Method, pump system and computer program product for generating a flow with a gradient composition

Abstract

A method for generating a flow having a gradient composition, the method comprising: Generating a plurality of pump strokes for a first pump in a system comprising at least a first pump and a second pump, each of the pump strokes for the first pump having a volume contribution based on a relative contribution of a first liquid to a gradient composition for a flow, the pump strokes of the first pump being generated at a pump stroke frequency; and Generating a plurality of pump strokes for the second pump, each of the pump strokes for the second pump having a volume contribution based on a relative contribution of a second fluid to the gradient composition for the flow, the pump strokes for the second pump being generated at the pump stroke frequency and blended over time with the pump strokes of the first pump, wherein an initiation of each of the pump strokes of the second pump is offset in time relative to an initiation of a corresponding pump stroke of the first pump such that variations in the flow rates of the first and second pumps based on the initiations of the pump strokes do not overlap over time.

Description

RELATED APPLICATIONThis application claims priority to U.S. Provisional Patent Application No. 61 / 936,385, filed February 6, 2014, and entitled "Method for High Pressure Gradient Chromatography Using Pump Stroke Control," which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTIONThe invention relates generally to the formation of high pressure gradients in liquid chromatography. More particularly, the invention relates to a method for forming high pressure gradients based on control of the pump strokes of the solvent pumps.BACKGROUNDIn high pressure gradient liquid chromatography, the contributions of two or more solvents to the mobile phase change over time. Generally, high pressure gradient pump systems in liquid chromatography use parallel pumps to deliver a plurality of liquids in defined proportions to achieve a specified final liquid composition. Typically, each pump in the system forms a combination of individual pump heads which are periodically replenished to maintain constant fluid flow. The refill process can cause disturbances or ripple (ripple) in the flow and pressure of the supplied liquid due to a variety of factors, such as solvent compressibility and hydraulic inertia. If the filling of one pump occurs during the pressure and flow disturbances resulting from the filling of another pump, it is possible that the solvent composition of the liquid being conveyed through the pump system does not exactly correspond to the desired solvent composition.US 4 883 409 A describes a pump system wherein the stroke volume moved by the piston is freely adjustable by controlling the angle through which the shaft of the drive motor is rotated during a stroke cycle.DE 11 2008 003 968 T5 describes a pump system having two periodically operating pump units and a control unit which tunes the respective phases of the two pump units to one another in a specific manner.The present invention provides an improved system and method over the strand of the art for increasing the accuracy of the solvent composition in high pressure gradient liquid chromatography.SUMMARYIn a first aspect, a method of generating a flow having a gradient composition includes generating a plurality of pump strokes for a first pump in a system including at least a first pump and a second pump. Each of the pump strokes for the first pump provides a volume contribution based on a relative contribution of a first liquid to a gradient composition to a flow. The pump strokes of the first pump are generated at a pump stroke frequency. A plurality of pump strokes are generated for the second pump. Each of the pump strokes for the second pump provides a volume contribution to the flow based on a relative contribution of a second liquid to the gradient composition. The pump strokes for the second pump are generated at the pump stroke frequency and are mixed over time with the pump strokes of the first pump. Initiation of each of the pump strokes of the second pump is offset in time relative to initiation of a corresponding pump stroke of the pump strokes of the first pump such that variations in the flow rates of the first and second pumps, based on the initiations of the pump strokes, do not overlap over time.In another aspect, a pump system includes a first pump, a second pump, and a processor in communication with the first and second pumps. The first pump is configured to promote volume contributions of a first liquid, each volume contribution occurring on a pump stroke of the first pump. The second pump is configured to promote volume contributions of a second liquid, each volume contribution occurring on a pump stroke of the second pump. The processor is configured to control the first and second pumps to have a same pump stroke frequency and the pump strokes of the first and second pumps mix over time (intermittent in time). The initiations of the pump strokes of the first and second pumps are offset in time such that variations in the flow rates of the first and second pumps, based on the initiations of the pump strokes, do not overlap over time. The processor changes the volume contributions of the first and second pumps over time after a predetermined gradient composition of a flow containing the first and second liquids.In yet another aspect, a computer program product for generating a flow having a gradient composition includes a computer readable storage medium. The computer readable storage medium includes computer readable program code. The computer readable program code includes computer readable program code configured to generate a plurality of pump strokes for a first pump in a system having at least the first pump and a second pump. Each of the pump strokes of the first pump makes a volume contribution to flow based on a relative contribution of a first liquid to gradient composition. The pump strokes of the first pump are generated at a pump stroke frequency. The computer readable program code further comprises computer readable program code configured to generate a plurality of pump strokes for the second pump. Each of the pump strokes of the second pump makes a volume contribution to the flow based on a relative contribution of a second liquid to the gradient composition. The pump strokes for the second pump are generated at the pump stroke frequency and mixed over time with the pump strokes of the first pump (intermittent). Initiation of each of the pump strokes of the second pump is offset in time relative to initiation of a corresponding one of the pump strokes of the first pump such that variations in the flow rates of the first and second pumps, based on the initiations of the pump strokes, do not overlap over time.BRIEF DESCRIPTION OF THE DRAWINGSThe foregoing and other advantages of this invention may be more readily understood in light of the following description taken in conjunction with the accompanying drawings, in which like reference numerals designate like elements and features throughout the several figures. For clarity, not every element is indicated in each figure. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention. Figure 1 is a block diagram of a liquid chromatography system including a binary solvent delivery system. FIG. 2 is a graph of the pressure pulses versus time associated with the pump strokes of the primary pump heads of two solvent pumps to generate a gradient of the mobile phases. FIG. 3 is a simplified graph showing how the pump strokes of one solvent pump change over time with respect to the pump strokes of another solvent pump in a binary solvent pump system with a resulting collision. FIG. 4 shows an embodiment in which each pump stroke of one pump is initiated at a time between successive initiations of pump strokes of another pump, such that the pump strokes of the two pumps mix over time without collisions. FIG. 5 is a simplified graphical representation according to an embodiment of a method in which the pump strokes of the two solvent pumps operate at the same pump stroke frequency and mix over time.DETAILED DESCRIPTIONReference in the specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is / is included in at least one embodiment of the invention. References to a particular embodiment in the specification do not necessarily refer to the same embodiment.During a binary gradient liquid chromatography process, the solvent contributions of the two solvent pumps change over time. The changes in solvent contributions are typically achieved by changing the pump stroke frequency (i.e., cycle time) of each solvent pump. Thus, it is possible for one of the pumps to initiate a pump stroke in one pump head at nearly or the same time as initiation of a pump stroke for one pump head in the other pump. Thus, a "collision" may occur during which the variation (i.e., "ripple") in the flow rate of one pump occurring at or shortly after initiation of the pump stroke overlaps the ripple in the flow rate of the other pump following stroke initiation. The collision may degrade the composition accuracy of the gradient of the mobile phase.Some pump systems include a control system that predicts a collision before it may occur. The control system responds to this possible collision by shortening the stroke of the pump head of one of the solvent pumps. This temporary modification of the pump strokes means that the subsequent initiation of a pump stroke occurs earlier than would occur if the nominal pump stroke were maintained. The process of shortening a pump stroke is repeated for possible future collisions to prevent their occurrence. The pump stroke can also be shortened under other conditions, such as high flow rates, high pressures and highly compressible solvents. Under such conditions, the opportunities to shorten the pump stroke to avoid collisions are substantially reduced and in some cases, sufficient opportunities to avoid collisions may not exist.In a brief overview, the invention relates to a method of generating a flow having a gradient composition. For example, the flow may be a gradient of the mobile phase used for liquid chromatography. In one embodiment, the pump strokes for a first pump and the pump strokes for a second pump occur at the same pump stroke frequency. Moreover, the initiations of the pump strokes of the second pump are mixed over time with the initiation of the pump strokes of the first pump. The initiations of the pump strokes of the two pumps are offset in time, so that deviations in the flow rates of the first and second pumps that occur at the initiation do not overlap over time. The pump stroke frequency may change over time as long as the initiations of the pump strokes of the second pump remain mixed with the initiations of the pump strokes of the first pump.The present invention will now be described in more detail with reference to embodiments thereof illustrated in the accompanying drawings. Although the present invention has been described in connection with various embodiments and examples, it is not intended to be limited to such embodiments. On the contrary, the present invention encompasses various alternatives, modifications, and equivalents as will be recognized by those skilled in the art. Those skilled in the art having access to this invention will recognize additional implementations, modifications, and embodiments, as well as other fields of use that are within the scope of the present invention as described herein.A block diagram of a liquid chromatography system 10 is shown in Figure 1 and includes a binary solvent delivery system 14 coupled to the inlet of a chromatographic column 18. The outlet of column 18 is coupled to a detector 22. An injection valve 26 introduces a sample containing one or more sample components into the mobile phase provided by the binary solvent delivery system 14. The sample components adsorb to the stationary phase in the column 18 to varying extents. Components with strong attractive force to the stationary phase move more slowly through the column 18 than components with weak attractive force. Thus, the components are separated according to the different travel speeds through the column 18 and elute at different times. The component with the lowest affinity for the stationary phase elutes first, while the component with the highest affinity for the stationary phase elutes last. Detector 22 analyzes the exiting stream by measuring a property related to the concentration and characteristic of the chemical composition. As an explicit example, the measured property may be a refractive index or the ultraviolet absorption.A processor module 30 controls the operation of the binary solvent delivery system 14, the sample injector 26, and the detector 22. A user interface 34, in communication with the processor module 30, allows a user to define various chromatographic measurement parameters and output and display operational and measurement data.In the illustrated binary solvent delivery system 14, a first pump 38 draws a first solvent A from a reservoir 42 and delivers the first solvent to a mixer 46 at a desired flow rate and pressure. a second pump 50 draws a second solvent B from a second reservoir 54 and delivers the second solvent to the mixer 46 at a desired flow rate and pressure. the solvents are mixed in the mixer 46 to produce a solvent mixture having the desired mobile phase properties. The flow rate of each solvent can be adjusted to vary the composition of the solvent mixture over time. Variation in solvent mixture over time is referred to as solvent gradient or gradient composition.During a gradient liquid chromatography process, the relative contributions of the two solvents A and B to the mobile phase change over time. Typically, the contribution of a solvent is defined by controlling the flow rate of the corresponding solvent pump. Each pump stroke provides a volume of solvent relative to the displacement volume of the pump head during the pump stroke. This "volume contribution" may differ from the displacement volume of the pump head due to the compressibility of the solvent. Higher flow rates are achieved by operating the solvent pump at a higher pump stroke frequency while maintaining a fixed stroke volume. As used herein, the term "pump cycle" means the time between initiations of two successive pump strokes.Solvent pumps may be configured in a variety of ways. For example, each solvent pump may be configured with two pump heads in a serial arrangement. Typically, one of the pump heads acts as a primary pump and the other pump head acts as an accumulator pump. In some configurations, the pump strokes of the primary pump and the accumulator pump operate in opposite phase. In an alternative configuration, the pump heads are configured in a parallel arrangement with each pump head operating in opposite phase to the other pump head. One pump head delivers solvent while the other pump head is filled with solvent.Regardless of the configuration of the pump heads, the flow rate of solvent delivered by a pump 38, 50 at the beginning of a pump stroke may vary due to a variety of factors including solvent compressibility and hydraulic inertia. To create a gradient of the mobile phase, the flow rates of the solvent pumps 38, 50 are varied over time. It is possible for one of the pumps 38 to initiate a stroke of one of its pump heads nearly simultaneously with the initiation of a stroke in one of the pump heads of the other pump 50. Consequently, the ripple in the flow rates of the two pumps 38, 50 may overlap and negatively affect the composition accuracy of the gradient of the mobile phase.FIG. 2 shows a graph of the pressure pulses associated with the pump strokes that transfer liquid from a primary pump head as a function of time for each of the two solvent pumps 38, 50. The pump stroke frequency of the solvent pump B 50 is seen to be lower than the pump stroke frequency of the solvent pump A 38. Line 66 represents the amount of solvent B present in the solvent mixture. A gradient imprecision in the form of a deviation from linearity is evident at time T' 1 and a second, smaller deviation is evident at time T' 2. Each change occurs at a corresponding time T' 1 or T' 2 as long as the initiations of the pump strokes of the two solvent pumps are nearly coincident.Figure 3 is a simplified graph over a shorter period of time showing how the pump strokes 58' of one solvent pump change over time with respect to the pump strokes 62' of the other solvent pump in a binary solvent pump system. During each pump stroke, small flow disturbances occur which for a short time may cause an over- or under-delivery of the volume contribution for the solvent concerned, resulting in a composition error. The pump strokes 58' of the solvent A are separated over time by a period ΔT A and the pump strokes 62' of the solvent B are separated over time by a period ΔT B. In order to increase the relative contribution of the solvent B relative to that of the solvent A, the pump stroke frequency of the pump B is increased and the pump stroke frequency of the pump A is decreased. The cycle time ΔT for each solvent pump is inversely proportional to the respective pump stroke frequency. Consequently, the cycle time ΔT B for solvent B decreases over time, while the cycle time ΔT A for solvent A increases over time. One or more "collisions" of pump strokes of the two solvent pumps may occur during a run of a gradient of the mobile phase, as shown at any time T C.According to one embodiment of a method for generating a flow having a gradient composition, such as a gradient of the mobile phase, each pump is operated at substantially the same pump stroke frequency. Each stroke of one pump 38 is initiated at a time between successive stroke initiations of the other pump 50 such that the pump strokes and associated pressure pulses 74 and 78 of the two pumps are mixed over time, as shown in FIG. 4. The pump strokes are controlled over time to achieve timely positioning of the pump strokes relative to each other while maintaining the proper gradient composition 78. Preferably, the pump strokes of one pump 50 are initiated approximately midway of the time that is between initiation of an immediately preceding pump stroke and initiation of an immediately following pump stroke of the other pump 38. Alternatively, initiation of one pump stroke of one pump may occur at any time over a range of appropriate times which is intermediate initiations of successive pump strokes of the other pump. More specifically, initiation of one pump stroke of one pump may occur at any time that is intermediate the initiation of successive pump strokes of the other pump and that avoids near simultaneous initiations where the flow rate disturbances of the two pump strokes would overlap over time.The initiations of the pump strokes of the two solvent pumps can be interpreted as two pulse trains (pulse trains) which are phase-shifted with respect to one another. Preferably, the phase difference corresponding to the time delay between the two pulse trains is about 180°, in order to keep the initiations of the pump strokes of one pump midway between the initiations of the pump strokes of the other pump, thus allowing deviations in the controlled parameters, such as pump stroke frequency and pump stroke volume. Other phase differences are possible as long as sufficient operating margins are maintained to ensure that the initiations of the pump strokes of the two pumps are not timely so that variations in the flow rates of the two pumps do not collide or overlap over time.FIG. 5 is a simplified graphical representation of the pump strokes of the two solvent pumps according to an embodiment of a method of the invention. Volume contributions during pump strokes 70' of solvent A decrease over time, whereas volume contributions during pump strokes 74' of solvent B are gradually increased. Unlike conventional techniques for generating a binary gradient of the mobile phase, as shown in Figure 2, the phase defined between initiations of the pump strokes of the two pumps remains substantially constant over the duration of the run of the gradient of the mobile phase. In an alternative embodiment, the pump stroke frequency of the two pumps may change during the course of the gradient; however, the relative phase between the pump strokes of the two pumps remains constant.Although the above description relates primarily to binary pump systems, the method according to the invention can be used in pump systems with three or more pumps. For example, a three pump system is operated so that all pumps operate at the same pump stroke frequency and each pulse train has a different phase. More specifically, the phases of the pump strokes for the two pumps with respect to the phase of the pump strokes of the third pump would preferably be 120° and 240°.For some gradients of mobile phase, there may be a time period where the volume contribution from one of the pumps is substantially less than the volume contribution from the other pump. For example, the contribution ratio of the solvents may be several percent or less. There is a minimum time for transfer from the pump heads and therefore it may be advantageous to operate the pump with the greater solvent contribution at a pump stroke frequency which is an integer multiple of the pump stroke frequency of the lower contribution solvent pump.According to another embodiment of a method for generating a flow having a gradient composition, one pump is operated at a pump stroke frequency that is an integer multiple of the pump stroke frequency of the other pump. For example, a "faster" pump contributing a substantially higher flow rate may be operated at twice the pump stroke frequency of a "slower" pump contributing a lower flow rate. Under these circumstances, two pump strokes of the faster pump occur between successive pump strokes of the slower pump. The timing of each pump stroke of the slower pump is controlled such that the pump stroke is initiated approximately midway between initiation of an immediately preceding pump stroke and initiation of an immediately following pump stroke of the faster pump. More generally, the ratio of pump stroke frequencies need not be a constant over the duration of the gradient run, as long as each pump stroke of the slower pump is initiated between the initiations of an immediately preceding pump stroke and an immediately following pump stroke of the faster pump.Although the invention has been illustrated and described with reference to specific embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the invention as set forth in the following claims.

Claims

A method of generating a flow having a gradient composition, the method comprising: generating a plurality of pump strokes for a first pump in a system comprising at least a first pump and a second pump, each of the pump strokes for the first pump having a volume contribution based on a relative contribution of a first liquid to a gradient composition for a flow, wherein the pump strokes of the first pump are generated at a pump stroke frequency; Generating a plurality of pump strokes for the second pump, each of the pump strokes for the second pump having a volume contribution based on a relative contribution of a second liquid to the gradient composition for the flow, wherein the pump strokes for the second pump are generated at the pump stroke frequency and are mixed over time with the pump strokes of the first pump, wherein initiation of each of the pump strokes of the second pump is time-shifted relative to initiation of a corresponding pump stroke of the first pump such that deviations in the flow rates of the first and second pumps based on the initiations of the pump strokes do not overlap over time.The method of claim 1, wherein each of the pump strokes of the second pump is initiated temporally midway between initiation of an immediately preceding pump stroke of the first pump and initiation of an immediately following pump stroke of the first pump.The method of claim 1 or 2, wherein for each of the pump strokes of the second pump, initiation of the pump stroke occurs after initiation of the pump stroke of the first pump by a constant time delay.The method of any of claims 1-3, wherein a phase difference between a sequence of consecutive pump strokes for the first pump and a sequence of consecutive pump strokes for the second pump is about 180°.The method of any of claims 1-4, wherein the first liquid and the second liquid are solvents, and wherein the flow is a gradient of a mobile phase containing the solvents.A pump system comprising: a first pump configured to deliver volume contributions of a first liquid, each of the volume contributions occurring during a pump stroke of the first pump; a second pump configured to deliver volume contributions of a second liquid, each of the volume contributions occurring during a pump stroke of the second pump; and a processor in communication with the first and second pumps, the processor configured to control the first and second pumps to have a same pump stroke frequency and the pump strokes of the first and second pumps mix over time, wherein the initiations of the pump strokes of the first and second pumps are time-shifted such that variations in the flow rates of the first and second pumps based on initiations of the pump strokes do not overlap over time, wherein the processor changes the volume contributions of the first and second pumps over time according to a predetermined gradient composition of a flow comprising the first and second liquids.The pump system of claim 6, wherein the first and second pumps are solvent pumps, and wherein the flow is a gradient of a mobile phase.The pump system of claim 7, further comprising a mixer comprising an inlet in communication with the first pump to receive the solvent from the first pump, and an inlet in communication with the second pump to receive the solvent from the second pump, and an outlet to provide the flow containing the first and second solvents.The pump system of any of claims 6-8, wherein both the first and second pumps are configured with two pump heads in a serial arrangement, and wherein one of the pump heads is a primary pump and the other pump head is an accumulator pump.The pump system of any of claims 6-9, wherein both the first and second pumps are configured with two pump heads in a parallel arrangement, and wherein the pump strokes of one of the pump heads are configured to operate in opposite phase to the pump strokes of the other pump head.The pump system of any of claims 6-10, wherein the processor is configured to change the pump stroke frequency of the first and second pumps.The pump system of any of claims 6-11, wherein the processor is configured to control the first and second pumps such that each initiation of the pump strokes of the second pump occurs approximately midway between each initiation of an immediately preceding pump stroke of the first pump and each initiation of an immediately following pump stroke of the first pump.The pump system of any of claims 6-12, wherein the processor is configured to control the first and second pumps such that for each of the pump strokes of the second pump, initiation of the pump stroke occurs after initiation of the pump stroke of the first pump with a constant time delay.The pump system of any of claims 6-13, wherein the processor is configured to control the first and second pumps such that a phase difference between a sequence of consecutive pump strokes of the first pump and a sequence of consecutive pump strokes of the second pump is about 180°.A computer program product for generating a flow having a gradient composition, comprising: a computer readable storage medium having computer readable program code embodied therein, the computer readable program code comprising: computer readable program code configured to generate a plurality of pump strokes for a first pump in a system comprising at least a first pump and a second pump, each of the pump strokes of the first pump comprising a volume contribution based on a relative contribution of a first liquid to a gradient composition for a flow, wherein the pump strokes of the first pump are generated at a pump stroke frequency; A computer readable program code configured to generate a plurality of pump strokes for the second pump, each of the pump strokes of the second pump comprising a volume contribution based on a relative contribution of a second liquid to a gradient composition to the flow, the pump strokes of the second pump being generated at the pump stroke frequency and mixed over time with the pump strokes of the first pump, wherein initiation of each pump stroke of the second pump is staggered over time relative to initiation of one of the pump strokes of the first pump such that variations in the flow rates of the first and second pumps based on the initiations of the pump strokes do not overlap over time.

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