Oxidation of Drugs during Drug Product Development: Problems and Solutions
Abstract
:1. Introduction
2. Oxidation Reactions
- Autoxidation (radical mediated);
- Nucleophilic/electrophilic (peroxide mediated);
- Oxidation that is mediated by single electron to dioxygen.
2.1. Autoxidation
2.2. Nucleophilic/Electrophilic (Peroxide Mediated)
2.3. Oxidation Mediated by Single Electron Transfer to Dioxygen
3. Drug Interactions with Excipient Impurities
3.1. Peroxides
3.2. Metals
4. Prevention
4.1. Peroxide Control Strategies
4.2. Storage Conditions
4.3. Antioxidants
- (a)
- Initiation inhibitors. Antioxidants can prevent radical chain reaction as they react with initiators of radical chain reactions. The most common representative of this group is ethylenediaminetetraacetic acid (EDTA), which can also acts as a heavy-metal chelating agent [81]. It is also necessary to pay attention to the type of metal that is complexed with EDTA. If iron ions are present, the addition of EDTA produces an iron–EDTA complex that, counterintuitively, accelerates the formation of hydroxyl radicals. On the other hand, an iron complex with diethylenetriaminepentaacetic acid does not accelerate the Fenton reaction. However, all of the studies that are described here were performed in aqueous solutions, so without additional testing it is difficult to assume the same applies to solid dosage forms [82].
- (b)
- (c)
- Antioxidants as reducing agents. Antioxidants can act as reducing agents by being selectively oxidized, to thus protect the substrate by competitive reactivity. Ascorbic acid, thiols (e.g., thioglycerol, thioglycollic acid), and polyphenols (e.g., propyl gallate) can act as such reducing agents (Figure 11).
4.4. Metal Control Strategies
4.5. Packaging
5. Oxidative Susceptibility Testing
- Prediction of whether or not a drug is sensitive to oxidation;
- Determination which specific oxidative degradation mechanism is involved and consequently how to prevent it;
- Obtaining the oxidative impurities that are formed under accelerated and long-term storage conditions as information that can be used to develop appropriate stability-indicative chromatographic methods [29];
- Controlling genotoxic impurities;
- A better, more detailed understanding of a drug.
5.1. Autoxidation
5.2. Nucleophilic/Electrophilic (Peroxide Mediated)
5.3. Transition Metal Ions
- Reactions with hydroperoxides;
- Activation of molecular oxygen;
- Direct reaction of metal complexes with the substrate.
6. New Stressors for Accelerated Oxidation Studies
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Conflicts of Interest
References
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Gabrič, A.; Hodnik, Ž.; Pajk, S. Oxidation of Drugs during Drug Product Development: Problems and Solutions. Pharmaceutics 2022, 14, 325. https://doi.org/10.3390/pharmaceutics14020325
Gabrič A, Hodnik Ž, Pajk S. Oxidation of Drugs during Drug Product Development: Problems and Solutions. Pharmaceutics. 2022; 14(2):325. https://doi.org/10.3390/pharmaceutics14020325
Chicago/Turabian StyleGabrič, Alen, Žiga Hodnik, and Stane Pajk. 2022. "Oxidation of Drugs during Drug Product Development: Problems and Solutions" Pharmaceutics 14, no. 2: 325. https://doi.org/10.3390/pharmaceutics14020325
APA StyleGabrič, A., Hodnik, Ž., & Pajk, S. (2022). Oxidation of Drugs during Drug Product Development: Problems and Solutions. Pharmaceutics, 14(2), 325. https://doi.org/10.3390/pharmaceutics14020325