Abstract:
A high pressure liquid chromatography (HPLC) capillary column device, system and method for processing a HPLC sample with a cartridge housing a packed capillary column; at least one inlet connection to the capillary column for a sample fluid; and at least one outlet connection from the capillary column for the sample fluid. The outlet connection is able to accommodate either a spray tip for atomizing the sample fluid or a transport tube for transporting the sample fluid from a spray tip column to a spray tip. Inlet connections enable supply of electrical power to the capillary column through electrical connections disposed within the cartridge housing; and gas for evaporating the sample liquid is supplied to at least one outlet connection from the capillary column for the sample fluid through a gas supply line within the cartridge housing. The temperature of the sample liquid can be controlled through a heat connection.

Description:
RELATED APPLICATIONS 
     This application is a continuation application claiming the benefit of the filing date of U.S. patent application, Ser. No. 11/576,385 filed Jan. 22, 2008, a 371 of international application number PCT/US2004/033079 filed on Oct. 7, 2004, the contents of each of which is incorporated by reference herein in its entirety. 
    
    
     BACKGROUND OF THE INVENTION 
     Capillary columns used for high pressure liquid chromatography (HPLC) are fragile and difficult to manipulate. A high level of care must be taken when handling and connecting the capillary to an HPLC system for analysis by a mass spectrometer. This is typically a tedious and time consuming process. Also, temperature control of the capillary column is generally difficult to establish. 
     SUMMARY OF THE INVENTION 
     It is an object of this invention to provide a HPLC system for interfacing between a chromatographic system and a mass spectrometer. 
     It is an object of this invention to provide a HPLC capillary column device of reduced size which also reduces the risk of damage and reduces handling time via a cassette cartridge arrangement. 
     It is an object of this invention to provide a HPLC capillary column device which enables accurate temperature control and heating capabilities. 
     The present invention is directed to a high pressure liquid chromatography (HPLC) capillary column device for processing a HPLC sample. The device has a cartridge housing, and the cartridge housing comprises: a packed capillary column inside the cartridge housing; at least one inlet connection to the capillary column for a sample fluid; and at least one outlet connection from the capillary column for the sample fluid. The outlet connection is able to accommodate one of a spray tip for atomizing the sample fluid and a transport tube for transporting the sample fluid from a spray tip column to a spray tip. An inlet connection enables supply of electrical power to the capillary column through electrical connections disposed within the cartridge housing; and an inlet connection enables supply of a gas to the at least one outlet connection from the capillary column for the sample fluid through a gas supply line disposed within the cartridge housing, with the gas supply line being fluidically coupled to the outlet connection. 
     The HPLC capillary column device can further comprise a heat connection enabling a heat supply to be coupled to the capillary column and the heat supply can control the temperature of the HPLC device during the HPLC processing. The heat supply can be either electrical or a heated fluid. Voltage applied to the sample liquid by the electrical power supply ionizes at least a portion of the sample liquid. 
     The invention can also be in the form of a cartridge for a high pressure liquid chromatography (HPLC) capillary column device for processing a HPLC sample, with the device comprising a cartridge housing as described above. 
     The housing can have a multi-sided cross-section and the capillary column can be disposed in a straight line from the inlet connection to the outlet connection, or alternatively, in a curvilinear line from the inlet connection to the outlet connection. 
     The housing can have a substantially curvilinear cross-section which can further comprise at least one portion that is not uniformly disposed with respect to the substantially curvilinear cross-section. The portion that is not uniformly disposed is capable of acting as an alignment key for the cartridge to be inserted into a mass spectrometer interface. 
     The present invention can be in the form of a high pressure liquid chromatography (HPLC) system for interfacing between a chromatographic system and a mass spectrometer. The HPLC system comprises: a HPLC capillary column cartridge cassette, the cartridge cassette including connections for controlling gas flow, temperature and voltage applied to a liquid sample within the capillary column. The cartridge cassette is capable of receiving a sample and chromatographic data from the chromatographic system. The system further comprises a mass spectrometer interface device, with the mass spectrometer interface device including a cartridge cassette holder for holding the HPLC capillary cartridge cassette. The cartridge cassette holder is capable of transmitting the liquid sample in a charged atomized condition to the mass spectrometer. In addition, the gas flow, temperature and voltage of the cartridge cassette are capable of being controlled by the mass spectrometer. 
     The present invention also provides a method of processing a sample from a HPLC capillary column device with the HPLC capillary column device comprising a cartridge for a packed capillary column. The method is performed by: choosing an appropriate cartridge for one of a procedure being conducted and a compound being detected; inserting the cartridge into a mass spectrometer interface; connecting a connection on the cartridge with a gas supply line supplied to the sample liquid through the gas supply line for evaporating at least a portion of the sample liquid; evaporating at least a portion of the sample liquid; connecting a connection on the cartridge with an electrical power supply line for atomizing the sample liquid at a liquid junction of the packed capillary column; atomizing the sample liquid at a liquid junction of the packed capillary column; and establishing flow from a chromatographic system and to a mass spectrometer through the mass spectrometer interface by injecting a sample liquid into the chromatographic system; 
     Furthermore, the method can also comprise the steps of maintaining temperature of the capillary column in a range of 5 to 70.degree. C. above ambient temperature; and analyzing, by the mass spectrometer, flow emerging as a spray from a stage of the mass spectrometer interface. A spray tip can be employed for the spray to the mass spectrometer. A transport tube can be employed for transporting the spray to the mass spectrometer, with the transport tube being either rigid or flexible. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a schematic view of the HPLC system of the present invention. 
         FIG. 2A  is a plan view of an HPLC capillary column device according to a first embodiment of the present invention having a spray tip. 
         FIG. 2B  is a plan view of an HPLC capillary column device according to an alternate arrangement of the first embodiment of the present invention having a transport tube to a spray tip. 
         FIG. 3  is a plan view of an HPLC capillary column device according to a second embodiment of the present invention having a spray tip. 
         FIG. 4A  is a plan view of an HPLC capillary column device according to a third embodiment of the present invention having a spray tip. 
         FIG. 4B  is an end view of the HPLC capillary column device according to the third embodiment of the present invention according to  FIG. 4A  having a spray tip. 
         FIG. 4C  is a perspective view of the HPLC capillary column device according to the third embodiment of the present invention of  FIGS. 4A and 4B . 
         FIG. 5A  is a plan view of an HPLC capillary column device according to an alternate arrangement of the third embodiment of the present invention having a transport tube to a spray tip. 
         FIG. 5B  is an end view of the HPLC capillary column device according to the alternate arrangement of the third embodiment of the present invention according to  FIG. 5A  having a transport tube to a spray tip. 
         FIG. 5C  is a perspective view of the HPLC capillary column device according to the alternate arrangement of the third embodiment of the present invention of  FIGS. 5A and 5B . 
         FIG. 6A  is a plan view of a fourth embodiment of the present invention of  FIG. 4 or 5A . 
         FIG. 6B  is an end view of the HPLC capillary column device according to the alternate arrangement of the third embodiment of the present invention according to  FIG. 6A  having a transport tube to a spray tip. 
         FIG. 6C  is a perspective view of the HPLC capillary column device according to the alternate arrangement of the third embodiment of the present invention of  FIGS. 6A and 6B . 
     
    
    
     DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS 
     The present invention provides an HPLC capillary column device which facilitates the interface of the device with a mass spectrometer. To facilitate the description of the present invention, the features of the prior art are described as follows. 
       FIG. 1  is a schematic view of the HPLC system of the present invention. HPLC capillary column cassette  200  is provided to facilitate the interface of the electrospray mass spectrometry unit. In particular, a spray tip, voltage source and connections  24  and  26 , and the desolvation gas flow are now readily interfaced with a mass spectrometer  340  having a front side  260 . The chromatographic system  230  provides the chromatographic spectra for a sample (not shown). The chromatographic spectra are output through a connection  235  to the HPLC column cassette  200 . The HPLC column cassette is then inserted into a cassette holder  250  of mass spectrometer interface device  240 . The mass spectrometer interface device  240  interfaces by means of a spray  255  of the sample which emerges from stage  252  which travels to the front side  260  of mass spectrometer  340 . Typically, the mass spectrometer  340  controls the parameters such as the temperature, desolvation gas flow and the applied voltage for the HPLC column cassette  200  but control can also be exerted from the mass spectrometer interface device  240  or from the chromatographic system  230 . Also, although the mass spectrometer interface device  240  is illustrated in  FIG. 1  as being separate from the chromatographic system  230  and from the mass spectrometer  340 , the interface device  240  can also be integral with either the chromatographic system  230  or the mass spectrometer  340 . In addition, the HPLC column cassette  200  can be designed into several different specific embodiments as follows. 
     First Embodiment 
       FIG. 2A  is a plan view of an HPLC capillary column device according to the first embodiment of the present invention. The HPLC pump and injector injects a liquid sample through an inlet connection  202  contained within the rear side surface  204  of a cassette cartridge  200 - 1 . The capillary column  160  is disposed within the cassette cartridge  200 . The capillary column is packed in a manner commonly applied by those skilled in the art. A heat source connection  206 , a voltage source connection  212 , and a gas source connection  216  are each contained within the front side surface  220  of the cassette cartridge  200 - 1 . 
     Heat provided through the column heat source connection  206 , sufficient to maintain the temperature of the HPLC device in a range typically of 5 to 70.degree. C. above ambient temperature, is conducted through a flow tube or channel  208  disposed internally within the cassette cartridge  200 - 1 . The heat source connection  206  is fluidically coupled, when the heat source is a heated fluid, or electrically coupled, when the heat source is an electrical resistance wire, to the flow tube or channel  208  that surrounds the capillary column  160  within the cassette cartridge  200 - 1  to provide a means for accurate temperature control and heating of the sample fluid within the capillary column  160 . 
     The voltage provided through the voltage source connection  212 , typically in the range of 4 KV DC, is directed by the voltage connections  241  and  261  to atomize and disperse the liquid sample emerging from the outlet  224  of the capillary column  160  that is within the conductive adapter  222  into a very fine spray of electrically charged droplets. The spray tip  280  immediately downstream of the capillary column outlet  224  within the conductive adapter  222  directs the sample spray  32  towards the mass spectrometer  340 . 
     The gas, typically but not limited to nitrogen, provided through the gas source connection  216  again provides desolvation gas flow at pressures and temperatures sufficient to increase the rate of evaporation of the solvent of the liquid sample during the electrospray ionization (ESI) process occurring as a result of the voltage applied through the voltage connections  241  and  261 . The gas source connection  216  is fluidically coupled to gas flow tube or channel  218  internally disposed within the cassette cartridge  200 - 1 , the gas flow tube or channel  218  in turn being fluidically coupled to the spray tip  280  through the conductive collar  222 . 
       FIG. 2B  is an alternate arrangement of the first embodiment disclosed in  FIG. 2A . The only difference is that instead of spray tip  280  being immediately downstream of capillary column  160 , the transport tube  360  is immediately downstream of capillary column  160 . In all other respects, the cassette cartridge  200  is identical to that disclosed in  FIGS. 1A and 1B . The application of the voltage for atomization at the voltage connections  241  and  261  occurs at the liquid junction  380 - 1 . The gas evaporates the liquid sample solvent within the conductive adapter  222 . 
     Second Embodiment 
       FIG. 3  is a plan view of a second embodiment of the present invention where cassette cartridge  200 - 2  contains the same components as illustrated in  FIG. 2A  for cassette cartridge  200 - 1 , including the spray tip  280 , but instead of a straight capillary column, such as capillary column  160  in  FIGS. 2A and 2B , a coiled capillary column  162  is provided instead within what is typically a circular enclosure  270  of radius R. In all other respects, the coiled capillary column cassette cartridge  200 - 2  is the same as cassette cartridge  200 - 1 . Furthermore, those skilled in the art recognize that while the coiled capillary column cassette cartridge  200 - 2  is shown with a spray tip configuration as in  FIG. 2A , the transport tube configuration described in  FIG. 2B  can be applied to the coiled column cartridge  200 - 2  as well. 
     Third Embodiment 
       FIG. 4A  is a plan view of the third embodiment of the present invention. The third embodiment differs from the first and second embodiments in that a tubular cartridge rather than a flat cartridge houses the capillary column. Specifically, the HPLC pump and injector  12  injects the liquid sample into inlet connection  802  of tubular cassette cartridge  804 . The tubular cassette cartridge  804  encloses the capillary column  806  typically along the centerline of the tubular cartridge  804 , which typically is comprised of, but is not limited to, a circular cross-section. A column heat block  808  in the tubular cassette cartridge  804  provides insulation of heat flow to the capillary column  806  that is provided through heat source connection  812 . The heat source connection  812  is formed on the outer surface of the tubular cassette cartridge  804  and, depending on whether the heat source is a heated fluid or an electrical resistance source, fluidically or electrically couples tube or channel  814  to the capillary column  806 . 
     Further downstream, at the outlet end of the tubular cassette cartridge  804 , a conductive adapter  818  surrounds a spray tip  828 . A voltage source connection  822  penetrates the conductive adapter  818  by way of voltage connections  824  and  826 . The voltage provided through the voltage source connection  822 , again typically in the range of 4 KV DC, is directed by the voltage connections  824  and  826  to atomize and disperse the liquid sample  14  emerging from the end of the capillary column  806  at the liquid junction interface  838  that is within the conductive adapter  818  into a very fine spray of electrically charged droplets. The spray tip  820  immediately downstream of the end of the capillary column  806  within the conductive collar  818  directs the sample spray  32  towards the mass spectrometer  240 , which in this case interfaces with the tubular cassette cartridge  804  by way of an interfacing port  844  contained within a cassette holder  850  that is contained within the mass spectrometer  240 . In this case, the cassette holder  850  is designed to facilitate the interconnection with the now tubular-shaped cartridge  804 , as discussed below for  FIGS. 4B and 4C . 
     As before with respect to the first and second embodiments, the gas, typically but not limited to nitrogen, provided through the gas source connection  834  again provides desolvation gas flow at pressures and temperatures sufficient to increase the rate of solvent evaporation during the electrospray ionization (ESI) process. The gas source connection  834  is fluidically coupled to gas flow tube or channel  836  internally disposed within the tubular cassette cartridge  804  and which in turn is fluidically coupled to the spray tip  820  through the conductive adapter  818 . 
       FIG. 4B  is an elevation view of the inlet end of the tubular cassette cartridge  804  of  FIG. 5A . The alignment key  840  is provided to facilitate proper insertion of the tubular cartridge  804  into the cassette holder  850  within the mass spectrometer interface  240 . 
       FIG. 4C  is a perspective view of the tubular cassette cartridge  804  of  FIG. 4A  showing the inlet connection  806 , the heat source connection  812 , the voltage source connection  822 , the gas source connection  834 , and the spray tip  820 . 
       FIG. 5A  is a plan view of an alternate arrangement of the third embodiment of the present invention illustrated in  FIG. 4A . The only difference is that instead of spray tip  820  being immediately downstream of capillary column  806 , the transport tube  842  is immediately downstream of capillary column  806 . As is the case for the transport tube  360  of  FIG. 2B , the transport tube enables transport of the atomized charged droplets to a mass spectrometer that is a distance away from the chromatographic system  230 . In all other respects, the tubular cassette cartridge  804  is identical to that disclosed in  FIG. 7A . As a result,  FIG. 5B  is identical to  FIG. 4B . The only difference between  FIG. 5C  and  FIG. 4C  is the presence of the transport tube  842  instead of the spray tip  820 . 
     Fourth Embodiment 
       FIG. 6A  is a plan view of a fourth embodiment of the present invention of  FIG. 4A or 5A . In this case, the tubular cassette cartridge  804  of  FIG. 4A  or of  FIG. 5A  incorporates, instead of a straight capillary column  806 , a coiled or helical capillary column  856  within the column heat block  808  Either a spray tip  820  or a transport tube to a spray tip  842  can be employed as is obvious to those skilled in the art. In all other respects, the tubular cassette cartridge  804 , as shown in  FIGS. 6A through 6C  can be constructed and used in a similar manner as shown in  FIGS. 4A-4C  and  FIGS. 5A-5C . 
     With respect to the method of using the first, second, third and fourth embodiments, referring to  FIG. 1 , the user chooses an appropriate cartridge, shown generically as cartridge cassette  200  to represent cartridge cassettes  200 - 1 ,  200 - 2  or  804  of  FIGS. 2A through 6C  as appropriate, for the procedure being conducted or the compound being detected. The user inserts either cartridge  200 - 1 ,  200 - 2  or  804  into the mass spectrometer interface  240  and makes the connections to the respective gas line  216  or  834 , the electrical power for the voltage connection  212  or  822  and from the temperature control mechanism as represented by column heat connections  206  or  812 . The user establishes flow from the chromatographic system  230  and to the mass spectrometer  340  through the mass spectrometer interface  240 . The sample is injected into the chromatographic system  230  and emerges from the stage  252  as a spray  255  to be analyzed by the mass spectrometer  340  to obtain the desired results. When using a cartridge with a transport tube, such as transport tube  360  in  FIG. 3B , or transport tube  842  in  FIGS. 5A and 5C  or the cartridge  200 - 2  in  FIG. 3  when equipped with a transport tube, the transport tube can be either rigid or flexible. The design of the stage  252  can be such that either a rigid or flexible transport tube can be accommodated, as is obvious to those skilled in the art. 
     The invention has now been explained with reference to specific embodiments. Other embodiments will be apparent to those of ordinary skill in the art in view of the foregoing description. It is not intended that this invention be limited except as indicated by the appended claims and their full scope equivalents.