Definition of impurity

The term impurity reflects unwanted chemicals that are present in APIs or that develop during formulation or upon aging of the API in the formulated drug product. The presence of such unwanted material, even in small amounts, could affect the efficacy and safety of pharmaceutical products. Several guidelines from the International Conference on Harmonization (ICH) address impurities in new drug substances, drug products, and residual solvents (3–6). As per the ICH guidelines on impurities in new drug products, impurities present below a 0.1% level do not need to be qualified unless the potential impurities are expected to be unusually potent or toxic (5). In all other cases, impurities should be qualified. If the impurities exceed the threshold limits and data are not available to qualify the proposed specification level, studies to obtain such data may be required. Several recent articles describe a designed approach and guidelines for isolation and identification of process-related impurities and degradation products using mass spectrometry, nuclear magnetic resonance (NMR) spectroscopy, high-performance liquid chromatography (HPLC), and Fourier transform infrared (FTIR) spectroscopy for pharmaceutical substances (7–9).

Figure 1: Degradation of hydrochlorothiazide. (ALL FIGURES ARE COURTESY OF THE AUTHORS)

Degradation products could result from the synthesis itself, storage, formulation of the dosage form, and aging (11). These degradation pathways are further discussed.

Synthesis-related impurities. Impurities in a drug substance or a new chemical entity originate mainly during the synthetic process from raw materials, solvents, intermediates, and byproducts. The raw materials are generally manufactured to much lower purity requirements than a drug substance, and thus, it is easy to understand why they can contain a number of components that can in turn affect the purity of the drug substance.

Figure 2: Reaction scheme for mirtazapine impurity. Ph. Eur is the European Pharmacopoeia. DMF is dimethylformamide. EtOAc is ethyl acetate.

1-Methyl-3-phenyl piperazine (see Figure 2) is present as an unreacted starting material that competes in all the stages eventually leading to the impurity keto-piperazine derivative of mirtazapine (see Impurity C, Figure 2)

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.

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:

• 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.
• 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).
• 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).