JP2006052968A - Washing method of supercritical fluid chromatography separator - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a washing method having a high washing effect and high washing convenience as compared with a conventional washing method in a washing method of a supercritical fluid chromatography separator. <P>SOLUTION: In the supercritical fluid chromatography separator having a separation part for separating a target substance from a sample using a supercritical fluid and a mobile phase containing a solvent and an extraction part for taking out the target substance from the mobile phase containing the target substance separated in the separation part, a back pressure valve is also provided on the downstream side of the extraction part in addition to a separating back pressure valve for adjusting the pressure of the mobile phase in the separation part. The internal pressures of the separation part and the extraction part are adjusted by the adjustment of pressure due to the back pressure valve and the mobile phase formed in the separation part is supplied to the extraction part to wash the extraction part. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  In the supercritical fluid chromatography separation apparatus, the present invention relates to a mobile phase flow path through which a mobile phase in which the supercritical state of the supercritical fluid is released, particularly a take-out section (hereinafter referred to as “fraction collector”) for taking out a target substance. It also relates to a method for cleaning the surroundings.

  Supercritical fluid chromatography separation devices are used for separation and production of optical isomers that are difficult to separate by ordinary separation methods in the field of pharmaceutical production, for example. Examples of the supercritical fluid chromatography separation device include a separation unit for separating a target substance from a sample injected into a mobile phase, and a fraction collector for taking out the target substance from a mobile phase containing the target substance. The apparatus which has these is mentioned. The separation part is usually provided with a back pressure regulator in order to keep the pressure of the mobile phase in the separation part constant.

  In the supercritical fluid chromatography separation device, the supercritical state of the supercritical fluid is released downstream of the back pressure regulating valve. Therefore, the component that has formed the supercritical fluid is released as a gas from the mobile phase, and the mobile phase splashes easily adhere to the fraction collector and its surroundings.

  If dirt in the fraction collector and its surroundings is mixed into the target substance, the quality and productivity of the target substance are lowered. Particularly in the field of pharmaceutical production, high quality is required. Therefore, the cleaning of the fraction collector is very important from the viewpoint of maintaining the product quality.

  In the supercritical fluid chromatography separation apparatus, as a method of washing the fraction collector and its surroundings, for example, a method of flowing an organic solvent as a washing liquid into the flow path of the mobile phase, a method of decomposing and washing the fraction collector and its surroundings It has been known.

  As a method of flowing the organic solvent into the flow path of the mobile phase, for example, the mobile phase solvent is supplied to the back pressure adjusting valve at the time of cleaning, and the mobile phase is supplied to the mobile phase flow path downstream of the back pressure adjusting valve. A method is known in which a cleaning liquid is supplied in accordance with the direction in which the gas flows and the flow path of the mobile phase is cleaned (see, for example, Patent Document 1).

  In the method of flowing an organic solvent in the mobile phase flow path, the cleaning liquid flows in the mobile phase flow path according to the direction in which the mobile phase flows. is there. For this reason, for example, the dirt adhering to the site that is difficult to come into contact with the cleaning liquid flowing through the flow path of the mobile phase, such as the above-described dirt due to splashes, may not be sufficiently removed.

The method of disassembling and cleaning the fraction collector and its surroundings is effective as a method of removing dirt adhering to a site that is difficult to contact with the cleaning liquid. However, since a high-pressure fluid flows through the fraction collector and its surroundings when the target substance is separated, it is necessary to perform an airtight test during assembly after decomposition. For this reason, the above-described disassembly and cleaning method requires a great amount of time and labor for the cleaning and the work accompanying it. Therefore, there is room for examination in the above-described decomposition cleaning method, particularly from the viewpoint of improving the productivity of products when manufacturing many types of products.
JP 2001-046804 A

  An object of the present invention is to provide a cleaning method for cleaning a supercritical fluid chromatography separation device, which has a higher cleaning effect and higher cleaning convenience than the conventional cleaning method described above.

  The present invention pays attention to the characteristics such as high diffusivity and low viscosity of the supercritical fluid, and a back pressure adjusting valve is provided on the downstream side of the fraction collector. It is possible to supply a mobile phase containing benzene to a fraction collector, and to provide a method for quickly and reliably washing the fraction collector and its surroundings.

  That is, the present invention is a method for washing a supercritical fluid chromatography separation apparatus for separating a target substance from a sample containing the target substance using a supercritical fluid as a mobile phase, The fluid chromatography separation device contains a separation part for separating a target substance from a sample injected into a mobile phase containing a supercritical fluid and a solvent, a target substance separated by the separation part, and Adjusting the internal pressure of the extraction part to extract the target substance from the mobile phase of the supercritical fluid released from the supercritical fluid and the predetermined pressure that maintains the supercritical state of the supercritical fluid in the mobile phase Pressure adjustment means that can perform, and at the time of cleaning, the pressure adjustment means is used to adjust at least the internal pressure of the extraction portion to the predetermined pressure, and the mobile phase is supplied from the separation portion to the extraction portion It provides a method of cleaning a taking-out unit by the mobile phase Te.

  According to the method, the mobile phase containing the supercritical fluid and the solvent is supplied from the separation unit to the extraction unit, and the dirt adhering to the extraction unit due to droplets or the like is easily removed by the high cleaning effect of the mobile phase. Washed. Further, according to the above method, since it is not necessary to disassemble the apparatus for supplying the mobile phase to the take-out unit, it is possible to perform highly convenient cleaning. In addition, since inspection work after cleaning such as an airtight test is greatly reduced, product productivity can be further improved.

  In the present invention, the separation unit includes mobile phase generation means for receiving a gas as a raw material of the supercritical fluid and generating a mobile phase, and the supercritical fluid chromatography separation device includes the supercritical fluid chromatography separation device. It further has a gas recovery means for recovering, as a gas, a component that forms the supercritical fluid from the mobile phase from which the supercritical state of the critical fluid is released, and supplying the recovered gas as a raw material of the supercritical fluid to the mobile phase generating means. When the pressure of the recovered gas supplied to the mobile phase generating means is higher than the pressure of the new gas supplied to the mobile phase generating means, the recovered gas is supplied to the mobile phase generating means in preference to the new gas. It is possible. According to such a method, the gas forming the supercritical fluid can be reused for the production of the supercritical fluid for the mobile phase, and the reuse of the recovered gas is prioritized for the mobile phase. A supercritical fluid can be generated.

  In the present invention, the separation unit includes a mobile phase generation unit that generates a mobile phase, a column for separating a target substance, a separation pressure adjustment unit that adjusts an internal pressure of the separation unit, and at least A bypass pipe for bypassing the column and supplying the mobile phase from the mobile phase generating means to the separation pressure adjusting means or supplying the mobile phase to the take-out section. It is possible to supply the take-out part via means or directly. According to such a method, the mobile phase can be supplied to the take-out section for washing without passing the mobile phase through a column or detector that is easily consumed by the passage of the high-pressure mobile phase.

ADVANTAGE OF THE INVENTION According to this invention, the internal pressure of the taking-out part of a supercritical fluid chromatography separation apparatus can be adjusted to the predetermined pressure with which a mobile phase is maintained. Accordingly, the mobile phase can be supplied also to the inside of the take-out unit, and the inside of the take-out unit can be washed with the mobile phase. Since the mobile phase contains a supercritical fluid and a solvent, the cleaning effect can be enhanced as compared with a conventional solvent cleaning method. The mobile phase is supplied to the take-out unit without requiring disassembly of the apparatus. Therefore, a high cleaning effect can be easily performed in a short time compared to the conventional disassembly and cleaning, and the convenience of cleaning can be enhanced.

  Therefore, according to the present invention, the cleaning time can be shortened or the amount of the cleaning agent used can be reduced while achieving a cleaning effect equivalent to or higher than that of the conventional cleaning method.

  In the present invention, from the mobile phase in which the supercritical state of the supercritical fluid is released, the component that forms the supercritical fluid is recovered as a gas, and the recovered gas is reused for the generation of the supercritical fluid for the mobile phase. It is more effective from the viewpoint of reducing gas consumption of raw materials for supercritical fluids and manufacturing costs, and it is even more effective when reused recovered gas is given priority over the use of new gas. is there.

  In the present invention, when the mobile phase generated by the mobile phase generation means is supplied to the separation pressure adjusting means or the take-out section via a bypass pipe that bypasses the column, the deterioration of the column due to the flow of the mobile phase during washing This is more effective from the viewpoint of suppressing the deterioration of the detector and realizing long-term use of the column and detector.

  In the present invention, a supercritical fluid chromatography separation device for separating a target substance from a sample containing the target substance is washed using the supercritical fluid as a mobile phase. The supercritical fluid chromatography apparatus contains a separation part for separating a target substance from a sample injected into a mobile phase containing a supercritical fluid and a solvent, and a target substance separated by the separation part. And a take-out part for taking out the target substance from the mobile phase from which the supercritical state of the supercritical fluid is released, and an internal pressure of the take-out part to a predetermined pressure that maintains the supercritical state of the supercritical fluid in the mobile phase Pressure adjusting means capable of adjusting the pressure. Such a supercritical fluid chromatography separation device can be configured by, for example, providing the pressure adjusting means in a supercritical fluid chromatography separation device having the separation part and the take-out part.

  The separation unit is not particularly limited as long as it is a means capable of separating a target substance from a sample injected into a mobile phase containing a supercritical fluid and a solvent. Specifically, the separation unit includes a mobile phase generation means for generating a mobile phase containing a supercritical fluid and a solvent, an injector for injecting a sample into the mobile phase, and a target substance in the sample. A separation column, a detector that detects a component in the mobile phase that has passed through the column, and a separation pressure adjusting means for adjusting the internal pressure of the separation unit can be used.

  The mobile phase generation means is not particularly limited as long as it can generate a mobile phase containing a supercritical fluid and a solvent. The mobile phase generation means may be a means for generating a mobile phase by mixing a supercritical fluid and a solvent, or mixing a liquefied gas and a solvent, and either pressing or heating the mixed fluid. One or both of them may be a means for generating the mobile phase by making the liquefied gas in the mixed fluid a supercritical fluid. A supercritical fluid or liquefied gas can be generated from a gas supplied as a raw material. Such mobile phase generation means can be constituted by a known device such as a heat exchanger or a high-pressure pump.

The supercritical fluid is a substance that is in one or both of a state of a critical pressure or higher and a critical temperature or higher (that is, a supercritical state). Examples of substances used as the supercritical fluid include carbon dioxide, ammonia, sulfur dioxide, hydrogen halide, nitrous oxide, hydrogen sulfide, methane, ethane, propane, butane, ethylene, propylene, halogenated hydrocarbons, water, and the like. Can be mentioned.

  As the solvent, one kind or two or more kinds are selected from various known solvents according to the kind of the target substance, the kind of the supercritical fluid, and the like. Examples of the solvent include methanol, lower alcohols such as ethanol and 2-propanol, ketones such as acetone, acetonitrile, ethyl acetate, and water.

  The injector is not particularly limited as long as it is a means capable of injecting a sample into the mobile phase. Examples of such an injector include an injector used in a high performance liquid chromatography apparatus, a sample introduction mechanism described in JP-A-5-307026, and the like.

  The column is not particularly limited as long as it has a separating agent capable of separating a target substance in a sample injected into a mobile phase. The separating agent is selected from various separating agents according to the target substance. The form of the separating agent is not particularly limited. For example, the separating agent may be packed in the column while being supported on a particulate carrier, or may be accommodated in the column while being supported on an integrated carrier accommodated in the column. And it may be accommodated in the column as an integral molded product made of the separating agent.

  For example, when the target substance is an optical isomer, it is preferable to use a polysaccharide having optical activity or a derivative thereof as the separating agent. Examples of the polysaccharide include cellulose and amylose. Examples of the polysaccharide derivatives include ester derivatives of cellulose and amylose, and carbamate derivatives of cellulose and amylose.

  The detector is not particularly limited as long as it can detect the target substance in the mobile phase that has passed through the column. Examples of the detector include an ultraviolet absorption spectrometer, a differential refractometer, and an optical rotation detector.

  The separation pressure adjusting unit is not particularly limited as long as the internal pressure of the separation unit can be adjusted to a pressure (separation pressure) that maintains the mobile phase generated by the mobile phase generation unit. For the separation pressure adjusting means, for example, a known back pressure valve (back pressure adjusting valve) can be used.

  The extraction part is not particularly limited as long as it is a means that contains the target substance separated by the separation part and can take out the target substance from the mobile phase from which the supercritical state of the supercritical fluid is released. Specifically, the take-out unit is a gas-liquid separation device such as a cyclone for gas-liquid separation of the mobile phase in which the supercritical state of the supercritical fluid is released, or a separated liquid phase is accommodated. It can be constituted by a low-pressure closed container or the like. The materials and forms of these devices are not particularly limited as long as they have strength that can withstand the predetermined pressure at which the supercritical fluid is maintained.

  In the present invention, one takeout part may be provided for the separation part, or a plurality of takeout parts may be received in parallel. Providing a plurality of extraction units in parallel is preferable from the viewpoint of extracting a plurality of target substances.

  The pressure adjusting means is not particularly limited as long as it is a means capable of adjusting the pressure of the extraction portion to the predetermined pressure that maintains the supercritical state of the supercritical fluid in the mobile phase. Specifically, a known back pressure valve (back pressure adjustment valve) provided on the downstream side of the extraction portion in the direction in which the mobile phase or gas-liquid separated gas flows can be used as the pressure adjusting means.

In the present invention, in the supercritical fluid chromatography separation apparatus described above, at the time of washing, at least the internal pressure of the take-out part is adjusted to the predetermined pressure using the pressure adjusting means, and the mobile phase is supplied from the separation part to the take-out part. The removal part is washed with the mobile phase.

  In the present invention, the internal pressure of the separation unit and the internal pressure of the extraction unit may be the same or different as long as the mobile phase containing the supercritical fluid and the solvent can be supplied from the separation unit to the extraction unit. Also good. Therefore, the internal pressure of the separation part and the internal pressure of the take-out part may be adjusted by the same means or by different means. For example, the internal pressure of the separation part may be adjusted by the pressure adjusting means for separation, and the internal pressure of the take-out part may be adjusted by the pressure adjustment means. In the present invention, it is preferable to adjust the internal pressures of both the separation unit and the extraction unit by the pressure adjusting unit from the viewpoint of easily adjusting the pressure and from the viewpoint of stably supplying the mobile phase for cleaning to the extraction unit. .

  In the take-out part, mobile phase droplets that accompany the cancellation of the supercritical state are likely to adhere, but the mobile phase supplied to the take-out part contains a supercritical fluid with excellent diffusivity, so that during normal separation In this case, since the droplets adhere to the portion where the fluid does not flow and contain a solvent having excellent dissolving power, the above-mentioned dirt such as the droplets is easily dissolved. Therefore, the take-out part is quickly and reliably washed by supplying the mobile phase.

  The supercritical fluid chromatography separation device may have other components other than the components described above. For example, the supercritical fluid chromatography separation device may further have a gas recovery means.

  The gas recovery means recovers, as a gas, a component that forms a supercritical fluid from a mobile phase in which the supercritical state of the supercritical fluid in the mobile phase is released, and uses the recovered gas as a raw material for the supercritical fluid. There is no particular limitation as long as it can be supplied to the generating means. The gas recovery means includes, for example, a gas recovery pipe that connects the pressure adjusting means and the mobile phase generation means, and a recovery gas-liquid separation device that separates a gas and a liquid phase from a fluid flowing through the gas recovery pipe can do. In the gas recovery means, a plurality of recovery gas-liquid separation devices may be provided in parallel with the pressure adjustment means.

  Examples of the recovery gas-liquid separation device include a cyclone, an apparatus that has an absorption liquid that absorbs the solvent from a recovery gas, or a solid adsorbent that adsorbs the solvent in a gas flow path.

  In the case where the supercritical fluid chromatography separation apparatus has the gas recovery means, the recovered gas can be reused to generate a supercritical fluid for a mobile phase. In such a case, when the pressure of the recovered gas supplied to the mobile phase generating means is higher than the pressure of the new gas supplied to the mobile phase generating means, the recovered gas is given priority over the new gas. Supplying to the generating means is preferable from the viewpoint of improving the recovery gas reuse efficiency. Such supply of the recovered gas is performed by, for example, connecting a new gas supply source and a mobile phase generation unit via a regulator or the like for supplying a new gas at an appropriate pressure (initial pressure). Can be done.

  Further, the supercritical fluid chromatography separation device may have, for example, a bypass pipe.

  As the bypass pipe, a pipe that bypasses at least the column, preferably bypasses the injector, the column, and the detector, and connects the mobile phase generating means and the separation pressure adjusting means or the extraction unit is used. it can.

The use of the bypass pipe at the time of washing is preferable from the viewpoint of suppressing the consumption of the column and the detector due to the passage of the high-pressure mobile phase and enabling the column and the detector to be used for a longer period. It is preferable to connect the mobile phase generating means and the separation pressure adjusting means with a bypass pipe from the viewpoint of removing dirt due to the splash immediately after the pressure adjustment by the separation pressure adjusting means is released. In addition, it is preferable to connect the mobile phase generation unit and the extraction unit with a bypass pipe from the viewpoint of more focused cleaning of the extraction unit.

  In addition, the supercritical fluid chromatography separation apparatus is appropriately provided with various devices such as a two-way valve, a three-way valve, a back pressure valve and a check valve, a high pressure pump, a heat exchanger, a cylinder, a pressure gauge, and the like. Can do.

  Moreover, in this invention, you may use together other washing | cleaning methods, such as washing | cleaning by cleaning agents, such as an organic solvent, and decomposition cleaning other than the washing | cleaning by the said mobile phase. For example, the method of the present invention may be applied after cleaning the cleaning agent. Further, for example, the container for taking out the product in the takeout part may be removed from the takeout part and cleaned in parallel with the cleaning of the supercritical fluid chromatography separation device.

  Embodiments of the method of the present invention will be described more specifically below.

<First embodiment>
First, the configuration of the supercritical fluid chromatography separation device used in the present embodiment will be described.

  As shown in FIG. 1, the supercritical fluid chromatography separation apparatus used in the present embodiment cools the cylinder 1 filled with high-pressure carbon dioxide and the carbon dioxide supplied from the cylinder 1 to liquefy the gas. A high-pressure pump 3 that quantitatively pumps the liquefied gas generated in the heat exchanger 2, a solvent tank 4 that contains a solvent, and a liquefied gas sent by the high-pressure pump 3 to the solvent tank 4 includes a high-pressure pump 5 for quantitatively supplying the solvent from 4 and a heat exchanger 6 for heating the fluid mixture of the liquefied gas and the solvent to convert the liquefied gas in the fluid mixture into a supercritical fluid. The cylinder 1 is a new gas supply source. The heat exchanger 2 to the heat exchanger 6 correspond to the mobile phase generating means.

  The supercritical fluid chromatography separation device also separates an injector 7 for injecting a sample containing a target substance (for example, an optical isomer) into the generated mobile phase, and a target substance in the injected sample. A column 8 for detecting the pressure, a detector 9 for detecting a substance in the mobile phase passing through the column 8, and a first back for maintaining the pressure in the system from the high pressure pump 3 to the detector 9 at a predetermined pressure. And a pressure valve 10. The first back pressure valve 10 corresponds to the separation pressure adjusting means. The first back pressure valve 10 from the cylinder 1 corresponds to the separation part.

  Further, the supercritical fluid chromatography separation device includes a plurality of gas-liquid separation devices 11 for gas-liquid separation of the mobile phase that has passed through the first back pressure valve 10, and a liquid phase separated by each gas-liquid separation device 11. A plurality of first tanks 12 that accommodate the first tank 12, a plurality of second tanks 13 that are connected corresponding to the first tanks 12, and the gas phase and second gas separated by the gas-liquid separator 11 And a second back pressure valve 14 for adjusting the pressure of the gas phase in the tank 13. The second tank 13 from the gas-liquid separator 11 corresponds to the take-out part. The second back pressure valve 14 corresponds to the pressure adjusting means.

Further, the supercritical fluid chromatography separation device includes a gas recovery pipe 15 connecting the second back pressure valve 14 and the heat exchanger 2, and a gas-liquid separation for separating liquid from the recovery gas flowing through the gas recovery pipe 15. It has the apparatus 16, the 3rd tank 17 in which the liquid phase isolate | separated with the gas-liquid separator 16 is accommodated, and the 4th tank 18 connected to the 3rd tank 17. FIG. The gas-liquid separator 16 corresponds to the recovery gas-liquid separator. The fourth tank 18 from the gas recovery pipe 15 corresponds to the gas recovery means.

  Further, the supercritical fluid chromatography separation device includes a regulator 19 for supplying carbon dioxide gas from the cylinder 1 at a predetermined pressure, and a check for preventing a backflow of gas from the heat exchanger 2 to the cylinder 1. A valve 20, a buffer tank 21 that stores the liquefied gas generated in the heat exchanger 2, a two-way valve 22 provided between the first back pressure valve 10 and each gas-liquid separator 11, Two-way valves 23 and 24 provided between the tank 12 and the second tank 13, and two-way valves provided between the pipes between the two-way valves 23 and 24 and the second back pressure valve 14. A valve 25, a check valve 26 for preventing a backflow of gas to each gas-liquid separator 11, and a two-way valve 27 provided between the third tank 17 and the fourth tank 18. Have.

  For the gas-liquid separators 11 and 16, for example, the gas-liquid separator shown in FIGS. 2 and 3 is used. This gas-liquid separator is formed along a cylindrical outer cylinder 31 having both ends open, a flange portion 32 that closes an opening at one end of the outer cylinder 31, and a tangent to the inner peripheral surface of the cross-sectional shape of the outer cylinder 31. And an inner cylinder that is open at the outer cylinder 31 and has both ends open, and extends through the flange 32 to the other end side of the outer cylinder 31 from the introduction section 33. 34, a jacket 35 that covers the outer peripheral wall surface of the outer cylinder 31 and forms a circulation path for the heat medium, and a mobile phase supply pipe 36 that is connected to the introduction portion 33 through the jacket 35.

  The jacket 35 is provided with a heat medium supply port 37 on the other end side and a heat medium discharge port 38 on one end side. The mobile phase supply pipe 36 passes through the jacket 35 from one end portion of the jacket 35, exits from the other end side of the jacket 35, and is connected to the introduction portion 33. The mobile phase supply pipe 36 is spirally wound around the outer periphery of the outer cylinder 31 in the jacket 35.

  The mobile phase supply pipe 36 is connected to the two-way valve 22 (the second back pressure valve 14 in the gas-liquid separator 16). The inner cylinder 34 is connected to the check valve 26 (the gas recovery pipe 15 connected to the heat exchanger 2 in the gas-liquid separator 16). The other end of the outer cylinder 31 is connected to the first tank 12. The supply port 37 and the discharge port 38 are connected to a heat medium circulating means (not shown).

  Note that the outer cylinder 31 has an elliptical or multi-walled inner peripheral wall shape for the purpose of causing a bias in the flow velocity of the mobile phase introduced into the outer cylinder 31 or applying an appropriate impact. A non-circular cylinder such as a square may be used.

  Next, separation of the target substance by the supercritical fluid chromatography separation device will be described. In the stage of separating the target substance, the second back pressure valve 14 is not used for pressure adjustment. For example, the second back pressure valve 14 is fully opened, or is isolated from a flow path such as a mobile phase by using a shut-off valve or the like.

  First, carbon dioxide is supplied from the cylinder 1 to the heat exchanger 2 at an appropriate initial pressure. The carbon dioxide cooled by the heat exchanger 2 becomes liquefied gas and is stored in the buffer tank 21. The liquefied gas stored in the buffer tank 21 is quantitatively pumped by the high-pressure pump 3 and supplied to the heat exchanger 6 while being pressurized to a predetermined pressure (for example, critical pressure) defined by the first back pressure valve 10. Is done.

  On the other hand, the solvent (for example, methanol) is quantitatively pumped from the solvent tank 5 by the high-pressure pump 5 toward the liquefied gas. The solvent is combined with the liquefied gas and mixed before being supplied to the heat exchanger 6. The fluid mixture of the liquefied gas and the solvent is supplied to the heat exchanger 6 and heated to a predetermined temperature (for example, a critical temperature or a set temperature of the column 8). By this heating, the liquefied gas in the mixed fluid becomes a supercritical fluid, and a mobile phase containing the supercritical fluid and the solvent is generated.

  A sample containing a target substance (for example, an optical isomer) is injected from the injector 7 into the generated mobile phase. The mobile phase into which the sample has been injected is sent to a column 8 that contains a separating agent (for example, a polysaccharide derivative) corresponding to the target substance. In the column 8, the target substance is separated from the sample. The target substance is detected by the detector 9. When the target substance is detected by the detector 9, any one of the two-way valves 22 is opened, and the other two-way valve 22 is closed. The mobile phase containing the target substance is sent to the first back pressure valve 10.

  The mobile phase that has passed through the first back pressure valve 10 is released from the pressure adjustment by the first back pressure valve 10, is decompressed, and is supplied to a predetermined gas-liquid separator 11. The mobile phase sent to the gas-liquid separator 11 is gas-liquid separated. Carbon dioxide forming the supercritical fluid is separated as a gas phase, and the target substance and solvent are separated as a liquid phase. The liquid phase is stored in the first tank 12 and further stored in the low pressure second tank 13. In the second tank 13, carbon dioxide is further released from the liquid phase.

  The liquid phase accommodated in the second tank 13 is taken out from the second tank 13. The solvent is separated from the liquid phase by a known method such as concentration under reduced pressure or vacuum distillation to obtain the target substance. The solvent may be purified as necessary and reused in the mobile phase.

  The carbon dioxide separated by the gas-liquid separator 11 is sent to the gas-liquid separator 16 via the second back pressure valve 14. The carbon dioxide released in the second tank 13 is also sent to the gas-liquid separator 16 via the two-way valves 24 and 25 and the second back pressure valve 14.

  When another target substance is detected by the detector 9, the two-way valve 22 corresponding to the gas-liquid separator 11 is closed. Then, the two-way valve 22 corresponding to the other gas-liquid separator 11 is opened, and the gas-liquid separation of the mobile phase containing the other target substance is similarly performed by the other gas-liquid separator 11.

  Carbon dioxide (recovered gas) sent to the gas-liquid separator 16 is gas-liquid separated by the gas-liquid separator 16. A small amount of liquid phase (solvent) contained in the recovered gas is stored in the third tank 17 and then stored in the fourth tank 18 and discarded.

  The recovered gas purified by the gas-liquid separator 16 is sent to the heat exchanger 2 through the gas recovery pipe 15. When the pressure of the recovered gas is higher than the initial pressure defined by the regulator 19, the recovered gas is supplied to the heat exchanger 2 and liquefied. When the pressure of the recovered gas is lower than the initial pressure defined by the regulator 19, new carbon dioxide gas from the cylinder 1 is supplied to the heat exchanger 2 and liquefied.

Next, the cleaning of the supercritical fluid chromatography separation device will be described.
At the time of cleaning, the two-way valve 24 is closed. When it is desired to wash the flow path of the mobile phase corresponding to the specific gas-liquid separation device 11, the two-way valves 22, 23, 25 corresponding to the gas-liquid separation device 11 are opened, and the flow path of the mobile phase desired to be washed is opened. decide. When it is desired to wash the flow path of the mobile phase corresponding to all the gas-liquid separators 11, the two-way valves 22, 23, 25 corresponding to all the gas-liquid separators 11 are opened. Note that the two-way valve 24 may be further opened.

  Next, the second back pressure valve 14 is operated in the closing direction so that the pressure in the flow path of the mobile phase becomes a predetermined pressure defined by the first back pressure valve 10, for example. The pressure of the flow path of the mobile phase is adjusted by the pressure valve 14. When the pressure of the mobile phase is adjusted, the first back pressure valve 10 is opened until it is fully opened, and the pressure adjustment by the first back pressure valve 10 is finished.

  By adjusting the pressure by the second back pressure valve 14 and opening the first back pressure valve 10, the mobile phase is supplied from, for example, the two-way valve 22 to the gas-liquid separator 11, and from the gas-liquid separator 11 to the first tank 12. , Through the two-way valves 23 and 25 and through the check valve 26 to the second back pressure valve 14. Since the supplied mobile phase contains a supercritical fluid, it has higher diffusibility than an organic solvent, and since it contains a solvent, it has high solubility in the target substance. Accordingly, the gas-liquid separator 11, the two-way valve, and the check valve are diffused to the details, and dirt such as solidified droplets in the flow path of the mobile phase is easily washed away.

  The mobile phase that has washed away the dirt in the flow path of the mobile phase passes through the second back pressure valve 14 to release the pressure adjustment by the second back pressure valve 14 and is sent to the gas-liquid separator 16. In the gas-liquid separator 16, the carbon dioxide forming the supercritical fluid is separated as a gas, and the solvent is separated as a liquid phase. The separated carbon dioxide gas is sent from the gas recovery pipe 15 to the heat exchanger 2 and reused for the production of a supercritical fluid. The separated liquid phase is stored in the third tank 17 and further stored in the fourth tank 18 and taken out.

  In addition, since the gas-liquid separation apparatuses 11 and 16 have the jacket 35, it is possible to adjust the temperature in the outer cylinder 31 at the time of gas-liquid separation. Therefore, at the time of cleaning, the temperature in the outer cylinder 31 is adjusted to a temperature different from that at the time of separation of the target substance (for example, adjusted to a higher temperature) from the viewpoint of enhancing the cleaning effect (melting power against dirt) by the mobile phase. Also good.

  Further, the composition of the mobile phase may be the same or different between the separation of the target substance and the washing. Therefore, at the time of cleaning, from the viewpoint of enhancing the cleaning effect by the mobile phase, for example, the content of the solvent in the mobile phase, the type of the solvent, heating by the heat exchanger 6, and pressure adjustment by the second back pressure valve 14, etc. The production conditions may be changed to conditions different from those used for separating the target substance.

  Further, at the time of washing, from the viewpoint of preventing the separation agent from being consumed, the column 8 may be removed, and the injector 7 and the detector 9 may be connected by a tube or an empty column.

  According to the present embodiment, using the second back pressure valve 14 provided on the downstream side of the gas-liquid separator 11 in the gas flow direction, the mobile phase and the gas upstream of the second back pressure valve 14 are used. Since the gas-liquid separation device 11, the first tank 12, and the second tank 13 contain the supercritical fluid and the solvent, the pressure of the flow path of the gas can be adjusted to the predetermined pressure. Phases can be supplied and these can be washed with the mobile phase. Therefore, it is possible to easily clean up the details as compared with cleaning with a normal liquid cleaning agent such as an organic solvent.

  Further, according to the present embodiment, the gas that has formed the supercritical fluid in the mobile phase is recovered, and a liquefied gas is generated using the recovered gas, and the supercritical fluid is generated from the liquefied gas. The consumption of new carbon dioxide can be reduced, which is advantageous in reducing the cost required for production and cleaning. In particular, it is even more advantageous when the supercritical fluid chromatography separation apparatus is constructed on a large scale such that the inner diameter of the column exceeds 10 cm, for example.

  Further, according to the present embodiment, the pressure of the new carbon dioxide gas (initial pressure) is regulated, and the back flow of the gas to the new carbon dioxide gas supply source (cylinder 1) is prevented. Therefore, the recovered gas can be automatically reused for generating the supercritical fluid according to the pressure of the recovered gas. Therefore, the recovered gas can be easily reused with a simple configuration.

Further, according to the present embodiment, since the liquid phase is separated from the recovered gas using the gas-liquid separation device 14, the purity of the recovered gas can be increased at the time of separation of the target substance, and at the time of cleaning. A highly purified recovered gas can be generated. Therefore, carbon dioxide can be recovered from the mobile phase both during separation and washing of the target substance.

  Moreover, according to this Embodiment, the liquid phase isolate | separated with the gas-liquid separator 11 is accommodated in the further low pressure 2nd tank 13, and the carbon dioxide released from the liquid phase is further collect | recovered by the 2nd tank 13. Therefore, the carbon dioxide recovery rate can be further improved, which is more advantageous for cost reduction.

  In addition, according to the present embodiment, since the gas-liquid separators 11 and 16 having the jacket 35 are used, the temperature in the gas-liquid separator is appropriately adjusted according to the purpose such as separation or cleaning of the target substance. Therefore, the separation efficiency of the target substance, the separation efficiency of the liquid phase, and the cleaning efficiency of the gas-liquid separation device 11 and the first tank 12 can be further improved.

<Second Embodiment>
As shown in FIG. 4, the supercritical fluid chromatography separation apparatus used in the present embodiment has a bypass pipe 41 and two-way valves 42 to 44, except that the supercritical fluid chromatography separation apparatus shown in FIG. It is configured in the same way.

  The bypass pipe 41 is a pipe that connects a pipe between the heat exchanger 6 and the injector 7 and a pipe between the detector 9 and the first back pressure valve 10. The two-way valve 42 is provided between the starting point of the bypass pipe 41 and the injector 7, and the two-way valve 43 is provided between the detector 9 and the end point of the bypass pipe 41. The two-way valve 44 is provided in the bypass pipe 41.

  In the case of separating the target substance, the two-way valves 42 and 43 are opened, the two-way valve 44 is closed, and the target substance is separated as described above.

  In the case of washing the supercritical fluid chromatography separation device, the two-way valve 44 is opened and the two-way valves 42 and 43 are closed. These two-way valves can be opened and closed at any time during washing, for example, after the washing of the injector 7, the column 8 and the detector 9, or the second back pressure valve 14. It may be after the start of pressure adjustment by.

  At the time of washing, the mobile phase generated by heating by the heat exchanger 6 passes through the bypass pipe 41 and is supplied to the first back pressure valve 10. The cleaning of the flow path of the mobile phase downstream of the first back pressure valve 10 by the supplied mobile phase is the same as in the first embodiment.

  According to the present embodiment, in addition to the effects of the first embodiment described above, the mobile phase is passed through the gas-liquid separation device 11 and its surroundings without passing through the injector 7, column 8, and detector 9 during cleaning. Can be supplied to. Therefore, the deterioration of the column 8 due to the passage of the mobile phase during washing can be prevented. In addition, for the detector 9, the supply of the mobile phase to the detector 9 can be stopped at the time of cleaning. Therefore, the supply of the mobile phase to the column 8 and the detector 9 can be stopped without the decomposition of the column 8 and the detector 9 at the time of washing downstream of the first back pressure valve 10. And the detector 9 can be used for a longer period of time.

  Further, according to the present embodiment, the injector 7, the column 8, and the detector 9 can be exchanged for the next production during the cleaning of the gas-liquid separator 11 and its surroundings. Therefore, the productivity when manufacturing a wide variety of products can be further improved.

It is a figure which shows roughly the structure of an example of the supercritical fluid chromatography separation apparatus used for this invention. It is sectional drawing which shows the longitudinal cross-section of the principal part of an example of the gas-liquid separator used for this invention. It is sectional drawing which shows the cross section of the principal part when the gas-liquid separator shown in FIG. 2 is cut | disconnected by the AA line. It is a figure which shows roughly the structure of the other example of the supercritical fluid chromatography separation apparatus used for this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Cylinder 2, 6 Heat exchanger 3, 5 High pressure pump 4 Solvent tank 7 Injector 8 Column 9 Detector 10 1st back pressure valve 11, 16 Gas-liquid separation device 12 1st tank 13 2nd tank 14 2nd Back pressure valve 15 Gas recovery pipe 17 Third tank 18 Fourth tank 19 Regulator 20, 26 Check valve 21 Buffer tank 22-25, 27, 42-44 Two-way valve 31 Outer cylinder 32 Flange part 33 Introduction part 34 Inner cylinder 35 Jacket 36 Mobile phase supply pipe 37 Heat medium supply port 38 Heat medium discharge port 41 Bypass pipe

Claims (3)

A method of washing a supercritical fluid chromatography separation device for separating a target substance from a sample containing the target substance using a supercritical fluid as a mobile phase,
The supercritical fluid chromatography separation device comprises:
A separation unit for separating the target substance from the sample injected into a mobile phase containing a supercritical fluid and a solvent;
A take-out part for taking out the target substance from the mobile phase containing the target substance separated in the separation part and released from the supercritical state of the supercritical fluid;
Pressure adjusting means capable of adjusting the internal pressure of the extraction portion to a predetermined pressure at which a supercritical state of the supercritical fluid in the mobile phase is maintained;
At the time of cleaning, at least the internal pressure of the extraction unit is adjusted to the predetermined pressure using the pressure adjusting means, the mobile phase is supplied from the separation unit to the extraction unit, and the extraction unit is cleaned by the mobile phase. Method. The separation unit has a mobile phase generation means for receiving a gas as a raw material of a supercritical fluid and generating the mobile phase,
The supercritical fluid chromatography separation device collects, as a gas, a component that forms a supercritical fluid from the mobile phase in which the supercritical fluid of the supercritical fluid in the mobile phase is released, and the recovered gas is used as a supercritical fluid. A gas recovery means for supplying the mobile phase generation means as a raw material;
When the pressure of the recovered gas supplied to the mobile phase generating means is higher than the pressure of the new gas supplied to the mobile phase generating means, the recovered gas is given priority over the new gas. The method according to claim 1, wherein the method is provided. The separation unit includes a mobile phase generation unit that generates the mobile phase, a column for separating the target substance, a separation pressure adjustment unit for adjusting an internal pressure of the separation unit, and at least the column. A bypass pipe for bypassing and supplying the mobile phase from the mobile phase generating means to the pressure adjusting means for separation or the take-out part,
The method according to claim 1 or 2, wherein the mobile phase generated by the mobile phase generating means is supplied to the take-out section via the separation pressure adjusting means or directly when washing.

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