AUTOMATED BUBBLE TRAP

Abstract: An automated bubble trap (10) for a liquid chromatography system includes a bubble trap (10) or reservoir (10) with level sensing devices (24) at spaced elevations so that the liquid chromatography system can be operated unattended on a day to day basis so long as the liquid level is maintained between the liquid sensing elevations (26, 28). The automated bubble trap (10) will correct a low level condition restoring the liquid level to proper limits. However, if a dry line condition is inferred, then the automated bubble trap (10) will shut down the system until the problem is resolved.

Description: AUTOMMΈD BUBBLE RAP BACKGROUND OF THE INVENTION The present invention is directed to liquid chromatograph and is particularly concerned with an automatic arrangement for trapping and removing air from a liquid chromatography feed sys¬ tem. In liquid chromatography a liquid sample is passed by a flowing stream of liquid solvent (the mobile phase) through a column packed with particulate matter (stationary phase). While passing through the column the various components in the sample separate from one another by adsorbing and desorbing from the stationary phase at different rates such that these individual components elute from the column at different times. The separated components then flow through a detector which responds to each component both qualitatively and quantitatively thereby providing information to the user about the separation achieved by the chromatography column. The particulate matter in the chromatography column is generally referred to as the chromatography media and the resolu¬ tion of a separation of the stream into individual components by the chromatography media is a primary measure determinant of the economic value of the chromatography. Accordingly it is necessary to protect the chromatography med from conditions which will ruin the media including the presen of air and the presence of icrobial contamination. The presence of air in a chromatography column fills t pores of the chromatography media and blocks the liquid samp from getting to the active sites of the media. Additionally t presence of air disrupts the flow of the liquid sample as it essential to achieve even flow of the liquid sample through t column. Microbial or bacterial contamination is a particular probl with low pressure chromatography in that the liquid phase aqueous and the gel media a carbohydrate. With water presen bacteria can grow interfering with the ability of the media t produce a clean , pure product. Accordingly it is highly desirable to prevent air from en tering the column and to provide a bubble trap that not only ex cludes air from entering the column but also is of sanitar design to inhibit the growth of bacteria within the chromatog raphy system and, in particular the chromatography column Bubble traps are a known technique in liquid chromatography fo protecting the chromatography column and more specifically th chromatography media. A typical bubble trap comprises a reser voir located at the down stream end of a system pump for deliver ing-a liquid to a chromatography column. The reservoir supplies the liquid to the chromatography column. Any air whether from air entrapped in the liquid^ or resulting from a slow leak, or from a dry line condition would be trapped in the upper portion of the reservoir above the level of the liquid therein. Heretofore bubble traps have not been automated or have been minimally automated. The result is that during unattended opera¬ tion common in liquid chromatography processes (some reaching days in duration) in the event of depletion of liquid in the bubble trap, air will eventually reach the liquid chromatography column. This problem can be holding volume; however, this also increases the difficulty of cleaning the bubble trap, already a major concern in the biophar ceutical industry and increases system holdup volume which degrades the system effectiveness in achieving the desired separation of the mixture being processed. SUMMARY OF THE INVENTION The present invention provides a bubble trap that enables trouble free unattended operation by combining automation, low fra fc - holdup volume and sanitary design. The bubble trap JΛT positioned in a liquid chromatography system at the down stream end of the system pump and upstream of the chromatography column. The «_ bubble trap functions as a reservoir for receiving the entir volume output of the system pump. The reservoir is preferabl though not necessarily transparent being made of glass o polysulfone for example and includes level detection devices a spaced elevations in the reservoir for the purpose of maintainin the liquid sample between the two elevations. This is ac¬ complished by refilling the trap in the event the liquid sample level falls below the first or lower level or closing down the chromatography system in the event the liquid level fails to rise above the higher or second level within a predetermined time period during refilling. The latter condition is indicative of a dry line condition in which the system pump is now pumping air into the reservoir. For some operations, as for example, loading the sample into the column the automated bubble trap may be temporarily bypassed. OBJECTS OF THE INVENTION It is an object of the invention to provide an automated bubble trap for a liquid chromatography system. It is another object of the present invention to provide an automated bubble trap which accommodates unattended multiday operation of a liquid chromatography system. Another object of the invention is to provide an automated bubble trap of sanitary design inhibiting the condition of bac¬ terial contamination of the chromatography column. Another object of the invention is to provide a practi low hold up volume bubble trap which minimizes the impact of trap on separation resolution. Other and further objects of the invention will occur those skilled in the art on employment of the invention in pr tice or with a full understanding of the following detai description of the invention. DESCRIPTION OF THE DRAWING A preferred embodiment of the invention has been chosen purposes of description and illustration and is shown in the companying drawing in which: Figure 1 is a simplified flow path of a portion of a liq chromatography system including a system pump, bubble trap an chromatography column. Figure 2 is a schematic view of an automated bubble detec according to the present invention. Figure 3 is a modification of the bubble trap of Figure 2 Figure 4 is another modification of the bubble trap Figure 2. Figure 5 is another modification of a bubble trap of the vention. Referring now to the drawing. Figure 1, the automated bub trap 10 of the invention is typically placed between a sys pump 12 and a liquid chromatography column 14. The bubble trap 10 (Figure 2) functions as a reservoir and is provided with inlet 16 and outlet 18 valves and a top exhaust valve. . The inlet and outlet valves are normally opened during operation while the exhaust valve is normally closed. A bypass valve 22 may be located between the inlet and outlet valves to the bubble trap so that the bubble trap can be bypassed for cer¬ tain operations such as sample loading of the liquid column. The bubble trap comprises a reservoir 10 of suitable con¬ struction and is generally tubular and preferably fabricated of transparent material such as glass. Other materials suitable for sanitary design may be used such as Teflon, polysulfone, stain¬ less steel, etc. The bubble trap is fitted with level sensing means 24 such as optical detectors for detecting liquid sample levels at spaced elevations in the bubble trap designated as lower and upper levels 26, 28. The level sensors can be of known construction operating on capacitance, mechanical/ ultrasonic or optical principles. The operation of the bubble trap is controlled by a controller 30 which receives inputs from the level sensors and sets the valves on the automated bubble trap according to the controller design. The valves may be diaphragm valves, can be of sanitary design and may be con¬ structed of stainless steel, polypropylene, Teflon, polyvinylidene/or some other material of suitable construction, ς During normal operation, the bubble tra controls the level of the liquid between the lower and upper sensing levels and will shut down the operation in the event the liquid level can not o maintained between these two elevations. During normal operation, the bubble trap will have inlet an outlet valves, open. If the liquid level falls below the lowe elevation, the system infers that air is being detected at th lower elevation, the outlet valve will close and the exhaus valve will open until the liquid level rises and it is detecte at the upper elevation. If upper level detection of liquid doe not occur within a preset time period, which will be dependent o the refill flow rate and on the bubble trap volume, then the sys tem will shut down because a dry inlet line condition is inferre and the condition must be corrected before continuing operation. The bubble trap may be automatically bypassed — for exampl during column loading — with inlet and outlet valves closed an with the bypass valve opened. For filling of the bubble trap th liquid inlet valve and exhaust valve will be open, and the out let valve closed. For draining the bubble trap the inlet valv is closed and the exhaust and outlet valves are opened. F o sanitary purposes the bubble trap can be thoroughly cleaned usin a preprogrammed procedure. For example, the bubble trap would b filled as described above with a cleaning solution until liqui is sensed at the upper level sensor, and then for an extra perio of time to ensure that the exhaust valve is cleaned. This fill ing operation may be followed by a soak period, then by a drain ing operation, and then by refilling with the operating solvent or buffer. In the preferred embodiment, the controller is a programmable logic controller (PLC) . It may also be a special¬ ized controller, a personal computer, or any controller capable of handling the inlet/outlet, timers, and logic required. There are several modifications of the automated bubble trap including location of the inlet valve through the side wall 32 of the reservoir (Fig. 3) which provides better mixing of the liquid sample in the bubble trap as well as better cleaning. In another modification shown in Fig. 4., the inlet, outlet, and bypass valves may be replaced by two three-way valves ' 34 so that the inlet, outlet, and bypass functions indicated above can be readily accomplished with two valves. In a further modification the liquid level sensor at the up¬ per elevation can be omitted. In this modification, when air is detected at the lower elevation, the pump will refill the bubble trap with liquid sample for a given time, dependent on the fill flow rate and bubble trap volume. If air is still detected at the lower elevation after the time elapsed for refill, then a dry line condition is inferred and the system will be shut down. In a further modification shown in Figure 5, the bubble trap 10 may be placed between the inlet tanks 36 (which are preferably pressurized) and the system pump 12. This is particularly useful for high pressure liquid chromatography (HPLC) applications where pressures downstream of the pump typically range from 500 to 2000 psig prohibiting the use of glass or plastic bubble traps. It is also useful in situations where introduc t ion of air can damage impair the performance of the pump. In is modification the e haust is selectively and preferably under vacuum. A primary, advantage of the automated bubble trap is that allows use of a smaller and lower hold up or reservoir volu bubble trap. Because of the automated nature of the design bubble trap so small as to require constant attention is now po ■ εible. This represents an enormous advantage in low pressu liquid chromatography operations where resolution and cleanline are primary concerns.

Claims: 1 o Having thus described the invention, I claim: 1. An automated bubble trap for liquid chromatography sys¬ tem comprising a pump for delivering the entire volume of liquid to a chromatography column, a bubble trap located in the liquid flow line between the pump and the chromatography column, the bubble trap including a reservoir, level detection means at upper and lower elevations in the bubble trap, a normally open inlet valve, a normally open outlet valve, a normally closed exhaust valve, controlling means for maintaining the liquid sample level between the upper and lower elevations, said controlling means for closing down the chromatography operation in the event the liquid level in the reservoir falls below the lower detection level and does not thereafter rise to the upper level within a predetermined time interval. 2. An automated bubble trap for a low pressure liquid chromatography system comprising a pump for delivering the entire volume of liquid sample to a chromatography column, a bubble trap located in the liquid flow line between the pump and the chromatography column, the bubble trap including a reservoir, level detection means at a given elevation in the bubble trap, normally open inlet and outlet valves, an exhaust valve for ex¬ hausting air from the reservoir, controlling means for maintain¬ ing the liquid sample level above the lower elevation, said con¬ trolling means for closing down the chromatography operation in the event the liquid level falls below the detection level and does not thereafter rise above the detection level within a predetermined time interval. 3. -Us automated bubble trap as defined in claim 1 or 2 which further includes a bypass valve for supplying liquid sample directly to the column. 4. An automated bubble trap as defined in Claim 3 in which two three-way valves comprise the inlet, outlet and bypass valves. 5. An automated bubble trap as defined in Claim 1 or 3 in which the liquid sample fill line enters the reservoir between the upper and lower elevations. 6. An automated bubble trap as defined in Claim 1 or 3 in which the bubble trap is of sanitary construction. 7. A method of trapping air in a liquid chromatograp system comprising the steps of supplying a liquid to a liqu chromatography column via a reservoir, maintaining the level the liquid in the reservoir between lower and upper elevations interrupting the supply of liquid to the column in the event t liquid level falls below the lower elevation, supplying liquid t the reservoir, and restoring the supply of liquid to the colum in the event the liquid level reaches the upper elevation withi a predetermined elapsed time. 8. A method according to Claim 7 which includes the ste of shutting down the liquid chromatography system in the even the liquid sample level does not reach the upper elevation durin the predetermined time elapsed. 9. An automated bubble trap for liquid chromatography sys tem comprising a pump for delivering the entire volume of liqui to a chromatography column, a bubble trap located in the liqui flow line between inlet connections to the system and the pump, the bubble trap including a reservoir, level detection means a upper and lower elevations in the bubble trap, a normally ope inlet valve, a normally open outlet valve, a normally closed ex haust valve, controlling means for maintaining the liquid sample level between the upper and lower elevations and for selectivel applying the presence of vacuum on the exhaust valve, said con¬ trolling means for closing down the chromatography operation in the event the liquid level in the reservoir falls below the lower detection level and does not thereafter rise to the upper level

Inventors: RANSOHOFF THOMAS C, RANSOHOFF, THOMAS, C.
Applicants: RANSOHOFF THOMAS C, RANSOHOFF, THOMAS, C.
Application year: 1991
Main classification: B01D15
IPC codes: B01D15, G01N21, G01N30