug substance or drug product to get an understanding of its degradation profile. Potential environmental conditions that can be used include 40°C and 75% relative humidity (RH), 50°C and 75% RH, 70°C and 75% RH, or 80°C and 75% RH. Oxidation, reduction, and pH-related degradations are... 

Oxidative degradation is as important as hydrolysis in the stability evaluation of new drug substances. The oxygen concentration in solution is a factor in many cases and often depends upon the solvent employed. It was reported that ascorbic acid is more stable in 90% propylene glycol or in Syrup USP than in water, presumably because of the lower oxygen concentration in these vehicles (Ravin and Radebaugh, 1990). 

In addition, one may consider the addition of an antioxidant since soft gelatin capsule shell is permeable to oxygen, resulting in oxidation of oxygen-sensitive, active drug substance. However,... 

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