Evaluating Impurities in Drugs (Part III of III) - Pharmaceutical Technology

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Evaluating Impurities in Drugs (Part III of III)
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.


Pharmaceutical Technology
Volume 36, Issue 4, pp. 76-86

Metabolite impurities

Metabolite impurities are byproducts formed in the body after a drug substance is ingested. During metabolism, the API and drug product in the body are exposed to various enzymes, from which metabolite impurities can be formed (26–34). Drug metabolism is traditionally divided into two phases: metabolic (i.e., hepatic) clearance and the Phase I and Phase II process. The division is based on the observation that a drug substance first undergoes oxidative attack (e.g., benzene to phenol), and the newly introduced hydroxyl function will undergo glucouronidation (e.g., phenol to phenyl glucouronic acid). Some metabolites are formed as impurities during the development of a process. Control of these process-related metabolite impurities in the final API may not be necessary if control of other metabolites has already occurred and taken into consideration. Tightening the limits, therefore, may not be needed.


Figure 5: Process impurities, thermal decomposition impurities, and metabolites of asenapine. CAS No. is Chemical Abstracts Service number.
Examples are asenapine N-oxide, asenapine desmethyl, and ciprofoxacin ethyl diamino impurity, which are formed as process impurities, but are also metabolites of the same process (see Figure 5). It put forth a question whether limiting such a metabolite impurity in the final API is still required.

Select analytical methodologies

The development of a new drug mandates that meaningful and reliable analytical data be generated at various steps of drug development. The drug also should exhibit excellent stability throughout its shelf-life. To meet these requirements, methodologies need to be developed that are sensitive enough to measure low levels of impurities. This need has led to analytical methods that are suitable for determining trace and ultra-trace levels (i.e., submicrogram) quantities of various chemical entities (35–39). Various methods are available for monitoring impurities.

Spectroscopic methods . Various spectroscopic methods can be used for characterization of impurities, such as UV-visible spectroscopy, FTIR spectroscopy, NMR spectroscopy, and mass spectrometry (MS).

Separation methods . Various separation methods can be used, including thin-layer chromatography (TLC), gas chromatography (GC), HPLC, capillary electrophoresis (CE), and supercritical fluid chromatography (SFC). A review of these methods is provided in the literature (39). CE is an electrophoretic method that is frequently lumped with chromatographic methods because it shares many of the common requirements of chromatography. A broad range of compounds can be resolved using TLC by using different plates and mobile phases. GC is a useful technique for quantification. It can provide the desired resolution, selectivity, and ease of quantification. This technique is useful for organic volatile impurities. SFC offers some of the advantages of GC in terms of detection and HPLC in terms of separation.

Hyphenated methods. The following hyphenated methods can be used effectively to monitor impurities: GC–MS; liquid chromatography (LC)–MS; LC–diode-array detection (DAD)–MS; LC–NMR; LC–DAD–NMR–MS; and LC–MS–MS.

Isolating impurities . It is often necessary to isolate impurities because the instrumental methods are not available or further confirmation is needed. The following methods have been used for isolation of impurities: solid-phase extraction, liquid–liquid extraction, accelerated solvent extraction, supercritical fluid extraction, column chromatography, flash chromatography, TLC, HPLC, CE, and SFC.


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