• PRODUCTION w
Better Control of Fine Chemicals Improved analytical methods based on instrumentation p r o v i d e n e w tools for p n a r m a c e u f icuis c o n t r o l
K ^ ^ ^ ^ ^ ^ ^ ^ ^ often cannot mainmethods, says Eli Lilly's W. B, Fortune. Well-known classical methods like determination of melting points and specific rotation, gravimetric or titrimetric analyses, or the use of identity tests based on color reactions too often are not specific enough, may at best provide only a small link in a long chain of circumstantial evidence. In fact, Fortune told the symposium on analysis of fine chemicals and pharmaceuticals, many tests found in control specifications, such as determinations of moisture, ash, sulfate, and chloride, frequently may b e actually superfluous. For today's needs, four criteria of purity for fine chemicals and pharmaceuticals must be met, Fortune told the Division of Analytical Chemistry symposium: • The product must be identified beyond question, using such tools as infrared spectrophotometry, x-ray spectrometry, chromatography, crystallography, and other physical chemistry measurements. • The product must be free from products of similar composition, as indicated b y paper, vapor phase, or partition chromatography or other partition techniques. • It must be proved pure by assay methods such as ultraviolet spectrophotometry, spectroscopy, nonaqueous titration, or other instrumental methods. • It must be pharmaceutically "elegant" and free of extraneous dirt or color, "Only when these criteria have been met, using precise instruments and truly analytical methods, should a product be labeled as a fine chemical or pharmaceutical." • Control
by
Paper
Chromatonrn-
phy. One good example of how modern procedures can be used for quality control is seen in paper chromatog4814
C&EN
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1956
raphy. As used by Pfizear's HL J. Pazdera and coworkers, the method provides a simple, cheap, and! effective tool for resolving compounds tihat are difficult to determine in natunaUy oocurring mixtures and pharmaceutical preparations. It provides a quantity of the desired substance in a piare state with so few attendant impurities that simple analyses can b e used for- quantitative work. The Pfizer group has successfully applied paper chromatography to the routine control of a nimober of pure pharmaceuticals by workimg out systems that can clearly resolve a milligram or more of material and. b y utilizing instrumental methods and micro techniques that can be handled readily by technicians or junior eheiraists. Once impurities that would interfere with determinations are removed by chromatography (usually -with descending systems so that the cshromatogram can b e run for a fixed time even if the solvent runs off the? paper), the specificity of the analytical method is not important. Commo:oly used are ultraviolet absorbance, colorimetry, nonaqueous titration, and ^olarography. Infrared procedures haves been developed but are usually cumbersome, according to Pazdera. Ultraviolet spectrophotometry has been used to determine hydrocortisone, neserpine, and hyroxyzine hydrochloride,, while colorimetric methods are successful with Viadril; man-hours of time required for these analyses range exclusive of time during which the chroma^ograrn is being developed and ehitedL, from one to 2.5 hours. Other new procedures laave also been developed for pharmaceutical control: • Morton Schmall and coworkers at Hoffmann-La Roche haver extended the use of their multibuffered ipaper method of chromatographic separation (C&EN, April 23, page 1982) to organic acidic compounds and have u s e d the technique to separate barbiturates and phenolic compounds in samall amounts (about 15 micrograms). • Fluorometric methods for analysis of 11-desmethoxyreserpine (Haxmonyl) are used b y J. A. Gordon and D . J.
H. J. Pazdera of Pfizer examines chromatogram with a fluorescent scanner to locate ultraviolet absorbing substances. Elution and assay follow Campbell of Abbott Laboratories. They treat a solution of the alkaloid in acetic acid with eerie sulfate to increase the intensity of its fluorescent spectrum, then measure fluorescence with a photofluorometer. • A colorimetric method for assay of cortisone, hydrocortisone, and related steroids has been worked out b y E . P. Schulz and J. D . Neuss of Merck, who find that alkaline solutions of certain steroids form two distinct colors (blue or yellow-brown) when refluxed -with 2,6-di-ter£-butyl-p-cresol. • Prednisolone can be distinguished from other steroids b y use of sulfuric acid-method reagent, according to Merck's C. R. Szalkowski, because it forms a deep magenta color with the mixture whereas other steroids develop yellow or fluorescent purple colors.
lubrication Under Radiation Many oils deteriorate when exposed to radiation, presenting problems to atomic power plants
Many stallations such as atomic power plants is a real problem. California Research has been working on a development program for radiation-resistant lubricants since 1948. Last week at the Division of Industrial and Engineering Chemistry, R. O. Bolt
