Determination of Impurities

Rice, G. W. Determination of Impurities in Whiskey Using Internal Standard Techniques, /. Chem. Educ. 1987, 64, 1055-1056. 

Generally, cmde sulfur contains small percentages of carbonaceous matter. The amount of this impurity is usually determined by combustion, which requires an exacting technique. The carbonaceous matter is oxidized to carbon dioxide and water the carbon dioxide is subsequently absorbed (18). Automated, on-stream determination of impurities in molten sulfur has been accompHshed by infrared spectrophotometry (35). 

The purity of commercial tin is under strict control at the smelters. Photometric, chemical, atomic absorption, fluorimetric, and spectrographic methods are available for the determination of impurities (17). 

Another example of multi-column analysis has been demonstrated for the determination of impurities in styrene. The marked compounds in the styrene sample (Figure 12.15(a)) were solvent flushed via a splitline, with the analysis being carried out with a cryotrapping separation (CTS) (see Figure 12.15(b)). The first column, was an Ultra-2 (25 m X 0.32 mm i.d., d( = 0.25 p.m) precolumn, while the main column was a DB-WAX (30 m X 0.32 mm, d = 0.25 p.m) with an FID being employed as the detection system. 

A study of the nomenclature problem indicates that only samples are analyzed elements, ions, and compounds are identified or determined. The difficulty occurs when the sample is nominally an element or compound (of unknown purity). Analysis of... (an element or compound) must be understood to mean the identification or determination of impurities. When the intent is to determine how much of such a sample is the material indicated by the name, assay is the proper word. ... 

The most common types of analyses are the identification test, the quantitative determination of active ingredients or major component, and the determination of impurities. The identification test provides data on the identity of the compound or compounds present in a sample. A negative result signifies that the concentration of the compound(s) in sample is below the DL of the analyte(s). The quantitative method for the major component provides data of the exact quantity of the major component (or active ingredients) in the sample, and a reported concentration of the major component must be higher than the QL. In a Determination of impurities test, one obtains data regarding the impurity profile of a sample, and can be divided into a limit test or quantitative reporting of impurities (see Table 1, which has been modified from Refs. [1] and [8]). 

CE is increasingly applied to analysis of proteins present at trace levels in biological materials or to determination of impurities and degradation products in formulations... 

FIGURE 1.25 HPLC determination of impurities in a levothyroxin (L-T4) formulation. Experimental conditions Column, Chiralpak QN-AX (150 rum x 4 rum ID) mobile phase, acetonitrile-50 mM ammonium acetate (60 40, v/v) (pHa 4.5) flow rate, 0.7 mLmiu UV detection, 240 nm temperature, 25 C. Sample, T4-200 tablets (Uni-Pharma, Greece) containing 0.2 mg L-T4 sodium per tablet the tablet was pulverized, suspended in methanol-10 mM sodium hydroxide (1 1 v/v) and after ultrasonication for 5 min the residues were removed by filtration. An aliquot of 10 xL of the filtrate was directly injected. (Reproduced from H. Gika et al., J. Chromatogr. B, 800 193 (2004). With permission.)... 

C. Assay of Main Compound and Determination of Impurities Methods... 

Novatchev, N., and Holzgrabe, U. (2002). Comparison of the suitability of capillary electrophoresis and thin-layer chromatography for determination of impurities In amino acids. Pharmeuropa 14(4), 640-647. 

The USP requirements for assay validation are very close to the ICH proposal. Here, three categories are distinguished. Category I corresponds to ICH assay, category II corresponds to ICH determinations of impurities. The additional category III includes analytical methods for the determination of performance characteristics (e.g., dissolution, drug release). For this category, the ICH assay characteristics are always sufficient. The objective of the analytical procedure... 

The hyphenation of CE with techniques allowing structural determination of impurities is the object of Chapter 18 Coupling CE and Microchip-based Devices and Mass Spectrometry of this book, but the potential of CE coupled to mass spectrometry (CE/MS) in impurity profiling has also been discussed elsewhere. ... 

Gorog, S. (2000). Identification and Determination of Impurities in Drugs. Vol. IV, Elsevier, Amsterdam. 

Carvalho, A. Z., Pauwels, J., De Greef, B., Vynckier, A.-K., Yuqi, W., Hoogmartens, J., and Van Schepdael, A. (2006). Capillary electrophoresis method development for determination of impurities in sodium cysteamine phosphate samples.. Pharm. Biomed. Anal. 42, 120—125. 

Stalberg, O., Westerlund, D., Rodby, U. B., and Schmidt, S. (1995). Determination of impurities in remoxipride by capillary electrophoresis using UV-detection and LIF-detection — principles to handle sample overloading effects. Chromatographia 41, 287—294. 

Hansen, S. H., and Sheribah, Z. A. (2005). Comparison of CZE, MEKC, MEEKC and non-aqueous capillary electrophoresis for the determination of impurities in bromazepam. /. Pharm. Biomed. Anal. 39, 322-327. 

Gilges, M. (1997). Determination of impurities in an acidic drug substance by micellar electrokinetic chromatography. Chromatographia 44, 191 —196. 

Validation of methods for quantitative determination of impurities includes precision studies. Repeatability is generally assessed by analysis of the same sample or samples prepared by the same analyst in replicate assays within a short duration of time. Repeatability should be assessed using (i) a minimum of nine determinations covering the specified range for the procedure (e.g., three concentrations/three replicates each) or (ii) a minimum of six determinations at 100% of the test concentration. Repeatability is evaluated by averaging the mean results from replicate assays and calculating the standard deviation (SD) and RSD. Repeatability of the method can be stated as either SD or RSD values. If an instrument is required for assay performance, then the same instrument should be used for the replicate assays. 

Rao RN, Nagaraju V. An overview of the recent trends in development of HPLC methods for determination of impurities in drugs. Journal of Pharmaceutical and Biomedical Analysis 33, 335-377, 2003. 

Determination of impurities in insulin-like growth factor with electrospray-mass spectrometry (ES-MS)... 

---