Drug impurity

Webster s definition for database is a large collection of data in a computer, organized so that it can be expanded, updated, and retrieved rapidly for various uses. An LC/MS database established for drug impurities contains multi-dimensional information such as relative retention times, UV spectra, molecular mass and substructural information. In order for the information to be updated and expanded, the methods used for information collection need to be unified. A generic LC/MS method allows relevant information to be collected in a consistent... 

Determination of elemental compositions is an important step towards the structural elucidation of drug impurities. Elemental composition of an unknown compound can only be derived from the measurement of its exact mass. In combination with the knowledge of the physiological or chemical process, elemental compositions alone may be enough to propose a correct structure. 

After a short introduction into the relevance of Impurity profiling for regulatory authorities, public health, and the pharmaceutical industry, an overview is presented based on the various modes of capillary electrophoresis that have been used in drug impurity analysis. The applications of capillary zone electrophoresis, non-aqueous capillary electrophoresis, micellar electrokinetic capillary chromatography, microemulsion electrokinetic capillary chromatography, capillary gel electrophoresis, and capillary electrochromatography are presented consecutively. 

In summary, it can be stated that the stationary phase and the mobile phase (buffer) pH are the most important factors determining the generic selectivity of a CS. The organic modifier composition and the column temperature can influence the selectivity locally, i.e., when separating a specific mixture of rather similar compounds, e.g., a drug impurity profile. 

To identify all compounds of the drug-impurities mixture, the use of an orthogonal set of systems can be beneficial. The expected selectivity differences between these systems combined with MS detection and the use of peak tracking and matching algorithms should enhance the chance that all different compounds occurring in the mixture can be identified. 

FIGURE 5 Critical regions in an HPLC chromatogram of a drug impurity profile with respect to potential selectivity challenges (I) co-elution of impurities, (2) highly retained (non-polar) compounds, (3) non-retained (polar) compounds, and (4) co-elution with the main compound. 

Analysis of non-steroidal anti-inflammatory drugs (ibuprofen, ketoprofen, naproxen, fenoprofen, flurbiproen, and suprofen) Impurity profiling of ketorolac, a chiral nonsteroidal antiinflammatory drug Impurity profiling of a non-steroidal analgesic drug... 

Besides CZE and NACE, micellar electrokinetic chromatography (MEKC) is also widely used, and ionic micelles are used as a pseudo-stationary phase. MEKC can therefore separate both ionic and neutral species (see Chapter 2). Hyphenating MEKC with ESI/MS is problematic due to the non-volatility of micelles, which contaminate the ionization source and the MS detector, resulting in increased baseline noise and reduced sensitivity. However, MEKC—ESI/MS was applied by Mol et al. for identifying drug impurities in galantamine samples. Despite the presence of non-volatile SDS, all impurities were detected with submicrogram per milliliter sensitivity and could be further characterized by MS/MS. 

Analysis of Drug Impurities Edited by Richard J. Smith, Michael L. Webb Copyright 2007 Blackwell Publishing... 

Broadly, the upper limits for the various impurities are set on the basis of toxicological considerations and process capabilities. On the basis of animal smdies, preferably with drug substance containing enhanced levels of impurities, a dose level that produces no adverse events in the animals is identified. This is converted to an equivalent of the oral dose level in humans. Although high-dose pharmaceuticals are different, for the majority of drugs, impurities above 0.05% are reported as unidentified impurities and included in the total impurity amount, impurities above 0.10% are identified and included in the specification, and impurities above 0.15% are toxicologically qualified. 

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