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In Part III of a three-part article, the authors examine various degradation routes of APIs, impurities arising from interactions in formulations, metabolite impurities, various analytical methods to measure impuritie, and ways to control impurities.
Impurities on aging. Generally, a longer stay on the shelf increases the possibility that impurities will occur. Such impurities can be caused
by several interactions as further described.
Interaction among ingredients. Vitamins are highly prone to instability after aging. For example, the presence of nicotinamide containing four vitamins
(nicotinamide, pyridoxine, riboflavin, and thiamin) caused the degradation of thiamin to a substandard level during a one-year
shelf life (20). Table I lists some examples of interactions among ingredients.
Hydrolysis. Many drugs are derivatives of carboxylic acids or contain functional groups susceptible to acid–base hydrolysis (e.g., aspirin,
atropine, and chloramphenical).
Oxidation. In pharmaceuticals, the most common form of oxidative decomposition is auto-oxidation through a free-radical chain process.
Drugs that are prone to oxidation include methotrexate, adinazolam, catecholamine, conjugated dienes (i.e., vitamin A), and
nitroso and nitrite derivatives. Olanzapine is especially prone to oxidative degradation in the presence of oxygen (see Figure
4) (21).
Photolysis. Photolytic cleavage on aging products occurs with APIs or drug products that are prone to degradation on exposure to UV
light. For example, the ophthalmic formulation of ciprofloxacin drops 0.3%, when exposed to UV light and undergoes photolysis
to form ethylene diamine, an analog of ciprofloxacin (22).
Decarboxylation. Carboxylic acid (–COOH) tends to lose carbon dioxide from carboxyl groups when heated. For instance, a photoreaction of
a rufloxacin enteric tablet coated with cellulose acetate phthalate and subcoated with calcium carbonate causes hydrolysis
of cellulose acetate phthalate. This reaction liberates acetic acid, which on reacting with calcium carbonate, produces carbon
dioxide as a byproduct.
pH. It is well understood that pH, particularly extreme levels of pH, can encourage hydrolysis of the API when ionized in an
aqueous solution. This situation necessitates buffer control if such a dosage form is required.
Packaging materials. Impurities may result from packaging materials (i.e., containers and closures (23).
Figure 4: Olanzapine impurities due to air, heating, and formulation.
Two impurities in olanzapine have been identified as 1 and 2 (see Figure 4) (24). The structures indicate that the two impurities
are degradation products resulting from oxidation of the thiophene ring of olanzapine.
From a regulatory perspective, forced degradation provides data to support the following (25):
Identification of possible degradants
Degradation pathways and intrinsic stability of the drug molecule
Validation of stability for indicating analytical procedures
Facilitation of the development of analytical methods to evaluate stability
Understanding the degradation of the API to a rational product.
Screening for possible formation of potential genotoxins.
Various issues are addressed in regulatory guidance (3–6). Some key issues are:
Forced degradation is typically carried out using one batch of material.
Forced-degradation conditions are more severe than accelerated stability testing, such as 50 °C; ≥ 75% RH; light conditions
exceeding ICH standards; high and low pH; and oxidation.
Photostability should be an integral part of forced-degradation study design (10).
Degradation products that do not form in accelerated or long-term stability may not have to be isolated or have their structure
determined.
Mass balance should be considered.
Various issues are not addressed in regulatory guidance (3-6). Some key issues not addressed are:
Exact experimental conditions (temperatures, duration, and extent of degradation)
Experimental design (left to the applicant's discretion).
