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Publications (8)30.23 Total impact

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    ABSTRACT: The rapid oxidation of rofecoxib under alkaline conditions has been previously reported. The oxidation was reported to involve gamma-lactone ring opening to an alcohol, which further oxidized to a dicarboxyclic acid. The oxidation was suspected to be mediated by peroxy radicals. This work further investigates the mechanism of oxidation under the alkaline solution conditions. The pH dependence of the oxidation reaction was determined in 50% acetonitrile/50% aqueous phosphate buffer (pH 9-12). The oxidation reaction products were also examined at early timepoints (from 40 s to several minutes) with only 5% water content. The evolution of hydrogen peroxide by the oxidation reaction was quantitatively followed by reaction with triphenylphosphine (TPP) and high-pressure liquid chromatography determination of the resultant triphenylphosphine oxideformed. Rofecoxib was exposed to the alkaline pH conditions in the presence of formaldehyde, and the primary reaction product was isolated and characterized by liquid chromatography-mass spectrometry and proton 1D, heteronuclear multiple quantum coherence (HMQC), gradient heteronuclear multiple bond correlation (gHMBC), and carbon 1D nuclear magnetic resonance techniques. Transient reaction products were examined for hydroperoxide groups by reaction with TPP. The oxidation reaction occurs only near pH 11 and above. In the presence of excess formaldehyde, oxidation products are no longer observed but a new product is observed in which two formaldehyde molecules have added to the methylene carbon atom of the gamma-lactone ring. The evolution of hydrogen peroxide corresponds quantitatively to the molar amount of the (minor) aldehyde oxidation product formed. It is demonstrated that the rofecoxib anhydride species is actually the primary product of the oxidation reaction. The existence of a transient hydroperoxide species is shown by reaction with TPP and concomitant conversion to a previously identified alcohol. The oxidation of rofecoxib under these high pH conditions is mediated by rofecoxib enolate ion formation. The enolate ion reacts with either formaldehyde or dissolved oxygen at the C5 position. In the case of oxygen, a transient hydroperoxide species is formed. The major and minor products of the oxidation derive from competitive routes of decomposition of this hydroperoxide. The major route involves a second enolate ion formation, which decomposes with heterolytic cleavage of the RO-OH bond to give the rofeocoxib anhydride and hydroxide ion. The anhydride is rapidly hydrolyzed under the alkaline conditions to give the observed rofecoxib dicarboxylate product. The minor hydroxy-furanone product is formed from hydroxide ion attack on the hydroperoxide intermediate.
    Pharmaceutical Research 11/2005; 22(10):1716-26. DOI:10.1007/s11095-005-6947-z · 3.95 Impact Factor
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    ABSTRACT: A rapid, sensitive and specific high-performance liquid chromatographic (HPLC) assay is reported for the determination of 4-amino-1-hydroxybutane-1, 1-diphosphonic acid (AHBuDP) monosodium salt trihydrate, a new inhibitor of bone resorption. The compound does not demonstrate any intrinsic UV properties and thus pre-column derivatization of the primary amino group of the drug with 9-fluorenylmethyl chloroformate (FMOC) at pH 9 in the presence of sodium citrate is required to facilitate UV detection of the analyte. Excess derivatization reagent is extracted with methylene chloride and an aliquot of the aqueous portion is assayed on a polymeric phase (Hamilton PRP-1) at 35 degrees C by reversed-phase HPLC. A mobile phase of 0.05 M citrate and 0.05 M phosphate buffer (pH 8.0)-acetonitrile-methanol (75:20:5, v/v/v) is utilized with UV detection at 266 nm. Application of the method to the analysis of AHBuDP in I.V. solution, tablet and capsule formulations is presented.
    Journal of Pharmaceutical and Biomedical Analysis 02/1989; 7(12):1719-27. DOI:10.1016/0731-7085(89)80186-4 · 2.83 Impact Factor
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    ABSTRACT: A flow injection (FI) method has been developed to determine simultaneously a drug with an ultraviolet chromophore, lovastatin, and butylated hydroxyanisole (BHA) in a tablet. The system involves ultraviolet (UV) absorbance detection for the drug and oxidative amperometric electrochemical detection for BHA. The method has been shown to be reproducible for routine determinations with an accuracy of +/-1% for lovastatin and +/-4% for BHA. Precision for both analytes was approximately +/-1% (RSD). The use of FI compared with HPLC for these determinations has led to a dramatic decrease in the time required per assay. The method with UV detection has been shown to be specific for the drug in the presence of potential autoxidation products as well as BHA and its oxidation products. The use of electrochemical detection in series allows the method to be simultaneously specific for low levels of BHA (40 microg/tablet) in the presence of its oxidation products as well as the drug and its potential autoxidation products.
    Journal of Pharmaceutical and Biomedical Analysis 02/1988; 6(3):271-6. DOI:10.1016/0731-7085(88)80053-0 · 2.83 Impact Factor
  • David J. Mazzo, Eva K.F. Fong, Stephen E. Biffar
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    ABSTRACT: Three test methods for determining in vitro drug release rate from transdermal delivery dosage forms were tested for equivalency of results, ease of implementation and precision. The ‘paddle-over-disk’ (POD) method is under consideration by the USP as a standarized method for release-rate testing of all transdermal delivery dosage forms. The ‘reciprocating disk’ (RD) and ‘diffusion cell’ (DC) methods are both commonly employed throughout the pharmaceutical industry. The three methods were demonstrated to be equivalent in terms of release rate profile (curve shape) and total drug released over the lifetime of the dosage form tested (Transderm-Scop). The precision for the RD method as measured by the mean relative standard deviation over all time points was 4.6%; the precision of the POD method was 5.4% and that for the DC method was 6.7%. Steady-state flux values derived from the POD and RD methods were equivalent (∼4 μg cm−2 h−1) but were ∼25% greater than the steady-state flux value derived from the DC method (∼3 μg cm−2 h−1). All three methods gave results which were within the specifications of the manufacturer (CIBA-GEIGY). The POD method was the easiest to use on a routine basis, required the least amount of specialized equipment and most resembled the current test methodology for dissolution testing of other dosage forms such as tablets or capsules.
    Journal of Pharmaceutical and Biomedical Analysis 02/1986; 4(5-4):601-607. DOI:10.1016/0731-7085(86)80006-1 · 2.83 Impact Factor
  • Journal of Chromatography A 01/1983; 257:400-404. DOI:10.1016/S0021-9673(01)88199-1 · 4.26 Impact Factor
  • Stephen Biffar, Donald Tibbets
    Journal of Chromatography A 03/1982; 237(1):169-173. DOI:10.1016/S0021-9673(00)88287-4 · 4.26 Impact Factor
  • The Journal of Organic Chemistry 03/1978; 43(5). DOI:10.1021/jo00399a034 · 4.64 Impact Factor
  • George D. Hartman, Stephen E. Biffar
    The Journal of Organic Chemistry 04/1977; 42(8). DOI:10.1021/jo00428a047 · 4.64 Impact Factor