Patent Application
20120198919
The present invention relates to a method for metering two or more liquids in controlled proportions, and to a liquid supply system. The present invention further relates to a liquid separation system, in particular in a high performance liquid chromatography application.
U.S. Pat. No. 4,018,685 discloses proportional valve switching for gradient formation. U.S. Pat. No. 4,595,496 discloses a liquid composition control for avoiding pump draw stroke non-uniformities. U.S. Pat. No. 4,980,059 discloses a liquid chromatograph. U.S. Pat. No. 5,135,658 discloses a coordinated chromatography system. U.S. Pat. No. 7,631,542 discloses a chromatography system with fluid intake management. U.S. Pat. No. 5,862,832 describes a gradient proportioning valve. International patent application WO 2010/030720 discloses a modulation of time offsets for solvent proportioning.
It is an object of the invention to provide an improved liquid supply capable of supplying composite liquids with high accuracy. The object is solved by the independent claim(s). Further embodiments are shown by the dependent claim(s).
A method for metering two or more liquids in controlled proportions in a liquid supply system and for supplying a resultant mixture is given, wherein the liquid supply system comprises a plurality of solvent supply lines, each fluidically connected with a reservoir containing a liquid, a proportioning valve interposed between the solvent supply lines and an inlet of a pumping unit, the proportioning valve configured for modulating solvent composition by sequentially coupling selected ones of the solvent supply lines with the inlet of the pumping unit, with the pumping unit being configured for taking in liquids from the selected solvent supply lines and for supplying a mixture of the liquids at its outlet; the method comprising: drawing in a first liquid into the pumping unit via a first solvent supply line; determining one or more switching points of time for switching between different solvent supply lines, the switching points of time being determined in a way that at said switching points of time, the liquid supplied to the pumping unit is in a predefined pressure range; switching from the first solvent supply line to a second solvent supply line at one of said switching points of time; drawing in a second liquid into the pumping unit via the second solvent supply line.
According to embodiments of the present invention, the switching points of time are chosen such that at the time of switching, the respective liquid is within the predefined pressure range. For example, the pressure range may be defined such that, at the point of switching, both a state of overpressure and a state of underpressure are avoided. In this case, at the point of switching from the first solvent to a second solvent, the solvent is neither in a compressed state nor in an expanded state. A compressed state or an expanded state of the solvent that is drawn in may cause compositional errors. Furthermore, due to the elasticity of the liquid supply system's tubing and the elasticity of other system components, a state of overpressure may e.g. lead to a corresponding dilation of the tubing, whereas a state of underpressure may e.g. correspond to a narrowing of the tubing. Hence, by avoiding a state of overpressure or a state of underpressure at the point of switching, compositional errors are reduced or even avoided.
According to a preferred embodiment of the invention, the method comprises monitoring pressure at the inlet of the pumping unit to determine the switching points of time for switching between different solvent supply lines.
According to a preferred embodiment of the invention, the method comprises determining the switching points of time in a way that at said switching points of time, the liquid supplied to the pumping unit essentially is neither in a state of overpressure nor in a state of underpressure.
According to a preferred embodiment of the invention, the method comprises determining the switching points of time in a way that at the switching points of time, substantially no energy is stored in a compression or in a decompression of the liquid supplied to the pumping unit or in any elastic deformation of the liquid supply system's tubing or of any other system component, said elastic deformation being due to overpressure or to underpressure of the liquid.
According to a preferred embodiment of the invention, the method comprises determining the switching points of time in a way that an actual pressure of the liquid supplied to the pumping unit is substantially equal to a predefined regular pressure at said switching points.
According to a preferred embodiment of the invention, the method comprises determining the switching points of time in a way that the liquid supplied to the pumping unit is substantially at a predefined regular pressure at said switching points of time.
According to a preferred embodiment of the invention, the method comprises determining the switching points of time in a way that the liquid supplied to the pumping unit is substantially at a predefined regular pressure at said switching points of time, with the predefined regular pressure being the liquid's average pressure in the low-pressure region of the liquid supply system.
According to a preferred embodiment of the invention, the method comprises determining the switching points of time in a way that the liquid supplied to the pumping unit is substantially at a predefined regular pressure at said switching points of time, with the predefined regular pressure being the liquid's final static pressure in the low-pressure region of the liquid supply system.
According to a preferred embodiment of the invention, the liquid supply system further comprises a pressure sensor located downstream of the proportioning valve, the pressure sensor being configured for monitoring a pressure of the liquid supplied to the pumping unit; the method further comprising at least one of: selecting the switching points of time in accordance with the pressure determined by the pressure sensor; comparing the pressure determined by the pressure sensor with a predefined regular pressure, and determining the switching points in a way that the actual pressure is substantially equal to the predefined regular pressure at said switching points.
According to a preferred embodiment of the invention, the method comprises determining the switching points of time in advance for different solvents and flow rates according to a predetermined model of the liquids' behavior.
According to a preferred embodiment of the invention, when liquid is drawn in from selected ones of the solvent supply lines, the liquid performs oscillations between a first state characterized by minimum pressure and a second state characterized by maximum pressure.
According to a preferred embodiment of the invention, at the switching points of time, the liquid supplied to the pumping unit may still be in a state of oscillation, with the liquid oscillating between a first state characterized by minimum pressure and a second state characterized by maximum pressure.
According to a preferred embodiment of the invention, at the switching points of time when switching between different solvent supply lines is effected, dynamic disturbances of the liquid supplied to the pumping unit do not have to be settled yet.
According to a preferred embodiment of the invention, when liquid is drawn in from selected ones of the solvent supply lines, the liquid performs oscillations between a first state characterized by minimum pressure and a second state characterized by maximum pressure, with a time period of said oscillations depending on at least one of the hydraulic capacity of the liquid and the liquid supply system's tubing, the hydraulic restriction of the liquid supply system's tubing, and the mass inertia associated with the liquid in the tubing.
According to a preferred embodiment of the invention, the pumping unit comprises a piston pump with a piston reciprocating in a pump chamber, the method comprising at least one of: moving the piston in a non-uniform manner to reduce oscillating dynamics of the liquids that are drawn in, with the piston being slowed down before switching is effected, and with the piston being accelerated after switching has been effected; moving the piston in a non-uniform manner to vary intake speed during an intake stroke, with liquids being accelerated and decelerated smoothly during the intake stroke; operating the pumping unit to control the speed of the liquids that are taken in in a way that pressure extremes are avoided; operating the pumping unit to control the speed of the liquids that are taken in by optimizing the speed dynamics with a function that has a continuous change in speed, with steep speed changes being reduced or even avoided; operating the pumping unit to control the speed of the liquids that are taken in by optimizing the speed dynamics with a function that has a continuous change in acceleration or deceleration, with the result that steep speed changes being reduced or even avoided; operating the pumping unit to control the speed of the liquids that are taken in by optimizing the speed dynamics with a function that results in actively damping the intake pressure.
A liquid supply system according to embodiments of the present invention is configured for metering two or more liquids in controlled proportions and for supplying a resultant mixture. The liquid supply system comprises a plurality of solvent supply lines, each fluidically connected with a reservoir containing a liquid; a proportioning valve interposed between the solvent supply lines and an inlet of a pumping unit, the proportioning valve configured for modulating solvent composition by sequentially coupling selected ones of the solvent supply lines with the inlet of the pumping unit; the pumping unit being configured for taking in liquids from the selected solvent supply lines and for supplying a mixture of the liquids at its outlet; a control unit configured for controlling operation of the proportioning valve, wherein switching between different solvent supply lines is effected at one or more switching points of time that are chosen in a way that at said switching points of time, the liquid supplied to the pumping unit is in a predefined pressure range.
According to embodiments of the present invention, the liquid supply system further comprises at least one of: a pressure sensor located downstream of the proportioning valve, the pressure sensor being configured for monitoring a pressure of the liquid supplied to the pumping unit; a flow sensor located downstream of the proportioning valve, the flow sensor being configured for determining a flow of the liquid supplied to the pumping unit.
According to embodiments of the present invention, the pumping unit comprises a piston pump with a piston reciprocating in a pump chamber.
According to embodiments of the present invention, the liquid supply unit further comprises an auxiliary chamber fluidically coupled to the inlet of the pumping unit, the auxiliary chamber including a force loaded element or active element therein.
According to embodiments of the present invention, the auxiliary chamber is configured for receiving a mixture of liquids contained in the pumping unit, for mixing the liquids, and for resupplying the liquids to the pumping chamber.
According to embodiments of the present invention, the control unit is further configured for controlling the pumping unit's operation in a way that the sequential mixture of liquids contained in the pumping unit is transferred via the pumping unit's inlet to the auxiliary chamber and from the auxiliary chamber back to the pumping unit before the inlet valve is closed and the blended liquid is delivered at the pumping unit's outlet, thereby mixing the liquids to form a more homogeneous composition.
A liquid separation system according to embodiments of the present invention is configured for separating compounds of a sample liquid in a mobile phase. The liquid separation system comprises: a liquid supply system as described above, the liquid supply system being configured to drive the mobile phase through the liquid separation system; a separation unit, preferably a chromatographic column, configured for separating compounds of the sample liquid in the mobile phase.
According to embodiments of the present invention, the liquid separation system further comprises at least one of: a sample injector configured to introduce the sample liquid into the mobile phase; a detector configured to detect separated compounds of the sample liquid; a collection unit configured to collect separated compounds of the sample liquid; a data processing unit configured to process data received from the liquid separation system; a degassing apparatus for degassing the mobile phases.
Embodiments of the present invention might be embodied based on most conventionally available HPLC systems, such as the Agilent 1290 Series Infinity system, Agilent 1200 Series Rapid Resolution LC system, or the Agilent 1100 HPLC series (all provided by the applicant Agilent Technologies—see www.agilent.com—which shall be incorporated herein by reference).
One embodiment of an HPLC system comprises a pumping apparatus having a piston for reciprocation in a pump working chamber to compress liquid in the pump working chamber to a high pressure at which compressibility of the liquid becomes noticeable, and to deliver said liquid at high pressure.
One embodiment of an HPLC system comprises two pumping apparatuses coupled either in a serial or parallel manner. In the serial manner, as disclosed in EP 309596 A1, an outlet of the first pumping apparatus is coupled to an inlet of the second pumping apparatus, and an outlet of the second pumping apparatus provides an outlet of the pump. In the parallel manner, an inlet of the first pumping apparatus is coupled to an inlet of the second pumping apparatus, and an outlet of the first pumping apparatus is coupled to an outlet of the second pumping apparatus, thus providing an outlet of the pump. In either case, a liquid outlet of the first pumping apparatus is phase shifted, preferably essentially 180 degrees, with respect to a liquid outlet of the second pumping apparatus, so that only one pumping apparatus is supplying into the system while the other is intaking liquid (e.g. from the supply), thus allowing to provide a continuous flow at the output. However, it is clear that also both pumping apparatuses might be operated in parallel (i.e. concurrently), at least during certain transitional phases e.g. to provide a smooth(er) transition of the pumping cycles between the pumping apparatuses. The phase shifting might be varied in order to compensate pulsation in the flow of liquid as resulting from the compressibility of the liquid. It is also known to use three piston pumps having about 120 degrees phase shift.
The separating device preferably comprises a chromatographic column providing the stationary phase. The column might be a glass or steel tube (e.g. with a diameter from 10 μm to 5 mm and a length of 1 cm to 1 m) or a microliquidic column (as disclosed e.g. in EP 1577012 A1 or the Agilent 1200 Series HPLC-Chip/MS System provided by the applicant Agilent Technologies, see e.g. http://www.chem.agilent.com/Scripts/PDS.asp?|Page=38308). For example, a slurry can be prepared with a powder of the stationary phase and then poured and pressed into the column. The individual components are retained by the stationary phase differently and separate from each other while they are propagating at different speeds through the column with the eluent. At the end of the column they elute separated, more or less one at a time. During the entire chromatography process the eluent might be also collected in a series of fractions. The stationary phase or adsorbent in column chromatography usually is a solid material. The most common stationary phase for column chromatography is silica gel, followed by alumina. Cellulose powder has often been used in the past. Also possible are ion exchange chromatography, reversed-phase chromatography (RP), affinity chromatography or expanded bed adsorption (EBA). The stationary phases are usually finely ground powders or gels and/or are microporous for an increased surface, though in EBA a liquidized bed is used. Furthermore, there also exist monolithic columns for fast high performance liquid chromatography separations.
The mobile phase (or eluent) can be either a pure solvent or a mixture of different solvents. It can be chosen e.g. to minimize the retention of the compounds of interest and/or the amount of mobile phase to run the chromatography. The mobile phase can also been chosen so that the different compounds can be separated effectively. The mobile phase might comprise an organic solvent like e.g. methanol or acetonitrile, often diluted with water. For gradient operation water and organic is delivered in separate bottles, from which the gradient pump delivers a programmed blend to the system. Other commonly used solvents may be isopropanol, THF, hexane, ethanol and/or any combination thereof or any combination of these with aforementioned solvents.
The sample liquid might comprise any type of process liquid, natural sample like juice, body liquids like plasma or it may be the result of a reaction like from a fermentation broth.
The liquid is preferably a liquid but may also be or comprise a gas and/or a supercritical liquid (as e.g. used in supercritical liquid chromatography—SFC—as disclosed e.g. in U.S. Pat. No. 4,982,597 A).
The pressure in the mobile phase might range from 2-200 MPa (20 to 2000 bar), in particular 10-150 MPa (100 to 1500 bar), and more particular 50-120 MPa (500 to 1200 bar).
The HPLC system might further comprise a sampling unit for introducing the sample liquid into the mobile phase stream, a detector for detecting separated compounds of the sample liquid, a fractionating unit for outputting separated compounds of the sample liquid, or any combination thereof. Further details of HPLC system are disclosed with respect to the aforementioned Agilent HPLC series, provided by the applicant Agilent Technologies, under www.agilent.com which shall be in cooperated herein by reference.
Embodiments of the invention can be partly or entirely embodied or supported by one or more suitable software programs, which can be stored on or otherwise provided by any kind of data carrier, and which might be executed in or by any suitable data processing unit. Software programs or routines can be preferably applied in or by the control unit.
Other objects and many of the attendant advantages of embodiments of the present invention will be readily appreciated and become better understood by reference to the following more detailed description of embodiments in connection with the accompanied drawing(s). Features that are substantially or functionally equal or similar will be referred to by the same reference sign(s). The illustration in the drawing is schematically.
In the example shown in
During an intake phase of the first piston pump 111, the inlet valve 113 is open, the outlet valve 114 is shut, and the first piston 115 moves in the downward direction. Accordingly, solvent supplied via the supply line 109 is drawn into the first pump chamber 117. During the downward stroke of the first piston 115, the proportioning valve 108 may switch between different liquid supply lines and hence between different solvents. Thus, during the downward stroke of the first piston 115, different solvents may be drawn into the first pump chamber 117 one after the other. In an alternative construction, there may be individual inlet valves for each liquid supply line 104 to 107, which then are controlled like and instead of proportioning valve 108.
During the downward stroke of the first piston 115, the second piston 118 performs an upward stroke and delivers a flow of fluid, and at the pumping unit's outlet 121, a flow of composite solvent at high pressure is provided.
After the respective amounts of different solvents have been drawn into the first pump chamber 117, the inlet valve 113 is shut, the first piston 115 starts moving in the upward direction and compresses the liquid contained in the first pump chamber 117 to system pressure. In an alternative construction, when the proportioning valve 108 is capable to withstand high pressure, an extra inlet valve 113 may be omitted. The outlet valve 114 opens, and during the following refill phase, the first piston 115 moves in the upward direction, the second piston 118 moves in the downward direction, and the composite solvent is transferred from the first pump chamber 117 to the second pump chamber 120. During the refill phase, the amount of composite solvent supplied by the first piston pump 111 usually exceeds the amount of composite solvent drawn in by the second piston pump 112, and hence, at the outlet 125, a continuous flow of composite solvent is maintained.
After a well-defined amount of composite solvent has been supplied from the first piston pump 111 to the second piston pump 112, the outlet valve 114 is shut, the second piston 118 moves in the upward direction, thus a continuous flow of composite solvent is maintained, while the first piston 115 starts moving in the downward direction, the inlet valve 113 is opened, and again different solvents are drawn into the first pump chamber 117.
The liquid supply system shown in
The liquid supply system shown in
With regard to the liquid supply system shown in
To gain an improved understanding of these compositional errors, a mixture of water and a small amount of acetone has been studied, whereby the amount of acetone has been increased in steps from 0% to 10%. As shown in
The reason for this behavior is related to the fluid dynamics and should be described here for the situation of solvent B. When the proportioning valve 108 switches from solvent A to solvent B, the volume of solvent B contained in liquid supply line 105 is fluidically connected, via the supply line 109, to the first pump chamber 117. The first piston 115 continues its downward movement, and due to the resulting underpressure in the first pump chamber 117, the volume of solvent B contained in the liquid supply line 105 is accelerated towards the first piston pump 111.
The resulting fluid dynamics are illustrated in
In order to level out the initial pressure difference in low damped systems, the speed of solvent B will raise above the intake speed of pump chamber 500. As shown in
The oscillations shown in
In
In contrast, in case solvent B is drawn in during a somewhat longer time interval 615, the volume of solvent B that is drawn in is in a compressed state when the proportioning valve switches back from solvent B to solvent A. Therefore, the amount of solvent B that is drawn in is actually too large. This corresponds to the case of 2% acetone tracer in
The same holds true for the somewhat longer time interval 616, which may for example correspond to the case of 3% acetone containing liquid in
According to embodiments of the present invention, it is attempted to reduce or even eliminate these compositional errors of the composite solvent by carefully choosing the switching point when the proportioning valve is switched back from solvent B to solvent A. Instead of just considering a linear relation of valve duty cycle, the control will also consider actual pressure conditions. In case the solvent in the pump chamber is in a state of overpressure at the switching point of time, the amount of solvent B that is drawn in is too large. In contrast, in case the solvent in the pump chamber is in a state of underpressure at the switching point of time, the amount of solvent B that is drawn in is too small. Therefore, at the switching point of time, the solvent in the pump chamber should be at regular pressure, or at least close to regular pressure. According to embodiments of the present invention, it is avoided that switching from solvent B to solvent A occurs at a point of time when the solvent contained in the pump chamber is either in a state of underpressure or in a state of overpressure, because both the state of underpressure and the state of overpressure lead to compositional errors of the composite solvent.
In the example of
In prior art solutions, the first piston of the first piston pump has performed a linear movement during the intake phase. This is illustrated in
According to embodiments of the present invention, the switching point for switching from solvent B to solvent A is chosen such that any oscillatory movements of the solvent in the first pump chamber do not disturb solvent composition. In particular, the switching point for switching from solvent B to solvent A is chosen such that the solvent in the first piston pump is neither in a compressed state nor in an expanded state at the point of switching.
It should be noted that during the intake phase, the outlet valve 114 of the first piston pump 111 shown in
For selecting a suitable switching point for switching from solvent B back to solvent A, it is useful to track pressure variations at the inlet of the pumping unit. For this purpose, a pressure transducer may be included in the flow path between the proportioning valve and the inlet valve of a pumping unit.
The inlet valve 808 of the pumping unit may be controlled by an inlet control 810, which is coupled with the system controller 806. The inlet control 810 is configured to open and shut the inlet valve 808 during the intake phase.
The pumping unit comprises a first piston pump 811 with a first piston 812, which is fluidically coupled, via an outlet valve 813, with a second piston pump 814, which comprises a second piston 815. The first piston 812 is driven by a first motor 816 with a first threaded bold 817, with a first spring 818 pressing the first piston 812 against the first threaded bolt 817. Similarly, the second piston 815 is driven by a second motor 819 and a second threaded bold 820, with a second spring 821 pressing the second piston 815 against the second threaded bolt 820. Both the first motor 816 and the second motor 819 are controlled by a pump drive control 822 and a position servo 823. The position servo 823 receives the actual position of the first motor 816 from the first encoder 824 and receives the actual position of the second motor 819 from the second encoder 825. The position servo 823 controls the operation of the first motor 816 and the second motor 819 in accordance with these feedback signals.
Optionally, the liquid supply system shown in
In the embodiment shown in
A third possibility is to determine optimum switching times for the proportioning valve 804 in advance for different solvents, different flow rates and different gradients, and to store the obtained optimum switching times in a table that is accessible to the system controller 806. For each situation, the system controller 806 may read an optimum switching point from the table and control the liquid supply system accordingly.
When two or more different liquids are consecutively drawn into the first piston pump, it may be desirable to further mix the different solvents, in order to obtain a homogenous composite solvent.
| Number | Date | Country | Kind |
|---|---|---|---|
| 1102219.1 | Feb 2011 | GB | national |
