Unidentified impurity

Fractionally distd under vacuum, then fractionally crystd twice from its melt. Impurities include acetic acid, methyl amine and H2O. For detailed purification procedure, see Knecht and Kolthoff, Inorg Chem 1 195 1962. Although /9-methylacetamide is commercially available it is often extensively contaminated with acetic acid, methylamine, water and an unidentified impurity. The recommended procedure is to synthesise it in the laboratory by direct reaction. The gaseous amine is passed into hot glacial acetic acid, to give a partially aq soln of methylammonium acetate which is heated to ca 130° to expel water. Chemical methods of purificatn such as extractn by pet ether, treatment with H2SO4, K2CO3 or CaO can be used but are more laborious. 

The contents of the receiver and trap are combined with the aid of a few drops of dichloromethane and distilled through a 15-cm. Vigreux column under reduced pressure. After only a few drops of forerun, the main fraction is 2.87-3.17 g. (60-66%) of 5-hexynal, b.p. 61-62° (30 mm.), w20d 1.4447, df 0.875 (Notes 11-13). Cas chromatographic analysis (Note 14) shows this material to contain 3-5% of unidentified impurities with longer retention times (Note 15). 

Fig. 3.107. Comparison of micro-HPLC separations of aromatic sulphonic acids in different mobile phases (a) 0.005 M tetrabutylammonium hydrogensulphate (TBAS) in 15 per cent (v/v) methanol in water (1) Laurent acid, (2) amino-F-acid, (3) Cleve-1,6- and Peri acids, (4) unidentified impurity, (5) Cleve-1,7-acid and (6) unidentified impurity, (b) 0.005 M tetrabutylammonium hydrogensulphate (TBAS) in 15 per cent (v/v) methanol in water with 0.01 M /Lcyclodextrin (CD) (1) Laurent acid, (2) amino-F-acid, (3) Cleve-1,6-acid, (4) Peri acids, (5) unidentified impurity, (6) Cleve-1,7-acid and (7) unidentified impurity. Column, Biosphere Si C18, 162 X 0.32 mm i.d. flow rate 5 pl/min, column temperature ambient, detection, UV, 220-230 nm. Reprinted with permission from P. Jandera et al. [164].

Baseline separation of the cephalosporin antibiotic cephradine, its main impurity cephalexin, and other related impurities was achieved by MEKC. The method was validated in compliance with the USP XXII analytical performance parameters and the results were comparable with a validated LC method, depicting CE to be a valuable alternative technique to LC in pharmaceutical quality control. In most cases, the amount of impurities relative to the main compound measured by MEKC is similar to that obtained by LC. However, some reports reveal that there are differences in number and amount of impurities between MEKC and LC analysis. MEKC permitted the determination of seven known and three unknown impurities in cefotaxime and the results were in good agreement with those of LC. ° MEKC yielded a higher amount of the cefotaxime dimer but a lower amount of an unidentified impurity with respect to LC. The differences may be due to the easier formation of the dimer in the aqueous sample solvent used in MEKC compared to the hydroorganic... 

Many acid-labile linkers are used to assemble combinatorial libraries. Compounds are cleaved in the final step by TFA/DCM solution with various concentrations for a certain period of time. Mild cleavage conditions may lead to incomplete cleavage of the desired compound from a solid support. On the other hand harsh conditions may cause compound degradation and side reactions. Harsh conditions will also cause the partial breakdown of resin and the leaching of unidentified impurities into the final products. Harsh cleavage conditions demand the stabihty of all compounds under such conditions. This may limit the scope of combinatorial synthesis... 

Broadly, the upper limits for the various impurities are set on the basis of toxicological considerations and process capabilities. On the basis of animal smdies, preferably with drug substance containing enhanced levels of impurities, a dose level that produces no adverse events in the animals is identified. This is converted to an equivalent of the oral dose level in humans. Although high-dose pharmaceuticals are different, for the majority of drugs, impurities above 0.05% are reported as unidentified impurities and included in the total impurity amount, impurities above 0.10% are identified and included in the specification, and impurities above 0.15% are toxicologically qualified. 

Figure 1.9 [18] illustrates the use of CE for the analysis of amoxicillin (AMOX) from various suppliers. Unidentified impurities (1 and 2) and degradant (DG) are seen, and the mixtures are spiked with ampicillin (AMP) and penicillin V (PENV). 

Figure 1.8 Use of capillary electrophoresis for separating the diastereomers quinine (QN) and quinidine (QD) (H-QN is hydroquinine, QD-N-OX is quinidine iV-oxide, H-QD is hydroquinidine, 3-OH-QD is 3-hydroxyquinidine, and asterisk is an unidentified impurity). Reprinted from [17], copyright 2001, with permission from Elsevier. (Capillary 47 cm X 75 pm i.d. (40 cm to detector) (Polymicro Technologies) running buffer 50 mM phosphoric acid containing 15 mM /3-cyclodextrin adjusted to pH 2.5 with NaOH voltage 7 kV current 21 pA injection at 0.5 psi for 4 s detector fluorescence (HeCd laser) excitation 325 nm, emission 450 nm.)...

Fig. 2. 500 MHz pulsed field gradient stimulated echo spectra of a mixture of choline chloride, acetone and TSP in D2O, obtained using the LED sequence as described in the text. A signal from an unidentified impurity is visible just to high field of the acetone resonance.

The final product specifications must contain a specific identity test. The full set of physical properties and physical constants that are characteristic of the substance must be measured and their appropriate values documented. And, very importantly, the purity of the final product must be demonstrated by a suitable chromatographic method. That chromatographic method must be able to measure the presence of impurities at concentrations of hundreds of a percent in order to be appropriate or acceptable for this purpose. Impurities present in the final product must be characterized. Those impurities which occur in final product at greater than 0.1% must be identified and tested for their biological properties, including toxicity, mutagenecity, etc. Ordinarily, impurities present in concentrations of 0.01 to 0.1% can be recorded as unidentified impurities, and impurities which occur at concentrations less than 0.01% are ordinarily just noted. 

The checkers recorded [oi]q8 +18.9° (CHCI3, c 1.85) for this material and noted some unidentified impurities in the 1H NMR spectrum. The submitters indicate that 3 mL of methanol can be added to the yellow liquid followed by filtration to remove precipitated solids. 

Tetrakis(dimethylamino)diboron is moisture sensitive. 1H NMR (CDCI3) 8 2.67 (s, 24 H). The checkers observed an unidentified impurity in the 1H NMR spectrum (8 2.51, s). The checkers also obtained a slightly better yield (72%) than reported by the submitters (67%) when a freshly opened bottle of sodium was used in this experiment. 

In contrast, diallylamino-substituted dyes copolymerized poorly with MMA, despite the reported polymerizability of other aliphatic (24-25) and aromatic (26) diallylamines. The concentration of dye-bearing repeat units m the polymer was far below the monomer feed concentrations. The possibility that these diallyl dye-monomers (or some unidentified impurity in them) acted as inhibitors of polymerization can be ruled out because the dye was found to be present uniformly in all molecular weight fractions and the molecular weights of the copolymers were again nearly identical to control samples of PMMA. Therefore, only a small amount of the diallyl amino substituted chromophores can be covalently incorporated into the crosslinked matrix because of the apparently unfavorable reactivity ratio. The balance of the chromophore remains simply dissolved in the mixture. 

Figure 3. Four parameter, simplex-optimized SFC separation of a 12-component mixture. Chromatographic conditions as in Vertex 13 of Table II. Sample components isoquinoline, n-octadecane (n-CigH3g), naphthalene, quinoline, acetophenone, undecylbenzene, benzophenone, 2 -acetonaphthone, diphenylamine, o-dioctylphthalate, unidentified impurity, N-phenyl-1-naphthylamine, phenanthrene quinone. Other conditions as described in the experimental section.

Beside the use of chromatography in isolation of new alkaloids, several analytical chromatographic determinations of bisbenzylisoquinoline alkaloids have been reported. A TLC method for resolution of components of commercial curare is described an unidentified impurity ( 1%), prisms, mp 275°C (dec.) (MeOH), which interferes with crystallization of d-tubocurarine can be removed in this manner (597). Four TLC systems for evaluation of tubocurarine chloride preparations have been developed (598). TLC-UV methods for analysis of tetrandrine in extracts of Stephania tetrandra are described (599,600). 

The NMR spectrum (Figure 12) was consistent with the dihydrohypoxanthine structure, though minor unidentified impurities are also present. 

After a few years scientists from Japan, Israel, France, USA, and other countries followed these studies. Whereas in the first papers the diamond electrodes, although of very good crystallinity, were not intentionally doped (their conductance was attributed to some unidentified impurities or point defects imparted by special thermal treatment), turning to boron-doped diamond samples [12] gave impetus to further progress in diamond electrochemistry. The number of laboratories involved in the studies of diamond electrodes is ever increasing in the last few years. 

Toxicological evaluation of identified and unidentified impurities from a container can help improve the safety index of drug products. The toxicological evaluation should take into consideration container closure system properties, drug product formulation, dosage form, route of administration, and dose regimen. A close correlation between chemical and toxicological information can provide better control on safety and compatibility of containers and closures. 

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