SOURCES OF IMPURITIES

Some of the more obvious sources of contamination of solvents arise from storage in metal drums and plastic containers, and from contact with grease and screw caps. Many solvents contain water. Others have traces of acidic materials such as hydrochloric acid in chloroform. In both cases this leads to corrosion of the drum and contamination of the solvent by traces of metal ions, especially Fe. Grease, for example on stopcocks of separating funnels and other apparatus, e.g. greased ground joints, is also likely to contaminate solvents during extractions and chemical manipulation. 

Solutions in contact with polyvinyl chloride can become contaminated with trace amounts of lead, titanium, tin, zinc, iron, magnesium or cadmium from additives used in the manufacture and moulding of PVC. V-Phenyl-2-naphthylamine is a contaminant of solvents and biological materials that have been in contact with black rubber or neoprene (in which it is used as an antioxidant). Although it was only an artefact of the separation procedure it has been isolated as an apparent component of vitamin K preparations, extracts of plant lipids, algae, livers, butter, eye tissue and kidney tissue [Brown Chem Br 3 524 1967]. 

Most of the above impurities can be removed by prior distillation of the solvent, but care should be taken to avoid plastic or black rubber as much as possible. 

From the preceding discussion, it should be clear that impurities can originate from various sources. The most obvious source of impurities is the synthesis, where intermediates and by-products may be carried into the API as impurities or become a source of other impurities resulting from them. 

All of these impurities are discussed in Chapter 4, which focuses on how these impurities are likely to alter dosage forms through chemical reactivity and physical changes to the systems. Additionally, some impurities can cause toxicological problems. These impurities may not directly affect the performance or stability of a dosage form, but must be controlled to make a safe drug product. 

It is of paramount importance to look for stereochemistry-related compounds, i.e., those compounds that have similar chemical structure but different spatial orientation. These compounds can be considered impurities in the API. Included in this group are various stereoisomers. The simplest case of chirality can be seen in a molecule that has one or more tetrahedral carbons with four different substituents (asymmetric carbon atom) such that its mirror image is not superimposable. Chiral molecules may also occur for a number of other reasons and must be factored into any evaluation of impurities.10-12 Stereoisomerism is possible in molecules that have any of the following characteristics  

Chiral molecules are frequently called enantiomers. Enantiomers are optical isomers that have the same chemical structure but different spatial arrangement, which leads to different optical rotation. It is important not to overlook them because the d-isomer of a compound can have different pharmacologic or toxicologic activity from that of the 1-isomer.11 Therefore, the undesired optical isomer is considered a chiral impurity of the API. Furthermore, it is important to remember that the number of chiral impurities increases with the increasing number of asymmetric carbon atoms in a molecule. 

A number of solvents that are used for the synthesis of the API or formulation of the drug product can be present in the drug product. The content of these solvents, which are commonly called organic volatile impurities (OVI), is generally determined by the OVI methods specified in the compendia. Their content is controlled by the guidelines offered by various bodies (see Chapter 2). Residual solvents can affect the stability of drug product (see Sections IV. D and E). 

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Inclusions, occlusions, and surface adsorbates are called coprecipitates because they represent soluble species that are brought into solid form along with the desired precipitate. Another source of impurities occurs when other species in solution precipitate under the conditions of the analysis. Solution conditions necessary to minimize the solubility of a desired precipitate may lead to the formation of an additional precipitate that interferes in the analysis. For example, the precipitation of nickel dimethylgloxime requires a plT that is slightly basic. Under these conditions, however, any Fe + that might be present precipitates as Fe(01T)3. Finally, since most precipitants are not selective toward a single analyte, there is always a risk that the precipitant will react, sequentially, with more than one species. 

The feed brine is also a source of impurities. It can contain dissolved and entrained air and so can contribute oxygen and nitrogen. The brine may also contain carbonate that was added during chemical treatment in order to remove dissolved calcium. The carbonate will be converted to carbon dioxide in the cell environment. 

Acid radical impurities constitute a serious but unavoidable source of impurities in a large number of pharmaceutical chemicals. However, the two most commonly found acid radical impurities are chloride (Cl ) and sulphate (S042 ) that evidently arise from the inevitable use of raw tap-water in various manufacturing operations. As these two acid radical impurities are found in abundance due to contamination, the Pharmacopoeia categorically stipulates limit tests for them which after due minor modifications are applicable to a number of pharmaceutical substances. 

Figure 1 is a simplified representation of the mannfacturing process of a drug product. Each of the potential classes of impnrities that might be present has been identified and numbered. This picture identifies sources and classes that are not specified in the ICH gnidelines, bnt that are clearly potential sources of impurities and interferences. 

The generic representation in Figure 1 illustrates the various types of impurities that may arise during the production of a dosage form. It is not all inclusive, as each dosage form has unique sources of impurities, but it includes most of the important ones. The sources of impurities increase with the increase in the number of components and the number of steps in the process. Each drug substance and excipient has its own impurity profile and the potential for interactions and reactions. 

Power plant boilers are either of the once-through or dmm-type design. Once-through boilers operate under supercritical conditions and have no wastewater streams directly associated with their operation. Drum-type boilers operate under subcritical conditions where steam generated in the drum-type units is in equilibrium with the boiler water. Boiler water impurities are concentrated in the liquid phase. Boiler blowdown serves to maintain concentrations of dissolved and suspended solids at acceptable levels for boiler operation. The sources of impurities in the blowdown are the intake water, internal corrosion of the boiler, and chemicals added to the boiler. Phosphate is added to the boiler to control solids deposition. 

In one study of the effects of additives,9 it was found that on electrochemical oxidation of rubrene, emission was seen in dimethylforma-mide, but not in acetonitrile. When water, n-butylamine, triethylamine, or dimethylformamide was added to the rubrene solution in acetonitrile, emission could be detected on simply generating the rubrene cation.9 This seems to imply that this emission involves some donor or donor function present in all but the uncontaminated acetonitrile system. The solvent is not the only source of impurity. Rubrene, which has been most extensively employed for these emission studies, is usually found in an impure condition. Because of its relative insolubility and its tendency to undergo reaction when subjected to certain purification procedures, and because the impurities are electroinactive and have relatively weak ultraviolet absorptions, their presence has apparently been overlooked, They became evident, however, when quantitative spectroscopic work was attempted.70 It was found, for example, that the molar extinction coefficient of rubrene in benzene at 528 mjj. rose from 11,344 in an apparently pure commercial sample to 11,980 (> 5% increase) after repeated further recrystallizations. In addition, weak absorption bands at 287 and 367 m, previously present in rubrene spectra, disappeared. 

Laj, P., J. M. Palais, and H. Sigurdsson, Changing Sources of Impurities to the Greenland Ice Sheet over the Last 250 Years, Atmos. Environ., 26A, 2627-2640 (1992). 

There are several possible sources of impurities in the electrolytes and reasons for their potential accumulation during use. Key amongst the sources, are the unavoidable side-reactions. Others include the widespread practice in electroplating processes of using the more convenient open systems that allow easier handling of workpieces. Consequently the absorption of atmospheric gases and particles might introduce impurities. 

Reaction rate oscillations have been observed during the CO oxidation reaction over Pt/Y-AI2O3 in an all Pyrex glass flow reactor. During our experimental study we have carefully tried to eliminate all known sources of Impurities and other possible extraneous interferences caused by temperature and flow controllers and by high volume recycle streams. The surface state of the catalyst has been monitored by the technique of IR transmission spectroscopy. During oscillations only the band at 2060 cm l has been found to oscillate. 

With binary compounds, an additional source of impurity levels can arise from non-stoichiometry. Thus, many oxides are either cation or anion deficient the former, such as Ni(1 x)0 (x 0.01) are p-type whereas the latter, such as TiO(2 x) (x 0.01) are n-type. The extent of non-stoichiometry varies with the partial pressure of 02 in a manner that can usually be calculated from point-defect theory, provided that x remains small. 

Pirolli and Teplyakov reported the deposition of copper films from the commercially available lOo precursor (CupraSelect ) on a Si(lOO) crystal at the molecular level, combining experimental surface analytical techniques with computational analysis. At — 173°C CupraSelect adsorbs without noticeable decomposition. Surface annealing results in the elimination of ViSiMes below 25 °C, while the hfac anion binds to the surface through a copper atom. Upon heating, hfac decomposes and constitutes the main source of impurities in the copper deposition process. ... 

Some of these terms indicate potential sources of impurities e.g., intermediates others tend to downplay the negativity, as exemplified by the use of the term related product. ... 

The penultimate intermediate in the pharmaceutical synthesis is generally required to meet certain preset specifications. However, the more demanding standards of purity for the drug substance are very rarely exercised at this stage. It is important to bear in mind that this step is the last possible source of impurities from the synthesis. The methods used for analysis at this stage should be rigorous, and the tightest economically and practically feasible specifications should be applied. 

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