Stability study of a drug product is critically important to ensure that the patient receives the correct dose of the active ingredient. Furthermore, for those drugs that can degrade to produce toxic materials, it is essential to determine the conditions under which this might occur so as to find methods of prevention or stabilization and/or to determine limitations in terms of shelf life and storage conditions.
In addition, the stability of excipients and their stability in combination with other excipients and drug substances can be a critical factor in achieving a stable marketable product.
Degradation can occur through a number of chemical/physiochemical and biological pathways –
- Hydrolysis
- Isomerization
- Oxidation
- Polymerization
- Solid-state phase transformation
- Dehydration or desolvation
- Cyclization
- Photolytic degradation
- Microbial growth
Importantly, the kinetics of instability can vary according to the route and hence rate of degradation. In addition, compounds, especially unsaturated fatty acids and oils, can degrade through different orders of reaction e.g. first, second, third etc. order kinetics. The chemical route of degradation depending on temperature.
Early preformulation studies should be designed to subject the drug or excipient to several “stress” conditions to identify key degradation pathways and the extent of degradation. From these studies it is possible to estimate the probable stability of the chemical or biological substance under the environmental conditions that it could be subject to during synthesis or extraction, manufacture, transport and storage.
Stress Study
ICH (International Conference on harmonization of regulatory requirements) Drug stability test guideline Q1A (r2) requires that the drug substance be tested under different stress conditions.
It is suggested that stress testing include the effect of -
- pH
- Temperature
- Humidity
- Light
- Oxidizing agents
Based on a knowledge of the stability characterizes of the drug substance and stress study, stability tests can be conducted on the drug product in the presence of various excipients.
Different Types of Degradation
Chemical Degradation
The chemical stability of a drug substance in the solid state can be evaluated under various temperature and humidity stress conditions. Pre-weighed samples are stored in stability cabinets in open vials or thin layers for periods of up 8 weeks under conditions such as:
- 40 °C
- 60 °C
- 80 °C
- 25 °C & 85% RH
- 40 °C & 75% RH
At pre-determined time intervals, e.g. 2 weeks, 4 weeks, 8 weeks, samples are removed, dissolved in an appropriate solvent, and analyzed using a robust, stability-indicating assay.
Hydrolytic Degradation
Hydrolysis can occur in many molecular species but particularly for carboxylic acid derivatives or substances containing a functional group based on carboxylic acid, e.g. ester, amide, lactone, lactam, imide and carbamate.
To identify and quantify potential degradation by this route, samples of the compound should be subject to stress testing in acidic and alkaline conditions, e.g. refluxing the drug in 0.1 n HCl and 0.1 n NaOH for 8–12 hours.
Stability in Solvents Used in Formulation
As with solubility evaluations at the preformulation stage, the stability of candidate drugs (and formulation excipients) in non-aqueous solvents that typically might be used in subsequent formulations or manufacturing processes should be examined.
Dimerization and Polymerization
Similar molecules may interact to produce complex structures—including dimers and polymers of various lengths and orientations. The potential for such interactions should be evaluated by examining the polymeric state of samples during stress testing for heat, light and solution stability.
Photo-stability
For those substances that may degrade when exposed to light, a number of opportunities exist to prevent or minimize instability through the choice of specialized coatings or packaging.
pH-dependent Stability
Stability tests should also be performed under several physiological and formulation pH conditions in order to understand the characteristics of the drug candidate under physiological conditions and to provide key information for the formulation of solution dosage forms.
Typically this would involve measuring stability at 37 °C in a range of buffer solutions e.g. pH 1, pH 4, pH 7 and pH 9 at intervals from 1 day up to 1 month.
Oxidative Stability
Drugs and excipients may be degraded by oxidation reactions of which there are two distinct types.
1. Oxidation through direct reduction reactions via atmospheric oxygen.
2. Oxidation by chain reaction involving the formation of per-oxy free radicals.
This, latter, route of degradation is most likely to occur in compounds with double carbon bonds; especially long-chain unsaturated fatty acids and oils.
The oxidation process involves several steps like- initiation, propagation, and termination, and can be catalyzed by heat, light, metals or free radicals.
If the chemical structure of the drug or excipient indicates that this route of oxidation is possible, then preformulation studies should subject samples of the substance to various elevated temperature stress conditions under open atmospheric conditions, i.e. in the presence of oxygen.
