JP2012035265A - Filtration membrane evaluation system - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a filtration membrane evaluation system which can determine the molecular weight fractionation of a filtration membrane in a short time even when using a plurality of molecular weight standard substances of different average molecular weights for three or more kinds or the like.SOLUTION: The filtration membrane evaluation system includes: a cross flow filtration device 1 which filters circulation liquid composed by dissolving the plurality of molecular weight standard substances; a liquid chromatography 2 which samples filtrate and the circulation liquid respectively from the cross flow filtration device 1 and obtains the chromatogram of the filtrate and the circulation liquid; and an analysis device 3 which can determine the molecular weight fractionation of the filtration membrane by analyzing the peak area of the plurality of molecular weight standard substances from the chromatogram of the filtrate and the circulation liquid, calculating the blocking rate of the molecular weight standard substances from the peak area of the filtrate and the peak area of the circulation liquid, and plotting the calculated blocking rate of the plurality of molecular weight standard substances.

Description

  The present invention relates to a filtration membrane evaluation system that facilitates an evaluation method of a filtration membrane, and in particular, a molecular weight cutoff (MWCO: Molecular) as an index of separation performance of an ultrafiltration membrane (UF membrane) or a nanofiltration membrane (NF membrane). (Weight Cut Off) relates to a filtration membrane evaluation system that can be easily determined.

  “Fractionated molecular weight (MWCO)” is defined as the minimum molecular weight that a filtration membrane can separate over 90%. In the measurement of the molecular weight cut off, the protein marker is generally used as a molecular weight standard substance, and filtration is performed with a filtration device. However, the lower the molecular weight, the more expensive it is. Furthermore, since proteins are charged, it is necessary to prepare a phosphate buffer or the like. Therefore, inexpensive polyethylene glycol (PEG) is used as a molecular weight standard substance. In the case of PEG, it can be used simply by dissolving in pure water or ion exchange water.

  The determination of the molecular weight cut-off is carried out by plotting each blocking rate obtained by liquid chromatography on a probability logarithmic paper as shown in FIG. 8, so that at least three points or more can be plotted on a log-log graph. preferable. For this reason, usually, three or more kinds of molecular weight standard substances (markers) having different average molecular weights are used, the molecular weight having a blocking rate of 90% is calculated on a logarithmic logarithmic paper, and used as an index of the separation performance of the NF membrane.

Conventionally, PEG as three or more kinds of molecular weight standard substances having different average molecular weights is prepared, and for each type of PEG, a filtrate and a circulating liquid that permeate a filtration membrane to be measured stored in a filtration device. (Stock solution) is sampled, the concentration is measured by liquid chromatography, and then the inhibition rate is calculated from the concentration. This is measured in series for three or more types of PEGs having different average molecular weights, and the molecular weight for blocking 90% or more is calculated from the obtained blocking rates of three or more types of PEGs (see Non-Patent Document 1). .
For example, when obtaining four types of samples, that is, PEG 6000 (manufactured by Wako Pure Chemical Industries, Ltd.) having an average molecular weight of 7500 as the first molecular weight standard substance, and PEG 4000 (manufactured by Wako Pure Chemical Industries, Ltd.) having an average molecular weight of 3000 as the second molecular weight standard substance. PEG1000 (manufactured by Wako Pure Chemical Industries, Ltd.) having an average molecular weight of 1000 is prepared as a third molecular weight standard substance, and PEG200 (manufactured by Wako Pure Chemical Industries, Ltd.) having an average molecular weight of 200 is prepared as a fourth molecular weight standard substance, and these four kinds of molecular weight standard substances are prepared. When the filtration membrane is evaluated by filtering individually in series, conventionally, the following serial procedure is used.

  (A) First, suppose that the first molecular weight standard substance PEG6000 is used. Thirty minutes after the start of total circulation filtration of PEG 6000, the filtrate and circulation liquid of PEG 6000 are sampled, and the concentration is measured by liquid chromatography. “Total circulation filtration” performs filtration under conditions of constant concentration while returning the filtrate to the tank.

  (B) Next, PEG 4000 as the second molecular weight standard substance is filtered, but before that, the filtration device and the filtration membrane to be measured are washed to remove PEG 6000. Pure water is supplied to the tank and circulated for about 30 minutes, and the final 10 minutes of the 30 minutes are washed while performing total circulation filtration. Thereafter, the cleaning liquid is once extracted and fresh pure water is supplied to the tank. Perform circulation and total circulation again, and sample the circulating fluid and filtrate.

  (C) The pure water sampling solution after washing is subjected to liquid chromatography, and it is confirmed that no peak appears, that is, PEG 6000 does not remain in the filtration device, and the washing treatment is confirmed.

  (D) When it is confirmed that the first molecular weight standard substance PEG6000 does not remain in the filtration device, the second molecular weight standard substance PEG4000 is filtered, and the same procedures as in the above (a) to (c) are performed. Perform proper processing.

  (E) When it is confirmed that the second molecular weight standard substance PEG4000 does not remain in the filtration device, the PEG1000 as the third molecular weight standard substance is filtered, and the same procedures as in the above (a) to (c) are performed. Perform proper processing.

  (F) When it is confirmed that the third molecular weight standard substance PEG1000 does not remain in the filtration device, the PEG 200 as the fourth molecular weight standard substance is filtered, and the same procedures as in the above (a) to (c) are performed. Perform proper processing.

As shown in Table 1, the evaluation time required to obtain four types of samples by individually filtering four kinds of molecular weight standard substances in series with such a conventional filter membrane evaluation method is 260 minutes. = 4 hours and 20 minutes:

  Note that the confirmation of the above water washing treatment may be performed separately for the analysis by liquid chromatography once confirmation has been obtained. As can be seen from Table 1, it takes about one hour to collect one kind of molecular weight reference material filtrate and circulating liquid. Therefore, according to the conventional filtration membrane evaluation method, three filtration membranes in series It takes about 3 hours to measure the types of molecular weight standards, and about 4 hours to measure the four types of molecular weight standards in series.

▲ Sen ▼ Takahira et al., “Evaluation of ultrafiltration inhibition characteristics by molecular size”, Chemical Engineering, Vol. 19, No. 6, 1993, p. 1105-1112

  It is an object of the present invention to provide a filtration membrane evaluation system capable of determining a fractionation molecular weight of a filtration membrane in a short time even when a plurality of molecular weight standards having different average molecular weights such as three or more types are used. .

  In order to achieve the above object, the embodiment of the present invention (a) circulates a circulating liquid obtained by simultaneously dissolving a plurality of molecular weight standard substances having different molecular weights in a solvent, and cross-flow filters the circulating liquid using a filtration membrane. (B) The filtrate and circulating liquid that permeated through the filtration membrane are sampled from the crossflow filtering apparatus, and a plurality of samples corresponding to a plurality of molecular weight standard substances are plotted on the horizontal axis from the sampled filtrate and circulating liquid. From the chromatogram of the filtrate with multiple peaks in parallel, the liquid chromatograph to obtain the chromatogram of the circulating fluid with multiple peaks corresponding to multiple molecular weight standards on the horizontal axis, and (c) from the chromatogram of the filtrate Each peak area corresponding to multiple molecular weight standards is analyzed, and each peak corresponding to multiple molecular weight standards is analyzed from the chromatogram of the circulating fluid. Analyze the area and use the peak areas determined from the chromatogram of the filtrate and the peak areas determined from the chromatogram of the circulating fluid to determine the rejection rate of multiple molecular weight standard substances and multiple molecular weight standard substances. And an analyzer that plots and displays the calculated blocking rates of a plurality of molecular weight standards on a probability logarithmic graph for each of the calculated molecular weight standards, and enables determination of the molecular weight cutoff of the filtration membrane. The gist of the present invention is a filtration membrane evaluation system.

  Note that a program for the analysis apparatus described in the embodiment of the present invention to realize the filtration membrane evaluation method is stored in a computer-readable recording medium, and this recording medium is read by a computer system, thereby Part of the evaluation method can be automated.

  According to the present invention, the number of molecular weight standard substances having different average molecular weights is n (n is a positive integer of 2 or more), and the number of molecular weight standard substances is the same as when individually measured in series. It is possible to provide a filtration membrane evaluation system capable of evaluating the evaluation result with an evaluation time of 1 / n.

It is a block diagram which shows the logical structure of the filtration membrane evaluation system which concerns on embodiment of this invention. It is a schematic diagram explaining the outline of the crossflow filtration apparatus which comprises the filtration membrane evaluation system which concerns on embodiment of this invention. It is a flowchart explaining the evaluation method of the filtration membrane which concerns on embodiment of this invention. It is a typical bird's-eye view which shows the outline of an example of the structure of the to-be-measured object (filtration membrane) of this invention. It is a figure which shows an example of the chromatogram of the circulating fluid which the liquid chromatograph measured in the filtration membrane evaluation system which concerns on embodiment of this invention. When a combination of PEG 6000 as the first molecular weight standard substance, PEG 4000 as the second molecular weight standard substance, PEG 1000 as the third molecular weight standard substance, and PEG 200 as the fourth molecular weight standard substance is selected, the peaks in the chromatogram overlap. Indicates that it must not be. It is a figure explaining that the blocking rate cannot be calculated in the combination of PEG6000, PEG4000, PEG1000, PEG400, PEG200 because the peaks of the chromatogram overlap. It is a figure which shows an example of the chromatogram of the filtrate which the liquid chromatograph measured in the filtration membrane evaluation system which concerns on embodiment of this invention. It is a schematic diagram explaining the probability logarithm paper which plotted the rejection data of 4 points | pieces calculated | required by the liquid chromatography in order to determine a molecular weight cut off. FIG. 9A shows the chromatogram of the circulating liquid of PEG 6000 and its peak area A _b1 , measured alone in the conventional method for evaluating a filtration membrane, and FIG. 9B shows the PEG 6000 measured singly. filtrate chromatogram that illustrates the peak area a _p1. FIG. 10 (a) shows the chromatogram of the circulating liquid of PEG 4000 and its peak area A _b2 , measured alone in the conventional method for evaluating a filtration membrane, and FIG. 10 (b) shows the PEG 4000 measured alone. It is a figure which shows the chromatogram of the filtrate of, and its peak area _Ap2 . 11 (a) it is measured alone in a conventional method for evaluating the filtration membrane, the chromatogram of the circulating fluid PEG1000 the peak area _{A b3,} FIG. 11 (b) was measured alone, PEG1000 It is a figure which shows the chromatogram and its peak area _Ap3 of the filtrate. 12 (a) it is measured alone in a conventional method for evaluating the filtration membrane, the chromatogram and the peak area _{A b4} of the circulating fluid in PEG 200, FIG. 12 (b) was measured alone, PEG 200 It is a figure which shows the chromatogram of its filtrate, and its peak area _Ap4 .

  Next, embodiments of the present invention will be described with reference to the drawings. In the following description of the drawings, the same or similar parts are denoted by the same or similar reference numerals. However, it should be noted that the drawings are schematic, and the relationship between the thickness and the planar dimensions, the ratio of the thickness of each layer, and the like are different from the actual ones. Therefore, specific thicknesses and dimensions should be determined in consideration of the following description. Moreover, it is a matter of course that portions having different dimensional relationships and ratios are included between the drawings.

  The following embodiments of the present invention exemplify apparatuses and methods for embodying the technical idea of the present invention. The technical idea of the present invention is based on the material and shape of component parts. The structure, arrangement, etc. are not specified below. The technical idea of the present invention can be variously modified within the technical scope described in the claims.

(Embodiment of the present invention)
As shown in FIG. 1, the filtration membrane evaluation system according to the embodiment of the present invention stores a filtration membrane to be measured and performs a crossflow filtration, and stores in the crossflow filtration device 1. The filtrate and circulating fluid (raw solution) that permeated through the filtered membrane are sampled, the liquid chromatograph 2 that measures the concentration, the cross-flow filtration device 1 and the liquid chromatograph 2 are controlled, and the separation performance of the filtration membrane And an analysis device 3 that determines the molecular weight cut-off of the filtration membrane.

  In the filtration membrane evaluation system according to the embodiment of the present invention, a plurality of molecular weight standard substances having different average molecular weights are sequentially filtered in series as in the prior art, and a sample solution for calculating separation performance is collected. Instead, a circulating solution (stock solution) in which a plurality of molecular weight standard substances having different average molecular weights are all dissolved in a solvent is prepared, and the plurality of molecular weight standard substances are filtered simultaneously (in parallel) with the crossflow filtration device 1 and filtered. The filtrate that has permeated through the membrane and the circulating fluid (stock solution) are sampled, and each concentration is measured by the liquid chromatograph 2.

  As described above, it is preferable to plot a plurality of molecular weight standard substance points (preferably at least three points or more) on the probability logarithmic graph in the determination of the fractional molecular weight. When measuring with the liquid chromatograph 2, it should be noted that the peaks of the chromatograms corresponding to the plurality of molecular weight standard substances do not overlap. For example, when four types of samples are obtained, a combination of PEG 6000 as a first molecular weight standard, PEG 4000 as a second molecular weight standard, PEG 1000 as a third molecular weight standard, and PEG 200 as a fourth molecular weight standard In the selected liquid chromatography, the retention time (the time at which the peak appears) is greatly different, so the peaks do not overlap as shown in FIG. 5, so these four types of molecular weight standards are mixed and the chromatogram is simultaneously displayed. It can be measured. Since the peak of the chromatogram appears from the one with the larger molecular weight, it becomes the peak of PEG6000, PEG4000, PEG1000, PEG200 in order from the left in FIG. However, for example, as shown in FIG. 6, in the combination of PEG6000, PEG4000, PEG1000, PEG400, and PEG200, the peaks of the chromatograms overlap, and therefore the analyzer 3 cannot calculate the blocking rate of each PEG, The molecular weight cannot be calculated. Therefore, when a fractional molecular weight of 1000 is assumed, three types of PEG are mixed with a combination of PEG200, PEG1000, and PEG4000. When a fractional molecular weight of 3000 is assumed, three types of PEG are combined with a combination of PEG1000, PEG4000, and PEG6000. When measuring with the liquid chromatograph 2 such as mixing, it is necessary to examine combinations of molecular weight standard substances so that the peaks of the chromatograms do not overlap. Even if the filtration conditions in the actual liquid are different, the rejection rate of different membranes is calculated under the same conditions (filtration pressure, filtration temperature, linear velocity) for collecting the sample to the liquid chromatograph 2 from the crossflow filtration device 1 By doing so, the difference in separation performance between the membranes can be evaluated equally.

  As shown in FIG. 2, the crossflow filtration device 1 constituting the filtration membrane evaluation system according to the embodiment of the present invention is connected to the measurement target (filtration membrane) 11 and the upstream side of the measurement target 11. Connected to the upstream piping 15b, the circulating fluid piping 15c connected to the downstream side of the measurement target 11, the filtrate piping 15e branched from the downstream side of the measurement target 11, the pump 12 connected to the upstream piping 15b, and the pump 12 Return supply pipe 15a, circulation tank 13 connected to supply pipe 15a, heat exchanger 14 connected to circulation liquid pipe 15c, return to circulation tank 13 connected to heat exchanger 14 to return circulation liquid (raw solution) to circulation tank 13 A pipe 15d is provided.

  The object to be measured (filtration membrane) 11 of the present invention is based on a cylindrical porous substrate 111 having a diameter of 10 to 50 mmΦ and a length of 300 mm to 2000 mm as shown in FIG. The cross-section in the direction perpendicular to the length is a monolith shape in which a plurality of flow paths 113 are formed in a lotus shape (however, FIG. 4 is an example of the object to be measured 11 and need to be limited to a lotus-like structure. Absent.). For example, in the case of a columnar shape with a diameter of 30 mmΦ and a length of 1000 mm, it is possible to configure a structure in which 37 cylindrical holes with a diameter of 3 mmΦ penetrate as the channel 113, but the number of channels 113 is 37. It is not limited to. The channel 113 may be formed in an arbitrary shape having a hexagonal cross section or a quadrangular cross section. Around the porous substrate 111 in the vicinity of the inlet side end surface shown on the left side of FIG. 4 and in the vicinity of the outlet side end surface shown on the right side of FIG. Yes. In FIG. 2, when the object to be measured (filtration membrane) 11 is stored in a filtration membrane storage case (not shown), the glaze seal (connecting collar portion) 112 near the inlet side end surface and the outlet side end surface is O. -A ring may be provided to realize a sealed structure with respect to the filtration membrane storage case (FIG. 2 is a schematic view, and the detailed illustration of the filtration membrane storage case is omitted).

  Among the plurality of flow paths 113 provided in a lotus shape, a space between two adjacent flow paths 113 becomes a partition wall of the filtration membrane 11. According to the structure of the measurement target (filtration membrane) 11 as shown in FIG. 4, for example, a circulating fluid (stock solution) prepared by dissolving a plurality of molecular weight standard substances having different molecular weights in a solvent (pure water) is shown in FIG. Is introduced into the flow path 113 from the inlet side end face shown on the left side, the circulating liquid (raw solution) is separated in the UF film or NF film formed on the inner wall of the flow path 113 or the laminated film of the UF film and the NF film. In addition, since it passes through the porous partition wall and is discharged from the outermost wall of the measurement target (filter membrane) 11, a plurality of molecular weight standard substances having different molecular weights can be separated. The porous base material 111 serving as the base material body of the filtration membrane 11 is formed as a columnar monolithic filter element made of a porous material by extrusion molding or the like. For example, alumina can be used from the viewpoint that the change in pore diameter is small and sufficient strength is obtained. However, other than alumina, a ceramic material such as cordierite, mullite, or silicon carbide can be used.

  Therefore, actually, the object to be measured 11 is sealed and stored in the filtration membrane storage case with an O-ring or the like, and as shown in FIG. 2, the upstream side pipe 15b, the circulating liquid pipe 15c, and the filtrate pipe 15e are What is necessary is just to make it connect with a filtration membrane storage case. A flow meter F1 and an upstream pressure gauge P1 are connected to the upstream pipe 15b, and a thermometer T2 and a downstream pressure gauge P2 are connected to the circulating fluid pipe 15c. If the pressure difference between the upstream pressure gauge P1 and the downstream pressure gauge P2 is made constant, the membrane permeation flow rate can be controlled to be constant.

  As shown in FIG. 2, a stop valve 21a is connected to the filtrate pipe 15e, a sampling pipe 22a is connected to the stop valve 21a, a stop valve 23a is connected to the sampling pipe 22a, and each stop valve 23a is a liquid. It is connected to an introduction pipe led to a first mobile phase container (not shown) for the filtrate of the chromatograph 2. If the stop valve 21a and the stop valve 23a are opened, the filtrate that has passed through the filtration membrane 11 passes through the filtrate pipe 15e, the stop valve 21a, the sampling pipe 22a, and the stop valve 23a, and the first mobile phase for the filtrate of the liquid chromatograph 2 Can be introduced into the container. On the other hand, a stop valve 21b is connected to the circulating fluid pipe 15c, a sampling pipe 22b is connected to the stop valve 21b, a stop valve 23b is connected to the sampling pipe 22b, and the stop valve 23b is connected to the liquid chromatograph 2. It is connected to an introduction pipe led to a second mobile phase container (not shown) for circulating fluid. If the stop valve 21b and the stop valve 23b are opened, the circulating liquid (raw solution) is moved through the circulating liquid pipe 15c, the stop valve 21b, the sampling pipe 22b, and the stop valve 23b for the second movement for the circulating liquid in the liquid chromatograph 2. It can be introduced into the phase vessel.

  As shown in FIG. 1, the analysis device 3 includes an input / output interface 31, and controls the cross-flow filtration device 1 and the liquid chromatograph 2 via the input / output interface 31. Receive the chromatogram of (stock solution). The analyzing apparatus 3 further includes a CPU (arithmetic processing unit) 32 having a peak area analyzing unit 321, a rejection rate calculating unit 322, a rejection rate plotting unit 323, a sampling control unit 324, and a liquid chromatograph control unit 325 as a logical structure. . The sampling control means 324 controls the stop valve 21a, the stop valve 23a, the stop valve 21b, and the stop valve 23b shown in FIG. Then, the sampling control means 324 samples the filtrate that has passed through the filtration membrane after a predetermined time has passed through the filtrate pipe 15e, the stop valve 21a, the sampling pipe 22a, and the stop valve 23a, and performs the first movement for the filtrate of the liquid chromatograph 2. Control to take into phase container. Further, the sampling control means 324 samples the circulating fluid (raw solution) through the circulating fluid piping 15c, the stop valve 21b, the sampling piping 22b, and the stop valve 23b after a predetermined time has passed, and the second for circulating fluid in the liquid chromatograph 2 is sampled. Control to take in mobile phase vessel.

  The liquid chromatograph control means 325 that the CPU 32 has as a logical structure controls the liquid chromatograph 2 via the input / output interface 31. For example, the liquid chromatograph control means 325 drives the liquid feed pump of the liquid chromatograph 2, and sends the circulating liquid from the second mobile phase container of the liquid chromatograph 2 to the analysis column of the liquid chromatograph 2, as shown in FIG. Acquire a chromatogram of such circulating fluid. Further, the liquid chromatograph control means 325 drives the liquid feed pump of the liquid chromatograph 2, sends the filtrate from the first mobile phase container of the liquid chromatograph 2 to the analysis column, and acquires the chromatogram of the filtrate. FIG. 7 shows a chromatogram of the filtrate of the filtrate. Since peaks appear from those having a large molecular weight, the peaks are PEG6000, PEG4000, PEG1000, and PEG200 in order from the left in FIG.

The peak area analyzing means 321 that the CPU 32 has as a logical structure is the peak area A _bi (i = 1 to k: k) corresponding to a plurality of molecular weight standard substances (PEG6000, PEG4000, PEG1000, and PEG200) from the chromatogram of the circulating liquid. Is generally a positive integer greater than or equal to 2, but in the following example, it will be described as k = 4 for convenience.) FIG. 5 shows the peak area _{A b3} of PEG1000 of the circulating liquid by hatching, for convenience of hatching for better illustrate the definition of the peak areas, the other of the circulating liquid PEG 6000, the PEG4000 and PEG200 The peak areas A _b1 , A _b2 and A _b4 are defined similarly. The respective peak areas of the circulating fluid in FIG. 5 are A _b1 = 219.37 mV · sec, A _b2 = 268.32 mV · sec, A _b3 = 249.03 mV · sec, and A _b4 = 212.67 mV · sec. The peak area analyzing means 321 further analyzes each peak area A _pi (i = 1 to 4) corresponding to a plurality of molecular weight standard substances (PEG 6000, PEG 4000, PEG 1000 and PEG 200) from the chromatogram of the filtrate. Figure 7 shows the peak area _{A p3} of filtrate PEG1000 by oblique lines, for convenience of hatching for better illustrate the definition of the peak areas, the peak area of PEG 6000, PEG 4000 and PEG200 other filtrate A _p1 , A _p2 and A _p4 are defined similarly. The peak areas of the filtrate in FIG. 7 are A _p1 = 4.4 mV · sec, A _p2 = 29.87 mV · sec, A _p3 = 116.18 mV · sec, and A _p4 = 202.03 mV · sec.

The rejection rate calculation means 322 that the CPU 32 has as a logical structure is based on the respective peak areas A _pi of the molecular weight standard materials of the filtrate and the respective peak areas A _bi of the molecular weight standard materials of the circulating fluid. Calculate R _obsi respectively:
R _obsi = (1−A _pi / A _bi ) × 100 (i = 1 to 4) (1)
From the peak areas A _pi and A _{bi of} each PEG, the blocking rates R _obsi (i = 1 to 4) in the films of PEG 6000, 4000, 1000, and 200 are R _obs1 = 98%, R _obs2 = 89%, R _obs3 = 53% and R _obs4 = 5%. The rejection rate plotting means 323 that the CPU 32 has as a logical structure plots the rejection rates R _obsi (i = 1 to 4) of a plurality of molecular weight standard substances on a probability logarithmic graph as shown in FIG. When the molecular weight (MW) of 90% inhibition is calculated backward from the plot on the probability logarithmic paper of FIG. 8 by the least square method, the molecular weight cut-off (MWCO) is 3000 in the case of FIG. Although not shown in the drawing, the CPU 32 has a fractional molecular weight determining means for calculating the molecular weight (MW) of 90% inhibition by a least square method from a plot on the probability logarithm paper as a logical structure, and automatically Alternatively, the molecular weight cut off may be determined.

The analysis device 3 further includes a chromatogram storage device 33 for storing the chromatogram of the filtrate and the circulating fluid detected by the detector of the liquid chromatograph 2, and each peak of the molecular weight standard substance of the filtrate analyzed by the peak area analysis means 321. The area storage device 34 for storing the area A _pi and the peak area A _bi of each of the molecular weight standard substances in the circulating fluid for each molecular weight standard substance, and the rejection ratio R of each of the plurality of molecular weight standard substances calculated by the rejection ratio calculation means 322 A blocking rate storage device 35 for storing _obsi for each molecular weight standard substance is provided. For this reason, the peak area analyzing means 321 provided in the CPU 32 reads out the chromatogram of the filtrate stored in the chromatogram storage device 33, and a plurality of molecular weight standard substances (PEG 6000, PEG 4000, PEG 1000, and PEG 200) from the read out chromatogram of the filtrate. Each peak area A _pi (i = 1 to 4) corresponding to is analyzed, and each peak area A _pi of the molecular weight standard substance of the filtrate as the analysis result is stored in the area storage device 34. The peak area analyzing means 321 further reads the circulating fluid chromatogram stored in the chromatogram storage device 33, and corresponds to a plurality of molecular weight standard substances (PEG 6000, PEG 4000, PEG 1000 and PEG 200) from the circulating fluid chromatogram read out. Each peak area A _bi (i = 1 to 4) is analyzed, and each peak area A _bi of the molecular weight standard substance of the circulating fluid, which is the analysis result, is stored in the area storage device 34. The rejection rate calculating means 322 included in the CPU 32 reads the respective peak areas A _pi of the molecular weight standard substances of the filtrate stored in the area storage device 34 and the respective peak areas A _bi of the molecular weight standard substances of the circulating liquid, a plurality of rejection R _Obsi molecular weight standards were calculated respectively, and stores the rejection R _Obsi of a calculation result molecular weight standards on rejection storage device 35. The rejection rate plotting means 323 provided in the CPU 32 reads out the rejection rates R _obsi (i = 1 to 4) of the plurality of molecular weight standard substances stored in the rejection rate storage device 35 and plots them on the probability logarithmic graph shown in FIG. .

  As shown in FIG. 1, the analysis device 3 of the present invention includes an input device 37 that receives input of data, commands, and the like from an operator, an output device 38 and a display device 39 that output analysis results, and a filter membrane. It includes a data storage device (not shown) that stores predetermined data necessary for analysis of separation performance, and a program storage device (not shown) that stores a filtration membrane separation performance analysis program and the like. The rejection rate plotting means 323 displays the probability logarithmic graph shown in FIG. 8 on the screen of the display device 39. To do. The input device 37, the output device 38, and the display device 39 send and receive data to and from the CPU 32 via the input / output interface 36. In FIG. 1, the input device 37 is configured by a keyboard, a mouse, a light pen, a flexible disk device, or the like. An analysis performer can specify input / output data and set an allowable error value and error level from the input device 37. Furthermore, it is possible to set analysis parameters such as the form of output data from the input device 37, and it is also possible to input an instruction to execute or stop the calculation. The output device 38 and the display device 39 are constituted by a printer device and a display device, respectively. The display device 39 displays input / output data, analysis results, analysis parameters, and the like. A data storage device (not shown) stores input / output data, analysis parameters, history, data being calculated, and the like.

(Evaluation method of filtration membrane)
A method for evaluating a filtration membrane according to an embodiment of the present invention will be described with reference to the flowchart of FIG. The filtration membrane evaluation method described below is an example, and it can be realized by various other procedures including this modification as long as it is included in the technical idea of the present invention. is there.

  (A) First, in step S101, a plurality of molecular weight standard substances having different molecular weights are dissolved in pure water as a solvent to prepare a circulating liquid (stock solution). Specifically, PEG6000, PEG4000, PEG1000, and PEG200 are dissolved in pure water so as to have a concentration of 200 to 500 ppm. Pure water may be water having a resistance value of 0.1 MΩ or more. Then, using the crossflow filtration device 1 shown in FIG. 2, in step S102, the temperature of the circulating fluid is controlled to 15 to 30 ° C. using the thermometer T2, and the upstream pressure gauge P1 and the downstream pressure gauge P2 The filtration membrane 11 is subjected to cross flow filtration under a filtration condition of 0.1-1 MPa pressure difference. For example, the circulating fluid is subjected to cross flow filtration under a filtration condition of 20 ° C. and a pressure difference of 0.1 MPa between the upstream pressure gauge P1 and the downstream pressure gauge P2. At this time, the linear velocity is controlled to be 2 m / sec or higher using the flow meter F1. If the linear velocity is low, the PEG layer is deposited on the membrane surface of the filtration membrane 11 and the rejection rate is due to the PEG layer. Therefore, by increasing the linear velocity, the deposition on the membrane surface of the filtration membrane 11 is increased. Prevent the filtration membrane 11 so that the rejection rate of the membrane itself can be measured. Although there is no particular upper limit on the linear velocity, it is not necessary to be about 4 m / sec or more from a practical point of view. For example, cross flow filtration may be performed by controlling the linear velocity to 3 m / sec. The filtrate that has passed through the filtration membrane 11 is returned to the circulation tank 13 via the filtrate pipe 15e as shown in FIG. 2, so that the concentration does not proceed even during the filtration.

  (B) After a predetermined time has elapsed after the start of the cross-flow filtration in step S102, the sampling control means 324 provided in the CPU 32 of the analyzer 3 in step S103 receives the stop valve 21a, the stop valve 23a, and the stop valve via the input / output interface 31. The valve 21b and the stop valve 23b are opened, and the filtrate that has permeated through the filter membrane 11 is passed through the filtrate pipe 15e, the stop valve 21a, the sampling pipe 22a, and the stop valve 23a, and the circulating liquid (raw solution) is passed through the circulating liquid pipe 15c and the stop valve 21b. The sample is sampled through the sampling pipe 22b and the stop valve 23b, and is taken into the first mobile phase container (not shown) for the filtrate and the second mobile phase container (not shown) for the circulating liquid, respectively. In step S104, the liquid chromatograph control means 325 provided in the CPU 32 of the analysis device 3 drives a liquid feed pump (not shown) of the liquid chromatograph 2 via the input / output interface 31 to start the analysis column from the first mobile phase container. The filtrate is sent to (not shown), and a chromatogram of the filtrate is obtained.

  (C) In step S105, the analyzer 3 further captures the chromatogram of the filtrate detected by the detector of the liquid chromatograph 2 via the input / output interface 31, and stores it in the chromatogram storage device 33. In step S106, the liquid chromatograph control means 325 further drives the liquid feeding pump of the liquid chromatograph 2 via the input / output interface 31, sends the circulating liquid from the second mobile phase container to the analytical column, and chromatographs the circulating liquid. Get a gram. In step S <b> 107, the analysis device 3 takes in the circulating fluid chromatogram detected by the detector of the liquid chromatograph 2 via the input / output interface 31 and stores it in the chromatogram storage device 33.

(D) In step S108, the peak area analyzing means 321 provided in the CPU 32 of the analyzing device 3 reads the chromatogram of the filtrate stored in the chromatogram storage device 33, and a plurality of molecular weight standard substances (from the chromatogram of the read filtrate. Each peak area A _pi (i = 1 to 4) corresponding to PEG 6000, PEG 4000, PEG 1000 and PEG 200) is analyzed.

(E) The peak area analyzing means 321 stores each peak area A _pi of the molecular weight standard substance of the filtrate in the area storage device 34 in step S109. Further, in step S110, the peak area analyzing means 321 reads out the circulating fluid chromatogram stored in the chromatogram storage device 33, and from the circulating fluid chromatogram read out, a plurality of molecular weight standard substances (PEG6000, PEG4000, PEG1000 and Each peak area A _bi (i = 1 to 4) corresponding to PEG200) is analyzed. In step S112, the peak area analyzing means 321 stores each peak area A _bi of the molecular weight standard substance of the circulating fluid in the area storage device 34.

(F) The rejection rate calculation means 322 included in the CPU 32 of the analysis apparatus 3 includes the peak area A _pi of the molecular weight standard substance of the filtrate and the molecular weight standard substance of the circulating liquid stored in the area storage device 34 in step S113. Each peak area A _bi is read out, and the blocking rates R _obsi of a plurality of molecular weight standards are calculated. The rejection rate calculation means 322 stores the rejection rate R _obsi of the molecular weight standard substance, which is the calculation result, in the rejection rate storage device 35.

(G) Further, the rejection rate plotting means 323 provided in the CPU 32 of the analysis device 3 calculates the rejection rates R _obsi (i = 1 to 4) of the plurality of molecular weight standard substances stored in the rejection rate storage device 35 in step S114. As shown in FIG. 8, the read out ratios R _obsi (i = 1 to 4) of a plurality of molecular weight standard substances are plotted on a probability logarithmic graph and displayed on the screen of the display device 39. From the plot on the probability log paper of FIG. 8, the molecular weight (MW) of 90% inhibition is calculated by the least square method. In the case of FIG. 8, the molecular weight cut-off (MWCO) is 3000.

According to the evaluation method of the filtration membrane according to the embodiment of the present invention, PEG 6000 as the first molecular weight standard substance, PEG 4000 as the second molecular weight standard substance, PEG 1000 as the third molecular weight standard substance, and the fourth molecular weight standard Because the combination of PEG200 as the material is selected and mixed:
Mixture sampling and chromatographic measurement: 30 minutes Washing water: 30 minutes Sampling and chromatographic measurement to confirm washing: 5 minutes Total 65 minutes. Compared to the evaluation time of 260 minutes = 4 hours and 20 minutes required when four types of samples are individually filtered in series, the evaluation time can be shortened to ¼. This evaluation time does not include the time for dissolving the molecular weight standard substance, but the time required for dissolving the four molecular weight standard substances simultaneously is shorter than the time for dissolving the molecular weight standard substance for each type. .

FIGS. 9 to 12 show a conventional method for evaluating a filtration membrane, in which PEG 6000 as a first molecular weight standard substance, PEG 4000 as a second molecular weight standard substance, PEG 1000 as a third molecular weight standard substance, and a fourth molecular weight standard substance The chromatogram when four types of samples are obtained by individually filtering the PEG200 as a series is shown. That is, FIG. 9A shows the chromatogram of the PEG 6000 circulating solution and its peak area A _b1 independently measured, and FIG. 9B shows the chromatogram of the PEG 6000 filtrate measured alone. The peak area _Ap1 is shown. FIG. 10 (a) shows the chromatogram of the circulating liquid of PEG 4000 and its peak area A _b2 measured independently, and FIG. 10 (b) shows the chromatogram of the filtrate of PEG 4000 and its peak measured independently. The area _Ap2 is shown. FIG. 11A shows the chromatogram of the PEG 1000 circulating solution and its peak area A _b3 , measured alone, and FIG. 11B shows the chromatogram of the PEG 1000 filtrate and its peak, measured alone. The area _Ap3 is shown. 12 (a) is measured alone, the chromatogram and the peak area _{A b4} of the circulating fluid in PEG200, FIG. 12 (b) was measured alone filtrate chromatogram and the peak of PEG200 The area _Ap4 is shown.

Table 2 shows the peak area A _bi of the circulating liquid, the peak area A _{pi of the} filtrate, and the blocking rate R _obsi when _PEG6000 , _PEG4000 , _PEG1000, and _PEG200 are simultaneously filtered in parallel according to the evaluation method of the filtration membrane of the present invention. :

On the other hand, the peak area A _bi of the circulating liquid, the peak area A _{pi of the} filtrate, and the blocking ratio R _obsi when _PEG6000 , _PEG4000 , _PEG1000, and _PEG200 are individually filtered in series according to the conventional method for evaluating a filtration membrane are _shown . Shown in 3:

  In Tables 2 and 3, the analysis was performed using Tosoh HLC-8220 for liquid chromatography and Tosoh TSKgel Super AW3000 and AW2500 for analysis columns. From the comparison of Table 2 and Table 3, it can be seen that there is no difference in the analysis results even if measured individually in series or mixed and measured in parallel. This shows a remarkable effect that it is possible with the evaluation time. This means that if the number of a plurality of molecular weight standard substances having different average molecular weights is 3, the same evaluation result as when three molecular weight standard substances are individually measured in series is obtained with an evaluation time of 1/3. If the number of a plurality of molecular weight reference materials having different average molecular weights is 5, the same evaluation result as when five molecular weight standard materials are individually measured in series is obtained as 1 / This means that the evaluation can be performed with an evaluation time of 5.

  That is, more generally speaking, according to the filtration membrane evaluation method of the present invention, if the number of the plurality of molecular weight standard substances having different average molecular weights is n (n is a positive integer of 2 or more), n The same evaluation result as when individual molecular weight standard substances are individually measured in series can be evaluated with an evaluation time of 1 / n.

(Filtration membrane evaluation program)
The series of filtration membrane evaluation operations shown in FIG. 3 can be executed by controlling the filtration membrane evaluation system shown in FIG. 1 by an algorithm program equivalent to FIG. This filtration membrane evaluation program may be stored in a program storage device (not shown) of a computer system that constitutes the filtration membrane evaluation system of the present invention. The filtration membrane evaluation program is stored in a computer-readable recording medium, and the recording medium is read into a program storage device of the filtration membrane evaluation system, thereby executing the series of filtration membrane evaluation operations of the present invention. be able to. Here, the “computer-readable recording medium” means a medium capable of recording a program such as an external memory device of a computer, a semiconductor memory, a magnetic disk, an optical disk, a magneto-optical disk, and a magnetic tape. To do. Specifically, a flexible disk, CD-ROM, MO disk, cassette tape, open reel tape, etc. are included in the “computer-readable recording medium”. For example, the main body of the analysis device 3 constituting the filtration membrane evaluation system can be configured to incorporate or externally connect a flexible disk device (flexible disk drive) and an optical disk device (optical disk drive). A flexible disk is inserted into the flexible disk drive, and a CD-ROM is inserted into the optical disk drive through the insertion slot, and a predetermined read operation is performed to analyze programs stored in these recording media. 3 can be installed in the program storage device. Further, by connecting a predetermined drive device, for example, a ROM as a memory device or a cassette tape as a magnetic tape device can be used. Furthermore, this program can be stored in a program storage device via an information processing network such as the Internet.

(Other embodiments)
As described above, the present invention has been described according to the above-described embodiments. However, it should not be understood that the description and drawings constituting a part of this disclosure limit the present invention. From this disclosure, various alternative embodiments, examples and operational techniques will be apparent to those skilled in the art.

  For example, in the description of the above embodiment, an example in which PEG is used as the molecular weight standard is shown, but the molecular weight standard is not limited to PEG, and other molecular weight standard such as dextran may be adopted. Assuming that the number of a plurality of molecular weight standard substances having different average molecular weights is n (n is a positive integer of 2 or more), the same evaluation result is obtained when the n molecular weight standard substances are individually measured in series. It can be easily understood that the technical idea of the present invention can be understood from the above description that the remarkable effect that the evaluation can be performed with the evaluation time of / n can be achieved.

  As described above, the present invention naturally includes various embodiments not described herein. Therefore, the technical scope of the present invention is defined only by the invention specifying matters according to the scope of claims reasonable from the above description.

DESCRIPTION OF SYMBOLS 1 ... Cross flow filtration apparatus 2 ... Liquid chromatograph 3 ... Analysis apparatus 11 ... Filtration membrane (measuring object)
DESCRIPTION OF SYMBOLS 12 ... Pump 13 ... Circulation tank 14 ... Heat exchanger 15a ... Supply piping 15b ... Upstream piping 15c ... Circulating fluid piping 15d ... Return piping 15e ... Filtrate piping 21a, 21b, 23a, 23b ... Stop valve 22a, 22b ... Sampling piping 31, 36 ... I / O interface 32 ... CPU
33 ... Chromatogram storage device 34 ... Area storage device 35 ... Rejection rate storage device 37 ... Input device 38 ... Output device 39 ... Display device 111 ... Porous base material 112 ... Glaze seal 113 ... Channel 321 ... Peak area analysis means 322 ... rejection rate calculation means 323 ... rejection rate plotting means 324 ... sampling control means 325 ... liquid chromatograph control means F1 ... flow meter T2 ... thermometer P1 ... upstream pressure gauge P2 ... downstream pressure gauge

Claims (3)

A cross flow filtration device that circulates a circulating liquid obtained by simultaneously dissolving a plurality of molecular weight standard substances having different molecular weights in a solvent, and cross-flow filters the circulating liquid using a filtration membrane;
The filtrate and the circulating liquid that permeate the filtration membrane are sampled from the crossflow filtration device, respectively, and a plurality of peaks corresponding to the plurality of molecular weight standard substances are plotted on the horizontal axis from the sampled filtrate and the circulating liquid. A chromatogram of the filtrate in parallel, and a liquid chromatograph for obtaining a chromatogram of the circulating fluid in which a plurality of peaks corresponding to the plurality of molecular weight standard substances are arranged in parallel on the horizontal axis;
Analyzing each peak area corresponding to the plurality of molecular weight standard substances from the chromatogram of the filtrate, analyzing each peak area corresponding to the plurality of molecular weight standard substances from the chromatogram of the circulating liquid, From the respective peak areas obtained from the chromatogram and the respective peak areas obtained from the chromatogram of the circulating fluid, the rejection rate of the plurality of molecular weight standard substances is determined for each of the plurality of molecular weight standard substances. An analysis device that calculates and plots the calculated rejection rates of the plurality of molecular weight standards on a probability logarithm graph and makes it possible to determine the molecular weight cut-off of the filtration membrane. Filtration membrane evaluation system. The analysis device is
A chromatogram storage device for storing a chromatogram of the filtrate obtained by the liquid chromatograph and a chromatogram of the circulating fluid;
An area storage device for storing the respective peak areas of the molecular weight standard substance of the filtrate and the respective peak areas of the molecular weight standard substance of the circulating liquid;
The filtration membrane evaluation system according to claim 1, further comprising: a rejection rate storage device that stores a rejection rate of each of the plurality of molecular weight standard substances. The analysis device is
Peak area analysis means for analyzing respective peak areas corresponding to the plurality of molecular weight standard substances from the chromatogram of the filtrate and analyzing respective peak areas corresponding to the plurality of molecular weight standard substances from the chromatogram of the circulating liquid When,
From the respective peak areas obtained from the chromatogram of the filtrate and the respective peak areas obtained from the chromatogram of the circulating liquid, the rejection rate of the plurality of molecular weight standard substances is determined for each of the plurality of molecular weight standard substances. And a blocking rate calculation means for calculating each of them,
The filtration membrane evaluation system according to claim 1, further comprising a CPU having a rejection rate plotting unit that plots the calculated rejection rates of the plurality of molecular weight standard substances on a probability logarithmic graph.

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