Impurities, organic evaluation

Organic impurities are often evaluated using HPLC analysis. The major part of the chapter will focus on the application of chromatographic methods to evaluate and limit these impurities. 

Residual solvents are the third general classification of impurities in pharmaceuticals. This class is described as inorganic or organic liquids used during the manufacturing process. Typically, these solvents can only be evaluated by gas chromatography and therefore will not be addressed in this chapter. 

This study evaluated the impurity profile of untreated water from a textile plant in Portugal [35]. The organic material was concentrated by extraction from 11 of water into dichloromethane and HPLC-NMR and HPLC-MS experiments were carried out using a reverse-phase separation with an acetonitrile/ D2O gradient elution with H NMR spectroscopic observation at 600 MHz. For the HPLC-NMR studies, the samples were further fractionated into two pools according to their HPLC retention times. The HPLC-NMR studies were carried out in the stop-flow mode and the combination of NMR and MS results yielded the identification or tentative identification of 14 compounds, comprising mainly surfactants, anthraquinone dyes and nonylphenol-related molecules. 

As an example, tablet samples for a product were prepared in an 85% organic medium and transferred into HPLC vials. An impurity peak was observed in some, but not all, of the tablet samples, blanks and standards. It was suspected that the solution in some of the vials may have come in contact with the HPLC Teflon caps and extracted a component from the cap. To evaluate this possibility, dissolving solvent was transferred into similar HPLC vials. These vials were capped with the Teflon caps and were kept inverted overnight to allow maximum contact of the solvent with the vial caps. A set of control samples were also prepared in which the vials were only filled halfway with dissolving solvent and care was taken not to allow the dissolving solvent to come into contact with the vial caps. These samples were analyzed by HPLC and, as shown in Fig. 10.3, confirmed the origin of the peak in question as being from the vial caps. In addition, the UV spectral analyses of the... 

Chiral separations can be considered as a special subset of HPLC. The FDA suggests that for drugs developed as a single enantiomer, the stereoisomeric composition should be evaluated in terms of identity and purity [6]. The undesired enantiomer should be treated as a structurally related impurity, and its level should be assessed by an enantioselective means. The interpretation is that methods should be in place that resolve the drug substance from its enantiomer and should have the ability to quantitate the enantiomer at the 0.1% level. Chiral separations can be performed in reversed phase, normal phase, and polar organic phase modes. Chiral stationary phases (CSP) range from small bonded synthetic selectors to large biopolymers. The classes of CSP that are most commonly utilized in the pharmaceutical industry include Pirkle type, crown ether, protein, polysaccharide, and antibiotic phases [7]. 

Many products appearing in the environment that are subject to regulatory actions are judged on the basis of one main active compound. In reality, however, the product in most cases consists of a mixture of additives and formulations for optimal functioning and also impurities and by-products from manufacturing. Also, as mentioned, the organisms are not exposed just to one product but rather to many products and different components. Thus, the situation is very complex and to get the full or at least the best picture, testing and evaluation for the ecotoxicity of complete products and mixtures should be considered. 

Examination of the synthetic route used in production allows for the prediction of potential residual synthetic impurities present in the drug substance. The API structure allows for the postulation of degradation pathways via hydrolytic, oxidative, catalytic, and other mechanisms. Both of these evaluations serve to facilitate the interpretation of (subsequent) identification tests. An examination of the physicochemical properties also allows for the rational establishment of method screening experiments by precluding certain conditions. For example, the use of normal-phase HPLC will be eliminated if the API is a salt or shows limited solubility in nonpolar organic solvents. Similarly, if the API (or suspected related substances) has no significant chromophore above 250 nm, the use of tetrahydrofuran (THE) and other solvents as mobile-phase components is severely limited. For compounds with an ionizable group, variation of pH will have considerable influence on elution behavior and can be exploited to optimize the selectivity of a reversed-phase separation. 

We have investigated the solvolytic stability and reactivity of polymer-bound borohydrides and have evaluated these materials in several applications such as solvent purification, arsine generation, and metal reduction. These polymer-bound borohydrides offer several advantages over sodium or tetraethylammonium borohydride. The primary advantages are the convenience of use and the minimal introduction of ionic species or organic by-products into the treated bulk media. With the polymer-bound borohydrides, the cation is bonded covalently to the insoluble resin while the borohydride anion or its oxidation product (borate) is retained by ionic bonding. Typically, boron at levels of less than 5 ppm is the only impurity introduced into the treated medium. 

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