David D. Wirth

Determination of fluoxetine hydrochloride enantiomeric excess using high-performance liquid chromatography with chiral stationary phases

Chromatographic methods using chiral stationary phases have been developed for the separation of fluoxetine hydrochloride enantiomers. Ovomucoid and tris(3,5-dimethylphenyl carbamate) cellulose stationary phases were used in the reversed- and normal-phase modes, respectively. Acceptable isomer separation was achieved at pH 3.5 with the ovomucoid phase. Isopropyl alcohol and methyl-tert- butyl ether mobile phase modifiers each provide complete resolution using the derivatized cellulose column. Better separation robustness was obtained with a column temperature of 1 degree C the isopropyl alcohol modifier. The methyl-tert-butyl ether system was robust at room temperature. Differences in relative enantiomer amounts of as little as 2% could be determined. The chromatographic conditions provided a much more discriminating test compared to an optical rotation method proposed for pharmacopeial use which had difficulty distinguishing individual enantiomers. The chiral chromatographic conditions were also applied to capsule formulations to demonstrate the presence of racemic fluoxetine hydrochloride.

Screening methods for impurities in multi-sourced fluoxetine hydrochloride drug substances and formulations

SummaryGradient high-performance liquid chromatography (HPLC) and gas chromatography were applied as screening methods for determination of impurities in fluoxetine hydrochloride drug substances and formulated products from multiple sources. Nuclear magnetic resonance spectroscopy was also used for identification of excipients and some residual solvents. Thirty potential impurities and excipients were investigated. Several impurities were observed in generic products using gradient HPLC that were not detected with isocratic pharmacopeial methods for fluoxetine hydrochloride. Analysis of drug substance samples and capsule formulations from many different suppliers showed a wide variation in quality which, in many cases, would go undetected using isocratic methods. The quality of the innovators product and some generic samples was high, but many generic samples contained high levels of impurities. A new impurity, N-benzyl fluoxetine, was observed in some generic samples at levels as high as 0.9%. The gradient HPLC method was also used for stability studies and established that generic capsules formulated with lactose were less stable under accelerated conditions than those formulated without lactose.

Ortho-hydroxyl assisted deoxygenation of phenones. Regiochemical control in the synthesis of monoprotected resorcinols and related polyphenolic hydroxyl systems

A method for the selective protection of polyphenolic hydroxyls is described. This approach relies on the deoxygenation of a benzylic ketone ortho to at least one of the phenolic hydroxyl groups.

Carboxylic sulfonic mixed anhydrides: General utility and application to the synthesis of ceftazidime

Abstract A high-yielding acylation process which utilizes a mixed anhydride of the type RCO2SO2CH3 for the synthesis of the cephalosporin ceftazidime is detailed. The mixed anhydride is conveniently prepared by addition of methanesulfonyl chloride to the triethylammonium salt of the acid 2a. Although known for some time, these anhydrides have not been used often in acylations. This lack of general utility is explained by side reactions, especially formation of the carboxylic symmetric anhydride in sterically unhindered systems.

Identification, synthesis and pharmacological activity of moxonidine metabolites

The metabolism of moxonidine, 4-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-6-methoxy-2-methyl-5-pyrimidinamine, LY326869, in rats, mice, dogs, and humans has been examined. At least 17 metabolites were identified or tentatively identified in the different species by HPLC, LC/MS and LC/MS/MS. The identities of seven of the major metabolites have been verified by independent synthesis. The metabolites are generally derived from oxidation and conjugation pathways. Oxidation occurred at the imidazolidine ring as well as the methyl at the 2 position of the pyrimidine ring. All seven metabolites were examined in the spontaneously hypertensive rats (3 mg kg(-1), i.v.) for pressure and heart rate. Only one, 2-hydroxymethyl-4-chloro-5-(imidazolidin-2-ylidenimino)-6-methoxypyrimidine, exerted a short-lasting decrease in blood pressure, albeit attenuated in magnitude compared to moxonidine.