Formulation-relatedimpurities
. Several impurities in a drug product or API can arise from interactions with excipients used to formulate the drug product.
In the process of formulation, a drug substance is subjected to various conditions that can lead to its degradation or other
deleterious reactions. For example, if heat is used for drying or for other reasons, it can facilitate degradation of thermally
labile drug substances. Solutions and suspensions are potentially prone to degradation due to hydrolysis or solvolysis. These
reactions also can occur in the dosage form at solid state, such as in the case of capsules and tablets, when water or another
solvent has been used for granulation.
There are two typical conditions in solid- and solution-state degradation studies. Typical conditions for the API in a solid
state might be 80 °C, 75% relative humidity (RH); 60 °C at ambient RH; 40 °C at 75% RH; and light irradiation. Typical conditions
for an API in the solution state might be: pH 1–9 in buffered media; with peroxide and/or free-radical initiator; and light
irradiation.
Figure 3: Degradation pathway of ketorolac.
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Figure 3 shows the degradation pathway of ketorolac in the solid and solution states (12–14).
Dosage form-related impurities.
Impurities related to the dosage form are significant because many times precipitation of the main ingredient requires various
factors, such as pH or leaching, to be altered (15). For example, the precipitation of imipramine hydrochloride with sodium
bisulfite requires a subsequent pH alteration of lidocaine hydrochloride solution in the presence of 5% dextrose in saline.
Method-related impurities.
A known impurity,1-(2,6-dichlorophenyl)indolin-2-one is formed in the diclofenac sodium ampuls. Formation of this impurity
depends on the initial pH of the preparation and the conditions of sterilization (i.e., autoclave method, 123 °C ± 2 °C) that
enforces the intermolecular cyclic reaction of diclofenac sodium, forming indolineone derivative and sodium hydroxide (16).
Environmental-related impurities
. Environmental-related impurities may result from the following:
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Temperature. Many heat-labile compounds, when subjected to extreme temperature, lose their stability. Keeping this in mind, extreme care
should be exercised to prevent them from degradation.
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Light (ultraviolet light). Exposure to light results in a photolytic reaction. Several studies reported that ergometrine and ergometrine injections
are unstable under tropical condition such as light and heat (17–19).
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Humidity. Humidity is one of the important factors when working with hygroscopic compounds. Humidity can be deleterious to bulk powders
and formulated solid dosage forms. Well-know examples are ranitidine and aspirin (19).
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