Alfred Sallmann

The history of diclofenac

The purpose in developing diclofenac sodium was to synthesize a nonsteroidal anti-inflammatory drug with high activity and outstanding tolerability. Factors considered were drug transport through biologic membranes, the atomic and spatial structure of the molecule, and the electronic structure. Based on analysis of other nonsteroidal anti-inflammatory drugs, it was postulated that an effective antirheumatic agent should have the following characteristics: an acidity constant between 4 and 5, a partition coefficient of approximately 10, and two aromatic rings twisted in relation to each other. The result was diclofenac sodium, which has an acidity constant of 4.0 and a partition coefficient of 13.4. The structural elements include a phenylacetic acid group, a secondary amino group, and a phenyl ring containing chlorine atoms, which cause maximum twisting of the ring. Experimental and clinical findings obtained to date have indicated that diclofenac sodium was synthesized on well-founded principles.

Characterization of a novel diclofenac metabolite in human urine by capillary gas chromatography-negative chemical ionization mass spectrometry.

A sensitive analytical method was developed to characterize diclofenac metabolites in small amounts of body fluids. Desalted and lyophilized urine samples were extracted with supercritical carbon dioxide directly or after acidic hydrolysis. The extracts were derivatized with N-tert.-butyldimethylsilyl-N-methyltrifluoroacetamide. The derivatives were separated by capillary gas chromatography and identified by negative chemical ionization mass spectrometry. Full mass spectra were obtained at a level of 1.10(-9) g/ml. With direct extraction, the metabolites could be analysed in one step as open-chained acids and as (cyclic) oxindoles. By acidic hydrolysis the conjugates were transformed to the oxindoles. With both methods, a new main metabolite, [2-[2,6-dichloro-4-hydroxy-3-methoxyphenyl)amino]phenyl]acetic acid, was identified The mechanism of its formation is discussed.