Impurities contaminated drugs

Impurities in drug substances and drug products continue to be a source of great concern, discussion, debate, and research. " These concerns and debates typically center on the potential safety risks associated with impurities due to contamination and the setting of acceptance criteria. However, the bulk of the work being performed in the pharmaceutical industry, with respect to impurities, is focused on the isolation, identification, qualification and quantification of impurities that are found as a result of the manufacturing process or through chemical decomposition. On the... 

Most of these products are legally considered neither food nor drugs and, therefore, are not regulated by the FDA (Dietary Supplement Health and Education Act, 1994). Toxicity may be related to the active Ingredlent(s) or to Impurities, contaminants, or adulterants In the product. See also Caffeine (p 142), Essential Oils (p 147), Salicylates (p 331), and Vitamins (p 366). 

Simple organic acids often possess chromophores, which makes direct UV detection possible, even at low wavelengths. CE can measure the presence of small ion contaminant impurities in drug substances. For example, an NACE method with indirect UV detection was used to monitor ammonium ion contaminant in pharmaceutical preparations with a limit of detection of 50 ppb [254]. A number of reviews have been published that will provide the reader with a comprehensive coverage of the status of CE for the analysis of ions and small molecules, including detection methods, quantification, and stoichiometric determinations [8,9,11,253,255,256]. Table 4.7 shows some recent analysis applications of CE for ion analysis. 

Orga.nic Colora.nts. The importance of coal-tar colorants cannot be overemphasized. The cosmetic industry, in cooperation with the FDA, has spent a great deal of time and money in efforts to estabUsh the safety of these dyes (see Colorants for food, drugs, cosmetics, and medical devices). Contamination, especially by heavy metals, and other impurities arising from the synthesis of permitted dyes are stricdy controlled. Despite this effort, the number of usable organic dyes and of pigments derived from them has been drastically curtailed by regulatory action. 

Process validation should be extended to those steps determined to be critical to the quality and purity of the enantiopure drug. Establishing impurity profiles is an important aspect of process validation. One should consider chemical purity, enantiomeric excess by quantitative assays for impurity profiles, physical characteristics such as particle size, polymorphic forms, moisture and solvent content, and homogeneity. In principle, the SMB process validation should provide conclusive evidence that the levels of contaminants (chemical impurities, enantioenrichment of unwanted enantiomer) is reduced as processing proceeds during the purification process. 

Methamphetamine can also come in the form of colored pills or tablets (Figure 2.2), which many users consider safer than raw powder because they are less likely to be laced with contaminants. However, pill and tablet forms of methamphetamine often do contain impurities. These forms often produce less of a rush (the immediate pleasurable feeling produced by a drug) compared to when the drug is injected or smoked. This is because the pills must be absorbed through the gastrointestinal (GI) tract prior to entering the bloodstream and subsequently the brain. 

As liquid chromatography plays a dominant role in chemical separations, advancements in the field of LC-NMR and the availability of commercial LC-NMR instrumentation in several formats has contributed to the widespread acceptance of hyphenated NMR techniques. The different methods for sampling and data acquisition, as well as selected applications will be discussed in this section. LC-NMR has found a wide range of applications including structure elucidation of natural products, studies of drug metabolism, transformation of environmental contaminants, structure determination of pharmaceutical impurities, and analysis of biofiuids such as urine and blood plasma. Readers interested in an in-depth treatment of this topic are referred to the recent book on this subject [25]. 

A pivotal step in the analytical process is sample preparation. Frequently liquid-liquid extractions (LLEs) are used. Solvents, pH, and multiple back extractions are all manipulated to increase selectivity and decrease unwanted contaminants before injection on the GC system. Solid phase extraction (SPE) is more convenient than it used to be because of an increase in commercially available SPE columns. SPE columns are packed with an inert material that binds the drug of interest, allowing impurities to pass through. As with LEE, solvent choices and pH affect retention and recovery. There are three commercially available types of SPE columns, diatomaceous earth (which uses the same principles as LLE), polystyrene-divinylbenzene copolymer, and mixed mode bonded silica (Franke and de Zeeuw, 1998). 

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. 

Contamination impurities are unexpected adulterating compounds found in the drug substance. 

For drug substances from plants, examples of contaminant impurities could be herbicides, for example, diquat and glyphosate, or pesticides, for example, carbofuran and endrin, sprayed in the environment. Additionally, heavy metals or polycyclic aromatic hydrocarbons, if present in the soil, may be absorbed through the root systems of the plants. Polycyclic aromatic hydrocarbons, if present in the air, may be absorbed through the leaves of the plant. These contaminants will be present as residues in the drug substance if the selection, cleaning, extraction, and purification processes do not reduce or eliminate them. 

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