WO2015123309A1

WO2015123309A1 - Apparatus and methods for controlling pressure limits and flow rates in a chromatographic system

Info

Publication number: WO2015123309A1
Application number: PCT/US2015/015435
Authority: WO
Inventors: Raaidah Saari-Nordhaus; James Anderson; Washington Mendoza; Romulus Gaita; Melissa GOLDE
Original assignee: Alltech Associates, Inc.
Priority date: 2014-02-11
Filing date: 2015-02-11
Publication date: 2015-08-20

Abstract

A chromatographic system and an associated method include a chromatographic column, a pump in fluid communication with the chromatographic column, and a pressure sensor configured to determine actual pressure of a solvent stream before it passes through the column. The system and method employ a controller adapted to operate based on a predetermined correspondence between flow rate and a system maximum allowable pressure setting. The controller is programmed to set the maximum allowable pressure setting based on a predetermined flow rate, the predetermined flow rate corresponding to a pump speed; receive actual pressure readings of the solvent stream from the pressure sensor; compare the actual pressure readings to the maximum allowable pressure setting; decrease the pump speed if the actual pressure is within a preset proximity to the maximum allowable pressure setting; and reset the maximum allowable pressure setting based on the flow rate that corresponds to the decreased pump speed.

Description

APPARATUS AND METHODS FOR CONTROLLING PRESSURE LIMITS AND FLOW RATES IN A CHROMATOGRAPHIC: SYSTEM

BACKGROUND

[0001] Liquid chromatography systems are used to separate and analyze components of a sample mixture. These systems use pumps to flow solvent and the sample through a column filled with a sorbent that separates components of the sample. Typically, a liquid sample in a solvent stream passes over -a solid adsorbent material in a column. Different components of the sample interact differently with the adsorbent material. If a component has a weak interaction with the adsorbent material, it flows through the column relatively quickly, if the component has a strong interaction, if flows through the column relatively slowly. Accordingly, different ^•components flow through the column at varying speeds, separating from, one another so that they may be analyzed and -collected.

f 0002] The pumps that move the solvent stream, through the system generate pressure in the system, which is generally a function of the flow rate. In known liquid chromatography systems, the maximum allowable pressure setting is fixed regardless of the chosen How rate for the solvent.

SUMMARY

[0003] The apparatus and methods described herein increase efficiency of liquid chromatography systems- by adjusting maximum allowable pressure setting and flow rates. The following presents a simplified summary in order to provide a basic understanding of some- aspects of the claimed subject matter. This -summary is not an. extensive overview, f t is not intended to identify key/critical elements or 10 delineate the scope of the claimed subject matter, its sole purpose is to present some concepts in a simplified form as a prelude to the more detailed description that is presented later.

[0004] A. chromatographic system and associated chromatography method include a chromatographic column in fluid communication with a solvent stream; a pump in fluid^' communication with the chromatographic column and; the solvent stream the pum located upstream- of the column and configured to pump at least one solvent; and a pressure sensor located, downstream of the pump and upstream of the chromatographic column and configured to determine actual pressure- of the fluid flow. The system and method employ a controller adapted to operate based on. a predetermined correspondence between flow rate of the solven t stream and the system maximum .allowable pressure setting. The controller is programmed to set the maximum^' allowable pressure, setting based on a predetermined .flow rate, the predetermined flow rate corresponding to a pump speed; receive actual pressure readings of the sol vent stream from the pressure se sor: co are the actual pressure readings to the maximum allowable pressure setting; decrease the. ump -speed if the. actual pressure is within a preset proximity to the- maximum allowable pressure setting; and reset the maximum allowable pressure setting based on the flo rate that corresponds to the decreased pump speed,

[©005] Alternatively, the chromatograp ic system arid associated chromatography method include a chromatographic column in fluid communication with .a solvent stream; a pump in fluid communication with the chromatographic column .and the solvent stream the pump located upstream of the column and configured to pump at least one solvent; and a pressure sensor located downstream of the pump and upstream of the chromatographic, column and configured to. determine actual pressure of the solvent stream. The system and method employ a controller adapted to operate based on a predetermined correspondence between flow rate -of the solvent stream and the system maximum .allowable pressure setting. The controller is programmed to set the maximum allowable pressure setting. ased on a predetermined flow rate,_, the predetermined flow rate corresponding to -a pump speed; receive actual pressure readings of the solvent stream from the pressure sensor; and compare the actual pressure readings to the maximum allowable pressure setting, if the actual pressure is within a preset proximity to the maximum allowable pressure: setting, the controller decreases the pump speed and resets the maximum allowable pressure setting based on the- new flow rate corresponding to the decreased pump speed.. If the actual pressure is less than the preset proximity to the maximum allowable pressure setting, the controller increases the pump speed and resets the maximum allowable pressure setting based on the new flow rate that corresponds to the increased pump speed.

[0006] Alternatively, the chromatographic system and associated^' chromatograph method may employ a controller adapted such that if the actual pressure is within a preset proximity to the maximum allowable pressure setting, the controller decreases the: pump speed and resets the maximum allowable pressure setting based on. the. flow rate that corresponds. to the decreased pump speed. If the actual pressure is less than the preset proximity to the maximum allowable pressure settin and the flow rate is less than the predetermined flow rate, the conti'Oller increases the pump speed and resets the maximum allowable pressure setting based on the flow rate that corresponds to the increased pump speed. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] The following description may be understood when read in conjunction with the appended drawings. For purposes of illustrating; the systems and methods for controlling pressure limits and flow rate in a chromatographic system, there is shown in the drawings exemplary constructions of this system an method; however, the system and method is not limited to the specific methods and insirumentahties disclosed,; In the drawings:

[0008] Fig, 1 i$ a schematic of an exemplary ^'.■embodiment of a liquid chromatography system having a single solvent pump and including a control system;

10009] Fig. 2 is an exemplary correspondence- curve of maximum allowable pressure setting to solvent flow rate that may be used by the control system in Fig. I ;

[0010] Fig. 3 is a schematic of an exemplary embodiment of a liquid chromatography system having multiple solvent pumps and including a control system; and

[0011] Fig, 4. is an exemplary correspondence curve of maximum ^'allowable, pressure, setting to solvent flow rate that may be used by the control system in Fig. 1.

[0012] Fig. 5 i a block diagram of one: embodiment of a computer system in whic aspects of the disclosed systems and methods ma be embodied

[0013] Fig. 6 is an exemplary user interface that may be. part of the control system in

Fig. ! :

[0014] Fig. 7 is an exemplary process that may be employed by the control system in

Fig. 1 ;

[0015] Fig. 8 is an exemplary process that may be employed by the control system in Fig. 1 ; and

[0016] Fig, 9 is. an exemplary process that may be employed by the control system in

Fig. 1.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[6017} The various aspects of th subject matter described herein are now described with reference to the drawings, ^"it should be understood, however, .that the drawings and detailed description relating thereto are not intended to limit the claimed subject matter to the particular form disclosed. Rather, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and. scope of the claimed subject matter.

[00.18] The following description relates to a liquid chromatography system 10 such as that shown in Fig. 1. The system 10 includes a chromatographic column 12 which is used to separate components of a sample S. The system 10 further includes a pump 14 located upstream of the column thai is configured to pum a solvent from a solvent holding tank I 6 to form solvent stream 18, Stream 1 8 is m fluid communication- with the- chromatographic- column 12. A first pressure sensor 20, located downstream of the pump 14 and upstream of the

chromatographic column 12, is configured to determine actual pressure of the stream .18 in ^■conjunction with a controller 30. Sample is injected into stream 1 8 upstream of chromatography column 1.2. Any means of solid or liquid loading known in the art may be used. As one example, injectio of the sample may be through, a valve, such, as valve 22, into the solvent stream .18.

[00. ] With reference to Fig. 2, controller 30 is configured to regulate the speed of pump 14, as well as the system maximum allowable pressure setting, based on pressure readings from ^'first pressure- sensor- .0, For liquid chromatography systems such as system 10,. the maximum allowable pressure setting inversely correlates to system flow rate. The maximum allowable pressure setting may be set at 80% of the pump stall pressure. Pump stall pressure is a function of a pump's flow rate. Controller 30 may be preprogrammed with series of

correspondence curves for various systems and configurations. An example of such a curve is shown in Fig, 2. Alternati vely, controller 30 ma be -preprogrammed with a lookup table that captures the correspondence between maximum allowable pressure setting and sol vent flow rate. Additionally, instead ^'of being preprogrammed, controller 30 may receive information related, to the correspondence of maximum allowable pressure- setting and solvent flow rate via sourees external to the system 10 using a network interface.

[0020] While Fig. 2 shows an exemplary correlation curve for a single pump, controller 30 may employ correlation curves that depend on_. the number of pumps J.4 being used for a chromatographic run. when a system 10 has multiple solvent pumps. Because the syste maximum allowable pressure corresponds- to the pump stall pressure, when more than -one pump is employed, the maximum allowable pressure setting does not decrease as significantly as flow rate increases compared to a single pump system,

[002! J With reference to Fig. .3, a liquid chromatography system 10 includes all of the elements shown in Fig. 1 , but also has a second pump 14 configured to pump solvent. rom a second solvent. holding tank 16. Both pumps 14 are configured to pump- solvent into the solvent stream at a preset percentage of the total solvent in the solvent stream 18. For any given chromatographic run, any one pump 14 may pump _.between 0 and 100% of the total solvent in the solvent stream 18. This percentage may remain constant during the run (isocratic elution). or may change (gradient elution). [06.22] With reference to Fig. 4, depending on the percentage of total sol vent thai, is pumped through each pump 14, the maximum allowable pressure setting may remain relatively stable, even as flow rate increases. In other words,, when two or more pumps are used, the maximum, allowable pressure setting for the system, is higher than that, of a one pump system even though the total flow rate is the same. For example, if two pumps each pump 50% of the solvent into the solvent stream 18, the maximum allowable pressure, setting decreases -only slightly in comparison to a single pump 16 pumping 100 percent of the solvent. As one of the pumps decreases from 50% and the other pump increases from 50%, the correlation curve will be between the 50/50 curve and the 1.00/0 and 0/100 curves. As described in relation to the correspondence curve in Fig, 2, controller 30 may be preprogrammed with a .lookup table that captures the correspondence between maximum allowable pressure setting and solvent flow rate. Additionally, instead of being preprogrammed, controller 30 may recei ve information related to the correspondence of maximum allowable pressure setting and solvent flow rate via sources external to the system 10 using a network interface,

[0023] While Fig. 3 shows two pumps 14 and two solvent, holding tanks 16, more than two pumps 14 and solvent holding tanks 1 6 may be employed. For example, four pumps 14 and solvent holding tanks 1.6 may be used. The inventors surmise that if four pumps 14 are

..employed, each pump 14 pumping 25% of the total solvent, the correspondence curve would decrease, even less, when compared to a tw pump. 50/50. configuration. Additionally,, each solvent holding tank 1.6^' may contain sol vents thai are different or the same as sol vents in other holding tanks 1 6.

[0024} ^'System flow rate is typically preselected based on the type of column being used and the type of sample being: processed. The preselected flow rate is. inversely related to the. maximum allowable pressure setting, and vice versa. After an initial flow rate is selected of determined, controller 30 determines the system, maximum pressure. As described in Examples I , 2, and 3, both the flow rate and the maximum allowable pressure setting may be changed during the course of a run.

[0025 j By monitoring actual pressure of stream 18 and -adjusting pump speed and the maximum allowable pressure setting, controller 30 is configured to minimize instances of system

-stalling that have occurred in prior systems when actual system pressure approaches or exceeds maximum allowable-pressure setting. Additionally, controller 30 may be configured to maximize system flow rate. Specifically, controller 30 uses the correspondence between maximum allowable pressure setting and solvent flow rate to increase the pump speed when the monitored actual pressure is below the predetermined proximity to the then -set maximum allowable pressure setting. Because the maximum allowable pressure setting inversely corresponds -to solvent flow rate, as solvent flow rate increases, maximum allowable pressure- setting decreases in order to. prevent system stalling,

|0026] Sample S may be introduced into a solvent stream IS at injection port 22, Different types of injection ports provide for different types of sample loading into a column. For example, injection port 22 may be part of a valve that provides fbr direct injection, solid loading, or both direct injection and solid loading into the column 12. Sample S and solvent from holding tank 16 pass over solid adsorbent materia] packed into column 12. Because different components, or fractions, of the samp le interact differently with the adsorbent material fractions of the sample separate from one another. Fractions with weak interactions flow through the column 12 relatively quickly while fractions with strong interactions flow through the column relatively slowly. As these fractions pass from the column 12. they can be separatel analyzed and collected. Specifically, the fractions with weak interactions leave the column first and are identified by detector 36 and then collected by fraction collector 38. Collector 38 may be omitted if the sysiem 10 is intended, o ly for analysis and not collection.

[0027] Detector 36 may be a. non-destructive -detector such an ultraviolet light detector, an optical absorbance detector, a refractive index detector (RID),. a fluorescence detector ( C), a chirai. detector (CD), or a conducti vity detector. Other types of detectors, including: destructive detectors, may be used instead of or in addition to a non-destructive detector. If a destructive detector is used. For example, an evaporative light scattering detector,, a mass spectrometer (MS), a condensation nueleation light scattering detector (CNLSD), and a corona discharge detector. Multiple non-destructive and/of destructive detectors may be used in system 10. When a non-destructive detector is used, whether with or without a non-destructive detector, portion of the column eluent is di verted to the destructive detector while the main flow of the eluent proceeds toward the collector. An example of such a system having both a destructive and nondestructive detector is shown in U.S. Patent 8,314,934, Destructive detectors may be_. used in conjunction with a -shuttle valve such that only a portion of the sample is removed from the sample stream and destroyed.

[0028] System 10 may further include -a second pressure sensor 34, located upstream or downstream of the column 12. For example, second pressure sensor 34 may be located downstream of the column 12 and upstream, of the detector 36 and the fraction collector 38.

Specifically, second pressure sensor 34 may be connected to controller 30 and located proximate the detector 36. Generally, detectors have a lower pressure rating than the maximum allowable pressure setting rating, if the second pressure sensor 34 indicates that the actual pressure proximate the detector 36 Is approaching the pressure rating of the detector, the controller 30 may decrease the speed of pump 14 o stop the pump 14 entirely in order to prevent damage to detector 36.

{0029} Second pressure sensor 34 may also he used to detect a blockage and/or leakage in the system in connection with preprogramming of the controller. For example, if second pressure sensor 34 indicates higher than normal pressure, while the first pressure sensor 20 indicates normal pressure, the controller 30 can he programmed to indicate that a blockage may ..exist in the detector 36 or fraction collector 38. Alternatively* if second pressure sensor 34 indicates normal pressure, while first pressure sensor 20 Indicates high pressure, the controller can be programmed to Indicate a possible blockage in column 12. A lower than normal pressure proximate the first pressure sensor 20 may indicate a leakage in the injection port 22 or column 12. Similarly, a lower than normal pressure -at second pressure sensor 34 may indicate a leakage in the detector 36 o fraction .collector 38.

^'(0030] With reference to Fig. 5, controller 30 includes a computer subsystem 620 that comprises a computer 641, which ma includ a variety of computer readable media. Computer readable media may be available media that ma be accessed by computer 641 and may Include volatile and/or nonvolatile media, removable and/or non-removable media. The system memory 622 may include computer storage media in the form of volatile and/or nonvolatile memory such ^•as read only memory (ROM) 623 and random, access memory (RAM) 660. A basic input/output system 624 (BIOS), containing the basic routines that help to transfer information between ^•elements within computer 641 , such as during start-up, may be stored in ROM 623. RAM 660 may contain data, and/or program modules that are immediately accessible to and/or presently- being operated on by processing unit 659- By way of exam ple, and not limitation, Fig. 5:

illustrates operating, system 625, application programs 626, other program modules 627, and program data 628, As. a further example, video content (e.g. video frames)_: and/or metadata (e.g. closed caption data), in one embodiment, may be stored in the system memory 622, as well as i any of a variety of non-volatile memory media discussed herein.

[0031] The computer 641 may also include other removable/non-removable, volatile/nonvolatile computer storage media. By way of example, the computer 641 may include a hard disk drive 670 that reads from or writes to non -removable, nonvolatile magnetic media, a magnetic disk drive 639 that reads from, or writes to a removable, nonvolatile magnetic disk 654, and an opiicai disk drive 640 that reads from or writes to a. removable, nonvolatile optical disk

653 such as a CD RO or other optical media. Other rernovable/non-reraovab!e,

volatile/nonvolatile computer storage media thai can be used in the exemplary .-operating_. environment include, but are not limited to, magnetic tape cassettes, solid-state drives, flash memory cards, digital versatile disks, digital video tape, solid state RAM, solid state ROM, and the like. Magnetic disk drive 639 and optical disk drive 640 may be connected to the system bus 621 fay a removable memory interface, such as interface 635, The drives and their associated computer storage media discussed herein, and illustrated in Fig. 5, may provide .storag of computer readable instructions, data structures, program modules and other data for the computer 641.

|0©32] A user may enter commands and information into, the computer 641 through, input devices such as a keyboard 651. and/or pointing device 652. commonly referred, to as a mouse, trackball, or touch pad. Other input devices (not shown) may include a microphone, joystick, game pad, satellite dish, scanner, or the like. These and other input devices may be connected to the processing unit 659 through a user input interface 636 that is- coupled to the system bus, but may be connected by other interface and/or bus structures, such as a parallel port, game port, or a universal serial ^'bus (USB) for example, The computer may connect to a local area network or wide area network, such as LAN 720 and/or WAN 730, through a network interface or adapter 637. A monitor 642 connects to th computer subsystem 620 and may e used to display a graphical user interface 32, such as the graphical user interface 32 shown in Fig. 6.

[0 33| As is apparent from the embodiments described herein, ail or portions of the various- systems, methods, and aspects of the present invention ma be embodied in hardware, software, or a combination of both. When, embodied in software, the methods and apparatus. of the present Invention, or certain aspects or portions thereof may be embodied in the form of program code (i.e., computer executable instructions). This program code may be stored on a computer-readable storage medium, such as a magnetic, electrical, or optical storage medium, including without limitation a floppy diskette, CD-ROM, CD-RW,_. DVD-ROM, DVD-RAM, magnetic tape, flash memory, solid-state drive, hard disk drive, or any other machine-readable storage medium, wherein, when the program code is loaded into and executed by a machine, such as a computer or server, the machine becomes an apparatus for practicing the invention. A computer on which the program code executes may include a processor, a storage medium readable by the processor (including volatile and/or non- volatile memory and/or storage elements), at least one input device, and/or at least one output device. The program code may be implemented in a high level procedural or object oriented programming language. Alternatively, the program code may be implemented in an assembl or machine language. In- ny case, the language ma be a compiled or interpreted language. When implemented on a general-purpose processor, the program code may combine with the processor to provide a unique apparatus that, operates analogously to specific logic circuits. As used herein, the terms "computer-readable medium" and "computer-readable storage medium" refer to physical, non-transitory storage media and do not encompass transitory media, such as signals.

[0034] Fig, 5 is a block diagram of an example computer subsystem 620 on which the embodiments described herein and/or -various components thereof, such as the server 160 may fee .implemented, For example, the functions performed by the entities described in the various embodiments above may be performed by one or more such example computer systems. For example, the -system described herein may be implemented in software (Le„ computer executable instructions or program code) executing on one or more such computer subsystems 620. It i-s understood, however, that the computer subsystem 620 is just one example of a suitable computing environment and is not Intended to suggest any limitation as to the scope of use or functionality of the presently disclosed subject matter. Neither should the computer subsystem 620 be interpreted as hav ing any dependency or requirement relating to any one or combination of components illustrated in Fig. 5. In some embodiments, the various depicted computing elements m y include modules or components configured to · instantiate · specific aspects of the present disclosure.

{0035} For example, the components used in this description may include specialized hardware components configured to perform f nction(s) by firmware.- or switches. In other example embodiments, components may include a general purpose processor, memory, etc., configured by -software instructions that embody logic operable to perform function(s). In example embodiments where modules or components include a. combination of hardware and software, an impiementer may write source code embodying logic and the source code may be compiled into machine readable code that can be processed by. the general purpose processor. Since the state of the art has evolved to a point where there is little difference between hardware, .software, or .a combination of hardware/software, the -selection of hardware versus software to effectuate specific functions is a design choice left to an impiementer. More specifically, a software process may be transformed into an equivalent hardware structure, and a.hardware structure may itself be -transformed foto an equivalent software process. Thus, the selection of a hardware implementation versus a software implementation is one -of design choice and left to the impiementer. Example 1

[ΘΘ36] According. to the apparatus and methods described herein, the system .10 is configured to begin processing based on a predetermined initial flow rate. Fo example, according to the method shown in Fig 7, a user enters a predetermined flow rate, Fj into user interface 32. Based on. Fj and a predetermined system pressure/flow rate correspondence (such as the curves shown in Figs, 2 and 4), the controller 30 caiculates an initial maximum pressure setting, P AX-J - The controller 30 sends a signal to pump 14 to operate at an initial speed, Vt, which corresponds to Fj . As pump 14 pumps solvent into the solvent stream 1 8, first pressure sensor 20 senses the actual pressure, FACT, downstream of pump 1 4 and upstream of column 12. Controller 30 then -compares- PMAX-I to PACT- Controller 30 is configured to determine if PACT is within a preset proximity to PMAX-I■ Controller 30 may determine if PACT is within the preset proximity to P A -S by determining if PACT is- within a predetermined pressure range to PMAX-I- For example, controller 30 may be configured to determine if P_ACT is equal to or greater than PMAX-I - Alternatively, controller 30 may determine if PACT is within 5- psi Of PMAX-I or if PACT is wi thin 95% of PMAX-I .

[0037] If PACT is .at or near PM -I, controller 30 decreases pump speed V^'i to Y₂. For example, controller 30^' may decrease pump speed by 1%, or by between. 1 % and 5%. Decreasing pump speed to Ys has two effects. First, the flow f te decreases from Fj to ^'F₂,. which decreases P_ACT such that CT does not -exceed Ρ.ΜΛΧ-Ϊ, which would cause the system to stall Second, because F₂ is less than F_{! S} controller 30 increases the maximum pressure setting to P_.MAX-2 according to the predetermined maximum allowable pressure setting/solvent flow rate correspondence. Regardless of whether the maximum pressure setting and pump speed are adjusted according to the methods described above, controller 30 continues to monitor PAC of the solvent stream 18 to minimize instances of system stalling by slowing the pum speed when PACT is within a preset proximity to PMA -! ·

Example 2

[0038] In addition to minimizing instances of system stalling, control lor 30 may further be configured to maximize solvent flow rate. With reference to Fig. 8, and as described above in relation to Example 1 , a user enters a. predeterm ned flow rate, Fj enters a predetermined flow rate, f 1 into user interface 32. Based on F₅ and a predetermined system pressure setting/flow rate correspondence (such as the curves shown in Figs. 2 and 4), the controller 30 calculates an initial maximum pressure setting, MA -I - The controller 30 send a signal to pump 14 to operate at an initial speed, V₍ that corresponds to F_T, As- pump 14 pumps solvent into the solvent -stream 18, first pressure sensor 20 senses the actual pressure.; P_AC , downstream of pump 14 and upstream of column 12. Controller 30 then com pares P_MAX-I to P_ACT- Similar to the method described in relation to Example J, if P_ACT is above, at, or near P A -I, controller 30 decreases pump speed V* to Vj. Decreasing, pump speed to V₂ .has two effects. First, the flow rate decreases from Fi to F_¾ whic decreases PACT such that PACT does not exceed ^AX which would. cause the system^' to stall. Second, because F₂ is less than F_l5 controller- 30 increases the maximum pressure setting to PMA -₂ according to the predetermined maximum allowable pressure setting/solvent flow rate correspondence.

[0039] The method described in relation to Fig. 8 has the added functionality of being able to increase pump speed when PACT is less than PMAX-I- Controlle -30 may determine if PACT is less than to PMAX-I by determining if P_AC_T is any value less than PM_AX-I Alternatively, .controller 30 may determine if P_ACT is outside a predetermined pressure range to PMAX-_I- For example, controller 30 may determine if P_AC_T ^'is less than.5 psi less than PM_AX-I < Controller 30 ^•may alternatively be configured to determine if PACT is less than a certain percentage of P A_X-!- For example, controller 30 may be configured to determine if P_ACT is less than 95% of P _AX-_W

[0040] If PACT is less than P _A -_I, controller 30 increases the pump speed from Vj to Y₂. For example, controller 30 may increase pump speed by 1%, or by between 1 % and 5%. Increasing pum speed to V₂ has two effects. First, the flow rate increases from F_¾ to F₂, which increases PA_CT- Second, because PV is greater than F controikr 30 decreases the maximum allowable pressure setting to P _AX-2 accordin ^'to the predetermined maximum allowable pressure setting/solvent flow rate correspondence. Increasing, the flow rate provide for higher throughput of the system 10.

[0041] Regardless of whether the maximum pressure setting and pump speed are adjusted according to the methods described above, controller 30 continues to monitor P_AC of the solvent stream 1.8 to minimize instances of system stalling by slowing the pump speed when P_ACT is within a preset proximity to PM_AX-J and/or to increase solvent flow rate.

Example 3

[0042 j Similar to Example 2, controller 30. may be configured to minimize instances of system stalling and maximize sol vent flow rate, while limiting pum .14 from, producing a solvent flow rate that is greater than the initial flow rate F^'r, This type of flow rate ceiling may be beneficial since some columns are not able to handle high flow rates. Specifically, for certain columns, the best resolution may be achieved at relatively low flow rates, even though the system could handle higher flow rates without stalling. [Θ 3 j With, reference to Fig. 9. and as described above, a user enters a predetermined flow rate, F_? enters a predetermined flow rate, F_t into user interface 32, Based on F_\ and a predetermined system pressure setting/flo rate COfrespondence (such as the curves shown in Pigs. 2 and 4). the controller 30 calculates an initial maximum pressure setting, P AX-;■ The controller 30 sends a signal to pump 14 to operate at an initial speed, V.s that -corresponds to Fj. As pump 14 pumps solvent into the solvent stream 1 8, first pressure sensor 20 senses the actual pressure, PACT, downstream, of pump 14 and upstream of colum 12, Controller 30 then compares PMAX-I to PACT- Similar to the method described, in relation Examples 1 and 2, if PACT is above, at, or near PMA -I* controller 30 decreases pump speed V i to Vz- Decreasing pump speed to Y₂ has two effects. First, the flow rate decreases from Fj which decreases PACT such thai PACT does not exceed P- AX which would cause the system to stall. Second, because F? is jess than Fj, controller 30 increases the -maximum pressure setting to PMA -2 ^'according to the predetermined maximum allowable pressure setting/solvent flow rate correspondence.

[0044] Similar to Example 2, the method described in relation to Fig- 9 increases the pump speed when P_ACT is less than to PMAX-I- However, in Example . 3, V'i is only increased when the flow rate i less than F(. Accordingly, controller 30 determines (1) if PACT less than PMAX-I ; and (2) ^'if me flow rate is less than Fi. If both of these conditions are present, controller 30 increases V$- to V¾. Based on the increased flow rate, and in accordance with the

predetermined maximum allowable pressure setting/solvent flow rate correspondence, controller 30 also decreases P AX-S to Ρ ΛΧ-2·

j0045| Similar to Examples I and 2, regardless of whether the maximum pressure setting and pump speed are adjusted according to the. methods described above, controller 30 continues to monitor P_Aer of the solvent stream 1 $ to minimize instances of system stalling by slowing the pump speed -when P_ACT: IS within a preset proximity to PMAX-I and/or to increase solvent flow rate, while ensuring that the solvent flow rate is less than or equal to F_}.

[0Q46J As the foregoing illustrates, the present invention is directed to an apparatus and methods for to controlling pressure limits and flow rates in a chromatographic system. Changes may be made to the embodiments described above without departing from the broad inventive concepts thereof. For example, as alternative to the processes described in Examples 1 -3, a predetermined maximum pressure setting, PMAX-I, may be used to calculate an initial flow rate Fj based on a predetermined^' sy stem pressure setting/flow rate correspondence, (such, as the curves shown, in. Figs, 2 and 4). Accordingly, the present invention is not limited to the particular embodiments disclosed, but is intended to cover all modifications that are within the spirit and scope of the invention as defined by the appended claims.

Claims

CLAIMS What is Claimed:

1 . A chromatographic system comprising:.

a chromatographic .column in fluid communication with a solvent stream;

a pump in fluid .-communication, with the chromatographic column and the solvent stream., the pump located upstream of the column and configured to pum -at feast one solvent;

a pressure sensor located downstream of the pump, and upstream of the chromatographic, column and configured to determine actual pressure of the sol vent stream; and

a controller adapted to operate based on a predetermined correspondence betw een flow rate of the at least one solvent and a. system maximum allowable pressure setting, the controller being programmed to:

set the .maximum allowable pressure setting based on a predetermined flow rate, the predetermined flow rate corresponding to a pump speed;

receive actual pressure readings of the solvent stream from the. pressure sensor; compare the actual pressure readings to the maximum allowable pressure setting; decrease the pump speed if the actual pressure is -^'within a preset proximit to the maximum allowable pressure setting; and

reset the maximum allowable pressure setting based on the flow rate that corresponds to the decreased pump speed.

2, The chromatographic system of claim t, wherein the controller is further adapted to repeat at least the. controller steps of receiving and comparing based on the previousl -set maximum allowable pressure setting.

3. The chromatographic system of claim I, wherein the controller is adapted to decrease the pump speed if the- ratio of the actual pressure reading to the maximum allowable pressure setting is within a preset range.

4, The chromatographic system of claim 1 , wherein the predetermined flow rate is a user- selected .flow rate.

5. The chromatographic system of claim 1 ,. wherein the pressure sensor is a first pressure sensor and the system further comprises a second pressure sensor disposed downstream from the first pressure sensor,

6. The chromatographic system of claim 1, wherein the pump is a first pump, the system further comprises at least one additional pump, and the predetermined correspondence between flow rate of the at least on solvent and the system maximum allowable pressure setting is based on a ratio .of solvent pumped by the first pump and the at least one additional pump.

7. The .chromatographic system of claim 1, wherein the^■predetermined flow rate is a user- selected flow rate -and wherein the controller is adapted to repeat at least the controller steps of receiving and comparing based on the previously set maximum allowable pressure .setting.

8. A method of controlling solvent flow in a chromatographic system comprising a chromatographic column, in. fluid -communication with a solvent stream, a pump in fluid .communication with the chromatographic column and the solvent stream, the pump located upstream of the column and configured to pump at least one solvent a pressure sensor located ^'downstream ©f the pump and upstream of the chromatographic column and configured to determine actual pressure of the solvent stream, and a controller adapted to operate based on predetermined correspondence between flow rate of the at least one solvent, and a system maximum allowable pressure setting, the method comprising:

setting the maximum allowable pressure setting based on a predetermined flow rate, the predetermined flow rate corresponding to a pump speed;

receiving actual pressure readings of the solvent stream from the pressure sensor: comparing the actual pressure readings to the maximum allowable pressure setting;

decreasing the pump speed if the actual pressure is within a preset proximity to the maximum allowable pressure setting; and

resetting the maximum allowable pressure setting based on the flow rate that corresponds to the decreased pump speed,.

9. The method of claim 8, further comprising a step of repeating at least the steps of receiving and. comparing based on the previously set maximu allowable pressure setting.

.

10. The method of claim 8, wherein the decreasing step includes decreasing the pump speed if the ratio of the actual pressure reading to the maximum allowable pressure setting is within a preset range,

1 1 , The method of claim 8, wherein the predetermined flow rate is a user-selected flow rate.

12. The .method of claim. 8, wherein the pressure sensor is a first pressure sensor and the system further comprises a second pressure sensor disposed downstream, from the first pressure sensor.

1:3. The method of claim 8, wherein the pump is a first pump, the system further comprises at least one additional pump, and the predetermined correspondence between fl ow rate of the a t least one solven and the system maximum allowable pressure setting is based on a ratio of solvent pumped by the first pump and the at least one additional pump.

1.4. The. method of claim 8, wherein the predetermined flow rate. is a user-selected flow rate and the method further comprises repeating at least the controller steps of receiving and comparing based on the previously set maximum allowable pressure setting.

15. A chromatographic system comprising:

a chromatographic column in fluid communication with a solvent stream;

a pump in fluid communication with the chromatographic column and the solvent stream, the pump located upstream of the column ;

a pressure sensor located downstream of the pump and upstream of the chromatographic cokurm_: and configured to determine actual, pressure of the solvent stream; and

a controller adapted to operate based on a predetermined correlation between flow rate of the at least one solvent and a system maximum allowable pressure setting, the controller being programmed to:

set the maximum allowable pressure setting based on a predetermined flow rate, the predetermined flow rate corresponding to a pump speed;

receive actual pressure readings of the solvent stream from the pressure sensor; compare the · actual pressure readings to the maximum al lowable pressure, setting; if the actual pressure is within a preset proximity to the maximum allowable pressure setting, decrease the pump speed and reset the maximum allowable pressure setting based on the flow rate that corresponds to the decreased .pump speed; or

if the actual pressure is less than the preset proximity to the maxim um allowable pressure setting, increase the pum speed arid reset the maximum allowable pressure setting based on the flow rate that corresponds to the increased pump speed.

16. The chromatographic system of claim 15, wherein the controller is further adapted to repeal at least the controller steps of receiving and comparing based on the previously set maximum allowable pressure setting.

17. The chromatographic system of claim 15, wherein the controller is programed to decrease the pump speed or reset the maximum allowable pressure setting, if the ratio of the actual pressure reading to the maximum allowable pressure setting is within a preset range.

18. The chromatographic system of claim 15, wherein the predetermined flow rate is a user- selected flow rate.

19. The chromatographic system of claim 15, wherein the pressure sensor is a first pressure sensor and the system further comprises a second pressure sensor disposed downstream from the first pressure sensor.

20. The chromatographic system of claim 15_... wherein the pum is a first pump, the system, further comprises at least one additional pump, and the predetermined correspondence between flow rate- of the -at least one solvent and the system maximum allowable pressure setting is based on a ratio of solvent pumped by the first pump and the at least one additional pump.

21. The chromatographic system of claim 15, wherein the predetermined flow rate is. a user- selected flow rate and wherein the controller is adapted repeat, at least, the controller steps of receiving and comparing based on the previously set maximum allowable pressure setting.

22. A method of controlling solvent flow in a chromatographic system comprising a chromatographic column in fluid communication with a solvent stream, a pump in fluid communication with the chromatographic column and th soi vent stream, the pump located upstfeam of the column and configured, to pump at least one solvent, a pressure sensor located downstream of the pump and upstream of the chromatographic column and configured to determine actual pressure of the solvent stream, and a controller adapted to operate based on a predetermined, correspondence between flow rate of the at least one solvent and a system maximum allowable pressure setting, the method comprising:

setting the maximum allowable pressur setting based on a predetermined flow rate, the predetermined flow rate corresponding to a pump speed;

recei ving actual pressure readings of the solvent stream from the pressure sensor; comparing the actual pressure readings to the maximum allowable pressure setting;

if the actual pressure is within a preset proximity to the maximum allowable pressure setting, decreasing the pump speed and resetting the maximum allowable pressure setting based on the flow rate that corresponds to the decreased pum speed; or if the actual pressure is less than the preset proximity to the. aximum allowable, pressure setting, increasing the pump speed and resetting the maximum allowable pressure setting based on the flow rate that corresponds to the increased pump speed.

.

23. The method of claim 22, further comprising a step of repeating at least the steps of recei ving and comparing based on the previously set maximum allowable pressure setting.

24. The method of claim 22, wherein the decreasing step, includes decreasing the pump speed if the ratio of the- actual pressure reading to the maximum allowable pressure -setting is within a preset range.

-25. The method of claim 22, wherein the predetermined flow rate is a user-selected ^'flow rate.

26. The method of claim 22, wherein the pressure sensor is a first pressure sensor and the system further comprises a second pressure sensor disposed downstream from the first pressure sensor,

27. The method of claim 22, wherein the pump is a first pump, the system further comprises at least one additional pump, and the predetermined correspondence between flow rate of the at least one solvent and the system maximum allowable pressure setting is based on a ratio of solvent pumped by the first pump and the at least one additional pump.

28, The method of claim 22, wherein the predetermined flow rate is a user-selecte flow rate and the method further comprises repeating at least the Controller steps of recei ving and

comparing based on the previously set maximum allowable pressure setting.

29, A chromatographic system comprising;

a chromatograp ic column in fluid communication with a solvent stream:

a pump in fluid communication with the chromatographic column and the -solvent -stream, the pump located upstream of the column;

a. pressure sensor located downstream of the um and upstream of the- chromatographic column and configured to determine actual pressure of the sol vent stream; and

a controller adapted to operate based on a predetermined correlation between flow rate of the -.at least one solvent and a system, maximum allowable pressure setting, the controller being programmed to:

set the maxim m allowable pressure setting based on a predetermined flow rate, the predetermined flow rate corresponding to a pump speed:

receive actual pressure readings of the solvent stream from- the pressure sensor; compare the actual pressure readings to the maximum allowable pressure setting; if the actual pressure is within a preset proximity to the maximum -allowable pressure setting:, decrease the pump speed and reset the maximum, allowable pressure settin based on the flow rate that corresponds to the decreased pump speed; or

if the actual pressure is less than the. preset proximity to the maximum allowable pressure setting and the- flow rate is less than the predetermined flow rate, increase the pump speed and reset the maximum allowable pressure .setting based on the flow rate that corresponds to the increased pump speed.

30, The chromatographic system of claim 29, wherein the controller is further adapted to repeat at least the controller steps of receiving and comparing based on the previously set maximum allowable pressure setting.

31 , The chromatographic system of claim 29, wherein the controller is programed to decrease the pump speed or reset the maximum allowable pressure setting if the ratio of the actual pressure reading to the maximum allowable pressure setting is within a preset range-.

32. The chromatographic system of claim 29, wherein the predetermined flow rate is a user- selected flow rate.

33. The chromatographic system of claim 29, wherein the pressure sensor is a first pressure sensor and the system furthe comprises a second pressure sensor disposed downstream from the first pressure sensor.

34. The chromatographic system ofelaim 29, wherein the pump is a first pump, the system further comprises at least one additional pump, and the predetermined correspondence between flow rate of the at ieasi one solvent and the system maximum allowable pressure setting is based on a ratio of solvent pumped by the first pump and the at least one additional pump.

35. The chromatographic system of elaim 29, wherein the predetermined flow rate is a user- selected flow rate and wherein the controller i adapted repeat at least the controller steps of receiving and · comparing. ^'based -on the previously set maximum allowable pressore setting.;

36. A method of controlling solvent flow in a chromatographic system comprising a chromatographic column in fluid, communication with a sol vent stream, a pump in fluid, communication with the chromatographic column and the solvent stream, the pum located upstream of the column and configured to pump at least one solvent, a pressure sensor located downstream of the pump and upstream of the chromatographic column, and configured to determine actual pressure of the solvent stream, and a controller adapted to operate based on a predetermined correspondence between flow rate of the at least one solvent and a system maximum allowable pressure setting, the method comprising:

setting the maximum allowable pressure setting based, on a predetermined flow rate, the predetermined flow rate corresponding to a pump speed;

receiving actual pressure readings of the solvent stream from the pressure sensor; comparing the actual pressure readings to the maximum allowable pressure setting;

if the actual pressure is within a preset proximity to the maximum allowable pressure setting, decreasing the pump speed and resetting the maximum allowable pressure setting based on the flow rate that corresponds to the decreased pump speed; of i f the actual pressure is less than the preset proximity to the maximum allowable. pressure setting and the flow rate is less than the. predetermined flow rate, increasing, the pump speed and resetting the maximum allowable pressure setting based on the flow rate that corresponds to the increased pump speed.

37. The method of claim 36, further comprising a step of repeating at least the steps of receiving and comparing based on the previously set maximum allowable pressure setting_*

38, The method of claim 36, wherein the decreasing step includes decreasing the pum speed if the rati o of the actual pressure reading to the maxim um allowable pressure setting is within preset range.

3.9. The method of claim 36, wherem the predetermined flow rate is · a/user-seleeted flow rate.

40. The method of claim 36, wherein the pressure sensor is a first pressure sensor and the system further comprises a second pressure. serssor disposed downstream from the first pressure sensor.

41. The method of claim 36, wherein the pump is a first pump, the system further comprises .at least one additional pump,., and the predetermined correspondence between flow rate, of the at least one solvent and the system, maximum allowable pressure setting is based on a ratio of solvent pumped by the first pump and the at least one additional pump.

42. The method of claim 36, wherein the predetermined flow rate is a user-selected flow rate and the method further comprises repeating at least the controller steps of receiving and comparing based on the previously set maximum allowable pressure setting.