Version 1.6.1
David Trew
Consulting Ltd
POTASSIUM PERMANGANATE AS AN ADDITION PROBE FOR DRUG DEGRADATION STUDIES
Drug degradation studies, under forcing conditions, are key activities in the early stages of the development program of a new medicine. Such studies provide information which can be used to:
- Confirm analytical methods comply with specificity requirement
- Demonstrate that chromatographic peaks due to degradation products can be adequately resolved
- Confirm that an analytical method is stability indicating
- Elucidate degradation pathways
- Identify potential toxicity issues
- Assist in identifying formulation strategies
The International Conference on Harmonisation of the Technical Requirements for Registration of Pharmaceuticals for Human Use in their Q1A guideline have recommended that new drug substances are exposed to the following stressed conditions:
- Acidic and basic hydrolysis
- Oxidation
- Thermolysis
- Photolysis
- Humidity
Many drugs are vulnerable to oxidative degradation. When probing a drug substance’s susceptibility to being oxidised hydrogen peroxide (H2O2) is the reagent that is commonly used to perform such studies. Oxidation by H2O2 can proceed through two mechanisms:
Free Radical Transfer
In Free radical transfer, which is the process involved in autoxidation, the initial step is the homolysis of the O-
…...(i)
The hydroxyl radicals are then able to react with a wide range of chemical moieties, such as saturated and unsaturated carbon hydrogen bonds.
Substitution Reactions
Hydrogen peroxide can also participate in various non-
…..(ii)
Oxidations by Potassium Permanganate
Potassium permanganate is a powerful oxidising agent and used in organic synthesis, under acidic, neutral and basic conditions, to achieve a range of transformations such as:
- Aldehyde to carboxylic acids
- Aliphatic amine to either an aldehyde or a ketone
- Primary alcohols to carboxylic acids and esters
- Thiols, sulfoxides, sulfones and disulfides to sulfonic acids
- Aliphatic nitro compounds to ketones
Potassium permanganate oxidations are accomplished through a number of mechanisms, including:
Hydrogen atom extraction
Permanganate ion abstracts an alpha hydrogen atom from primary, secondary and tertiary amines, as shown in scheme 1, the yield the radical 2. A second permanganate ion then abstracts the amino hydrogen atom from 2 to yield the iminium ion 3; Which then undergoes hydrolysis to yield an aldehyde or ketone 4.
Scheme 1
Formation of Ester Intermediates
Permanganate ion can perform a nucleophilic addition to an aldehyde 5 across the carbonyl double bond to form the permanganate ester of a gem-
The reaction mechanisms by which potassium permanganate achieves oxidation are quite different to that of hydrogen peroxide. Hydrogen peroxide achieves oxidation either by the addition of hydroxyl radicals or by the addition of electrophilic HO+ species. In contrast permanganate achieves oxidation by either hydrogen atom extraction or nucleophilic addition reaction to for permanganate ester intermediates.
The products of the respective reactions are also quite different; the reaction of a tertiary amine with hydrogen peroxide yields an amine oxide whereas the analogous reaction permanganate yields ether a ketone or an aldehyde.
In conclusion employing permanganate in addition to hydrogen peroxide offers the potential to identify additional drug degradation products and pathways.
For further information please visit my drug degradation page
Scheme 2