Subsidiary colors in D&C Red No. 34 and its lakes: Synthesis, structural characterization, and analysis by ultra-performance liquid chromatography

Abstract

Abstract D&C Red No. 34 is the calcium salt of 3-hydroxy-4-[(1-sulfo-2-naphthalenyl)azo]-2-naphthalenecarboxylic acid. Its lakes are insoluble pigments formed by precipitating the dye anion onto an insoluble substratum, typically rosin. Subsidiary colors are colored impurities that are positional isomers of the dye anion or have higher or lower numbers of substituent groups. D&C Red No. 34 and its lakes are color additives listed in the U.S. Code of Federal Regulations (CFR) for use in externally applied drugs and cosmetics. These color additives are required to be batch certified by the U.S. Food and Drug Administration (FDA) to ensure compliance with the CFR requirements, including a limit of not more than four percent subsidiary colors in the straight color. There is no specified limit for subsidiary colors in the lakes, but the impurities may be analyzed for compliance with good manufacturing practices. In this paper, the syntheses of seven D&C Red No. 34 subsidiary colors are reported. Various combinations of impurities in the two intermediate starting materials for the dye, 2-amino-1-naphthalenesulfonic acid and 3-hydroxy-2-naphthalenecarboxylic acid, were used to synthesize the new compounds, which were purified by recrystallization and fully characterized by elemental analysis, ultra-performance liquid chromatography (UPLC), nuclear magnetic resonance spectroscopy, infrared spectroscopy, and visible spectrophotometry. The new compounds were used as reference materials in UPLC analyses of test samples from 33 certified lots of D&C Red No. 34 and its lakes. FDA is currently using these new reference materials for batch certification of the color additives.