Dynamic adjustment of set points for heating / cooling elements of a chromatography column using available information

Abstract

Exemplary embodiments can determine the temperature setpoint of the outlet heater or cooler (114) based on available information without requiring user input or with only minimal user input. Exemplary embodiments can estimate the temperature setpoint of the outlet heater (114) based on available information such as the pressure increase along the column (110), the temperature at the inlet (6) of the column (110), and the volumetric flow rate. In some cases, the estimate can be normalized for column dimensions such as length and diameter. A tailing factor can also be used to determine the estimate. The estimate is computationally not burdensome and can be recalculated while the column is in use.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 009,695, filed April 14, 2020, the entire contents of which are incorporated herein by reference. Background Technology

[0003] Thermal management of chromatographic columns can be challenging. For example, radial thermal gradients can form in a column, where the mobile phase flowing through the center of the column has a different temperature than the mobile phase flowing through the outer radial portions of the column, or where the temperature of the mobile phase entering the column is colder / hotter than the temperature of the column oven / ambient environment. When both the flow rate and pressure drop are too large, the mobile phase flowing through the column undergoes frictional heating on the stationary phase. This, combined with the radial heat dissipation allowed when the column is not placed under strictly adiabatic conditions, produces this difference in radial temperature. In other cases, such as with supercritical fluid chromatography (SFC), the center of the column is colder than the radial portions due to Joule-Thompson cooling. This radial thermal gradient can cause band broadening and degrade the performance of the chromatographic system.

[0004] One way to avoid radial thermal gradient problems is to place the column in a column oven to match the column wall temperature from inlet to outlet. The column oven can be set to a temperature that compensates for frictional temperature rise or Joule-Thomson cooling reduction, thus reducing heat transfer from the radial region of the column and consequently decreasing the radial thermal gradient.

[0005] Another approach is to insulate the column. Insulating the column reduces radial heat transfer and thus reduces the radial thermal gradient. A particularly promising method for insulating the column is to use a vacuum jacket around the entire or a significant portion of the column.

[0006] Another thermal management challenge for systems using insulation instead of a column oven is ensuring there is no temperature mismatch between the inlet / outlet temperature of the column wall and the ambient temperature. This mismatch can lead to radial heat flux at both ends of the column, causing band broadening as the analyte experiences different thermodynamic conditions across the column cross-section. To avoid this mismatch, heaters can be positioned at the column inlet and outlet. Summary of the Invention

[0007] According to an exemplary embodiment, the chromatography system includes a column having an inlet for receiving a mobile phase containing an analyte and an outlet through which the mobile phase exits after flowing through the column. The system also includes an outlet heater or cooler positioned to heat or cool the outlet of the column, and a controller for controlling the amount of heating or cooling by the heater or cooler, the controller being configured to control the outlet heater or cooler to achieve a setpoint temperature at the outlet, wherein the controller is configured to set the setpoint temperature of the outlet heater or cooler based on estimates calculated from the temperature at the column inlet, the flow rate of the mobile phase, and pressure increments.

[0008] The pressure increment can be either the pressure increment along the column or the pressure increment across the system. The flow rate can be either the flow rate of the pump in the chromatography system or the flow rate through the chromatography column.

[0009] The chromatographic system may include a vacuum-insulated jacket for insulating at least a portion of the column, and may include an inlet heater positioned to apply heat to the mobile phase at the column inlet. The chromatographic system may also include an inlet sensor for sensing the temperature at or near the column inlet. Flow rate and pressure increments used to estimate the amount of temperature increase or decrease are achieved by the mobile phase flowing through the column. This estimation may additionally be based on at least one dimension of the column and / or peak asymmetry in the chromatographic data of the column. At least one dimension of the column may include at least one of the column length or the column diameter.

[0010] The chromatography system may also include an inlet heater or cooler positioned to heat or cool the column inlet, having a setpoint temperature, and the controller may assume that the temperature at the column inlet is the setpoint temperature of the inlet heater or cooler. Alternatively, the chromatography assembly may also include a temperature sensor adjacent to the inlet, and the controller may assume that the temperature at the column inlet is the temperature sensed by the temperature sensor. The column may be a liquid chromatography column or a supercritical fluid chromatography column. The chromatography system may include a control loop for maintaining the outlet temperature at a setpoint.

[0011] The controller can estimate the setpoint temperature (Tout) of the outlet heater or cooler as follows:

[0012] Tout = Tin + (ln(∆P × Fv) + offset) / adjustment factor,

[0013] Where Tin is the temperature of the mobile phase at the inlet of the chromatographic column.

[0014] ln is the natural logarithm, ∆P is the pressure increment of the column, Fv is the flow rate of the mobile phase through the column, offset is the offset value, and the adjustment factor is a certain value.

[0015] According to an exemplary embodiment, a controller for controlling an outlet heater or cooler of a chromatographic column includes processing logic for receiving the temperature at the column inlet, receiving the magnitude of a pressure increment, receiving the flow rate, and determining a temperature setpoint for the outlet heater or cooler based on the temperature at the column inlet, the magnitude of the pressure increment, and the flow rate of the mobile phase. The controller also includes a signal generator for generating a control signal for controlling the temperature setpoint of the outlet heater or cooler.

[0016] The temperature received at the inlet can be one of the following: the temperature of the mobile phase at or near the inlet, the inlet temperature, the temperature setpoint of the mobile phase heater or inlet heater, or the inlet temperature. The column can be part of a chromatographic system, and the pressure increment is one of the pressure increment on the column or the pressure increment on the chromatographic system. The flow rate of the mobile phase can be the flow rate through the column or the flow rate of the pump or the pump speed. The flow rate can be the mass flow rate of the mobile phase, which can be directly measured by a mass flow sensor or derived from the composition, temperature, and volumetric flow rate.

[0017] The processing logic can be a microprocessor, a field-programmable gate array (FPGA), an application-specific integrated circuit (ASIC), or an electrical circuit system. The controller can be used with either a gas chromatography column or a liquid chromatography column.

[0018] According to an exemplary embodiment, a method is practiced for setting a desired setpoint for an outlet heater or cooler used to heat or cool the outlet of a chromatographic column in a chromatographic system. In this method, an estimate of the desired temperature setpoint of the outlet heater or cooler is determined using processing logic, at least in part, based on volumetric flow rate, pressure change, and the temperature at the column inlet. Tailing factors of the chromatographic data from the column can also be used as factors in the estimate. The desired setpoint of the outlet heater or cooler is set to the determined estimate via a control signal.

[0019] Volumetric flow rate can refer to the flow rate of the mobile phase through the column or the flow rate of the pump in the chromatography system. Pressure variations can occur on the column or in the system. Inlet temperature can be one of the following: the temperature setpoint of the mobile phase heater, the temperature setpoint of the inlet heater, the temperature sensed at the inlet, or the temperature of the mobile phase at or near the inlet.

[0020] Determining this estimate may include setting the expected setpoint (Tout) as follows:

[0021] Tout = Tin + (ln(∆P x Fv) + offset) / adjustment factor,

[0022] Wherein is the temperature of the mobile phase at the inlet of the chromatographic column.

[0023] ln is the natural logarithm.

[0024] ∆P is the pressure increment of the chromatographic column.

[0025] Fv is the flow rate of the mobile phase through the chromatographic column.

[0026] The offset is the offset value, and

[0027] The adjustment factor is a certain value.

[0028] The processing logic can be one of an electrical circuit system, a microprocessor, a microcontroller, a field-programmable gate array (FPGA), or an application-specific integrated circuit (ASIC). Attached Figure Description

[0029] Figure 1 An exemplary chromatographic system suitable for practicing exemplary embodiments is shown.

[0030] Figure 2 A block diagram is shown depicting the calculation of the estimated value of the desired temperature setpoint.

[0031] Figure 3A A graph depicting empirical data illustrating the relationship between the natural logarithm of the product of volumetric flow rate and pressure drop along the column and the outlet temperature of the chromatographic column.

[0032] Figure 3B The optimal temperature increment values ​​are described for different flow rates and tailing factors based on a set of empirical data.

[0033] Figure 3C A curve showing the relationship between power x tailing factor and the optimal temperature increment was plotted to demonstrate the linear relationship in the empirical data.

[0034] Figure 4A and Figure 4B Illustrative graphs depict different column pressure increments with different optimal outlet temperatures.

[0035] Figure 5 A graph depicts a chromatographic system that exhibits better performance using an exemplary embodiment compared to a method using a column oven.

[0036] Figure 6 A block diagram of a suitable control loop for the outlet heater is depicted. Detailed Implementation

[0037] One of the difficulties in using an outlet heater with a column employing a vacuum jacket insulation lies in determining the appropriate outlet heater temperature setpoint (i.e., the target temperature the outlet heater is expected to achieve). Using thermodynamic equations, the setpoint can be determined based on numerous parameters, including the mobile phase flow rate through the column, mobile phase temperature, mobile phase composition, column dimensions (such as length and diameter), column thermal conductivity, column inlet temperature, and column pressure drop. Unfortunately, many of these parameters are not available to the outlet heater control system and may require user input. Because the setpoint is dynamic, the problem is complex.

[0038] This exemplary implementation addresses these difficulties by determining the temperature setpoint of the outlet heater or cooler based on available information without requiring or with minimal user input. The exemplary implementation estimates the temperature setpoint of the outlet heater or cooler based on available information such as pressure increments along the column, temperature at the column inlet, and volumetric flow rate. In some cases, the estimate can be normalized for column dimensions such as length and diameter. This estimate is computationally inefficient and can be recalculated when the column is in use.

[0039] As will be discussed below, empirical data demonstrate that the estimates determined using this method can produce near-optimal results. Therefore, the efficiency of the system (i.e., the number of theoretical plates for the peaks) can be improved, and consequently, the productivity and performance of the chromatographic system can be enhanced.

[0040] The principles applied to heaters in the exemplary embodiments can also be applied to coolers or combined heating / cooling elements. Therefore, the exemplary embodiments can also be used in environments using an outlet cooler instead of an outlet heater. The chromatographic column in the exemplary embodiments can be a liquid chromatography column or a supercritical fluid column. The column can be a packed column, an open-tube column, or a packed capillary column. For packed columns with an inner diameter of approximately 1 mm or more, radial gradients appear to be of particular interest.

[0041] Figure 1 An illustration of an illustrative chromatography system 100 in which exemplary embodiments can be practiced is depicted. The chromatography system 100 includes a pump 102 for pumping a mobile phase (such as a solvent) to a column 110. An injector 104 is positioned in the flow path leading to the column 110. The injector 104 injects an analyte sample into the flow of the mobile phase from the pump 102. In some embodiments, the injector 104 may include a valve, a pump, a sample loop, and connections to an analyte source. A mobile phase heater / cooler 106 can heat or cool the mobile phase before it enters the column 110. An inlet heater / cooler 112 heats or cools the column at or near the inlet of the column 110. An outlet heater / cooler 114 heats or cools the column at or near the outlet of the column 110.

[0042] The chromatographic column 110 may be surrounded by a vacuum insulation jacket 108. The vacuum insulation jacket is shown as surrounding the entire column and heaters 112 and 114. In an alternative embodiment, the vacuum insulation jacket 108 surrounds only the column or a substantial portion of the column. A vacuum chamber may be formed between the exterior of the column 110 and the wall of the jacket 108. The vacuum chamber can be formed by evacuating air or atmospheric gas from the space surrounding the column, thereby creating a vacuum chamber (with minimal atmospheric gas) as an insulation layer. One embodiment may also form the insulation layer around the column by replacing the air or atmospheric gas in the space surrounding the column with an inert gas, and then evacuating the inert gas from the space surrounding the column, thereby creating a vacuum chamber (with minimal inert gas) as an insulation layer. Some embodiments may utilize a pressure approximately equal to or less than 10... -3 ATM vacuum. In one embodiment, the vacuum insulation jacket 108 can typically be made of any suitable material capable of withstanding a vacuum without venting. For example, the vacuum insulation jacket 108 can be made of one or more of steel, copper, brass, aluminum, or other metals.

[0043] Temperature sensors A, B, C, D, E, and F can be positioned relative to column 110. Figure 1 In the illustrative components depicted, temperature sensors A and B are positioned near the front end of the chromatographic column 110, and temperature sensors C and D are positioned near the rear end of the chromatographic column 110. Temperature sensor E is positioned adjacent to the inlet of the chromatographic column 110, and temperature sensor F is positioned adjacent to the outlet of the chromatographic column 110. Temperature sensor AF can be a high-precision sensor.

[0044] It should be understood that Figure 1 The chromatographic components depicted are merely illustrative and not limiting. Other component configurations are possible in practical exemplary embodiments.

[0045] The temperature setpoint of the outlet heater / cooler 114 is set to correct for temperature variations in the mobile phase exiting the column 110 at the outlet. The temperature setpoint of the outlet heater / cooler 114 is set by determining an estimate using available information. Figure 2Various information is described that can be used to calculate an estimate of the desired setpoint 212 for use as the outlet heater / cooler 114. This estimate can be determined by the pressure drop along column 202, the inlet temperature of column 204, and the volumetric flow rate through column 206. A calculator or controller 210 can use these values ​​202, 204, and 206 to generate an estimate for the desired setpoint 212, which will be described in more detail below. The calculator or controller 210 can be implemented as, for example, a programmable computer, a microprocessor, an electrical circuit system, a microcontroller, a field-programmable gate array (FPGA), or an application-specific integrated circuit (ASIC).

[0046] Exemplary embodiments recognize that the pressure increment along column 202 or through the system, the inlet temperature of column 204, the column inlet temperature, and the volumetric flow rate through the column or the flow rate of the pump in the system are readily available values ​​and can be used, for example, to generate an accurate estimate of the desired setpoint when a heater is employed. Exemplary embodiments recognize that the difference between the temperature at the column outlet and the temperature at the column inlet is proportional to the volumetric flow rate multiplied by the pressure drop and a measure of peak asymmetry in the chromatographic data of the column, such as the USP tailing factor. The tailing factor is a measure of peak tailing. The tailing factor is the distance from the leading edge to the trailing edge of the peak divided by twice the distance from the centerline of the peak to the leading edge, where all measurements are performed at 5% of the maximum peak height. The temperature difference between the column outlet and the column inlet can be expressed as:

[0047] T out –T in ~ Fv × ∆ P × Tf (Formula 1)

[0048] in T out It is the temperature at the outlet of the column. T in It is the temperature at the entrance of the column. Fv It is the volumetric flow rate, ∆ P It is the pressure drop along the column. Tf It is a United States Pharmacopeia (USP) tailing factor.

[0049] In another exemplary embodiment, the temperature difference between the column outlet and the column inlet is proportional to the volumetric flow rate multiplied by the pressure drop and then by the column length. The tailing factor can also be used in combination with other listed factors.

[0050] Figure 3A Depicting ln(Fv × ∆P) and T out –Tin The graph 300 shows the temperature difference (such as point 304) and... ln(Fv × ∆P) Curve 302. This graph clearly shows the linear relationship, which can be represented as:

[0051] ln(Fv × ∆P) = 0.0957 T out – T in ) + 5.443 (Formula 2)

[0052] The above equation applies to a 2.1 × 100 mm column packed with 1.6 µm particles under various MP compositions, volumetric flow rates, and inlet temperatures. It includes an empirically derived offset of 5.443 and an adjustment factor. Using Equation 3 and solving for the outlet temperature, the following is obtained:

[0053] T out = ( ln(Fv × ∆P) – 5.443) / 0.0957 + T in. (Formula 3)

[0054] In an exemplary implementation, Formula 3 can be used to generate an estimate of the desired temperature setpoint of the outlet heater. T in The temperature is determined by a temperature sensor (e.g., temperature sensor E) near the outlet or by a temperature setpoint of the inlet heater or cooler (e.g., heater or cooler 112).

[0055] The empirical data for deriving these formulas primarily come from steady-state experiments, i.e., isocratic experiments. However, a broader application of these formulas is to their use in procedural gradient elution separation. Experiments show that, although the relationship is derived from isocratic conditions, it still applies to non-steady-state environments for gradient separation. In this case, the exit target is set based on the initial isocratic portion of the gradient after the column is balanced to the initial conditions.

[0056] Can T in Select the setpoint of the heater near the inlet (i.e., at or near the inlet), the setpoint of the mobile phase heater located before the inlet, the sensor value of the mobile phase temperature at or near the inlet, or the sensor value of the temperature at the inlet. Flow rate Fv The flow rate can be selected as the volumetric velocity of the flowing phase through the column or the flow rate of the pump in the system. The pressure increment ∆P can be selected as the pressure increment along the column or through the system.

[0057] In some implementations, it may be desirable to normalize the formula for column dimensions different from those used in the above-described case for deriving Formula 3. Therefore, column dimension 208 can also be used as input to the calculator / controller 210. To account for columns of different lengths, Formula 3 may need to be divided by a normalization factor proportional to the length.

[0058] Some empirical data also indicate that the best estimate of the temperature difference between the outlet and the inlet is affected by the tailing factor. Figure 3B This is a histogram 310 showing the optimal difference between the outlet and inlet temperatures for different tailing factors. Each tailing factor is associated with a bar. The bars are grouped according to the corresponding flow rates of 0.4 mL / min, 0.6 mL / min, and 0.85 mL / min. The y-axis represents the optimal increment between the outlet and inlet temperatures. It can be seen that the optimal increment increases with increasing tailing factor. For example, bars 312, 314, 316, 318, and 320 illustrate this correlation.

[0059] Figure 3C This indicates that the optimal increment is linearly related to the volumetric flow rate, pressure drop, and tailing factor (as described in Equation 1). Figure 330 depicts the power × Tf The relationship between power and the optimal increment. Power can be related to... Fv × ∆ P Equal. Line 332 can be drawn from the point where the inlet temperature is 30°C and the other line 334 can be drawn from the point where the inlet temperature is 50°C and the other line 334.

[0060] One meaning of Formula 3 is T out It changes with the increase of pressure. This can be... Figure 4A and Figure 4B This can be seen from the text. Figure 4A Graph 400 depicts the relationship between the processed trays and the outlet temperature of the liquid chromatography column. As shown by the shaded band 402, for low pressure increments with different solvent compositions, the optimal temperature for processing the most trays is approximately 50°C. Conversely, for... Figure 4B The high-pressure increment shown in graph 406 has an optimal temperature of approximately 70°C, as indicated by shaded band 408.

[0061] exist Figure 5Graph 500 depicts a comparison of column performance in a column oven versus insulated vacuum-jacketed columns. Diamond-shaped points reflect plates treated with the column oven, while triangular points reflect plates treated with the insulated vacuum-jacketed column using the method described herein, with the outlet heater set to the desired set point. Up to a flow rate of 0.5 mL / min, the performance of the two methods is largely comparable. However, as the flow rate increases, the method of the exemplary embodiment outperforms the method using a column oven.

[0062] The chromatography unit can use a PID control loop to adjust the heater to achieve the desired set point. Figure 6 Example 600 of such a control loop is depicted. As described above, the desired temperature setpoint for the outlet heater 602 is determined by an error node 604 and compared with the temperature at the column outlet acquired by a temperature sensor 606 located at or near the outlet. The error node 604 calculates an error signal between these two values. The error node 604 can be implemented in hardware or software and simply acts as an adder that calculates the difference between the two values ​​(i.e., the desired temperature setpoint of the outlet heater 602 and the temperature measured by the temperature sensor 606). The resulting difference can be encoded in a signal passed to a control system 608 that generates a control signal. This control signal is sent to the outlet heater 610 to regulate the heat generated by the outlet heater 610.

[0063] As mentioned above, in some cases, coolers can be used instead of heaters at the inlet and outlet of the chromatographic column. For example, for a CO2 mobile phase, the mobile phase can undergo adiabatic cooling as it passes through the column. In this case, an outlet cooler is required. Equation 3 above can still be used, but... T out Less than T in .

[0064] While exemplary embodiments have been described herein, those skilled in the art will understand that various changes in form and detail may be made without departing from the intended scope defined by the appended claims.

Claims

1. A chromatographic system, comprising: A chromatographic column having an inlet for receiving a mobile phase containing an analyte and an outlet through which the mobile phase exits after flowing through the column; An outlet heater or cooler is positioned to heat or cool at the outlet of the chromatographic column; A controller for controlling the amount of heating or cooling applied by the heater or cooler, the controller being configured to control the outlet heater or cooler to achieve a setpoint temperature at the outlet of the column, wherein the controller is configured to set the setpoint temperature of the outlet heater or cooler based on estimates calculated according to the temperature at the inlet of the chromatographic column, the flow rate of the mobile phase, and pressure increments. The controller wherein the setpoint temperature T of the outlet heater or cooler is... out The estimate is: T out = T in + (ln(∆P × F v () + offset) / adjustment factor, Where T in It is the temperature of the mobile phase at the inlet of the chromatographic column. ln is the natural logarithm. ∆P is the pressure increment of the chromatographic column. Fv is the flow rate of the mobile phase through the chromatographic column. The offset is the offset value, and The adjustment factor is a value.

2. The chromatographic system of claim 1 further includes an inlet heater or cooler, said inlet heater or cooler being positioned to heat or cool the mobile phase at or near the inlet of the chromatographic column.

3. The chromatography system according to claim 1 further includes a vacuum insulation jacket for isolating at least a portion of the chromatography column.

4. The chromatographic system of claim 1, wherein the pressure increment is one of the pressure increment along the chromatographic column or the pressure increment on the system.

5. The chromatography system of claim 1, wherein the flow rate is a flow rate setting of the pump in the chromatography system or a flow rate through the column.

6. The chromatography system of claim 1 further includes an inlet sensor for sensing the temperature at or near the inlet of the chromatography column.

7. The chromatographic system of claim 1, wherein the flow rate and the pressure increment are used to estimate the amount of temperature increase or decrease achieved by the mobile phase passing through the chromatographic column.

8. The chromatographic system of claim 1, wherein the estimate is further based on at least one size of the column and / or peak asymmetry in the chromatographic data of the column.

9. The chromatography system of claim 8, wherein the at least one dimension of the liquid chromatography column includes at least one of the length of the column or the diameter of the column.

10. The chromatography system of claim 1, wherein the chromatography system further comprises an inlet heater or cooler, the inlet heater or cooler being positioned to heat or cool the mobile phase at the inlet of the chromatography column, the inlet heater or cooler having a setpoint temperature, and wherein the controller assumes that the temperature at the inlet of the chromatography column is the setpoint temperature of the inlet heater.

11. The chromatography system of claim 1, wherein the chromatography system further comprises a temperature sensor adjacent to the inlet, and wherein the controller assumes that the temperature at the inlet of the chromatography column is the temperature sensed by the temperature sensor.

12. The chromatographic system according to claim 1, wherein the chromatographic column is a liquid chromatography column.

13. The chromatographic system according to claim 1, wherein the chromatographic column is a supercritical fluid chromatographic column.

14. The chromatography system of claim 1, further comprising a control loop for maintaining the temperature at the outlet at the setpoint.

15. A method for setting a desired temperature setpoint for an outlet heater or cooler, said outlet heater or cooler being used to apply heating or cooling to the outlet of a chromatographic column in a chromatographic system, the method comprising: The processing logic is used to determine an estimate of the desired temperature setpoint of the outlet heater or cooler based on volumetric flow rate, pressure change, and the temperature at the inlet of the chromatographic column. as well as The desired temperature setpoint of the outlet heater or cooler is set to the determined estimated value via a control signal. Determining the estimated value includes determining the estimated value of the desired temperature setpoint Tout as follows: Tout = Tin + (ln(∆P × Fv) + offset) / adjustment factor, Wherein is the temperature of the mobile phase at the inlet of the chromatographic column. ln is the natural logarithm. ∆P is the pressure increment of the chromatographic column. Fv is the flow rate of the mobile phase through the chromatographic column. The offset is the offset value, and The adjustment factor is a value.

Images