WO2005016930A2 - Procedes pour detecter du morphinone - Google Patents

Procedes pour detecter du morphinone Download PDF

Info

Publication number
WO2005016930A2
WO2005016930A2 PCT/US2004/023754 US2004023754W WO2005016930A2 WO 2005016930 A2 WO2005016930 A2 WO 2005016930A2 US 2004023754 W US2004023754 W US 2004023754W WO 2005016930 A2 WO2005016930 A2 WO 2005016930A2
Authority
WO
WIPO (PCT)
Prior art keywords
sample solution
hydromoφhone
mobile phase
concentration
hydromorphone
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2004/023754
Other languages
English (en)
Other versions
WO2005016930A3 (fr
Inventor
Saji K. Thomas
Dale M. Roberts
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Euro Celtique SA
Original Assignee
Euro Celtique SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Euro Celtique SA filed Critical Euro Celtique SA
Publication of WO2005016930A2 publication Critical patent/WO2005016930A2/fr
Publication of WO2005016930A3 publication Critical patent/WO2005016930A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
    • G01N33/9486—Analgesics, e.g. opiates, aspirine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N2030/022—Column chromatography characterised by the kind of separation mechanism
    • G01N2030/027—Liquid chromatography

Definitions

  • An improved method is disclosed for detecting the presence of morphinone in a hydromorphone preparation.
  • the amount of impurity must usually be present above a certain threshold level which depends upon the assay technique utilized. For example, if a particular assay has a limit of quantitation of 100 ppm for a particular impurity in a sample, that assay would generally be unable to determine if the impurity were present in any amount less than 100 ppm. Such limitations can be especially problematic in assaying pharmaceutical preparations for the presence of toxic impurities.
  • Hydromorphone hydrochloride (commercialized as Dilaudid®, Laudicon®, Hydromorphan®) is a narcotic analgesic widely prescribed for the treatment of pain (Physicians Desk Reference, 55 th Ed., p. 1619 (2001); Merck Index, 12 th Ed., 4847).
  • the precise mechanism of action of hydromorphone is not known, although it is believed to involve interaction with opiate receptors in the central nervous system.
  • There is no intrinsic limit to the analgesic effect of hydromorphone like morphine, even the most severe pain can be relieved given a sufficient amount of hydromorphone.
  • Hydromorphone is also a centrally acting narcotic anti-tussive, which acts directly on the cough reflex center.
  • Typical HPLC detection and quantitation of impurities in hydromorphone may be performed in accordance with Example 5 of U.S. Patent Nos. 6,512,117 and 6,589,960 to Harclerode et al.
  • the '117 and '960 patents describe the detection and quantitation of impurities in hydromorphone compositions carried out using an elution gradient high performance liquid chromatography (HPLC) method. This method can be used to resolve and quantitate 8-hydroxyhydromorphone, morphine, dihydromorphine, hydromorphone N-oxide, hydromorphone, and 2,2-bishydromorphone, which are impurities of hydromorphone.
  • HPLC high performance liquid chromatography
  • Morphinone another impurity found in hydromorphone preparations, can be hepatotoxic.
  • the limit of quantitation of morphinone in hydromorphone preparations utilizing HPLC according to art-recognized procedures is about 500 ppm. This is problematic in view of the hepatotoxic potential of morphinone.
  • the present invention provides, in part, a method of determining the amount of morphinone contained in a hydromorphone preparation comprising: (a) preparing a first sample solution comprising hydromorphone from the hydromorphone preparation, with the hydromorphone in the first sample solution at a concentration sufficient to quantify an amount of morphinone contained therein utilizing an HPLC system; (b) preparing a second sample solution comprising hydromorphone from the hydromorphone preparation, with the hydromorphone in the second sample .
  • the invention is directed to a method of determining the amount of morpliinone contained in hydromorphone preparation, comprising: (a) preparing a first sample solution comprising hydromorphone from the hydromorphone preparation, with the hydromorphone in the first sample solution at a concentration from about 10 mg/ l to about 50 mg/ml for analysis in an HPLC system; (b) preparing a second sample solution comprising hydromorphone from the hydromorphone preparation, with the hydromorphone in the second sample solution at a concentration sufficient to quantify the hydromorphone contained therein using the HPLC system, wherein the second sample solution has a concentration of hydromorphone less than that of the first sample solution; (c) analyzing the first sample solution using the HPLC system to obtain a measurable peak area of morphinone; (d) analyzing the second sample solution using the HPLC system to obtain a measurable peak area of hydromorphone; and (e) determimng the amount of morphinone present in the hydromorphone preparation based on the analysis of the first and second sample solutions
  • the invention is directed to a method of determining the amount of morphinone contained in a hydromorphone preparation, comprising: (a) preparing a first sample solution comprising hydromorphone from the hydromorphone preparation, with the hydromorphone in the first sample solution at a concentration from about 10 mg/ml to about 50 mg/ml for analysis in an HPLC system; (b) preparing a second sample solution comprising hydromorphone from the hydromorphone preparation, with the hydromorphone in the second sample solution at a concentration from about 0.01 mg/ml to about 5 mg/ml for analysis in the HPLC system; (c) analyzing the first sample solution using the HPLC system to obtain a measurable peak area of morphinone; (d) analyzing the second sample solution using the HPLC system to obtain a measurable peak area of hydromorphone; (e) determining the amount of morpliinone in the hydromorphone preparation by dividing the peak area of morphinone in the first sample solution by (the peak area of hydromorphone in the second sample solution).
  • the invention is directed to a method of determining the amount of morphinone contained in a hydromorphone preparation, comprising: . (a) preparing a first sample solution comprising hydromorphone from the hydromorphone preparation, with the amount of hydromorphone in the first sample solution at a concentration sufficient to quantify an amount of morphinone contained therein using an HPLC system; (b) preparing a second sample solution comprising hydromorphone from the hydromorphone preparation, with the amount of hydromorphone in the second sample solution at a concentration sufficient to quantify an amount of hydromorphone contained therein using the HPLC system, wherein the second sample solution has a concentration of hydromorphone that is less than that of the first sample solution; (c) analyzing the first sample solution using the HPLC system comprising a first mobile phase adjusted to an apparent pH of about 6.5 to about 7.5 and an HPLC column maintained at a temperature of about 20 degrees C to about 60 degrees C, to obtain a measurable peak area of morphinone; (d) analyzing the second sample solution using the
  • the invention is directed to a method of determining the amount of morphinone contained in a hydromorphone preparation, comprising: (a) preparing a first sample solution comprising hydromorphone from the hydromorphone preparation, with the hydromorphone in the first sample solution at a concentration from about 10 mg/ml to about 50 mg/ml for analysis in an HPLC system; (b) preparing a second sample solution comprising hydromorphone from the hydromorphone preparation, with the hydromorphone in the second sample solution at a concentration from about 0.01 mg/ml to about 5 mg/ml for analysis in an HPLC system; (c) analyzing the first sample solution using an HPLC system comprising a first mobile phase adjusted to an apparent pH of about 6.5 to about 7.5 and an HPLC column maintained at a temperature of about 20 degrees C to about 60 degrees C to obtain a measurable peak area of morphinone; (d) analyzing the second sample solution using the HPLC system to obtain a measurable peak area of hydromorphone; and (e) determining the amount
  • the invention is directed to a method of determining the amount of morphinone contained in a hydromorphone preparation, comprising: (a) preparing a first sample solution comprising hydromorphone from the hydromorphone preparation, with the hydromorphone in the first sample solution at a concentration sufficient to quantify an amount of morphinone contained therein using a first HPLC system; (b) preparing a second sample solution comprising hydromorphone from the hydromorphone preparation, with the hydromorphone in the second sample solution at a concentration sufficient to quantify the hydromorphone contained therein using a second HPLC system, wherein the second sample solution has a concentration of hydromorphone that is less than that of the first sample solution; .
  • hydromorphone includes both the hydromorphone free base and any salt form of hydromorphone that can be formed, including any pharmaceutically acceptable salt of hydromorphone, e.g., hydromorphone hydrochloride.
  • compositions include, but are not limited to, metal salts such as sodium salt, potassium salt, secium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic a ine salts such as. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoro acetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such as arginate, asparginate, glutamate and the like.
  • the pharmaceutically acceptable salts can include anhydrous forms and hydrous forms
  • hydromorphone preparation means any composition of matter containing hydromorphone that can be quantified for morphinone and hydromorphone utilizing the methods of the present invention.
  • the hydromorphone preparation can be, e.g., a hydromorphone active pharmaceutical ingredient e.g., hydromorphone hydrochloride U.S.P., which is utilized in the formulation of a pharmaceutical dosage form.
  • the hydromorphone preparation can be a final dosage form, or an intermediate stage preparation for a final dosage form, that can be tested for the presence of morphinone for, e.g., quality assurance purposes.
  • ppm as used herein with respect to morphinone is parts per million to a sample of hydromorphone active pharmaceutical ingredient.
  • the hydromorphone active pharmaceutical ingredient can be uncombmed with other ingredients, or combined with other ingredients, e.g., in a dosage form.
  • RRF relative response factor
  • HPLC techniques known in the art chromatographic peaks representing morphinone at levels below 500 ppm cannot be accurately quantified.
  • the present invention provides an HPLC method to detect the presence of morphinone in an amount less than 500 ppm. This method involves overloading the concentration of hydromorphone in a first sample solution in order to increase the peak area of morphinone to a level that can be accurately determined. Certain adjustments in HPLC conditions can also be implemented to "sharpen" the morphinone HPLC peak.
  • the increased concentration of the overloaded hydromorphone in the first sample solution results in an increase in the peak area of hydromorphone beyond the upper threshold that can be measured accurately.
  • a second sample solution is prepared at a lower concentration of hydromorphone, to produce a chromatographic peak for hydromorphone that is on-scale, and the area of which can be accurately quantified.
  • This second solution can be prepared by diluting a portion of the first sample solution, by preparing a less concentrated solution, or by any other method, as long as the differences in concentration are known.
  • the peak area of morphinone from the high concentration first sample solution, and the peak area of hydromorphone from the lower concentration second sample solution can be used to calculate the amount (e.g., percentage) of morphinone in the hydromorphone preparation being analyzed.
  • An example of making such a calculation is by dividing the peak area of morphinone by (the peak area of hydromorphone multiplied by (the concentration of hydromorphone in the first sample solution divided by the concentration of morpliinone in the second sample solution) multiplied by the morphinone RRF) to obtain a quotient. The quotient can then be optionally multiplied by 100 to obtain a percentage.
  • the method of the present invention can provide for the detection of morphinone levels in a hydromorphone preparation where the morphinone is present in an amount of less than 500 ppm, more preferably less than 400 ppm, more preferably less than 300 ppm, more preferably less than 200 ppm, more preferably less than 100 ppm, more preferably less than 50 ppm, more preferably less than 25 ppm, and more preferably less than 10 ppm.
  • the method of the present invention provides for the detection of morphinone levels in a hydromorphone preparation where the morphinone is present in an amount of from about 1 ppm to 499 ppm or from about 1 ppm to about 100 ppm; preferably from about 1 ppm to about 10 ppm, or from about 1 ppm to about 5 ppm; more preferably from about 5 ppm to about 25 ppm or from about 5 ppm to about 10 ppm.
  • An HPLC system typically includes at least the following components: an HPLC column packed with a suitable stationary phase; a mobile phase; a pump for directing the mobile phase through the column; and a detector for detecting the presence of compounds eluting from the column.
  • the HPLC system is an adsorption chromatography system, an ion-exchange chromatography system, a size exclusion chromatography system, or the like.
  • the HPLC system is an adsorption chromatography system such as, for example, a normal phase chromatography system or a reverse phase chromatography system.
  • the system is a reverse, phase chromatography system. Reverse-phase chromatography involves contacting a solution of a desired compound with a solid, hydrophobic support, or stationary phase, under conditions whereby the compound is adsorbed to the support. The compound is then eluted, after washing, by rinsing the support with an apolar organic solvent (i.e., the mobile phase).
  • an apolar organic solvent i.e., the mobile phase
  • the stationary phase can comprise a support such as alumina, or can be a silica-based support, to which is bonded various non-polar organic groups.
  • bonded phases may be prepared, for example, by reacting surface silanol groups on the silica with an organo- chlorosilane, as known in the art.
  • Silica-based supports include, for example, spherical silica particles, irregular silica particles or particulate substrates coated with silica. The particle size and porosity should be appropriately selected for separation of the specific components in the assay.
  • the mobile phase selected for reverse-phase HPLC should have low toxicity and viscosity and be readily available in pure form.
  • the mobile phase may be selected from the group consisting of water, miscible lower alcohols (e.g. methanol, n-propanol, or isopropanol), tetrahydrofuran, dioxane, acetonitrile, and mixtures thereof.
  • the temperature and pH of the system may be modified to preferred parameters, such as those discussed below.
  • the resolution between hydromorphone and morphinone according to U.S. P. methodology is preferably at least 3, preferably at least 4, more preferably at least 5, and most preferably at least 6.
  • the mobile phase of the HPLC system is modified in order to control the pH on the column.
  • the mobile phase is adjusted to an apparent pH of from about 6.5 to about 7.5, preferably to an apparent pH of from about 6.8 to about 7.2 and most preferably to an apparent pH of about 7.0.
  • the temperature of the column of the HPLC system is controlled. In certain embodiments, the temperature of the column is maintained from about 20 degrees C to about 60 degrees C, preferably from about 30 degrees C to about 50 degrees C, more preferably from about 40 degrees C to about 45 degrees C, and most preferably at about 45 degrees C.
  • the signahnoise ratio of the system is preferably at least 5:1, preferably at least 10:1, more preferably at least 15.T and most preferably at least 20:1.
  • the methods of the present invention include the use of at least one mobile phase, which acts as a carrier for the sample solution.
  • the chemical interactions of the mobile phase and sample with the column determine the degree of migration and separation of the components of the sample.
  • the methods of the present invention include the use of a first mobile phase and a second mobile phase.
  • the methods of the present invention include performing HPLC through the use of isocratic elution (isocratic mobile phase) or gradient elution (gradient mobile phase).
  • isocratic elution for example, compounds are eluted using a mobile phase having a constant composition. The compounds migrate through the column at onset, with each compound migrating at a different rate, resulting in separation of the compounds.
  • gradient elution for example, different compounds may be eluted as the composition of the mobile phase changes, e.g., by increasing the strength and/or the concentration of the organic solvent.
  • the sample may be injected during application of a "weaker" mobile phase through the system.
  • the mobile phase may be gradually or incrementally changed by, e.g., increasing the fraction of the mobile phase comprising the organic solvent, resulting in elution of retained compounds.
  • the mobile phase(s) of the present invention preferably includes an eluent comprising, for example, acetonitrile, dioxane, ethanol, methanol, isopropanol, tetrahydrofuran, water, or a mixture thereof.
  • the mobile phase is acetonitrile.
  • the mobile phase is methanol.
  • the methods of the present invention utilize a first mobile phase and a second mobile phase
  • the first mobile phase may comprise one solvent or a combination of solvents
  • the second mobile phase consists of an organic solvent.
  • Typical adsorbents in the HPLC column for use in the present invention include, for example and without limitation, EB-Sil C18, Prodigy ODS, Selectosil C18, Ultracarb ODS, Zorbax ODS, Kromasil C18, LiChrospher RP-18, Inertsil ODS-2, Nucleosil C18, Spherisorb ODS, Hypersil C18, Novapak C18, and Symmetry C18.
  • the adsorbent is Waters Symmetry C18.
  • the eluent for use in the HPLC methods of the present invention comprises acetonitrile, sodium phosphate monobasic monohydrate, sodium dodecyl sulfate, water, or a mixture thereof.
  • the mobile phase(s) utilized in the present invention for isocratic elution comprises from about 50% (v/v) aqueous medium to about 85% aqueous medium, and preferably from about 60% aqueous medium to about 75% aqueous medium. In certain embodiments, the mobile phase comprises from about 50% acetonitrile to about 15% acetonitrile, preferably from about 40% acetonitrile to about 25% acetonitrile. In certain embodiments, the mobile phase comprises about 50% aqueous medium and about 50% acetonitrile, preferably about 60% aqueous medium and about 40% acetonitrile, or about 75% aqueous medium and about 25% acetonitrile. In certain of the above ranges for acetonitrile, methanol can be substituted for all of, or a portion of the acetonitrile. Alternatively, an appropriate gradient elution profile may be selected to carry out the methods of the present invention.
  • the mobile phase(s) of the present invention is (are) delivered at a rate of from about 1.0 to about 2.0 ml per minute, preferably at a rate of about 1.5 ml per minute.
  • an "HPLC compatible detector” is any detector capable of generating a measurable or detectable signal when a compound elutes from the column of an HPLC. Where component absorbance varies widely, it may be necessary to utilize more than one detector. A detector capable of detecting a desired component is not “incompatible” simply due to its inability to detect a non-desirbd component.
  • the detector can be a refractive index detector, an ultra-violet detector, a fluorescent detector, a radiochemical detector, an electrochemical detector, a near-infrared detector, a mass spectroscopy detector, a nuclear magnetic resonance detector, a light scattering detector, or any other detector known in the art.
  • the detector is an ultra-violet detector.
  • the ultra-violet detector is selected from the group consisting of a fixed wavelength detector, a variable wavelength detector and a diode array detector.
  • the ultra-violet detector is a fixed wavelength detector.
  • the fixed wavelength detector measures at a wavelength of from about 200 n to about 275 nm, preferably at a wavelength of about 220 run.
  • the present invention comprises the use of two sample solutions, a first, more concentrated sample solution used to detect the morphinone and a second, less concentrated sample solution used to detect the hydromorphone.
  • concentration of the sample of hydromorphone for use in the first sample solution is from about 10 mg/ml to about 50 mg/ml; preferably, from about 15 mg/ml to about 35 mg/ml; and more preferably about 25 mg/ml.
  • the concentration of hydromorphone in the second sample solution is from about 2 times to about 500 times less than the concentration of hydromorphone in the first sample solution; preferably from about 10 times to about 250 times less than the concentration of hydromorphone in the first sample solution; more preferably from about 50 times to about 100 times less than the concentration of hydromorphone in the first sample solution.
  • the concentration of hydromorphone in the second sample solution is from about 0.01 mg/ml to about 10 mg/ml, preferably about 0.10 mg/ml to about 2 mg/ml, and more preferably about 0.25 mg/ml.
  • the HPLC apparatus comprises an auto injector with a preferable injection volume of from about 10 microliters to about 100 microliters, from about 25 microliters to about 75 microliters, or about 50 microliters.
  • EXAMPLE 1 A preparation of hydromorphone HC1 was dissolved in 0.85% phosphoric acid solution and analyzed for morphinone content by HPLC using a 5 ⁇ m reverse-phase, Waters Symmetry C18 column (3.9 x 150 mm) at 45 °C and a mobile phase (prepared as described below) consisting of acetonitrile, water, sodium phosphate monobasic monohydrate and sodium dodecyl sulfate, the mobile phase adjusted to an apparent pH of 7.0. Quantitation was achieved by measuring the peak area response at 220nm. Calculation was based on area normalization and a relative response factor of 1.44 for morphinone to hydromorphone HC1.
  • the relative response factor is relative to hydromorphone HC1.
  • Example 1 The reagents used for Example 1 were as follows:
  • HPLC System 1. HPLC pump capable of delivering mobile phase at 1.5 mL/minute; 2. Multiwavelength detector set at 220 nm; 3. Autoinjector capable of 50 ⁇ L injections for standard and sample solutions; 4. Integrator or suitable data recording system; 5. Waters Symmetry C column (3.9 x 150 mm, 5 microns); 6. Column heater capable of maintaining a constant temperature of 45 °C. Pre- column plumbing is preferably heated to column oven temperature to minimize peak fronting of the hydromorphone.
  • Hydromorphone HC1 WRS Hydromorphone HC1 WRS, USP reference standard was weighed and transferred into a 100-mL amber glass light-sensitive volumetric flask. The material was dissolved and diluted to volume with 0.85% phosphoric acid.
  • sample solutions were prepared as follows: 1. First Sample Solution (High Concentration) (Equivalent to 25 mg/mD 50 ⁇ 5 mg of hydromorphone HC1 API sample material was weighed to the nearest 0. Img and placed into a suitable container. The sample material was dissolved with 2.0 mL of 0.85% phosphoric acid and mixed well.
  • Second Sample Solution (Low Concentration) (Equivalent to 0.25 mg/mL) 1.0 mL of the high sample solution was pipetted into a 100-mL amber glass light- sensitive volumetric flask and diluted to volume with 0.85% phosphoric acid and mixed well.
  • HPLC conditions for Example 1 The HPLC conditions for Example 1 were as follows:
  • the resolution between hydromorphone and morphinone is preferably at least 3, preferably at least 4, more preferably at least 5, and most preferably at least 6.
  • Example 2 Fifty ⁇ L of the hydromorphone HC1 API first sample solution and second sample solution were each subjected to HPLC analysis , and the resulting chromatograms were examined by changing the Y-scale of area count (Y-axis) to observe and quantify the morphinone and hydromorphone HC1 peaks. These chromatograms could be reintegrated if necessary.
  • the morphinone peak was identified using the relative retention time for morphinone (see Table 1 above), and the amount of morphinone was quantified according to the calculation below.
  • EXAMPLE 2 In Example 2, the following calculations were performed using the results obtained in Example 1, above.
  • Baseline Start Time (min) [approximate Morphinone retention time (min)] - B/2
  • Baseline End Time (min) [approximate Morphinone retention time (min)] + B/2
  • the baseline noise in microvolts (note that Millennium will calculate peak height in v and the conversion to ⁇ v is necessary) was deteraiined for a blank solution (0.85% phosphoric acid) at the approximate two-minute window for morphinone.
  • the signal to noise ratio for morphinone at 0.05% level was calculated according to the following equation.
  • Percent of Morphinone Peak Area of Morphinone of High Sample Solution x 100 % Peak Area of Hydromorphone HCl of Low Sample Solution x 100 x Morphinone RRF
  • Peak area of morphinone of high sample solution 10353.5
  • Peak area of hydromorphone HCl of low sample solution 14625724 Morphinone

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Analytical Chemistry (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Cell Biology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Emergency Medicine (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé pour détecter la présence de morphinone dans une préparation comprenant de l'hydromorphone.
PCT/US2004/023754 2003-08-08 2004-07-23 Procedes pour detecter du morphinone Ceased WO2005016930A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US49397403P 2003-08-08 2003-08-08
US60/493,974 2003-08-08

Publications (2)

Publication Number Publication Date
WO2005016930A2 true WO2005016930A2 (fr) 2005-02-24
WO2005016930A3 WO2005016930A3 (fr) 2005-04-28

Family

ID=34193196

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/023754 Ceased WO2005016930A2 (fr) 2003-08-08 2004-07-23 Procedes pour detecter du morphinone

Country Status (1)

Country Link
WO (1) WO2005016930A2 (fr)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6512117B1 (en) * 1999-11-09 2003-01-28 Abbott Laboratories Hydromorphone and hydrocodone compositions and methods for their synthesis

Also Published As

Publication number Publication date
WO2005016930A3 (fr) 2005-04-28

Similar Documents

Publication Publication Date Title
Gan et al. Validation of a high-performance liquid chromatography method for tramadol and o-desmethyltramadol in human plasma using solid-phase extraction
El Mahjoub et al. High-performance liquid chromatographic method for the determination of benzodiazepines in plasma or serum using the column-switching technique
Guo et al. Chiral separation of ketoprofen on an achiral C8 column by HPLC using norvancomycin as chiral mobile phase additives
Long et al. A non-derivative method for the quantitative analysis of isosteroidal alkaloids from Fritillaria by high performance liquid chromatography combined with charged aerosol detection
Capella-Peiró et al. Direct injection micellar liquid chromatographic determination of benzodiazepines in serum
CN104749269A (zh) 一种利用hplc测定阿格列汀原料药及制剂中对映异构体杂质的方法
Schmidt et al. Stereoselective determination of the enantiomers of methadone in plasma using high-performance liquid chromatography
Patil et al. Development and validation of a liquid chromatography method for the simultaneous determination of eight water-soluble vitamins in multivitamin formulations and human urine
Kim et al. Determination of terbutaline enantiomers in human urine by coupled achiral–chiral high-performance liquid chromatography with fluorescence detection
Yamamoto et al. Novel methylcellulose-immobilized cation-exchange precolumn for on-line enrichment of cationic drugs in plasma
De Orsi et al. HPLC determination of warfarin and acenocoumarol in raw materials and pharmaceuticals
Bose et al. Micellar liquid chromatography determination of some biogenic amines with electrochemical detection
CN115856159A (zh) 隐形眼镜护理液中的羟丙基甲基纤维素含量的检测方法
Gauvin et al. High-performance liquid chromatographic determination of vinorelbine in human plasma and blood: application to a pharmacokinetic study
Cherkaoui et al. Validated capillary electrophoresis method for the determination of atropine and scopolamine derivatives in pharmaceutical formulations
Carlucci et al. Determination of alfuzosin in human plasma by high-performance liquid chromatography with column-switching
Batzias et al. New simple liquid chromatographic method for the determination of trimethoprim, sulfadiazine and N4-acetylsulfadiazine in plasma of broilers
Awni et al. Antipyrine, indocyanine green, and lorazepam determined in plasma by high-pressure liquid chromatography.
Elrod Jr et al. Determination of isoproterenol sulfate on surfaces using high-performance liquid chromatography with electrochemical detection
Cherkaoui et al. Development and validation of liquid chromatography and capillary electrophoresis methods for acarbose determination in pharmaceutical tablets
Osinski et al. Determination of methylnaltrexone in clinical samples by solid-phase extraction and high-performance liquid chromatography for a pharmacokinetics study
del Rosario Brunetto et al. Development and validation of a rapid column-switching high-performance liquid chromatographic method for the determination of lamotrigine in human serum
CN107328874B (zh) 一种盐酸帕洛诺司琼光学异构体的拆分试剂及分离检测方法
RU2330281C1 (ru) Способ определения количественного состава многокомпонентного лекарственного препарата противопростудного, антиаллергического действия
Chen et al. Determination of apovincaminic acid in human plasma by high-performance liquid chromatography using solid-phase extraction and ultraviolet detection

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
122 Ep: pct application non-entry in european phase