Impurities quantitation

Validation Parameter Identification Impurities (Quantitation) Impurities (Limit) Assay... 

Validation parameter Identification Testing for impurities Quantitative Limit test Assay... 

Method Performance Parameter Identification Test Impurity Test Limit Impurity Quantitative Test Impurity Test Assay Test... 

Characteristic Identification Testing for Impurities Quantitation Limit Assay (dissolution content/potency)... 

Validation characteristics Minimum number Identity Analytical procedure Impurities Quantitative Limit Assay ... 

Another approach to measuring purity is to determine impurities quantitatively after resolution by chromatography. The idea is to look at the impurities as a reflection of purity (i.e., a substance is considered pure when no impurity is found). Because the detection of a minute amount of substance impurity is precise, the sensitivity of determination is generally high. Thus, minute amounts of impurities can be detected. The presence of impurities can best be detected by TLC, CE, HPLC, or GLC. 

Type of analytical procedure characteristics Identification Testing for impurities Quantitation Limit Assay dissolution (measurement only) content/ potency... 

NMR spectroscopy is perhaps not quite so popular as F in pharmaceutical development because of the lower number of drug substances containing phosphorus. However, it has importance in biochemistry and the same potential for impurity quantitation as F, and there are many structural problems where it can help, for example in Wittig reactions, ylides, phosphate esters, nucleotides and phospholipids [57]. Two-dimensional methods for phosphorus have been reviewed [58]. The latter reference also reviews H-X, X-X and X-Y correlation experiments for other heteronuclei. Given the relative dearth of tertiary literature on phosphorus NMR in chemistry, the book by Berger etal. [38] is particularly useful. 

Quantitative tests provide an estimate of the concentration of a specific impurity. This type of test is normally required for the determination of signal or toxic impurities and is used with increasing frequency for ordinary impurities. Quantitative tests are based on techniques that provide a high degree of accuracy and precision such as gas chromatography (GC) and liquid chromatography (LC). 

A number of w orkers have employed dehydrohalogenation with ethanolic alkali as a basis for estimating />,/> -dicophane. At ordinary temperatures OTN ethanolic alkali will remove HCl quantitatively from the pure substance without further decomposition of the molecule but in commercial samples isomers and other impurities interfere. The most important impurity quantitatively is o,/) -dicophane, which may be present to the extent of 8 to 21 per cent this isomer reacts much more slowly to ethanolic alkali and the amount of chloride liberated under specified conditions can be related to the content of />,/>-dicophane by means of a regression equation. Such an equation has been given by Wain and Martin and under the specified conditions should give a close approximation to the/>, -dicophane content ... 

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. 

It is evident from the figure that impurities can complicate the use of NMR integrals for quantitation. Further complications arise if the relevant spins are not at Boltzmaim equilibrium before the FID is acquired. This may occur either because the pulses are repeated too rapidly, or because some other energy input is present, such as decoupling. Both of these problems can be eliminated by careful timing of the energy inputs, if strictly accurate integrals are required. 

In a similar way HjC=C=C(0CH3)(SnBuj), n 1.4955 (undistilled) was prepared in almost quantitative yield from 0.12 mol of butyllithium in 75 ml of hexane and 75 ml of diethyl ether, 0.14 mol of methoxyallene and 0.10 mol of tributyl-tin chloride. The product contained 8-10% of an impurity, possibly Bu3Sn-CH2CEC-0CH3. 

In a gravimetric analysis a measurement of mass or change in mass provides quantitative information about the amount of analyte in a sample. The most common form of gravimetry uses a precipitation reaction to generate a product whose mass is proportional to the analyte. In many cases the precipitate includes the analyte however, an indirect analysis in which the analyte causes the precipitation of another compound also is possible. Precipitation gravimetric procedures must be carefully controlled to produce precipitates that are easily filterable, free from impurities, and of known stoichiometry. 

The parameter r continues to measure the ratio of the number of A and B groups the factor 2 enters since the monofunctional reagent has the same effect on the degree of polymerization as a difunctional molecule with two B groups and, hence, is doubly effective compared to the latter. With this modification taken into account, Eq. (5.40) enables us to quantitatively evaluate the effect of stoichiometric imbalance or monofunctional reagents, whether these are intentionally introduced to regulate or whether they arise from impurities or side reactions. 

In current industrial practice gas chromatographic analysis (glc) is used for quahty control. The impurities, mainly a small amount of water (by Kad-Fischer) and some organic trace constituents (by glc), are deterrnined quantitatively, and the balance to 100% is taken as the acetone content. Compliance to specified ranges of individual impurities can also be assured by this analysis. The gas chromatographic method is accurately correlated to any other tests specified for the assay of acetone in the product. Contract specification tests are performed on product to be shipped. Typical wet methods for the deterrnination of acetone are acidimetry (49), titration of the Hberated hydrochloric acid after treating the acetone with hydroxylamine hydrochloride and iodimetry (50), titrating the excess of iodine after treating the acetone with iodine and base (iodoform reaction). 

The conventional method for quantitative analysis of galHum in aqueous media is atomic absorption spectroscopy (qv). High purity metallic galHum is characteri2ed by trace impurity analysis using spark source (15) or glow discharge mass spectrometry (qv) (16). 

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. 

Analysis. Indium can be detected to 0.01 ppm by spectroscopic analysis, using its characteristic lines in the indigo blue region, at wavelengths 4511.36, 4101.76, 3256.09, and 3093.36 nm. Procedures for the quantitative deterrnination of indium in ores, compounds, alloys, and for the analysis of impurities in indium metal are covered thoroughly in the Hterature (6). 

Contaminant by-products depend upon process routes to the product, so maximum impurity specifications may vary, eg, for CHA produced by aniline hydrogenation versus that made by cyclohexanol amination. Capillary column chromatography has improved resolution and quantitation of contaminants beyond the more fliUy described packed column methods (61) used historically to define specification standards. Wet chemical titrimetry for water by Kad Eisher or amine number by acid titration have changed Httle except for thein automation. Colorimetric methods remain based on APHA standards. 

A study was conducted to measure the concentration of D-fenfluramine HCl (desired product) and L-fenfluramine HCl (enantiomeric impurity) in the final pharmaceutical product, in the possible presence of its isomeric variants (57). Sensitivity, stabiUty, and specificity were enhanced by derivatizing the analyte with 3,5-dinitrophenylisocyanate using a Pirkle chiral recognition approach. Analysis of the caUbration curve data and quaUty assurance samples showed an overall assay precision of 1.78 and 2.52%, for D-fenfluramine HCl and L-fenfluramine, with an overall intra-assay precision of 4.75 and 3.67%, respectively. The minimum quantitation limit was 50 ng/mL, having a minimum signal-to-noise ratio of 10, with relative standard deviations of 2.39 and 3.62% for D-fenfluramine and L-fenfluramine. 

Impurities in bromine may be deterrnined quantitatively (54). Weighing the residue after evaporation of a bromine sample yields the total nonvolatile matter. After removing the bromine, chloride ion may be deterrnined by titration with mercuric nitrate, and iodide ion by titration with thiosulfate water and organic compounds may be detected by infrared spectroscopy sulfur may be deterrnined turbidimetricaHy as barium sulfate and heavy metals may be deterrnined colorimetricaHy after conversion to sulfides. 

The hterature consists of patents, books, journals, and trade Hterature. The examples in patents may be especially valuable. The primary Hterature provides much catalyst performance data, but there is a lack of quantitative results characterizing the performance of industrial catalysts under industrially reaHstic conditions. Characterizations of industrial catalysts are often restricted to physical characterizations and perhaps activity measurements with pure component feeds, but it is extremely rare to find data characterizing long-term catalyst performance with impure, multicomponent industrial feedstocks. Catalyst regeneration procedures are scarcely reported. Those who have proprietary technology are normally reluctant to make it known. Readers should be critical in assessing published work that claims a relevance to technology. 

Reagents similai to those used in the analysis of chloiine are commonly employed in the quantitation of gaseous and aqueous chloiine dioxide as well as its reaction coproducts chlorine, chlorite, and chlorate. The volatihty of the gas from aqueous solutions as well as its reactivity to light must be considered for accurate analysis. Other interferences that must be taken into account include other oxidizers such as chloramine, hydrogen peroxide, permanganate, and metal impurities such as ferrous and ferric iron. 

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. 

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