WO1999025450A1 - Improvement in chemical analyses - Google Patents
Improvement in chemical analyses Download PDFInfo
- Publication number
- WO1999025450A1 WO1999025450A1 PCT/US1998/016055 US9816055W WO9925450A1 WO 1999025450 A1 WO1999025450 A1 WO 1999025450A1 US 9816055 W US9816055 W US 9816055W WO 9925450 A1 WO9925450 A1 WO 9925450A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- molecular weight
- compounds
- weight compounds
- low molecular
- high molecular
- Prior art date
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
- B01J20/286—Phases chemically bonded to a substrate, e.g. to silica or to polymers
- B01J20/287—Non-polar phases; Reversed phases
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28002—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their physical properties
- B01J20/28004—Sorbent size or size distribution, e.g. particle size
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
- B01J20/28016—Particle form
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
- B01J20/28078—Pore diameter
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
- B01J20/282—Porous sorbents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
- B01J20/282—Porous sorbents
- B01J20/283—Porous sorbents based on silica
-
- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/38—Flow patterns
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2220/00—Aspects relating to sorbent materials
- B01J2220/50—Aspects relating to the use of sorbent or filter aid materials
- B01J2220/54—Sorbents specially adapted for analytical or investigative chromatography
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2220/00—Aspects relating to sorbent materials
- B01J2220/50—Aspects relating to the use of sorbent or filter aid materials
- B01J2220/58—Use in a single column
-
- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/32—Control of physical parameters of the fluid carrier of pressure or speed
- G01N2030/324—Control of physical parameters of the fluid carrier of pressure or speed speed, flow rate
-
- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/38—Flow patterns
- G01N2030/387—Turbulent flow of mobile phase
-
- 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
- G01N30/50—Conditioning of the sorbent material or stationary liquid
- G01N30/52—Physical parameters
- G01N2030/524—Physical parameters structural properties
-
- 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
- G01N30/50—Conditioning of the sorbent material or stationary liquid
- G01N30/52—Physical parameters
- G01N2030/524—Physical parameters structural properties
- G01N2030/525—Physical parameters structural properties surface properties, e.g. porosity
-
- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/8813—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample biological materials
-
- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
-
- 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
- G01N30/62—Detectors specially adapted therefor
- G01N30/72—Mass spectrometers
- G01N30/7233—Mass spectrometers interfaced to liquid or supercritical fluid chromatograph
Definitions
- This application relates to chemical analyses, and more particularly methods and apparatus for analysis of mixtures of relatively low molecular weight organic compounds (e.g. less than about a few kilodaltons) with relatively high molecular weight (e.g. one or more orders of magnitude larger than the low molecular weight (mw) compounds.
- relatively low molecular weight organic compounds e.g. less than about a few kilodaltons
- relatively high molecular weight e.g. one or more orders of magnitude larger than the low molecular weight (mw) compounds.
- metabolic and stability data can be obtained by subjecting a combinatorial or other like complex mixture to forced degradation in vitro or in-vivo metabolic conditions, and then analyzing the treated sample with parallel processing by liquid chromatography and mass spectrometry.
- Such metabolites obtained from in-vivo or in-vitro processing are usually carried in serum plasma having components that typically exhibit molecular weights of 100 kilodaltons or greater, before spectral analysis of the mixture.
- the mixture usually requires pretreatment, as by precipitation techniques or the like, to remove the high molecular weight proteins to prevent interference with the operation of the mass spectrograph and/or the HPLC.
- U.S. Patent 5,164,090, issued November 17. 1992 to W.W. Hirth seeks to avoid pretreatment by flowing whole blood through a chromatographic column specifically formed of porous particles of known internal surface reverse phase resin (ISRP) comprising hydrophobic inner pore surfaces and hydrophilic outer particle surfaces.
- ISRP internal surface reverse phase resin
- Mechanical blockage of the system by blood cells is obviated by using particles large enough (e.g.
- the particle pores are small enough the prevent penetration by proteinaceous substances but large enough to be penetrated by free hydrophobic components that are retained proportionately to their affinity for the hydrophobic surfaces in the pores.
- a hydrophobic solvent is used to elute the hydrophobic materials from the particles for subsequent detection.
- This system typically employs bed flow rates of about 1 to 1.5 ml/min, which with the maximum bead and column dimensions specified can be shown to yield a reduced velocity of less than 100, a clearly laminar flow through the column and a typical analysis time of about 12 or more minutes.
- a principal object of the present invention is to provide apparatus for and method of rapidly separating the components of a mixture of relatively low molecular weight compounds (typically less than about 1 kd for purposes of the present invention) from compounds having relatively high molecular weights substantially an order of magnitude greater or more than said low molecular weight compounds (i.e. typically 10 kd. or greater for purposes of the present invention).
- Yet another object of the present invention is to provide improved chromatographic apparatus and methods for extremely fast analytical separation of solutes of widely varying molecular weights.
- the present invention therefore is directed to novel methods of and apparatus for separating compounds of a mixture of compounds of at least two widely disparate molecular weights by flowing the mixture through a chromatographic body, preferably in the form of a column packed with a substantially uniformly distributed multiplicity of rigid, solid, porous particles having chromatographically active surfaces, average diameters of not less than about 30 ⁇ m, and average pore diameters sufficiently small to substantially preclude passage of those compounds of relatively high molecular weight into the pores of the particles.
- the mixture is compelled to flow through the interstitial volume between the particles of the column at a reduced velocity greater than about 5000, i.e. flow turbulently, until a band of the compounds of the relatively higher molecular weight have exited the column.
- the relatively high molecular weight compounds (hereinafter referred to as heavyweight compounds) have exited the column
- the relatively low molecular weight compounds hereinafter referred to as lightweight compounds
- the eluted lightweight compounds are recovered at the exit of the column separately from the relatively heavyweight compounds.
- the recovered fraction containing the relatively lightweight compounds is further analyzed by spectrographic analysis, for example by being fed directly into a mass spectrometer or the like. In such case, it is preferred to provide, at the output of the column, an eluant flow rate that will match the acceptable input flow rate to the spectrometer, usually a laminar flow rate.
- the foregoing and other objects of the present invention will in part appear obvious, and will in part appear hereinafter.
- the invention accordingly comprises the apparatus possessing the construction and arrangement of parts exemplified in the following detailed disclosure , and the method comprising the several steps and the relation and order of one or more of the steps with respect to the others, the scope of the application of which will be indicated in the claims.
- Fig. 1 is a schematic diagram of apparatus embodying the principles of the present invention
- Fig. 2 is a trace of an ultraviolet detector showing a graphical representation in coordinates of absorbance vs. time, of the separation of a compound of relatively large molecular weight from compounds of relatively low molecular weight as described in Example 1 ;
- Fig. 3 is a trace of an ultraviolet detector showing a graphical representation in coordinates of absorbance vs. time, of the separation of a compound of relatively high molecular weight from compounds of relatively low molecular weight as described in Example 2;
- Fig. 4 is a trace of a mass spectrometer detector showing a graphical representation in coordinates of absorbance vs. time, of the separated target molecule after separation from the high molecular weight compound, as described in Example 3.
- Fig. 4 is a trace of a mass spectrometer detector showing a graphical representation in coordinates of absorbance vs. time, of the separated target molecule after separation from the high molecular weight compound, as described in Example 3.
- Fig. 1 includes a chromatographic body 20 formed preferably as a column of a packed multiplicity of rigid, solid particles 22 having substantially uniform mean diameters of greater than about 30 ⁇ m.
- mean diameter as used herein is intended to mean the average or mean diameter or cross-section dimension of a particle regardless of its configuration, and should not be construed as limited to particles that are necessarily a regularly shaped solids.
- the particles in the column are formed from substantially incompressible materials, i.e. the time rate of change of the particles under pressure of about 5 x 10 3 psi remains substantially zero, so the particles resist plastic deformation or fracture even at relatively high pressures.
- the interstitial volume between the particles in the column should preferably be greater than about 45 % of the total volume of the column.
- Particles 22 are preferably porous, the intraparticle pores having mean cross-section dimensions carefully selected to substantially preclude entrance into the pores by the heavyweight compounds that will be processed through the column, but admit into those pores, lightweight compounds that are to be processed simultaneously with the heavyweight compounds.
- the surfaces of the particles are chromatographically active, either per se as well known in the art, or by treatment with any of the multitude of stationary phase layers well known in the art so as that both the exterior particle surfaces and the internal pore surfaces of the particles are chromatographically active hydrophobic surface exposed to the entire mixture of compounds to be separated.
- heavyweight compounds to be separated are components of blood plasma (typically albumin plasma protein of mw. approximately 65 kd, immunoglobulins of mw of about 150 kd, and the like)
- blood plasma typically albumin plasma protein of mw. approximately 65 kd, immunoglobulins of mw of about 150 kd, and the like
- pores with cross-section dimensions in the range of about 6 ⁇ A will substantially exclude such compounds, i.e. will prevent transit of those compounds into the pores of the particles and therefore restrict chromatographic bonding of those heavyweight compounds primarily to only the very limited external surface area of the particles.
- the exposure time of those compounds to the chromatographically active surface areas is also very short, so the extent of loading of the relatively heavyweight compounds on the column particles is extremely limited.
- these relatively heavyweight compounds are substantially not trapped and pass through the column in a tight band very quickly.
- the lightweight compounds that are intended to be processed simultaneously for separation from the heavyweight compounds being typically less than 1 kd, can readily access the pores of the chromatographically active particles. Accordingly such smaller molecules tend to be readily trapped on the exterior surface and the much large area of the interior pore surfaces of the particles. It will be understood that the optimum maximum pore cross-section dimensions are therefore determined in accordance with the geometry and the molecular weight of the heavyweight compounds that are expected to be processed.
- the apparatus of Fig. 1 includes means, such as pump 24 coupled through column switching valve 25 to the proximal end of column 20, for flowing through at least a major portion of the interstitial volume between particles
- a fluid mixture (from an appropriate source such as reservoir 26 or loop injector 27 at a reduced velocity that is substantially above 5000.
- the invention also includes pump 28 for alternatively flowing eluant fluid through valve 25 to column 20 from eluant source 29 to elute from particles 22 such relatively lightweight compounds as may have been chromatographically bound upon passage of the initial flow of the mixture through the column.
- the flow from pump 28 may be at linear velocities that render the flow through column 20 laminar as will be described hereinafter, but may also be at linear velocities high enough to render the flow turbulent, particularly if one desires to limit band spreading of the eluted solute as an inverse function of the Reynolds number for the eluant flow and a direct function of the diffusion coefficient of the solute in the eluant fluid. These latter considerations provide very quick separation between the possibly several lightweight compounds, with very sharp peaks or high resolution.
- the embodiment of Fig 1 includes means, in the form of detector 30 coupled to the distal end of column 20, for detecting the bands of compounds exiting the column.
- the detector is an optical detector, such as an ultraviolet detector of varying wavelength capability, or a mass spectrometer.
- Means, in the form of diverter valve 32 at the input of detector 30, are provided for directing the flow stream from column 20 to either a waste container (as, for example, for the high molecular weight compounds) or detector 30 (as, for example, for the low molecular weight compounds).
- Means such as an appropriately programmed digital computer and electromechanical relays for operating valves 25 and 32, can be provided for automating operation of the system, and being well-known and well within the capabilities of those skilled in the art, need not be described further here. It will be recognized that with turbulent flow of the eluant fluid through column 20, the various compounds of relatively low molecular weight will be separated chromatographically into separate bands as will appear hereinafter; in such case, detector 30 serves as means for spectrally identifying each of the several relatively lightweight compounds eluted.
- the upper limit of the flow rate of liquid into the input of most commercially available mass spectrographs is usually not more than 3 ml/min.
- the apparatus of Fig. 1 includes bypass loop 34 selectively connecting the output from valve 25 to the input to valve 32.
- bypass loop 34 selectively connecting the output from valve 25 to the input to valve 32.
- the sample mixture was introduced into a Model 2300 HTLC system (Cohesive Technologies, Acton, MA) having a chromatographic column 20 dimensioned 1 mm x 50 mm, and containing packed, porous silica particles of average size 60 ⁇ m, derivatized with a coating of C, g to constitute a reverse phase column.
- the latter exhibited an interstitial volume between the particles of greater than 45% of the total volume of the column, the majority of the channels between the particles having mean cross-section dimensions substantially less than about 5 ⁇ m.
- the mixture was fed through the column at a reduced velocity substantially greater than about 5,000 (at a flow rate of 10 ml/min) so that the flow was clearly turbulent. As shown in Fig.
- the large molecular weight compound exited the column first within 10 seconds, and was channeled to a detector (Linear UV VIS Model 205) operating at 280 nm.
- a detector Linear UV VIS Model 205 operating at 280 nm.
- the valve was switched and a linear gradient for 0% to 100% acetonitrile over 30 seconds at a flow rate of 0.8 ml/min was run.
- the smaller molecular weight compound was spectrally identified in the ultra-violet detector at 254 nm, the peaks showing partial separation of the relatively low molecular weight compounds from each other and from the relatively large molecular weight compound, all within less than 50 seconds total analysis time.
- FIG. 3 shows an ultraviolet detector trace at 280 nm. and 254 nm. of a sample of target molecules of methyl and propyl paraben in human plasma, flowed through the same equipment as in Example 1, at a flow rate of 10 ml/min using 10 mM ammonium acetate aqueous solution as the mobile phase, subsequently eluted with a second mobile phase of acetonitrile.
- the gradient used was to linearly increase the mobile phase to 100% acetonitrile over 30 seconds. It will be seen that substantially all of the plasma exits the column in less than about 10 seconds and the target lower molecular weight compounds exit in between about 30 to about 50 seconds.
- Fig. 4 shows a mass spectrometer trace of absorbance vs. time for a target molecule of lidocaine.
- the sample mixture was flowed through the same equipment as in Example 1, at a flow rate of 10 ml/min.
- the sample mixture contained lidocaine spiked at a concentration of 100 pg/ ⁇ l into rabbit plasma.
- the rabbit plasma was eluted from the column in approximately 10 seconds and channelled to waste.
- a linear gradient of from 0 to 100% acetonitrile was then run at a flow rate of 1 ml/min and the column effluent directed into a mass spectrometer (Micromass) using a flow splitter that split the flow at a ratio of 2: 1.
- Fig. 4 indicates the output of the mass spectrometer in which the lidocaine was identified as to mass number, eluting within 60 seconds of total analysis time.
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP98938262A EP1039959A4 (en) | 1997-11-19 | 1998-07-31 | Improvement in chemical analyses |
AU86829/98A AU8682998A (en) | 1997-11-19 | 1998-07-31 | Improvement in chemical analyses |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/974,336 | 1997-11-19 | ||
US08/974,336 US6110362A (en) | 1997-11-19 | 1997-11-19 | Chemical analysis |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999025450A1 true WO1999025450A1 (en) | 1999-05-27 |
Family
ID=25521912
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1998/016055 WO1999025450A1 (en) | 1997-11-19 | 1998-07-31 | Improvement in chemical analyses |
Country Status (5)
Country | Link |
---|---|
US (2) | US6110362A (en) |
EP (1) | EP1039959A4 (en) |
AU (1) | AU8682998A (en) |
IN (1) | IN186867B (en) |
WO (1) | WO1999025450A1 (en) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3476417B2 (en) * | 2000-06-05 | 2003-12-10 | 株式会社島津製作所 | Analytical method by liquid chromatography |
AU2002243220A1 (en) * | 2000-11-21 | 2002-07-01 | Waters Investments Limited | Mobile phase dilution scheme for enhanced chromatography |
US6635173B2 (en) * | 2000-12-28 | 2003-10-21 | Cohesive Technologies, Inc. | Multi column chromatography system |
US8017015B2 (en) * | 2006-10-20 | 2011-09-13 | Quest Diagnostics Investments Incorporated | Monolithic column chromatography |
JP5173691B2 (en) * | 2008-09-17 | 2013-04-03 | 株式会社 資生堂 | Hydrophilic interaction chromatography packing |
EP3185016B1 (en) | 2010-10-29 | 2021-06-23 | Thermo Fisher Scientific OY | System layout for an automated system for sample preparation and analysis |
WO2012058516A1 (en) | 2010-10-29 | 2012-05-03 | Thermo Finnigan Llc | Method and system for liquid chromatograph with compressibility and viscosity monitoring to identify fluids |
US9404900B2 (en) | 2012-12-21 | 2016-08-02 | Thermo Finnigan Llc | System for analysis of phase-I and phase-II metabolites and parent compounds without hydrolysis |
WO2015011522A1 (en) | 2013-07-23 | 2015-01-29 | Tubitak Ume | Multi-task sample preparation system with reconfigurable modules for on-line dilution, enzymatic digestion and fractionation |
WO2019157297A1 (en) * | 2018-02-08 | 2019-08-15 | Wiederin Daniel R | Inline dilution and autocalibration for icp-ms speciation analysis |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997016724A2 (en) * | 1995-11-02 | 1997-05-09 | Cohesive Technologies Inc. | High performance liquid chromatography method and apparatus |
Family Cites Families (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1148661A (en) * | 1965-05-11 | 1969-04-16 | Victor Pretorius | Improvements relating to chromatography |
US4208284A (en) * | 1965-05-11 | 1980-06-17 | Hahn Hans H | Apparatus for distribution separation processes |
GB1452896A (en) * | 1972-12-21 | 1976-10-20 | Nat Res Dev | Packing materials |
FR2328508A1 (en) * | 1975-10-22 | 1977-05-20 | Atomic Energy Authority Uk | POROUS GELS, THEIR PROCESS FOR OBTAINING AND APPLICATIONS |
US4512897A (en) * | 1981-07-28 | 1985-04-23 | Amf Incorporated | Molecular separation column and use thereof |
SE464816B (en) * | 1985-10-15 | 1991-06-17 | Nilsson Kjell | MACROPOROUS PARTICLES, PROCEDURES FOR ITS PREPARATION AND ITS APPLICATION |
JPH0669521B2 (en) * | 1986-12-23 | 1994-09-07 | 三菱化成エンジニアリング株式会社 | Chromatographic separation method |
US5228989A (en) * | 1989-07-06 | 1993-07-20 | Perseptive Biosystems, Inc. | Perfusive chromatography |
US5019270A (en) * | 1989-07-06 | 1991-05-28 | Perseptive Biosystems, Inc. | Perfusive chromatography |
US5164090A (en) * | 1989-11-06 | 1992-11-17 | E. R. Squibb & Sons, Inc. | Process for the direct chromatographic analysis of drugs and metabolites in whole blood samples using internal surface reverse phase technology |
US5328603A (en) * | 1990-03-20 | 1994-07-12 | The Center For Innovative Technology | Lignocellulosic and cellulosic beads for use in affinity and immunoaffinity chromatography of high molecular weight proteins |
DE4018778A1 (en) * | 1990-06-12 | 1991-12-19 | Braun Melsungen Ag | ADSORPTION MATERIAL FOR THE SELECTIVE REMOVAL OF LDL AND / AND VLDL |
AU3936993A (en) * | 1992-03-27 | 1993-11-08 | Perseptive Biosystems, Inc. | Rapid hypersensitive flowthrough immunodetection system |
US5360971A (en) * | 1992-03-31 | 1994-11-01 | The Research Foundation State University Of New York | Apparatus and method for eye tracking interface |
US5256298A (en) * | 1992-04-22 | 1993-10-26 | Powell Paul E | Continuous-belt separator/reactor and method |
US5268097A (en) * | 1992-06-19 | 1993-12-07 | Sepracor Inc. | Passivated and stabilized porous mineral oxide supports and method for the preparation and use of same |
US5387347A (en) * | 1993-09-15 | 1995-02-07 | Rothchild; Ronald D. | Method and apparatus for continuous chromatographic separation |
US5503933A (en) * | 1994-02-25 | 1996-04-02 | Purdue Research Foundation | Covalently bonded coatings |
ES2140209T3 (en) * | 1996-01-19 | 2000-02-16 | Cohesive Tech Inc | HIGH PERFORMANCE LIQUID CHROMATOGRAPHY PROCEDURE AND DEVICE. |
US5795467A (en) * | 1996-10-23 | 1998-08-18 | Schloss Engineered Equipment, Inc. | Adjustable inlet for waste water treatment apparatus |
-
1997
- 1997-11-19 US US08/974,336 patent/US6110362A/en not_active Expired - Lifetime
-
1998
- 1998-07-31 AU AU86829/98A patent/AU8682998A/en not_active Abandoned
- 1998-07-31 EP EP98938262A patent/EP1039959A4/en not_active Withdrawn
- 1998-07-31 WO PCT/US1998/016055 patent/WO1999025450A1/en active Application Filing
- 1998-09-10 IN IN2038MA1998 patent/IN186867B/en unknown
-
2000
- 2000-01-03 US US09/476,257 patent/US6149816A/en not_active Expired - Lifetime
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997016724A2 (en) * | 1995-11-02 | 1997-05-09 | Cohesive Technologies Inc. | High performance liquid chromatography method and apparatus |
Also Published As
Publication number | Publication date |
---|---|
IN186867B (en) | 2001-11-24 |
US6149816A (en) | 2000-11-21 |
EP1039959A1 (en) | 2000-10-04 |
EP1039959A4 (en) | 2006-10-25 |
AU8682998A (en) | 1999-06-07 |
US6110362A (en) | 2000-08-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6808635B2 (en) | Multi column chromatography system | |
AU661349B2 (en) | Protein chromatography system | |
Steuer et al. | Comparison of high-performance liquid chromatography, supercritical fluid chromatography and capillary zone electrophoresis in drug analysis | |
Sherma | Review of HPTLC in drug analysis: 1996-2009 | |
EP0591407B1 (en) | Method and apparatus for detecting trace contaminants | |
US6149816A (en) | Chemical analyses | |
Schäfer et al. | Alkyl diol silica: restricted access pre-column packings for fast liquid chromatography-integrated sample preparation of biological fluids | |
D’Orazio et al. | Use of vancomycin chiral stationary phase for the enantiomeric resolution of basic and acidic compounds by nano-liquid chromatography | |
de Vries et al. | Direct column liquid chromatographic enantiomer separation of the coumarin anticoagulants phenprocoumon, warfarin, acenocoumarol and metabolites on an α1-acid glycoprotein chiral stationary phase | |
US5968361A (en) | Rapid method for separation of small molecules using reverse phase high performance liquid chromatography | |
Hellgeth et al. | FTIR Detection of liquid chromatographically separated species | |
Theodoridis et al. | Automated sample treatment by flow techniques prior to liquid-phase separations | |
Novotny | Recent developments in analytical chromatography | |
Karger et al. | Automated sample cleanup in HPLC using column-switching techniques | |
Oda et al. | On-line determination and resolution of the enantiomers of ketoprofen in plasma using coupled achiral—chiral high-performance liquid chromatography | |
Lamprecht et al. | Determination of carvedilol in human plasma by high-performance liquid chromatography applying on-line deproteination and column switching | |
Kupiec et al. | High-performance liquid chromatography | |
Rajput et al. | Short Review on Comparative Study of Chromatography | |
Novotny | Capillary chromatography in the condensed mobile phases: From the concepts to analytically useful separations and measurements | |
Ramon et al. | Nano-liquid chromatography | |
AU2013203558B2 (en) | Methods and apparatus for analyzing samples and collecting sample fractions | |
Bachhav et al. | Review of High Performance Liquid Chromatography and Its Applications | |
Cope et al. | Some aspects of pharmaceutical analysis using high performance liquid chromatography | |
Mozdzanowski et al. | Detection methods | |
EP3376222A1 (en) | Baseline correction for liquid chromatography / mass spectroscopy |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
NENP | Non-entry into the national phase |
Ref country code: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1998938262 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 1998938262 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: CA |