Dynamic light scattering type particle size distribution measurement device, dynamic light scattering type particle size distribution measurement method, and dynamic light scattering type particle size distribution measurement program

Abstract

A dynamic light scattering type particle size distribution measurement device is provided with: a light irradiation unit that irradiates a sample flowing through a flow path with light; a light detection unit that detects light scattered by the sample; a particle size distribution calculation unit that calculates the particle size distribution of the sample on the basis of the light intensity obtained by the light detection unit; a flow velocity acquisition unit that acquires the flow velocity of the sample flowing through the flow path; and a particle size distribution correction unit that corrects the particle size distribution calculated by the particle size distribution calculation unit on the basis of the flow rate acquired by the flow rate acquisition unit.

Description

Technical Field

[0001] This invention relates to a dynamic light scattering particle size distribution measuring device, a dynamic light scattering particle size distribution measuring method, and a dynamic light scattering particle size distribution measuring procedure. Background Technology

[0002] In the past, among the particle size distribution measuring devices used to determine the particle size distribution of a sample, dynamic light scattering (DLS) particle size distribution measuring devices can be cited. DLS is a method for determining particle size distribution based on the fluctuation of scattered light caused by the Brownian motion of particles in the sample.

[0003] As an example of an online measurement device in such a dynamic light scattering particle size distribution measurement apparatus, as shown in Patent Document 1, an apparatus can be described as follows: Liquid is drawn from a flow path containing particles and introduced into a liquid storage section; light from a light source is irradiated onto the particles introduced into the liquid storage section; and the particle size distribution is measured using dynamic light scattering, utilizing the scattered light generated by the Brownian motion of the particles. This allows for the measurement of the particle size distribution of nanoscale particles. Existing technical documents Patent documents

[0004] Patent Document 1: Japanese Patent Application Publication No. 2002-22642 Summary of the Invention The problem to be solved by the present invention

[0005] However, even in the production process of nanoparticles, such as lipid nanoparticles, whose use in pharmaceuticals is of great interest, there is a need to determine the particle size distribution of these tiny nanoparticles. In this production process, since the flow of the liquid containing the nanoparticles cannot be stopped, it is necessary to determine the particle size distribution of the sample while the liquid is flowing (hereinafter referred to as inline determination).

[0006] However, in the aforementioned dynamic light scattering particle size distribution measuring device, if the particle size distribution is measured while a liquid containing nanoparticles is flowing, the flow rate of the liquid has an effect, resulting in a smaller particle size being measured compared to when the liquid is not flowing. Therefore, the aforementioned dynamic light scattering particle size distribution measuring device is difficult to perform with high precision online, limiting it to online measurement.

[0007] When the flow rate of the liquid containing nanoparticles is sufficiently slow compared to the Brownian motion of the particles, the effect of the liquid flow rate is almost negligible. Therefore, even in the aforementioned dynamic light scattering particle size distribution measuring device, online measurement is possible. However, the flow rate at which the effect of flow rate can be ignored is usually much lower than the flow rate of the liquid in the generation process, making it impractical to use the generation process at such flow rates.

[0008] Therefore, the present invention was made in view of the above-mentioned problems, and its objective is to provide a dynamic light scattering particle size distribution measuring device capable of performing online measurement of particle size distribution with high precision while the sample is flowing in a flow path. Methods for solving problems

[0009] That is, the dynamic light scattering particle size distribution measuring device of the present invention is characterized by comprising: a light irradiation unit for irradiating a sample contained in a test liquid flowing in a flow path with light; a light detection unit for detecting light scattered by the sample; a particle size distribution calculation unit for calculating the particle size distribution of the sample based on the light intensity signal obtained by the light detection unit; a flow rate acquisition unit for acquiring the flow rate of the test liquid flowing in the flow path; and a particle size distribution correction unit for correcting the particle size distribution calculated by the particle size distribution calculation unit based on the flow rate acquired by the flow rate acquisition unit.

[0010] In such a dynamic light scattering particle size distribution measuring device, the particle size distribution correction unit corrects the particle size distribution calculated by the particle size distribution calculation unit based on the flow rate obtained by the flow rate acquisition unit. Therefore, in the corrected particle size distribution, the influence of flow rate, which is less affected by the flow of the liquid being tested, can be reduced. As a result, high-precision online measurement can be performed without stopping the flow of the sample in the flow path. In particular, dynamic light scattering particle size distribution measuring devices are suitable for measuring the particle size distribution of nanoparticles with a diameter of, for example, less than 100 nm with high precision. However, dynamic light scattering particle size distribution measuring devices are easily affected by flow rate. On the other hand, in the dynamic light scattering particle size distribution measuring device of the present invention, the particle size distribution can be obtained with high precision even when the sample containing nanoparticles is flowing.

[0011] As a specific method for calculating the particle size distribution based on the flow rate correction of the detected liquid, the following method can be cited: it further includes a relational data storage unit, which stores relational data representing the relationship between the particle size of particles with known particle size and the flow rate of the detected liquid, and the particle size distribution correction unit corrects the particle size distribution calculated by the particle size distribution calculation unit based on the flow rate obtained by the flow rate acquisition unit and the relational data stored in the relational data storage unit.

[0012] As a specific method for correcting particle sizes that are measured to be smaller than those measured when the flow rate is 0 due to the influence of flow rate, the following method can be used: the relational data consists of true particle size and apparent particle size, where the true particle size is the particle size of the particles when the flow rate of the liquid being tested is 0, and the apparent particle size is the particle size measured at the flow rate of the liquid being tested. The particle size distribution correction unit obtains the apparent particle size corresponding to the flow rate obtained by the flow rate acquisition unit from the relational data storage unit, and corrects the apparent particle size to the true particle size, thereby correcting the particle size distribution.

[0013] Here, when comparing the frequency distribution when the flow rate of the tested liquid is 0 with the frequency distribution when the tested liquid flows in the flow path, it is easy to compare and simplify the rewriting of the frequency distribution graph if the scale of the horizontal axis is set to the apparent particle size in both frequency distributions. Therefore, in the frequency distribution when the tested liquid flows in the flow path, it is preferable to change the scale of the horizontal axis to the apparent particle size.

[0014] Therefore, preferably, the particle size distribution correction unit calculates a frequency distribution by correcting the apparent particle size to the true particle size, the frequency distribution being a particle size distribution representing the frequency of the particle size relative to the true particle size. After calculating the frequency distribution, the particle size distribution correction unit sets the scale of the horizontal axis of the frequency distribution to the apparent particle size and corrects the frequency of the frequency distribution with the scale of the horizontal axis set to the apparent particle size, so that the cumulative distribution obtained from the frequency distribution with the scale of the horizontal axis set to the true particle size is consistent with the cumulative distribution obtained from the frequency distribution with the scale of the horizontal axis set to the apparent particle size.

[0015] Preferably, the relational data storage unit stores multiple relational data of multiple particles with different known particle sizes, and the particle size distribution correction unit corrects the particle size distribution calculated by the particle size distribution calculation unit based on the flow rate obtained by the flow rate acquisition unit and the relational data of the multiple particles.

[0016] With this configuration, the relational data storage unit stores relational data for multiple particle sizes, and the particle size distribution correction unit corrects the particle size distribution based on this relational data. Therefore, among multiple particle sizes, the influence of flow velocity can be reduced, resulting in a more accurate particle size distribution. In particular, larger particles are more susceptible to the influence of flow velocity. By correcting the particle size distribution based on the relational data for larger particle sizes, the particle size distribution correction unit can reduce the influence of flow velocity and obtain a more accurate particle size distribution for larger particle sizes.

[0017] Preferably, the relational data is a correction function, which is a function representing the change in particle size relative to the change in flow rate of the detected liquid, and the particle size distribution correction unit corrects the particle size distribution calculated by the particle size distribution calculation unit based on the flow rate obtained by the flow rate acquisition unit and the correction function.

[0018] With this configuration, once the flow rate is obtained by the particle size distribution correction unit, the unit can use a correction function to calculate the particle size affected by the obtained flow rate. Then, the unit can use the correction function to correct the particle size affected by the flow rate.

[0019] To further reduce the impact of flow velocity and obtain a more accurate particle size distribution, the following method can be used: the particle size distribution correction unit corrects the distribution width or mode of the particle size distribution calculated by the particle size distribution calculation unit based on the flow velocity obtained by the flow velocity acquisition unit.

[0020] When the sample is in laminar flow, the variation in flow velocity is smaller compared to when the sample is in turbulent flow. Therefore, the influence of flow velocity can be more accurately incorporated into the particle size distribution. Therefore, it is preferable that the light irradiation unit irradiates the sample flowing in the flow path in a laminar flow state.

[0021] With this configuration, the particle size distribution can be measured when the sample flows in a laminar state in the flow path. Therefore, compared with the measurement under turbulent conditions, a particle size distribution that has been more accurately corrected for the influence of flow velocity can be obtained.

[0022] Preferably, the position where the liquid being tested flows within the flow path at the flow rate obtained by the flow rate acquisition unit is the same as the focal point of the light irradiated by the light irradiation unit.

[0023] With this configuration, the position of the light irradiation unit and the position of the flow velocity acquisition unit become the same. Therefore, the particle size distribution calculated by the particle size distribution calculation unit becomes a particle size distribution affected by the flow velocity acquired by the flow velocity acquisition unit. As a result, the flow velocity in the particle size distribution to be corrected becomes the same as the flow velocity used during the correction. Therefore, the particle size distribution correction unit can correct the particle size distribution more accurately.

[0024] Specifically, preferably, the light irradiation unit irradiates the sample with light that has a focal point at a position that becomes the average flow velocity of the sample flowing in the flow path, the flow velocity acquisition unit acquires the average flow velocity of the sample flowing in the flow path, and the particle size distribution correction unit corrects the particle size distribution calculated by the particle size distribution calculation unit based on the average flow velocity.

[0025] With this configuration, the average flow rate can be calculated correctly and easily using known general formulas. The particle size distribution correction unit corrects the particle size distribution calculated by the particle size distribution calculation unit based on the average flow rate. Compared with the case where the particle size distribution is corrected based on a flow rate other than the average flow rate, the influence of the sample flow on the particle size distribution can be reduced more accurately and easily.

[0026] As a specific example of the dynamic light scattering particle size distribution measuring device, a probe-type dynamic light scattering particle size distribution measuring device can be cited.

[0027] A dynamic light scattering particle size distribution determination method is characterized by: irradiating a sample flowing in a flow path with light; detecting the light scattered by the sample; calculating the particle size distribution of the sample based on the light intensity obtained by the light detection unit; obtaining the flow rate of the liquid being tested flowing in the flow path; and correcting the particle size distribution calculated by the particle size distribution calculation unit based on the flow rate obtained by the flow rate acquisition unit.

[0028] If configured in this way, the same effect as the aforementioned dynamic light scattering particle size distribution measuring device can be achieved.

[0029] A dynamic light scattering particle size distribution measurement program is characterized in that the program is used in a dynamic light scattering particle size distribution measurement device, the device comprising: a light irradiation unit for irradiating a sample flowing in a flow path with light; and a light detection unit for detecting the light scattered by the sample. The program enables a computer to function as a particle size distribution calculation unit, a flow rate acquisition unit, and a particle size distribution correction unit. The particle size distribution calculation unit calculates the particle size distribution of the sample based on the light intensity obtained by the light detection unit. The flow rate acquisition unit acquires the flow rate of the liquid being tested flowing in the flow path. The particle size distribution correction unit corrects the particle size distribution calculated by the particle size distribution calculation unit based on the flow rate acquired by the flow rate acquisition unit.

[0030] If configured in this way, the same effect as the aforementioned dynamic light scattering particle size distribution measuring device can be achieved. Invention Effects

[0031] According to the present invention configured in this way, a dynamic light scattering particle size distribution measuring device can be provided to perform online measurement of particle size distribution with high precision while the sample is flowing in a flow path. Attached Figure Description

[0032] Figure 1 This is a schematic diagram illustrating a dynamic light scattering particle size distribution measuring device according to one embodiment of the present invention. Figure 2 This is a graph showing the particle size distribution calculated by the particle size distribution calculation unit in the same embodiment. Figure 3 This is a schematic diagram illustrating the correction of particle size distribution in the dynamic light scattering particle size distribution measuring device of the same embodiment. Figure 4 (a) is a graph showing the particle size distribution before correction in the same embodiment, (b) is a graph showing the frequency distribution with the actual representative particle size set as the scale on the horizontal axis, and (c) is a graph showing the frequency distribution with the representative particle size calculated by the particle size distribution calculation unit set as the scale on the horizontal axis. Figure 5 This is a schematic diagram illustrating the correction of particle size distribution in other embodiments. Figure 6 This is a schematic diagram illustrating a dynamic light scattering particle size distribution measuring device in other embodiments. Detailed Implementation

[0033] Hereinafter, an embodiment of the dynamic light scattering particle size distribution measuring apparatus using the analytical device of the present invention will be described with reference to the accompanying drawings. Furthermore, for ease of understanding, some of the drawings shown below may be appropriately omitted or depicted schematically with exaggerated reference numerals. The same reference numerals are used to label the same constituent elements, and descriptions are appropriately omitted.

[0034] <Device Structure> The dynamic light scattering particle size distribution measuring apparatus 100 of this embodiment measures the particle size distribution of a sample containing nanoparticles such as lipid nanoparticles in a liquid being tested, using dynamic light scattering. Furthermore, the state in which the liquid containing the sample flows in the flow path L refers to a state in which the effect of flow velocity cannot be ignored when measuring particle size distribution using dynamic light scattering.

[0035] Specifically, the dynamic light scattering particle size distribution measuring device 100 includes: a light irradiation unit 10 that irradiates light onto a sample flowing in a flow path L; a light detection unit 20 that detects the light scattered by the sample; and a calculation unit 30 that calculates the particle size distribution of the sample. The configuration of each part will be described below.

[0036] The light irradiation unit 10 includes a light source 11 that emits light. The light source 11 is, for example, a laser light source. Furthermore, the light emitted from the light source 11 is guided into the flow path L via, for example, an irradiation optical system 12 such as a condenser lens, and irradiates the sample flowing in the flow path L. In this embodiment, the light irradiation unit 10 irradiates light toward a transmission window M provided in the piping constituting the flow path L.

[0037] In this embodiment, the laser light source 11 irradiates light with a polarization direction parallel to the flow direction of the liquid being tested. Furthermore, to irradiate in a polarization direction parallel to the flow direction of the liquid being tested, a polarizing plate may be provided along the optical path from the light source 11 to the point where the light irradiates the sample.

[0038] The light detection unit 20 includes: a detection optical system 21, which is an optical system for detecting scattered light from a sample; and a photodetector 22, which converts the scattered light focused by the detection optical system 21 into an electrical detection signal; and so on. Furthermore, in this embodiment, the photodetector 22 is, for example, a photomultiplier tube (PMT). Additionally, in this embodiment, the detection optical system 21 is common to the illumination optical system 12, but it can also be provided separately from the illumination optical system 12.

[0039] The arithmetic unit 30 is a general-purpose or special-purpose computer equipped with a CPU and memory. According to a program stored in a predetermined area of ​​the memory, the CPU and its peripheral devices work together to perform the functions of a particle size distribution calculation unit 31, a flow rate acquisition unit 32, a relational data storage unit 33, and a particle size distribution correction unit 34. Furthermore, in addition to a computer, the arithmetic unit 30 can also be a digital arithmetic device such as a field-programmable gate array (FPGA). The configuration of each part of the arithmetic unit 30 will be described below.

[0040] The particle size distribution calculation unit 31 calculates the particle size distribution based on the light intensity signal obtained by the light detection unit 20. Specifically, the particle size distribution calculation unit 31 analyzes the wave signal generated by the Brownian motion of the particles based on the light intensity signal obtained by the light detector 22, and calculates the particle size corresponding to the wave signal.

[0041] More specifically, the particle size distribution calculation unit 31 calculates the autocorrelation function g2(t) based on the time variation of the wave signal. In this embodiment, the autocorrelation function g2(t) is the superposition of waves caused by multiple particles of different sizes. The calculated autocorrelation function g2(t) is represented by the following mathematical formula 1.

[0042] [Mathematical Expression 1] Furthermore, i represents the particle size column with the smallest unit width in the particle size distribution, Γ iA is the representative particle size in particle size column i. i It represents the intensity of scattered light from all particles, specifically from the particle size Γ. i The weighting coefficient for the contribution of the scattered light intensity, n is the maximum value of the particle size column, and is a device constant determined by the device constituting the particle size distribution calculation unit 31.

[0043] Here, the weighting coefficient A of each particle size series i is calculated in one step by fitting the autocorrelation function obtained through measurement using mathematical formula 1. i The calculated weighting coefficient A i Corresponding to the frequency of particle size distribution. The result is as follows: Figure 2 As shown, the particle size distribution calculation unit 31 calculates the frequency distribution, which represents the frequency distribution for all representative particle sizes Γ. i The frequency of particle size distribution.

[0044] The flow rate acquisition unit 32 acquires the flow rate of the liquid being tested flowing in the flow path L. Specifically, the flow rate acquisition unit 32 acquires the flow rate measured by the flow rate sensor FM, which measures the flow rate of the liquid being tested.

[0045] The relational data storage unit 33 stores relational data representing the relationship between the particle size of particles with known particle size and the flow rate of the liquid being detected. In this embodiment, the relational data is a correction function F, which is a function representing the change in particle size relative to the change in the flow rate of the liquid being detected.

[0046] Here, for example, a correction function F is constructed for a known standard particle size using polystyrene latex. Specifically, the correction function F is constructed by calculating the particle size (hereinafter also referred to as the apparent particle size) at different flow rates, compared to the particle size when the flow rate of the liquid containing the standard particles is 0. More specifically, as... Figure 3 As shown, for example, a particle size D1 with a flow rate of 0 for a liquid containing standard particles, the apparent particle size D1 is calculated at different flow rates. Then, a correction function F1 for the particle size D1 is constructed by connecting the points of the apparent particle size.

[0047] In this embodiment, for particles with a diameter D2 different from the diameter D1 when the flow rate of the liquid containing the standard particles is 0, and for particles with a diameter D3 different from the diameter D1, correction functions F1, F2, and F3 are created respectively, identical to the correction function F1 for diameter D1. The created correction functions F1, F2, or F3 are stored in the relational data storage unit 33. Furthermore, in Figure 3 In this model, there are three correction functions F and three particle sizes, but the number of correction functions F and particle sizes is not limited.

[0048] Then, the particle size distribution correction unit 34 corrects the particle size distribution calculated by the particle size distribution calculation unit 31 based on the flow rate obtained by the flow rate acquisition unit 32. In this embodiment, the particle size distribution correction unit 34 corrects the particle size distribution calculated by the particle size distribution calculation unit 31 based on the flow rate obtained by the flow rate acquisition unit 32 and the correction function stored in the relational data storage unit 33.

[0049] Specifically, the particle size distribution correction unit 34 obtains the flow velocity measured by the flow velocity sensor FM from the flow velocity acquisition unit 32, and obtains the representative particle size Γ of the particle size distribution calculated by the particle size distribution calculation unit 31 from the relational data storage unit 33. i The corresponding correction function. The representative particle size Γ of the particle size distribution calculated by the particle size distribution calculation unit 31. i The apparent representative particle size is affected by the flow rate of the liquid being tested. Therefore, the particle size distribution correction unit 34 uses a particle size distribution Γ that represents the particle size. i The corresponding correction function is used to calculate the representative particle size Γg when the flow rate of the detected liquid is 0. i (Hereinafter also referred to as the true representative particle size Γg) i ).

[0050] In this embodiment, the particle size distribution correction unit 34 calculates the representative particle size Γ of all particle size columns of the frequency distribution calculated by the particle size distribution calculation unit 31. i Correction is performed. The particle size distribution correction unit 34 obtains the representative particle size Γ of each particle size column from the relational data storage unit 33. i The corresponding correction function. Then, the particle size distribution correction unit 34 uses the corresponding correction function for each representative particle size Γ. i The corresponding correction functions are calculated for each representative particle size Γ. i The true representative particle size Γg i Then, the particle size distribution correction unit 34 calculates the frequency distribution, which represents the true representative particle size Γg. i The frequency of particle size distribution. The results, such as... Figure 4 As shown in (b), the representative particle sizes Γ of the scale forming the horizontal axis of the frequency distribution are... i To each true representative particle size Γg corresponding to each correction function i Offset, and each representative particle size Γ i The corresponding frequencies also shift in accordance with this offset. Furthermore, in Figure 4 In (b), the overall shape of the frequency distribution remains unchanged because the frequency of the particle size is not corrected.

[0051] Here, the representative particle size Γ for the entire particle size series is... i When correction is performed, it is compared with the representative particle size Γ iSometimes the corresponding correction function is not stored in the relational data storage unit 33. In this case, the particle size distribution correction unit 34 can also correct the representative particle size Γ corresponding to the correction function that is not stored in the relational data storage unit 33. i Correction is performed. For example, when correcting a representative particle size ΓX that is smaller than the representative particle size Γ2 and larger than the representative particle size Γ1, the particle size distribution correction unit 34 calculates a correction function FX corresponding to the representative particle size ΓX by linearly interpolating the correction function F1 corresponding to the representative particle size Γ1 and F2 corresponding to the representative particle size Γ2. Then, the particle size distribution correction unit 34 calculates the true representative particle size ΓgX based on the correction function FX, in the same manner as the correction of the representative particle size described above.

[0052] Here, when comparing the frequency distribution when the flow rate of the tested liquid is 0 with the frequency distribution when the tested liquid flows in the flow path L, the scale of the horizontal axis is set to the apparent representative particle size Γ in both frequency distributions. i In this case, comparisons are easy, and rewriting the frequency distribution graph becomes simple. Therefore, in the frequency distribution when the tested liquid flows in the flow path L, it is preferable to transform the scale of the horizontal axis to the apparent representative particle size Γ. i Therefore, the particle size distribution correction unit 34 can also set the scale of the horizontal axis of the frequency distribution to the apparent representative particle size Γ. i The scale of the horizontal axis is set to the apparent representative particle size Γ. i The frequency distribution is corrected so that the scale of the horizontal axis is set to the true particle size Γg. i The cumulative distribution obtained from the frequency distribution is compared with the apparent representative particle size Γ, where the scale of the horizontal axis is set. i The cumulative distribution obtained from the frequency distribution is consistent.

[0053] Specifically, the particle size distribution correction unit 34 is based on setting the scale of the horizontal axis to the true particle size Γg. i The frequency distribution was calculated by setting the scale of the horizontal axis to the actual particle size Γg. i The cumulative distribution. The particle size distribution correction unit 34 obtains the mode of the particle size, the particle size with a cumulative frequency of 10% (D10), the particle size with a cumulative frequency of 50% (D50), or the particle size with a cumulative frequency of 90% (D90) from the calculated cumulative distribution.

[0054] After calculating and setting the scale of the horizontal axis to the actual particle size Γg i After the cumulative distribution, the particle size distribution correction unit 34, as shown Figure 4 As shown in (c), the horizontal axis of the frequency distribution is scaled toward the apparent representative particle size Γ. i The offset is then corrected. The particle size distribution correction unit 34 then adjusts each representative particle size Γ. i The frequency of the particle size is used to set the scale of the horizontal axis to the actual particle size Γg.i The cumulative distribution and the setting of the horizontal axis scale to represent the particle size Γ i The cumulative distribution obtained from the frequency distribution is consistent. Specifically, the particle size distribution correction unit 34 has a scale on the horizontal axis representing the particle size Γ. i In the frequency distribution, adjustments are made for all representative particle sizes Γ. i The frequency, so that the scale of the horizontal axis represents the particle size Γ. i The cumulative distribution, such as D10, D50, or D90, and the scale on the horizontal axis represent the true representative particle size Γg. i The cumulative distribution is consistent with, for example, D10, D50, or D90.

[0055] <Dynamic Light Scattering Particle Size Distribution Measurement Method> Next, the analytical method using the dynamic light scattering particle size distribution measuring device 100 of this embodiment will be described.

[0056] When the test liquid containing nanoparticles flows in the flow path L, if the light source 11 irradiates light onto the sample via the illumination optical system 12, the nanoparticles in the sample will cause light scattering. The photodetector 22 converts the intensity of the scattered light into a light intensity signal via the detection optical system 21 for detection. Additionally, the flow rate sensor FM measures the flow rate of the test liquid, and the flow rate acquisition unit 32 acquires the flow rate of the test liquid measured by the flow rate sensor FM.

[0057] If a light intensity signal is detected, the particle size distribution calculation unit 31 analyzes the wave signal based on the light intensity signal and calculates the particle size based on the wave signal. The particle size calculated here is smaller than the particle size calculated when the liquid being detected is stationary due to the influence of the flow rate of the detected liquid. In this embodiment, the particle size distribution calculation unit 31 performs the above-mentioned particle size calculation on all light intensity signals detected by the light detection unit 20 to calculate the particle size distribution.

[0058] If the particle size distribution is calculated, the particle size distribution correction unit 34 obtains the flow rate obtained by the flow rate acquisition unit 32. Additionally, the particle size distribution correction unit 34 obtains a correction function from the relational data storage unit 33.

[0059] Then, the particle size distribution correction unit 34 uses multiple correction functions obtained from the relational data storage unit 33 to correct multiple particle sizes affected by the flow rate, and corrects the particle size distribution calculated by the particle size distribution calculation unit 31. The corrected particle size distribution can be output to a display unit D, such as a display.

[0060] <Effects of this implementation method> According to the dynamic light scattering particle size distribution measuring device 100 of this embodiment, the particle size distribution correction unit 34 corrects the particle size distribution calculated by the particle size distribution calculation unit 31 based on the flow rate obtained by the flow rate acquisition unit 32. Therefore, in the corrected particle size distribution, the influence of flow rate, such as the relatively small particle size measurement due to the flow rate of the liquid being tested, can be reduced. As a result, online measurement with high accuracy can be performed without stopping the flow of the sample in the flow path L. In particular, the dynamic light scattering particle size distribution measuring device 100 of this embodiment can obtain the particle size distribution of a sample containing nanoparticles that are easily affected by flow rate with high precision by online measurement.

[0061] Furthermore, according to this embodiment, the relational data storage unit 33 stores correction coefficients for each of the multiple particle sizes, and the particle size distribution correction unit 34 corrects the particle size distribution based on the correction coefficients for each of the multiple particle sizes. Therefore, the influence of flow velocity can be reduced among the multiple particle sizes, and a more accurate particle size distribution can be obtained. In particular, larger particles are more easily affected by flow velocity. The particle size distribution correction unit 34 corrects the particle size distribution based on the correction coefficients for larger particle sizes, thereby reducing the influence of flow velocity among larger particle sizes and obtaining a more accurate particle size distribution. In this embodiment, since the particle size distribution correction unit 34 corrects the particle size distribution across all particle size columns, it can more accurately correct the particle size distribution.

[0062] Furthermore, in this embodiment, the relational data is a correction function, which represents the change in particle size relative to the change in flow rate of the sample. Therefore, when the particle size distribution correction unit 34 obtains the flow rate from the flow rate acquisition unit 32, the particle size distribution correction unit 34 can use the correction function to calculate the particle size affected by the flow rate. Then, the particle size distribution correction unit 34 can use the correction function to correct the particle size affected by the flow rate.

[0063] <Other Implementation Methods> Furthermore, the present invention is not limited to the embodiments described above.

[0064] In the above embodiment, the particle size distribution correction unit 34 calculates the representative particle size Γ of all particle size columns of the particle size distribution calculated by the particle size distribution calculation unit 31. i Correction can be performed, but it is also possible not to use the representative particle size Γ for all particle size columns. i Correction is performed. For example, the particle size distribution correction unit 34 can also correct the representative particle size Γ corresponding to the mode in the particle size distribution calculated by the particle size distribution calculation unit 31. iCorrection is performed. In this case, the position of the mode shifts towards a larger particle size, and the overall particle size distribution also shifts parallel to this shift. As a result, the shape of the particle size distribution after correction by the particle size distribution correction unit 34 remains unchanged. Furthermore, in addition to the mode, the particle size distribution correction unit 34 can also correct the representative particle size Γ corresponding to the median, average, diameter with a cumulative frequency of 10% (D10), diameter with a cumulative frequency of 90% (D90), or other diameters with any proportion of cumulative frequency. i Perform corrections.

[0065] In the above embodiment, the particle size distribution correction unit 34 corrects the particle size distribution by correcting each particle size of the particle size distribution calculated by the particle size distribution calculation unit 31. However, the particle size distribution correction unit 34 can also correct the distribution width or mode of the particle size distribution calculated by the particle size distribution calculation unit 31. Specifically, as... Figure 5 As shown, the particle size distribution correction unit 34 increases the distribution width of the particle size distribution compared to the particle size distribution before correction. Furthermore, the particle size distribution correction unit 34 can also correct the position of the mode of the particle size distribution to a position of a particle size larger than the position of the mode of the particle size distribution before correction, and correct the magnitude of the mode to be smaller. This further reduces the influence of flow velocity, resulting in a more accurate particle size distribution.

[0066] In the above embodiments, the dynamic light scattering particle size distribution measuring device 100 can also perform the measurement when the liquid being tested flows in a laminar flow state in the flow path L. Specifically, as... Figure 6 As shown, a rectification section Z can be provided in the flow path L upstream of the position irradiated by the light irradiation unit 10 to rectify the liquid to be tested into a laminar flow state, so that the light irradiation unit 10 irradiates the liquid to be tested flowing in a laminar flow state in the flow path L. Therefore, compared with the case where the liquid to be tested is flowing in a turbulent state in the flow path L, the dynamic light scattering particle size distribution measuring device 100 can more accurately correct the influence of flow velocity. Furthermore, the rectification section Z can be, for example, a small-diameter flow path such as a capillary tube, and the entire flow path L can also be constructed from this small-diameter flow path.

[0067] In the above embodiment, the position of the detected liquid within the flow path L measured by the flow velocity sensor is not particularly limited, but it is also possible to make the position of the detected liquid flowing within the flow path L at the flow velocity obtained by the flow velocity acquisition unit 32 the same as the focal point of the light irradiated by the light irradiation unit 10. For example, the flow velocity sensor can measure the flow velocity of the detected liquid at the focal point of the light irradiated by the light irradiation unit 10. If this is configured, the position of the light irradiated by the light irradiation unit 10 is the same as the position of the flow velocity measured by the flow velocity sensor FM, so the particle size distribution calculated by the particle size distribution calculation unit 31 is affected by the flow velocity measured by the flow velocity sensor FM. As a result, since the flow velocity that affects the particle size distribution to be corrected is the same as the flow velocity used during the correction, the particle size distribution correction unit can more accurately correct the particle size distribution.

[0068] For example, the particle size distribution correction unit 34 can also correct the particle size distribution based on the average flow velocity. Specifically, such as Figure 6 As shown, the light irradiation unit 10 irradiates light with a focal point at the position where the flow velocity of the liquid being tested flowing in the flow path L becomes the average flow velocity, and the flow velocity acquisition unit 32 acquires the average flow velocity of the liquid being tested. Here, the average flow velocity acquired by the flow velocity acquisition unit 32 can be, for example, the maximum flow velocity calculated by the computing device, or the average flow velocity measured by the flow velocity sensor. Therefore, compared with the case where the particle size distribution is corrected based on a flow velocity other than the average flow velocity, the influence caused by the flow velocity can be reduced more accurately and simply in the particle size distribution. In addition, besides the average flow velocity, the particle size distribution correction unit 34 can also correct the particle size distribution based on, for example, the maximum flow velocity, as long as the position where the liquid being tested flows in the flow path at the flow velocity acquired by the flow velocity acquisition unit 32 is the same as the focal point of the light irradiated by the light irradiation unit 10.

[0069] In the above embodiments, as a specific example of the dynamic light scattering particle size distribution measuring device 100, a probe-type dynamic light scattering particle size distribution measuring device can be cited, but it is not limited to a probe-type dynamic light scattering particle size distribution measuring device as long as it is a device that measures particle size distribution by dynamic light scattering.

[0070] In the above embodiments, the relational data is a correction function that represents the change in particle size relative to the change in flow rate of the sample. However, the relational data is not limited to the correction function. For example, the relational data may also be a correction coefficient for particle size that makes the correction affected by the flow rate, or a correspondence table between each particle size and each flow rate.

[0071] In the above embodiment, the dynamic light scattering particle size distribution measuring device 100 includes a relational data storage unit 33, but it may also omit the relational data storage unit 33. Specifically, the particle size distribution correction unit 34 only needs to correct the particle size distribution based at least on the flow rate obtained by the flow rate acquisition unit 32.

[0072] The relational data storage unit 33 stores correction functions F1, F2, and F3 corresponding to multiple particle sizes D1, D2, and D3, but it can also store a correction function corresponding to a single particle size. In this case, the particle size distribution correction unit 34 can also obtain the correction function stored in the relational data storage unit 33 and calculate correction coefficients corresponding to other particle sizes based on the correction function.

[0073] In the above embodiment, a correction function is created by calculating the particle size distribution calculation unit 31, assuming different flow rates, and connecting the points of the assumed particle size. However, this is not a limitation. For example, a correction function can also be created by calculating the flow rate at different particle sizes and connecting the points of the flow rate.

[0074] In the above embodiment, the flow rate acquisition unit 32 acquires the flow rate measured by the flow rate sensor, but the flow rate acquired by the flow rate acquisition unit 32 is not limited to this. For example, the flow rate acquisition unit 32 may also acquire the flow rate calculated based on the flow rate measured by the flow sensor that measures the flow rate of the detected liquid flowing in the flow path L. In addition, the flow rate acquisition unit 32 may also acquire the flow rate obtained by converting the pressure measured by the pressure sensor that measures the pressure of the detected liquid flowing in the flow path L, for example, using Bernoulli's theorem. Furthermore, the flow rate acquisition unit 32 may acquire any physical property value that can be converted into a flow rate.

[0075] Furthermore, various modifications and combinations of embodiments are possible as long as they do not violate the spirit of this invention. Industrial applicability

[0076] According to the present invention, a dynamic light scattering particle size distribution measuring device is provided that can perform online measurement of particle size distribution with high precision while the sample is flowing in a flow path. Explanation of reference numerals in the attached figures:

[0077] 100: Dynamic light scattering particle size distribution measuring device; 10: Light irradiation unit; 20: Light detection unit; 30: Calculation unit; 31: Particle size distribution calculation unit; 32: Flow rate acquisition unit; 33: Relational data storage unit; 34: Particle size distribution correction unit; F: Correction function; L: Flow path.

Claims

1. A dynamic light scattering particle size distribution measuring device, wherein, The dynamic light scattering particle size distribution measuring device includes: The light irradiation section irradiates the sample contained in the liquid being tested flowing in the flow path with light; The photodetector detects the light scattered by the sample. The particle size distribution calculation unit calculates the particle size distribution of the sample based on the light intensity signal obtained by the light detection unit. The flow rate acquisition unit acquires the flow rate of the detected liquid flowing in the flow path; and The particle size distribution correction unit corrects the particle size distribution calculated by the particle size distribution calculation unit based on the flow rate obtained by the flow rate acquisition unit.

2. The dynamic light scattering particle size distribution measuring device according to claim 1, wherein, The dynamic light scattering particle size distribution measuring device also includes a relational data storage unit, which stores relational data representing the relationship between the particle size of particles with known particle size and the flow rate of the liquid being tested. The particle size distribution correction unit corrects the particle size distribution calculated by the particle size distribution calculation unit based on the flow rate obtained by the flow rate acquisition unit and the relational data stored in the relational data storage unit.

3. The dynamic light scattering particle size distribution measuring device according to claim 2, wherein, The relationship data consists of true particle size and apparent particle size. The true particle size is the particle size when the flow rate of the tested liquid is 0, and the apparent particle size is the particle size measured at the flow rate of the tested liquid. The particle size distribution correction unit obtains the apparent particle size corresponding to the flow rate obtained by the flow rate acquisition unit from the relational data storage unit, and corrects the apparent particle size to the actual particle size, thereby correcting the particle size distribution.

4. The dynamic light scattering particle size distribution measuring device according to claim 3, wherein, The particle size distribution correction unit corrects the apparent particle size to the true particle size and calculates a frequency distribution, which is a particle size distribution representing the frequency of particles with respect to the true particle size. After calculating the frequency distribution, the particle size distribution correction unit sets the scale of the horizontal axis of the frequency distribution to the apparent particle size, and corrects the frequency of the frequency distribution with the scale of the horizontal axis set to the apparent particle size, so that the cumulative distribution obtained from the frequency distribution is consistent with the cumulative distribution obtained from the frequency distribution with the scale of the horizontal axis set to the apparent particle size.

5. The dynamic light scattering particle size distribution measuring device according to claim 3 or 4, wherein, The relational data storage unit stores multiple relational data for multiple particles with different known particle sizes. The particle size distribution correction unit corrects the particle size distribution calculated by the particle size distribution calculation unit based on the flow rate obtained by the flow rate acquisition unit and the relationship data of the plurality of particles.

6. The dynamic light scattering particle size distribution measuring device according to any one of claims 2 to 5, wherein, The relationship data is a correction function, which is a function representing the change in particle size relative to the change in the flow rate of the detected liquid. The particle size distribution correction unit corrects the particle size distribution calculated by the particle size distribution calculation unit based on the flow velocity obtained by the flow velocity acquisition unit and the correction function.

7. The dynamic light scattering particle size distribution measuring device according to any one of claims 1 to 6, wherein, The particle size distribution correction unit corrects the distribution width or mode of the particle size distribution calculated by the particle size distribution calculation unit based on the flow velocity obtained by the flow velocity acquisition unit.

8. The dynamic light scattering particle size distribution measuring device according to any one of claims 1 to 7, wherein, The light irradiation unit irradiates the sample contained in the liquid being tested, which is flowing in a laminar state in the flow path.

9. The dynamic light scattering particle size distribution measuring device according to any one of claims 1 to 8, wherein, The position where the liquid being tested flows within the flow path at the flow rate obtained by the flow rate acquisition unit is the same as the focal point of the light irradiated by the light irradiation unit.

10. The dynamic light scattering particle size distribution measuring device according to any one of claims 1 to 9, wherein, The light irradiation unit irradiates the sample with light at a focal point where the flow velocity of the tested liquid flowing in the flow path reaches the average flow velocity. The flow rate acquisition unit acquires the average flow rate of the detected liquid flowing in the flow path. The particle size distribution correction unit corrects the particle size distribution calculated by the particle size distribution calculation unit based on the average flow velocity.

11. The dynamic light scattering particle size distribution measuring device according to any one of claims 1 to 10, wherein, The dynamic light scattering particle size distribution measuring device is a probe-type dynamic light scattering particle size distribution measuring device.

12. A dynamic light scattering method for determining particle size distribution, wherein, Irradiate the sample contained in the liquid being tested flowing in the flow path with light; Detect the light scattered by the sample; The particle size distribution of the sample is calculated based on the detected light intensity. Obtain the flow rate of the detected liquid flowing in the flow path; The calculated particle size distribution is corrected based on the obtained flow rate.

13. A dynamic light scattering-based particle size distribution determination procedure, wherein, The dynamic light scattering particle size distribution measurement program is used in a dynamic light scattering particle size distribution measurement device, which includes: a light irradiation unit for irradiating light onto a sample contained in a liquid being tested flowing in a flow path; and a light detection unit for detecting the light scattered by the sample. The dynamic light scattering particle size distribution measurement program enables the computer to function as a particle size distribution calculation unit, a flow rate acquisition unit, and a particle size distribution correction unit. The particle size distribution calculation unit calculates the particle size distribution of the sample based on the light intensity obtained by the light detection unit. The flow rate acquisition unit acquires the flow rate of the detected liquid flowing in the flow path. The particle size distribution correction unit corrects the particle size distribution calculated by the particle size distribution calculation unit based on the flow rate obtained by the flow rate acquisition unit.

Images