Quantitative impurity determinations

As noted in Section 4.2.4.2, NMR may be particularly useful for impurity profiling because of the simplicity of the fluorine spectrum. Mistry etal. showed that fluorine-containing impurities in bulk dmg could be detected and quantitated down to approximately 0.1 mole% (by comparison with HPLC-UV traces) [205]. 

These workers also measured the diffusion constants for each resonance to discriminate between monomeric and dimeric impurities. 

NMR is also very useful for detecting and quantitating non-drug-related impurities or counterions, such as trifluoroacetate or PFg . Ion chromatographic methods may also be used for this purpose but F NMR provides a simple method, provided that sufficient relaxation time is allowed between acquisitions as these species have TjS of 2-4 s (dg-DMSO, 300 K). 

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For many years, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) methods have been used as an essential tool to determine the hydrodynamic size, monitor product purity, detect minor product or process-related impurities, and confirm batch-to-batch consistency of protein and antibody products. ITowever, gel-based techniques have several limitations, such as lack of automation, varying reproducibility, and a limited linear range. SDS-PAGE is also labor-intensive and generates large volume of toxic waste. Most importantly, the technique does not provide quantitative results for purity and impurity determination of proteins and antibodies. 

For impurity tests (limit impurity test, quantitative impurity test) and assay tests, the accent lies on the ability to determine or discriminate for the analyte in the presence of other interferants. Selectivity can be assessed by spiking samples with possible interferants (e.g., degradation products) [55,56,72]. 

Fe203, Ti02, MgO, and CaO are nearly always present in kaolinite samples and K20 and Na20 are usually present. Most samples either have excess Si02 or A1203-Mineral impurities such as quartz, anatase, rutile, pyrite, limonite, feldspar, mica, montmorillonite, and various iron and titanium oxides are commonly present in addition to a number of other minerals. Si and Al, in the form of hydroxides, apparently can occur as coatings on the kaolinite layers. Although many of these impurities are usually identified, seldom is the analysis sufficiently quantitative to determine if all the deviation from the ideal composition is due to these impurities. 

The quantity and volume of samples required for impurity determination by CZE are very small probably less than 5 uL of volume is required for a well-designed injector, and only a few nanoliters (i.e., a few nanograms) are actually injected. However, it is experimentally simpler if that sample is present in a relatively concentrated solution, 0.05-2 mg/mL, when UV detection is being used. Our focus was not to achieve ultra-low detection limits such as might be required for trace level contaminants or for quantitation of trace levels of natural products. For those applications, the most common approach has been the use of a laser-based detector, preferably combined with a fluorescent label on the analyte. With this combination, extremely low limits of detection can be achieved (9, 22-25). 

Whatever the sample matrix, ensure that blank matrices are available for recovery and selectivity studies. For impurity determinations, it is best to have impurity standards and degradation products available for selectivity studies and quantitative validation. For quantitative analysis of individual major components or impurities, internal standards are usually necessary to ensure precise quantitation. 

Setting the limits for determining whether the instrument is still within acceptable performance criteria should be entirely the responsibility of the end user. The vendor can assist in providing guidelines as to how the instrument should function on delivery, but the operational qualification is intended to determine whether the instrument is still operating to within the specifications which the user defined upon purchase. For example, if the intended analysis is quantitation of a main component in a drug formulation, then detector noise which affects sensitivity may be of lesser importance than injection precision. Conversely, where the instrument is used for impurity determination, especially where the reported data is (area/area) %, then sensitivity and therefore detector noise may be of more importance than injector precision. If limits are indicated by the manufacturer, then these may be used directly if appropriate, but the user should be aware that the decision is his or hers. The limits for an OQ/PV should not... 

When impurity reference standards are available only in limited quantities, relative response factors (RRFs) to the active ingredient can be used to quantitate impurity concentrations. RRFs can be determined spectrophotometrically by comparing the molar absorptivity of the impurity to that of the active component. However, in our experience, RRFs determined by HPLC by comparing peak area responses of the impurity to those of the active ingredient have been more accurate than those determined by spectrophotometric method. 

As with GC, HPLC can be used qualitatively for identification or quantitatively to determine how much of a compound is present. Some examples of the use of HPLC in qualitative work include identification of impurities and toxicity screening. Some examples of the use of HPLC in quantitative work are drug testing in athletes and in sports supplements, pharmacokinetic studies of drugs pharmaceutical assays and fatty acid analysis. ... 

This chapter will look at the use of CE for pharmaceutical analysis and will include descriptions of the various modes of CE and their suitability for quantitative and qualitative analysis of pharmaceutical compounds. Practical applications of CE for the analysis of pharmaceuticals will be covered, these applications include drug assay, impurity determination, physicochemical measurements, chiral separations, and the analysis of small molecules. A section covering the approach to CE method development for pharmaeeutical analysis will include guidelines to selecting the best mode of CE for an intended separation. Extensive data will be provided on successful pharmaceutical separations with references to extra source material for the interested reader. This chapter will provide a comprehensive and up to date view of the role and importance of CE for the analysis of pharmaceuticals and will provide the reader with practical information and real data that will help them to decide if CE is suitable for an intended separation. 

Relative purity measured by LC-UV or LC-ELSD is higher than quantitative purity determined by weight percentage of the compound. This suggests that there are undetectable impurities in the sample. These may include inorganics, TFA, plastic extracts, solvents. 

IPC method validation is similar to the drug substance and product method validation however, special consideration should be given to the sample reactivity and stability. IPC method validation requires coordination with the process chem-ist/engineers to provide fresh reaction and process samples for the analysis. Table 1 has a list of in-process validation parameters that should be evaluated for chromatographic IPC limit and quantitative tests. These parameters are based on the ICH guidelines.The IPC analyses are categorized into RAP (COR and impurity determination) and solution concentration assays (%, w/v % v/v and mg/mL). 

C. C. Bard, T. J. Porro, and H. L. Rees, Quantitative Infrared Determination of Trace Impurities in Solids Using Frac-... 

These effects can be illustrated more quantitatively. The drop in the magnitude of the potential of mica with increasing salt is illustrated in Fig. V-7 here yp is reduced in the immobile layer by ion adsorption and specific ion effects are evident. In Fig. V-8, the pH is potential determining and alters the electrophoretic mobility. Carbon blacks are industrially important materials having various acid-base surface impurities depending on their source and heat treatment. 

The fermentation-derived food-grade product is sold in 50, 80, and 88% concentrations the other grades are available in 50 and 88% concentrations. The food-grade product meets the Vood Chemicals Codex III and the pharmaceutical grade meets the FCC and the United States Pharmacopoeia XK specifications (7). Other lactic acid derivatives such as salts and esters are also available in weU-estabhshed product specifications. Standard analytical methods such as titration and Hquid chromatography can be used to determine lactic acid, and other gravimetric and specific tests are used to detect impurities for the product specifications. A standard titration method neutralizes the acid with sodium hydroxide and then back-titrates the acid. An older standard quantitative method for determination of lactic acid was based on oxidation by potassium permanganate to acetaldehyde, which is absorbed in sodium bisulfite and titrated iodometricaHy. 

Polymerization-grade chloroprene is typically at least 99.5% pure, excluding inert solvents that may be present. It must be substantially free of peroxides, polymer [9010-98-4], and inhibitors. A low, controlled concentration of inhibitor is sometimes specified. It must also be free of impurities that are acidic or that will generate additional acidity during emulsion polymerization. Typical impurities are 1-chlorobutadiene [627-22-5] and traces of chlorobutenes (from dehydrochlorination of dichlorobutanes produced from butenes in butadiene [106-99-0]), 3,4-dichlorobutene [760-23-6], and dimers of both chloroprene and butadiene. Gas chromatography is used for analysis of volatile impurities. Dissolved polymer can be detected by turbidity after precipitation with alcohol or determined gravimetrically. Inhibitors and dimers can interfere with quantitative determination of polymer either by precipitation or evaporation if significant amounts are present. 

The paper describes the different chemical sensors and mathematical methods applied and presents the review of electronic tongue application for quantitative analysis (heavy metals and other impurities in river water, uranium in former mines, metal impurities in exhaust gases, ets) and for classification and taste determination of some beverages (coffee, bear, juice, wines), vegetable oil, milk, etc. [1]. 

Metal impurities can be determined qualitatively and quantitatively by atomic absorption spectroscopy and the required purification procedures can be formulated. Metal impurities in organic compounds are usually in the form of ionic salts or complexes with organic compounds and very rarely in the form of free metal. If they are present in the latter form then they can be removed by crystallising the organic compound (whereby the insoluble metal can be removed by filtration), or by distillation in which case the metal remains behind with the residue in the distilling flask. If the impurities are in the ionic or complex forms, then extraction of the organic compound in a suitable organic solvent with aqueous acidic or alkaline solutions will reduce their concentration to acceptable levels. 

In Total Reflection X-Ray Fluorescence Analysis (TXRF), the sutface of a solid specimen is exposed to an X-ray beam in grazing geometry. The angle of incidence is kept below the critical angle for total reflection, which is determined by the electron density in the specimen surface layer, and is on the order of mrad. With total reflection, only a few nm of the surface layer are penetrated by the X rays, and the surface is excited to emit characteristic X-ray fluorescence radiation. The energy spectrum recorded by the detector contains quantitative information about the elemental composition and, especially, the trace impurity content of the surface, e.g., semiconductor wafers. TXRF requires a specular surface of the specimen with regard to the primary X-ray light. 

NAA is a quantitative method. Quantification can be performed by comparison to standards or by computation from basic principles (parametric analysis). A certified reference material specifically for trace impurities in silicon is not currently available. Since neutron and y rays are penetrating radiations (free from absorption problems, such as those found in X-ray fluorescence), matrix matching between the sample and the comparator standard is not critical. Biological trace impurities standards (e.g., the National Institute of Standards and Technology Standard Rference Material, SRM 1572 Citrus Leaves) can be used as reference materials. For the parametric analysis many instrumental fiictors, such as the neutron flux density and the efficiency of the detector, must be well known. The activation equation can be used to determine concentrations ... 

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. 

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