466 ORDINARY IMPURITIES
This test, where called for in the individual monograph, is provided to evaluate the presence of ordinary impurities in official articles. Ordinary impurities are defined as those species in drug substances and/or drug products that have no significant, undesirable biological activity in the amounts present. These impurities may arise out of the synthesis, preparation, or degradation of compendial articles. In certain instances, impurities that pose a potential health risk may be detected. Because these impurities would not be individually identified by the strict use of this General Chapter, a separate evaluation may be necessary to ensure that the detected impurities fit the requirements set forth in the definition of Ordinary Impurities. Selections of tests and assays allow for anticipated amounts of impurities that are unobjectionable for the customary use of the article.
Reporting and Specifications— The value of 2.0%, unless otherwise specified in the individual monograph, was selected as the general limit for the total amount of ordinary impurities in monographs where documentation did not support adoption of other values.
Where a monograph sets limits on concomitant components and/or specified impurities/degradation products, these species are not to be included in the estimation of ordinary impurities unless so stated in the individual monograph. Concomitant components are defined as species characteristic of many drug substances that are not considered to be impurities in the Pharmacopeial sense. Examples of concomitant components are geometric and optical isomers (or racemates) and antibiotics that are mixtures. Any component that can be considered a toxic impurity because of significant undesirable biological effect is not considered to be a concomitant component.
Methodology— Unless otherwise specified in an individual monograph, estimation of the amount and number of ordinary impurities is made by relative methods rather than by strict comparison to individual Reference Standards. Nonspecific detection of ordinary impurities is also consistent with this classification.
Typical evaluation methods used for ordinary impurities are thin-layer chromatographic (TLC) techniques. See Chromatography 621 for a general discussion of the thin-layer chromatographic technique. Tests for related substances or chromatographic purity may also be used to evaluate the presence of ordinary impurities. Other methods (e.g., HPLC, HPTLC, etc.) may also be used with adequate justification as an alternate method. Unless otherwise specified in the individual monograph, use the following method.
Test Solution— Prepare, in the solvent specified in the monograph, a solution of the substance under test having an accurately known final concentration of about 10 mg per mL. [Note—Heat or sonication may be used to dissolve the drug substance where use of such does not adversely affect the compound. ]
Standard Solutions— Prepare, in the solvent specified in the monograph, solutions of the USP Reference Standard or designated substance having accurately known concentrations of 0.01 mg per mL, 0.05 mg per mL, 0.1 mg per mL, and 0.2 mg per mL. [Note—Heat or sonication may be used to dissolve the drug substance where use of such does not adversely affect the compound. ]
Procedure— Use a thin-layer chromatographic plate coated with a 0.25-mm layer of chromatographic silica gel mixture, and the Eluant specified in the monograph. Apply equal volumes (20 µL) of the Test Solution and Standard Solutions to the plate, using a stream of nitrogen to dry the spots.
Allow the chromatogram to develop in a pre-equilibrated chamber until the solvent front has moved about three-fourths of the length of the plate. Remove the plate from the chamber, and air-dry. View the plate using the visualization technique(s) specified. Locate any spots other than the principal spot in the chromatogram of the Test Solution, and determine their relative intensities by comparison with the chromatograms of the appropriate Standard Solutions. See discussion above with regard to reporting and specifying total ordinary impurities.
key for visualization techniques
(1) Use UV light at 254 nm and at about 366 nm.
(2) Use Iodoplatinate TS.
(3) Solution A—Mix 850 mg of bismuth subnitrate with 40 mL of water and 10 mL of glacial acetic acid.
Solution B—Dissolve 8 g of potassium iodide in 20 mL of water. Mix A and B together to obtain a Stock Solution which can be stored for several months in a dark bottle. Mix 10 mL of the Stock Solution with 20 mL of glacial acetic acid, and dilute with water to make 100 mL, to prepare the spray reagent.
(4) Ninhydrin Spray—Dissolve 200 mg of ninhydrin in 100 mL of alcohol. Heat the plate after spraying.
(5) Acid Spray—In an ice bath, add slowly and cautiously, with stirring, 10 mL of sulfuric acid to 90 mL of alcohol. Spray the plate, and heat until charred.
(6) Acid–Dichromate Spray—Add sufficient potassium dichromate to 100 mL of sulfuric acid to make a saturated solution. Spray the plate, and heat until charred.
(7) Vanillin—Dissolve 1 g of vanillin in 100 mL of sulfuric acid.
(8) Chloramine T–Trichloroacetic Acid—Mix 10 mL of a 3% aqueous solution of chloramine T with 40 mL of a 25% alcoholic solution of trichloroacetic acid. Prepare immediately before use.
(9) Folin-C—Add 10 g of sodium tungstate and 2.5 g of sodium molybdate to 70 mL of water, add 5 mL of 85% phosphoric acid and 10 mL of 36% hydrochloric acid, and reflux this solution for 10 hours.
(10) KMnO4—Dissolve 100 mg of Potassium Permanganate in 100 mL of water.
(11) DAB—Mix 1 g of p-dimethylaminobenzaldehyde in 100 mL of 0.6 N hydrochloric acid.
(12) DAC—Mix 100 mg of p-dimethylaminocinnamaldehyde in 100 mL of 1 N hydrochloric acid.
(13) Ferricyanide—Mix equal volumes of a 1% ferric chloride solution and a 1% potassium ferricyanide solution. Use immediately.
(14) Fast Blue B—Reagent A—Dissolve 500 mg of Fast Blue B Salt in 100 mL of water.
Reagent B—0.1 N sodium hydroxide.
Spray first with A, then with B.
(15) Alkaline Ferric Cyanide—Dilute 1.5 mL of a 1% potassium ferricyanide solution with water to 20 mL, and add 10 mL of 15% sodium hydroxide solution.
(16) Iodine Spray—Prepare a 0.5% solution of iodine in chloroform.
(17) Expose the plate for 10 minutes to iodine vapors in a pre-equilibrated closed chamber, on the bottom of which there are iodine crystals.
(18) Solution A—Dissolve 0.5 g of potassium iodide in 50 mL of water.
Solution B—Prepare a solution of 0.5 g of soluble starch in 50 mL of hot water.
Just prior to use, mix equal volumes of Solution A and Solution B.
(19) PTSS—Dissolve 20 g of p-toluenesulfonic acid in 100 mL of alcohol, spray the plate, dry for 15 minutes at 110, and view under UV light at 366 nm.
(20) o-Tolidine Spray—Dissolve 160 mg of o-tolidine in 30 mL of glacial acetic acid, dilute with water to make 500 mL, add 1 g of potassium iodide, and mix until the potassium iodide has dissolved.
(21) Mix 3 mL of chloroplatinic acid solution (1 in 10) with 97 mL of water, followed by the addition of 100 mL of potassium iodide solution (6 in 100) to prepare the spray reagent.
(22) Iodine–Methanol Spray—Prepare a mixture of iodine TS and methanol (1:1).
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