|Publication number||US3536450 A|
|Publication date||Oct 27, 1970|
|Filing date||Jun 11, 1969|
|Priority date||Jun 11, 1969|
|Publication number||US 3536450 A, US 3536450A, US-A-3536450, US3536450 A, US3536450A|
|Inventors||Dus Karl M, Lindroth Sidney, Pabst Ronald E, Smith Rosalind M|
|Original Assignee||Univ California|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (4), Referenced by (20), Classifications (21)|
|External Links: USPTO, USPTO Assignment, Espacenet|
Oct. 27, 1970 K. M. DUS ETAL 3,536,450
SYSTEM FOR ANALYZING COMPOUNDS 7 Original Filed April 5, 1966 4 Sheets-Sheet 1 fjaJ INVENTORS ROSAL/ND M. SMITH KARL M. BUS RONALD E. P4887 SIDNEY L/NDROTH Oct. 21, 1970 M, Dus E1- AL 3,536,450
SYSTEM FOR ANALYZING COMPOUNDS Original Filed April 5, 1966 4 Shets-Sheet 2 mvEN'roRs ROSAL/ND M. sM/m 4 KARL M. DUS
RONALD E. P4857 SIDNEY LINDRQTH Oct. 27, 1970 K. DUS ETAL 3,536,451
SYSTEM FOR ANALYZING COMPOUNDS mvamoas Q ROSALIND M. SMITH KARL M. DUS
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AFToR/vns Oct. .1970 K. M. DUS ETAL 3,5365450 SYSTEM FOR ANALYZING COMPOUNDS Original Filed April 5, 1966 *4 Sheets-Shet 4 INVENTORS ROSAL/ND M. SMITH KARL M.
RONALD E. PABST" w m 21%;-
A TTORNE YS United States Patent O 3,536,450 SYSTEM FOR ANALYZING COMPOUNDS Karl M. Dus, Rosalind M. Smith, Ronald E. Pabst, and Sidney Lindroth, San Diego, Calif., assignors to The Regents of the University of California Continuation of application Ser. No. 540,330, Apr. 5, 1966. This application June 11, 1969, Ser. No. 845,593 Int. Cl. GOln 31/08 US. Cl. 23-253 3 Claims ABSTRACT OF THE DISCLOSURE A system of analyzing chemical mixtures. Buffers having different characteristics are forced sequentially through samples of the chemicals to be analyzed and the resultants are passed sequentially through a substance having chromatographic characteristics. Thereafter, the resultant mixture is subjected to means for effecting quantitative analysis of the components.
The development of this invention was supported by grants-in-aid from the National Institute of Health (TRG 1045-02 and HD 01262-04).
CROSS REFERENCE TO RELATED APPLICATION This application is a continuation of the inventors copending application, Ser. No. 540,330, filed Apr. 5, 1966, now abandoned.
BACKGROUND OF THE INVENTION Field of the invention The application is directed to chemical analyzers.
Description of the prior art The closest prior art known to applicants is the system shown in the L. T. Skeggs Pat. No. 3,230,048 issued 1 an. 18, 1966.
SUMMARY OF THE INVENTION The system includes mechanism for performing the steps of introducing a plurality of samples of mixtures into the respective upstream ends of a chromatographic column means including, in one embodiment, one chromagraphic container, and in another embodiment, a plurality of chromatographic containers and causing buffers from a plurality of sources to flow, respectively, through respective inlets and out of a single outlet of a valve of the type having a plurality of inlets and a single outlet. The buffers emanating from the outlet of said valve are caused to flow under pressure into the inlet and sesquentially through respective outlets of a chromatographic container selector valve of the type having a single inlet and a plurality of outlets. The buffers are then transferred sequentially from the respective outlets of the chromatographic container selector valve over the respective samples, and through the chromatographic column means. Then the resultant mixture is caused to flow through means for measuring, respectively, the quantity of the components of the chemicals.
In one embodiment, the fluid mixture analysis system of this invention comprises a plurality of chromatographic column, each including an inlet and an outlet and each containing a porous material that has a different strength afiinity for each of the components to be analyzed. Means, in communication with the chromatographic column outlets, is provided for measuring the quantity of the components as they pass from the chromatographic columns.
The system also comprises mechanism for rendering the respective buffer conduits sequentially communicative with the chromatographic columns. This means includes a valve having a plurality of inlets, each in communication with a respective buffer conduit, and an outlet in sequential communication with the chromatographic column inlets. The mechanism also includes means for rendering the outlets sequentially communicative with the inlets of a series of chromatographic columns.
Means is also provided for transferring the buffers through the conduits, chromatographic container and component measuring means.
In another embodiment of this invention, the system comprises mechanism for storing mixture samples and for automatically introducing such samples into a chromatographic column at a predetermined time. This mechanism includes a plurality of sample containers, each having an inlet and an outlet. The mechanism also includes a valve including a housing forming an inlet and a plurality of outlets. The inlet is in communication with the outlet of the buffer selector valve and the outlets are each in communication with the inlet of a respective sample container. This mechanism also includes means for rendering the valve inlet sequentially communicative with the respective valve outlets.
The system also comprises a third valve similar to those described above except that the valve housing includes a plurality of inlets that correspond to the number of sample containers that are in communication with the respective sample container outlets. The valve includes a single outlet and it is in communication with the chromatographic column.
Other features and the advantages of the present invention will be apparent from the following description, reference being had to the accompanying drawings wherein preferred embodiments of the invention are illustrated.
In the drawings:
FIG. 1 is a diagrammatical view of one embodiment of the mixture analysis system of the invention;
FIG. 2 is a diagrammatical view of another embodiment of the mixture analysis system of this invention;
FIG. 3 is a detailed view of the means for storing the samples as shown in FIG. 2;
FIG. 4 is an electrical diagram depicting the timing circuitry employed to control operation of the means for rendering the valve inlets and outlets sequentially communicative; and
FIG. 5 is a partial view of the timing wheel included in the system shown in FIG. 1.
Referring to the drawings in detail, and more particularly to FIG. 1, the fluid mixture analysis system 11 of this invention is for illustrative purposes as adapted to be used with an amino acid analyzer, such as Beckman Spinco Model B, asp roduced by the Spinco Division of Beckman Instruments, Inc. of Palo Alto, Calif., with a sixty centimeter long ion exchange column 13. This embodiment includes six chromatographic columns 13, which columns contain a material having an affinity for the components to be analyzed and which are chromatographic columns, as is well known to those skilled in the art. When a system of this type is utilized to analyze amino acids, such columns generally contain sodium salt of a sulfonated polystyrene resin, which resin serves to effect ion exchange with the amino acid sample, but it will be understood that this system is not limited to the use of such resin. The columns 13 each includes an inlet 15 and an outlet 17. The columns 13 extend through a tank 19 that is maintained at a controlled temperature, as by circulating water through the tank, to assure that the columns 13 are maintained at a constant temperature thereby stabilizing the elution pattern.
Couplings 21 are provided and each is in communication with each of the respective column inlets 15 by a sample container in the form of a circuit 16 and such couplings are separable thereby providing means whereby a mixture sample may be introduced to the top of each individual column 13.
Means 22, communicative with each column 13, is provided for measuring the quantity of the respective components as they pass from any one of the columns. The means 22 may be a colorimeter as is well known to those skilled in the art. The recording chart is shown at 23 and is used to record the results of each analysis. The means 22 is in communication with the column outlets 17 via a usual reaction coil 25 and mixing manifold 27. The reaction coil 25, in communication with the mixing manifold 27 through conduit 29, is connected to the columns 13 by the respective conduits 39 and 33, which conduits are connected by toggle valves 35.
The toggle vlaves are also connected to a drain manifold 37 via the respective conduits 31. Thus, the fluid passing through the outlets 17 may be directed either to the drain manifold 37 or to the mixing manifold 27. Also, the individual columns 13 may be isolated from the reaction coil 25 thereby removing the reaction coil back pressure while new samples are being inserted.
The system 11 is adapted to analyze amino aids and a subsysystem 40 is included for supplying the usual reagent such as ninhydrin, triketohydrindene hydrate, for reaction with the amino acid sample to prepare it for quantitative analysis by the colorimeter 22. This subsystem includes a reagent storage container 41.
The container 41 is slightly pressurized by nitrogen gas from a high pressure nitrogen gas bottle 43 through conduits 45 and 47. Container 49 is in communication with conduit 45 via conduit 53, thereby communicating the nitrogen gas pressure from conduit 45 to container 49. Container 49 includes water and is connected to container 51 by a conduit 57 thereby providing for water transfer between containers 49 and 51. Container 51 is open to the atmosphere at 59. Thus, the ninhydrin is isolated from the atmosphere and as the level of the ninhydrin is lowered in the container 41, water will be transferred from container 51 to container 49, thereby forcing nitrogen gas from container 49 to container 41 to replace the volume of ninhydrin removed. A conduit 61 extends up through the container from near the bottom and connects to a conduit 63 that is in communication with a pump 65. The pump 65 is connected to the manifold 27 by the conduit 67. The pump 65 thus provided for transferring the reagent from the storage container 41 to the mixing manifold 27.
Four buffer storage containers 69, 71, 73 and 75 have conduits 77, 79, 81 and 83, respectively, in communication therewith and extending therefrom. A rotary valve is provided for sequentially and intermittently communicating the conduits 77, 79, 81 and 83 with the respective columns 13. The valve 85 includes a housing 87 that forms a chamber 89, having four inlets 91 and an outlet 93. The inlets 9-1 are arranged circularly and the outlet 93 is disposed directly opposite the center of the circle so defined. The inlets 91 are each in communication with a respective conduit 77, 79, 81 or 83 and the outlet 93 is in communication with a conduit 94 which, in turn, is in communication with the columns 13.
A core 95 is disposed in the chamber 89 and is rotatable on an axis extending from the center of the circle defined by the inlets 91 to the outlet 93. The core closely fits the inner surfaces of the housing 87 in the areas of the inlets 91 and outlet 93 and includes a passage 97 extending from any one of the inlets 91 to the outlet 93.
Rotation of the valve core 95 is preferably effected by a twenty-four volt direct current motor 99 as shown schematically in FIG. 4. The motor 99 is operably connected to the valve core 95 by a usual Geneva drive mechanism (not shown) to provide for intermittently stopping the core With the passage 97 communicative with an inlet 91.
The electrical circuitry shown in FIG. 4 is provided to control electric current to the motor 99. The manual power-on switch is shown at 101 and the valve manual actuation switch is shown at 103. Microswitch 104 contacts 105 are provided for automatic actuation of the valve 85. A motor driven timing wheel 107 (see FIG. 5), that is rotated at a uniform rate, is provided with a plurality of holes 109, that are uniformly spaced on the circumference 111 of a circle and that are adapted to frictionally retain microswitch actuation pins 113. The pins 113 are adapted to act on the microswitch 104 actuation arm 106 to effect electrical contact between the contacts 105 as the wheel 107 is rotated. The pins 113 are arranged in the holes 109 to effect rotation of the valve core 95 at the desired time, thus providing for automatically timing the flow from each of the respective buffer containers 69, 71, 73 and 75.
A second set of holes 115, is included in the wheel 107 and the holes are spaced on the circumference 117 of a circle. These holes are adapted to accept and frictionally retain microswitch actuation pins 119 which pins are adapted to co-operate with a second microswitch 120 actuation arm 122, the purpose of which second switch will be made apparent later in this specification.
A usual transistor 121 is provided to trigger a silicon unijunction transistor 123. A relay 125 is actuated by the current supplied by the transistor 123.
The shaft of the motor 99 bears and rotates a cam, represented by the dotted line 129, for acting on the normally closed switch to thus break the circuit after a complete revolution of the motor 99.
Indicator lights 131 are indexed to the rotational position of the core 95 to indicate the positioning of the passage 97 with respect to the respective inlets 91.
The system 11 of this invention includes a sample container selector valve 133 of substantially the same construction as the valve 85 except it has only one inlet 135 and six outlets 137. The inlet 135 is in communication with the outlet 93 via conduit 94 and each of the outlets 137 is in communication with a respective column 13 via a respective conduit 139.
Rotation and positioning of valve 133 is accomplished in substantially the same manner as described above in connection with valve 85 except that there are six points on the Geneva mechanism rather than four. Also, the microswitch contacts, included in the electrical circuitry, are closed by the cooperating contact pins 119 described above.
A pump 141 is provided for effecting rapid transfer of the buffers from valve 85 to valve 133 and through the columns 13.
From the foregoing, it will be apparent that when it is desirable to analyze several chemical mixture samples, a sample may be placed in the top of each of the columns 13 by disconnecting the couplings 21 and inserting the samples. The operation of this system 11 will be described for analysis of amino acids, but it will be understood that the system 11 is in no way limited to be used for such analysis. Containers 69 and 71 preferably contain the usual first and second buflfers .2 N sodium citrate pH 3.25 and pH 4.25. It has been discovered that by employing 1.4 N sodium citrate pH 6.5 as a third buffer and 0.7 N sodium citrate-sodium carbonate pH 10.89 as the fourth buffer, the eluting time is reduced substantially and complete analysis can be accomplished with only one column and resin. Accordingly, containers 73 and 75 contain such third and fourth buffers, respectively.
The four buffers are selected to permit the resolution of all natural amino acids commonly found in proteins on a single column in contrast to the conventional separation of these compounds using a method employing two columns containing different resins. This mode of operation has the following advantage: Incorporation of the regeneration of the column into the stepwise fourbuffer elution program makes the analysis a cyclic operation. Moreover, continuous operation means efiective utilization of the expensive instrument twenty-four hours a day with no loss of time during the night or over weekends.
The pins 113 and 119 are arranged in the timing wheel 107 so that when operation of the systems 11 is commenced, the first pin 113, to effect the actuation arm 106, does so at the time when it is desirable to switch from the buffer in container 69 to the buffer in container 71. The second pin 1-13 to effect the actuation arm 106, is spaced from the above mentioned pin 113 sufficiently to provide the proper time lapse for transfer of the desired amount of buffer from container 71 and initiates switching to container 73. The third pin 113 is likewise spaced to provide the desired amount of buffer transfer from the container 73 and will act to initiate switching to container 75. The fourth pin 113 is likewise spaced to provide the desired amount of flow from container 75 and will act to initiate switching back to container 69.
The first pin 119 to initiate switching of the circuitry associated with the valve 133 is preferably disposed so as to initiate such switching after valve 85 has been switched back to communication with container 69 for a period of time, and suflicient buffer from that container has been pumped through the just used column 13 to reequilibrate it and leave it ready to receive a new sample.
It will be clear that the next four pins 113 to act on the actuation arm 106 are disposed similarly to the above described four pins 113 and that the second pin 119 to act is disposed so as to act a sufficient period of time after the latter pin 113 to allow a suitable equilibration period for the second used column 13. Similar pin 113-119 arrangement is continued around the timing wheel 107 to initiate sequential communication of all four containers 69, 71, 73 and 75, sequentially with all six columns 13. In particular aplications, it may be desirable to choose a timing wheel 107 speed that coincides with the time required for one complete chromatogram. In the case of amino acid analysis a chromatogram can be completed in four hours and if the timing wheel 107 speed is such that it turns through a complete revolution in four hours, only four pins 113 and one pin 119 will be required in the timing wheel. Such an arrangement will tend to minimize variations in timing between the analysis cycles for various samples.
After the samples have been placed in the containers 16, the core 95 of valve 85 being oriented so that the included passage 97 is in communication with container 69, the system is activated by starting pumps 65 and 141, depressing the manual button 101, and starting the timing wheel 107. Steady rotation of the timing wheel 107 will cause all four containers 69, 71, 73 and 75 to be rendered sequentially communicative with all six columns 13 and the respective buffers will be sequentially pumped into the respective columns 13, over the samples, and out the respective outlets 17.
During the above described operation ninhydrin is introduced to the manifold and reacts with each component as it passes through the manifold 27 and reaction coil 25. The mixture passes through the coil 25 and to the means 22 where the quantitative determination takes place and is recorded on chart 23 for each of the six samples. It will be clear that after the sample included in any one of the six containers 16 has been subjected to all four buffers and the column has been re-equilibrated, indexing of the column selector valve will render this particular sample container non-communicative with the buffer flow and a new sample may be inserted and it will be analyzed in turn without interrupting the continuous operation. This new sample may then be analyzed auto matically after completion of the five intervening analyses. If desired, the order of samples to be analyzed can still be rearranged manually, at will, by the manual switch 103.
The embodiment of this invention shown in FIG. 2 is substantially the same as that shown in FIG. 1, except that the valve 133 is replaced with a dual valve arrangement 143, as shown in FIG. 3, which arrangement includes valves 145 and 147. These valves are substantially the same as valve 85, except that valve 145 includes a single inlet 149 and a plurality of outlets 151, and valve 147 includes a like plurality of inlets 153 and a single outlet 155. The valve cores included in valves and 147 are operated by a Geneva drive 156 which is actuated by motor 99 and associated electrical circuitry similar to that described in reference to valve 85.
The cores 95 are driven through a common drive mechanism 157 so that synchronized positioning of the cores 95 is .maintained.
A plurality of sample containers or tubes 158, each of which includes an inlet 159 and an outlet 161, is communicatively connected between the valves 145 and 147. Only one of these tubes 158 is shown in FIG. 3. Each of the inlets 159 is connected to a respective outlet 151, and each of the outlets 161 is connected with a respective inlet 153 so that the respective passages 97 are simultaneously communicative with respective tubes 158. The tubes 158 each include a coupling 163 similar to couplings 21, providing for opening the tube '157 to insert samples to be analyzed.
The inlet 149 is in communication with the pump 141 via conduit 165 and the outlet 155 is in communication with the inlet 15 of the column 13 via conduit 167. It will be noted that this embodiment also differs from the embodiment shown in FIG. 1 in that there is only a single column 13 but this system can also accomplish automatic analysis of a plurality of samples since the various samples can be stored in the tubes 158 and can be automatically introduced into the column '13 in squential order. In this embodiment, the concept of continuous operation can be realized at substantial savings in resin and supporting facilities as compared to the multicolumn system described above. In addition, it offers enhanced reproducibility of performance because all analyses are performed on the same column. Using this embodiment of the invention as an accessory, continuous operation may be attained by any conventional column chromatography instrument without major modifications.
The column 13 is encased in a jacket 169 that includes an inlet 171 and an outlet 173. An annular space 170 is formed between the column 13 and the jacket 169 for circulating a thermostatic fluid such as water, for maintaining the column 13 at a constant temperature.
From the foregoing, it will be clear that the system shown in FIG. 2 operates substantially the same as that shown in FIG. 1, except that after valve 85 has rendered all four buffer containers 69, 71, 73 and 75, sequentially communicative with the tube 158 containing the first sample to be analyzed, and has returned communicatively to container 69 for a suitable equilibration period, the cores 95 in valves 145 and 147 will be rotated synchronously to render the respective included passages 97 communicative with the tube 158 containing the second sample to be analyzed. The core 95 included in valve 85 will then be rotated through its four positions again and after communicative positioning with container 69 for a period of time suflicient to provide the desired equilibration of the column 13, the cores 95 included in valves 1-45 and 147 will be synchronously rotated to communicatively position the respective included passages with the tube 158 containing the third sample, etc.
From the foregoing, it will be apparent that the systems of this invention provide relatively simple, reliable, efiicient and accurate means for automatically analyzing chemical mixtures. It will also be clear that the method herein set forth for analyzing amino acids is extremely efiicient in that by employing six storage containers 158 and a six port dual valve arrangement 143, six complete amino acid analyses can be performed on a single column automatically in twenty-four hours, without interruption or attendance. The same holds true for any number of analyses, as for instance, if it were desirable to provide for a four day series of unattended analyses, twenty four storage containers 158 and a twenty four port dual valve arrangement 143 would be employed.
l. A fluid compound analysis system comprising:
(A) a plurality of sample containers for containing the fluids to be analyzed;
(B) chromatographic column means connectible with the sample containers;
(C) means connected with the chromatographic column means for effecting quantitative analysis of the fluids after they pass from the column means;
(D) a plurality of conduits for butters;
(E) means for rendering the respective buffer conduits sequentially communicative and then non-communicative with the chromatographic column means for the flow of buffers through said column means, Which sequence means includes:
(1) a rotatable buffer selector valve including a housing having a plurailty of inlets, each in communication, respectively, with a butter conduit, and having a single outlet,
(2) a conduit connected with the outlet of the valve,
(3) means for rendering the valve inlets sequentially communicative and non-communicative with the valve outlet,
(4) rotatable sample selector valve means connected with the outlet of the buffer selector valve and connected with the chromatographic column means for connecting the outlet of the buffer selector valve in sequence With the said column means through the sample containers,
(5) means for effecting flow of all buffers sequentially through each sample container and through the chromatographic column means sequentially, said latter means including means synchronizing the rotation of the buffer selector valve and the sample selector valve means;
(F) a pump in the outlet conduit from the butter selector valve for effecting rapid transfer of the butters through the sample selector valve means and the chromatographic column means.
2. A system as defined in claim 1, characterized in that the chromatographic column means includes a plurality of chromatographic columns, each connected, respectively, with a sample container, and further characterized in that the rotatable sample selector valve means comprises:
(E)(4) (a) a rotatable valve having a single inlet connected With the outlet conduit of the buffer selector valve, downstream of the pump, and having a plurality of outlets connectible with the sample containers;
and further characterized in that said means for elfecting synchronized rotation of the butter selector valve and the sample selector valve means elfects sequential connection of the inlet and outlets of the said selector valve 3. A system as defined in claim 1, characterized in that the chromatographic column means comprises a single chromatographic column, and further characterized in that the rotatable sample selector valve means comprises:
(E)(4) (a) a rotatable valve having a single inlet connected with the outlet of the buffer selector valve and a plurality of outlets connected, respectively, with the sample containers, and
(b) a rotatable valve having a plurality of inlets Which are connected, respectively, with the sample containers and having a single outlet connected with the single chromatographic column means;
and further characterized in that the means for effecting flow of all buffers sequentially through each sample container and through the single column means includes means for synchronizing the rotation of the buffer selector valve, the sample selector valve and the third mentioned valve.
References Cited UNITED STATES PATENTS 2,751,034 6/1956 Ringo et a1. 137-625.11 X 3,028,225 4/1962 Sheen 23253 3,230,048 1/1966 Skeggs 23-253 3,357,233 12/1967 Roof 73-422 X JOSEPH SCOVRONEK, Primary Examiner US. Cl. X.R. 23-259; 7361.1
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|U.S. Classification||422/70, 422/261, 73/61.56, 422/81|
|International Classification||G01N30/06, G01N30/38, G01N30/00, G01N30/34, G01N30/46, G01N35/00, G01N30/24, G01N30/20|
|Cooperative Classification||G01N30/24, G01N30/466, G01N30/20, G01N35/00, G01N2030/202|
|European Classification||G01N35/00, G01N30/24, G01N30/20, G01N30/46E|