Mallinckrodt, Inc.

Mallinckrodt Medical, Inc.

Other

Thomas J Dunn

David H White

Mills T Kneller

Youlin Lin

David M Wong

Narciso Ocampo Doran, Iii

Rebecca A Wallace

Michelle M Jones

Mark E Bosworth

Richard G Johnson

Warren E Hall

Raghavan Rajagopalan

Leon R Lyle

Allan R Bailey

Edward L Derrenbacker

William R Clingan

Vojko B Jovanovic

Process for producing ioversol

The present invention discloses a new process for producing ioversol (marketed as OPTIRAY.RTM.) comprising:

A diagnostic composition suitable for administration to a warm-blooded animal comprising hirudin or a molecule capable of interacting with the hirudin receptor labeled with a radionuclide by means of a chelate ligand capable of administration to an animal to produce reliable visual imaging of thrombus.

Radiolabelled peptide compounds

The use of reverse osmosis as an alternative or substitute method for the purification of a crude diagnostic agent. X-ray contrast agent, magnetic resonance imaging agent, or radiopharmaceuticals are purified by passing through a cross-linked reverse osmosis membrane.

Purification of X-ray contrast agent, magnetic resonance imaging agent,

An improved process for the reversed phase chromatographic decolorization, separation, and purification of water-soluble, nonionic contrast media compounds from solutions containing nonionic compound impurities involves the steps of (a) packing a chromatographic column with a chromatographic packing material; (b) passing through the column a solution containing a water-soluble, nonionic contrast media compound and nonionic compounds as impurities at a loading ratio between approximately 10 to 1 and 1.5 to 1 wt. packing material/total wt. nonionic compounds; and (c) eluting the column to produce an eluate containing substantially pure, water-soluble, nonionic contrast media compound or MRI agent. The process can be economically practiced on a factory scale and efficiently removes non-polar impurities difficult to remove by conventional methods.

Reversed phase chromatographic process

The use of reverse osmosis as an alternative or substitute method for the purification of a crude diagnostic agent. In the purification process a crude Ioversol solution is contacted with a cross-linked membrane under pressure, forcing the low molecular weight impurities within the crude Ioversol solution through the membrane pores and retaining Ioversol molecules.

Purification of crude Ioversol using reverse osmosis

A process for removing impurities from an aqueous feed mixture comprising a reaction solution produced by catalytic hydrogenation of nitrobenzene in an acid aqueous medium. An aqueous feed mixture comprising the reaction solution is contacted with an extractant comprising aniline for extraction from the feed mixture of 4,4'-diaminodiphenylether, thereby providing a primary raffinate that contains p-aminophenol and is contaminated with aniline. The primary raffinate is contacted at a pH of between about 5.5 and about 8.0 with a purifying solvent, the purifying solvent comprising an organic solvent effective for extraction of aniline from the primary raffinate, thereby producing a purified raffinate comprising p-aminophenol. Also described is a unified process for the preparation of N-acetyl-p-aminophenol in which p-aminophenol contained in the aforesaid purified raffinate is acetylated without prior separation of solid p-aminophenol from the raffinate.

Purification of p-aminophenol compositions and direct conversion to

An improved process for the recovery and extractive purification of p-aminophenol is disclosed. The process involves contacting an aqueous feed solution prepared by catalytic reduction of nitrobenzene in acid medium and containing 4,4-diaminodiphenyl ether, aniline and other minor amine by-products with a base to adjust the pH of the solution to 4.0-5.0, and then extracting the resulting aqueous feed solution with a mixture of aniline and toluene to selectively dissolve 4,4'-diaminodiphenyl ether in the aniline-toluene mixture and to produce an aqueous phase containing principally p-aminophenol and an organic aniline-toluene phase cotaining p-aminophenol, 4,4'-diaminodiphenyl ether and other amine by-products. The ratio of aniline to toluene is within the range between approximately 4 parts by volume aniline to 1 part by volume toluene and approximately 1 part by volume aniline to 4 parts by volume toluene, preferably a ratio of 1:1. After separation of the aqueous phase from the organic phase, the p-aminophenol of improved purity is recovered from the aqueous phase. Further efficiency in the overall yield of p-aminophenol is achieved by back-extracting the organic phase with a basic solution of potassium or sodium hydroxide to produce an aqueous layer containing the basic solution and substantially all of the p-aminophenol formerly contained in the organic phase and then recycling the aqueous layer for use as a portion of the base used to adjust the pH of the original aqueous feed solution to the range of 4.0 to 5.0. Another feature disclosed is the fractional countercurrent extraction of the original aqueous feed solution having a pH of 4.0 to 5.0 with an aniline-toluene mixture and an ammonium sulfate solution, aniline sulfate or sulfuric acid to selectively dissolve 4,4'-di-aminodiphenyl ether in the aniline-toluene mixture and to produce an aqueous phase from which a greater yield of p-aminophenol of improved purity may be obtained.

Process for the purification of p-aminophenol

This invention relates to the field of organic chemistry, and more particularly, to a method for the preparation of p-aminophenol.

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Cedar Hill, MO, United States of America

Thomas J Dunn