NL2032163B1 - Method for diluting a suspension and for determining a particle size or a particle size distribution therein - Google Patents
Method for diluting a suspension and for determining a particle size or a particle size distribution therein Download PDFInfo
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- 239000002245 particle Substances 0.000 title claims abstract description 189
- 238000000034 method Methods 0.000 title claims abstract description 94
- 239000000725 suspension Substances 0.000 title claims abstract description 80
- 238000009826 distribution Methods 0.000 title claims abstract description 58
- 238000007865 diluting Methods 0.000 title description 4
- 239000003085 diluting agent Substances 0.000 claims description 96
- 239000000523 sample Substances 0.000 claims description 93
- 238000010790 dilution Methods 0.000 claims description 85
- 239000012895 dilution Substances 0.000 claims description 85
- 239000012530 fluid Substances 0.000 claims description 45
- 230000008569 process Effects 0.000 claims description 34
- 238000001514 detection method Methods 0.000 claims description 33
- 238000005259 measurement Methods 0.000 claims description 26
- 238000012360 testing method Methods 0.000 claims description 16
- 239000006070 nanosuspension Substances 0.000 claims description 15
- 239000012470 diluted sample Substances 0.000 claims description 13
- 238000002156 mixing Methods 0.000 claims description 13
- 230000003068 static effect Effects 0.000 claims description 13
- 238000006073 displacement reaction Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
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- 230000002572 peristaltic effect Effects 0.000 claims description 3
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
- G01N1/38—Diluting, dispersing or mixing samples
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
- G01N15/02—Investigating particle size or size distribution
- G01N15/0205—Investigating particle size or size distribution by optical means
- G01N15/0211—Investigating a scatter or diffraction pattern
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
- G01N2015/0038—Investigating nanoparticles
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
- G01N15/02—Investigating particle size or size distribution
- G01N15/0205—Investigating particle size or size distribution by optical means
- G01N15/0211—Investigating a scatter or diffraction pattern
- G01N2015/0222—Investigating a scatter or diffraction pattern from dynamic light scattering, e.g. photon correlation spectroscopy
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
- G01N15/02—Investigating particle size or size distribution
- G01N2015/0283—Investigating particle size or size distribution using control of suspension concentration
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- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
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- Pathology (AREA)
- Dispersion Chemistry (AREA)
- Sampling And Sample Adjustment (AREA)
Abstract
An object of the present invention is to provide an improved low-invasive method for determining a particle size or a particle size distribution in a flowing suspension. Itis a further object of the invention to provide a method for continuously determining a particle size or particle size distribution in a flowing suspension having extreme high particle turbidity, concentrations and/or complex rheology that allows for continuous monitoring thereof. The invention relates to a method wherein use is made of a microdilution device for continuously sampling a flowing suspension for determining a particle size or a particle size distribution.. The invention is further related to a microdilution device for determining a particle size or a particle size distribution.
Description
P35698NLO0/SBI
METHOD FOR DILUTING A SUSPENSION AND FOR DETERMINING A PARTICLE SIZE
OR A PARTICLE SIZE DISTRIBUTION THEREIN
The invention is related to a method for determining a particle size or a particle size distribution in a suspension fluid flow, wherein use is made of a microdilution device. The invention is further related to a microdilution device for determining a particle size or a particle size distribution.
Synthesis, manufacturing and processing of nano- and microparticles or droplets in a fluid, a suspension, is common in various industries. For example, particulates consisting of poorly water soluble crystalline active pharmaceutical ingredients (APIs) in water, where the particles consist of defined sizes in the nano and micro range are being used in the pharmaceutical industry. The utility of such nano or micronized APIs relates to the fact that changes in average particle size can influence drug product properties such as e.g. bioavailability and dissolution rate. By accurately controlling and monitoring the API crystal particle size during drug manufacturing, more desirable drug products can be made as compared to those made using conventional particles. Nanoparticles may also be used in many other fields such as in the food industry or the cosmetics industry, either as naturally occurring components or as artificially added components. Several methods of nano/microparticle manufacturing are exceedingly common in industry, ranging from bottom up methods (e.g. synthesis, self assembly) to top down methods (e.g. beadmilling, high pressure homogenisation). Nanoparticle suspensions comprise particles with particle sizes in the range of 1 — 1000 nm and microparticle suspension comprise particles with particle sizes in the rage of 1 — 1000 micrometer.
Due to the increasing use of nanoparticles in processes and increasing demands for monitoring these processes, e.g. to characterize effects of variations in the process or to ensure quality during routine production, there is a growing need for methods, in particular non-invasive methods, to characterize the nano/microparticles during these processes, in particular in suspension. In many cases, the particle size and particle size distribution are the attributes of most interest. Methods for continuous and minimally or non-invasive measurements, i.e. without disruption the process, determining of particle size and particle size distribution are therefore highly desired.
WO 2019/125155 A1 describes a method for monitoring a property of nanoparticles in a flowing suspension that comprises providing a sample comprising the flowing suspension.
The method further comprises non-invasively monitoring a size distribution of nanoparticles of the flowing suspension using Fourier domain low-coherence interferometry (FDLCI), wherein the monitoring comprises deriving a time and optical path length resolved light scattering signal and deriving information indicative of the size of the nanoparticles from the path-length resolved signal fluctuations.
WO 2019/125155 A1 shows an example of a method to measure particle size and size distribution inline, i.e. directly in the process flow, without sample preparation/dilution.
However, particle size and particle size distribution may not be measured accurately inline for (i) suspensions exhibiting very high turbidity or absorption, or for (ii) suspensions in which high particle concentrations, particle interactions or additives cause non-Newtonian flow behavior (rheology) and/or complex relation between particles diffusion rate and size. Case (i) is usually associated with high concentrations or high optical contrast of suspended particles that strongly reduce the mean free path of light from an optical sensor. Traditional optical methods (Laser Diffraction and DLS) suffer strongly from such small mean free path, the method in WO 2019/125155 A1 allows measurement over extended turbidity range, yet remains unsuited for extremely turbid samples. Case (ii) is relevant for sizing methods based on characterization of particle diffusion (standard DLS) or diffusion and flow (WO 2019/125155 A1). For example, in suspensions with high particle and/or co-formulant concentrations, the fluid viscosity, aggregation state (e.g. solid or liquid) may vary depending on shear, which may negatively affect inline measurements and lead to inaccurate measurements.
A solution to measuring particle size or particle size distribution in such complex suspensions is to sample an amount of the suspension from the process and measure the desired properties in the sample away from the process, i.e. non-continuously or offline. This has as a downside that the monitoring of suspension manufacturing/synthesis processes is less reliable because the suspension is not monitored continuously and the measurement is essentially only a snapshot of the process; relevant and possibly fast changes in particle size or particle size distribution cannot be detected using such methods.
An object of the present invention is to provide an improved low-invasive method for determining a particle size or a particle size distribution in a flowing suspension. It is a further object of the invention to provide a method for continuously determining a particle size or particle size distribution in a flowing suspension having extreme high particle turbidity, concentrations and/or complex rheology that allows for continuous monitoring thereof.
The object of the invention is achieved by the method according to claim 1.
The method of the invention makes use of a microdilution device for continuously sampling a flowing suspension for determining a particle size or a particle size distribution. By creating an underpressure in the device channel of the microdilution device compared to the suspension in the process, a controlled flow rate below 1 mL/min of the sample of the suspension to the device channel is achieved. This low flow rate allows to minimally invasively dilute and mix the sample continuously which allows to continuously reduce the concentration of particles in the suspension, making the diluted fluid flow suitable for determining the particle size or particle size distribution, e.g. using a method or device of WO 2019/125155 A1.
The microdilution device comprises a device channel through which the sample flow may flow. The device channel is connected or connectable to the suspension flow that is to be measured, for example the device channel is connected or connectable to a process channel of the process containing the suspension flow. The device channel is connected or connectable to the nanosuspension flow via a connector for extracting a sample flow of the suspension flow. The connector may be customizable such that the connector is connectable to various types of process, e.g. having different flow rates, viscosities or pressures, of suspension flows. This allows the method to be used on a variety of processes. The microdilution device may be connectable to various suspension flows depending on the need of the user, e.g. to monitor particle size or particle size distribution in various stages of a process.
The microdilution device further comprises a pressure controller, e.g. a pump, for controlling a pressure difference between the device channel and the suspension flow, e.g. over the connector. By controlling a pressure difference, a steady sample flow having a desired flow rate may be provided. The pressure controller may be provided adjacent to the connector for improved pressure control. For example, when the suspension flow has a higher pressure, the pressure controller may not have to work hard to provide a suitable underpressure as related to the atmospheric pressure, whereas when the suspension flow has a lower pressure, the pressure controller may have to be suitably operated to provide the desired underpressure.
The specific underpressure that has to be generated depends on properties of the suspension flow, e.g. the process, such as the particle size and/or particle size distribution, the concentration of particles, e.g. nanoparticles or additives, the temperature of the suspension, the pressure of the suspension and the viscosity of the suspension.
The microdilution device further comprises a diluent channel which is connected to the device channel, e.g. downstream of the pressure controller, for providing a diluent to the device channel. The diluent channel may have a different cross-section compared to, a part of, the device channel. For example, the sample flow may have a flow rate of 0.5mL/min, while the required diluent flow rate is 1mL/min, so the diluent flow channel and the device channel downstream of the diluent flow channel may have to be suitable for larger flow rates compared to the device channel upstream of the diluent channel.
The microdilution device further comprises a mixer provided downstream from the diluent channel, e.g. in the device channel, for mixing the diluent with the sample flow in the device channel. In order to reduce the concentration of particles the diluent and the sample flow may have to be mixed. The mixer may be embodied as an active mixer, e.g. by using a mechanical mixer, or through a passive/static mixer, e.g. using a static micromixer. Passive mixers may mix the sample flow with the diluent using a variety of mechanisms, e.g. based on chaotic advection, inertial force mixing, split and recombine mixing or multi-lamination mixing.
The microdilution device further comprises a particle size detection device, e.g. such as disclosed in WO 2019/125155, located downstream from the mixer for measuring the particle size or particle size distribution in the diluted fluid flow.
The method comprises, when the device channel is connected to the suspension flow: - operating the pressure controller to create an underpressure in the device channel over the connector, creating a sample flow of suspension fluid through the connector to the device channel with a flow rate below 1 mL/min; - providing a diluent to the sample flow from the diluent channel, diluting the sample flow with the diluent by a dilution factor; - using the mixer to mix the sample flow with the diluent flow; - operating the particle size detection device to measure a particle size or particle size distribution of the diluted fluid flow.
The sample flow is diluted by a diluent, the diluent may be water or other suitable diluents such as organic solvents, such as ethanol, ethyl acetate or dioxolane. Additives may be added to the water to control properties of the diluted liquid such as its ionicity, its pH, or the effect of the diluent on potential agglomeration of particles in the suspension. The amount of diluent, and thus the dilution factor which is a measure for how much the sample is diluted with the diluent, may depend on a minimal flow rate for which the sample flow and diluent flow 5 may be mixed by the mixer.
The particle size detection device may be based on optical sensors measuring mean free path of light in the diluted sample. Other particle size detection devices may also be suitable for the method. These devices may include devices based on ultrasound, laser diffraction,
DLS, coulter counting, and several other known devices.
In embodiments, the method further comprises, for determining the dilution factor:
D measuring particle sizes, e.g. of the nanosuspension flow, for a range of test dilution factors; and
DD choosing the dilution factor in a subrange of the range of test dilution factors, in which subrange the measured particle sizes are independent of the test dilution factor.
It was found that the measured particle sizes may depend on the dilution factor that was used, particularly when the dilution factor is too big or too small. In order to ensure that the correct, e.g. actual, particle size is measured the dilution factor that is used in the method of claim 1 is determined by performing multiple measurements of the particle sizes for a range of test dilution factors, e.g. wherein for each measurement the dilution factor is increased slightly, and then choosing the dilution factor for use in measuring the particle size in the nanosuspension flow in a subrange of the range of test dilution factors, in which subrange the measured particle sizes are independent of the dilution factor.
For example, for the integration of the microdilution loop with the measurement device discussed in WO 2019/125155, it was found that incorrect dilution factors can give rise to measurement errors that negatively impact measurement quality of the particle size and the particle size distribution of the diluted flow. For example, if the dilution factor is too low, the concentration of ingredients of the original suspension that influence the solvent viscosity of the diluted fluid flow is too high and the measurement returns particle sizes and particle size distributions that are too high due to a mismatch in real versus assumed solvent viscosity. On the other hand, it was found that if the dilution factor is too high, an error based on number fluctuations can occur which also lead to the measured particle size and particle size distribution to be too high. By letting the dilution factor depend on a previously determined dilution factor which can be measured without errors, and in particular looking at the measured sizes and size distribution, the dilution factor which gives the correct values may be used in the method. The dilution factor may be varied continuously to determine the preferred dilution factor, or the preferred dilution factor may be determined based on a series of discrete measurements. For example, in an experiment it was found that a dilution factor between 40 and 80 times results in accurate measurements of particle sizes and the particle size distribution. Importantly, the choice of a suitable dilution factor is also highly dependent on the specific particle size measurement technique utilized in combination with the online microdilution device.
In embodiments, the connector is a Luer connector comprising a male connector part and a mating female connector part, preferably wherein the female connector part is provided on the process channel and wherein the male connector part is provided on the device channel, preferably wherein the female connector part comprises a membrane for closing the female connector part when the male connector part is not mated. A Luer connector may be a Luer slip, Luer taper or Luer lock. A luer connector may comprise a female connector part, e.g. a needle, and a male connector part, e.g. a receiver for the needle. The female connector part may be provided on the process channel and may comprise sealing means, e.g. a membrane, to seal the process channel when the connector is not attached. An advantage of this type of connector is that a single male connector part may be provided on the device channel and various female connector parts may be provided on various points of the process channel to allow the method to be used at these various points, moving the male connector from one female connector to the next. Other connector are possible, such as those based on sterile connectors, sampling gaskets, or hypodermic sampling ports provided on the process channel.
In embodiments, the pressure controller comprises a micro-peristaltic pump, a vacuum pump, osmotic pump, dispensing pump, a syringe pump, a positive displacement pump, or a piezo pump that is provided on the device channel between the connector and the diluent channel.
The pressure controller, in particular a micro-peristaltic pump, a vacuum pump, osmotic pump, dispensing pump, a syringe pump, a positive displacement pump, or a piezo pump, may be operated depending on the pressure in the suspension flow as compared to the pressure that is prevalent in the loop (which is typically atmospheric). For example, when there is a high pressure in the suspension flow, little underpressure has to be generated by the pump.
In embodiments, the microdilution device comprises a flow measurement and control system, preferably based on a Proportional Integral Derivative (PID) control system, comprising a first flow sensor provided in the diluent channel and a second flow sensor provided between the mixer and the particle size detection device, wherein the method further comprises: - measuring a flow rate of the diluent through the diluent flow channel with the first flow sensor; - measuring a flow rate of the diluted fluid flow with the second flow sensor; - determining the flow rate of the sample flow through the connector based on the measured diluent flow rate and the measured diluted fluid flow rate; and - operating the pressure controller to control the sample flow rate based on the determined sample flow rate, e.g. by changing the pressure if the determined sample flow rate deviates from a predetermined sample flow rate.
By measuring the flow rate in the diluent flow channel and the flow rate of the diluted fluid flow, the flow control system may determine the flow rate of the sample flow through the connector. This allows the pressure controller to be operated to control the sample flow rate.
In embodiments, the flow control system automatically operates the pressure controller to control the sample flow rate to a desired flow rate. The first flow sensor and/or the second flow sensor may be embodied as mass flow meters with a measurement principle based on the Coriolis effect. In certain embodiments, the dilution factor may be determined using any measurement technique that is inherently or complimentarily part of the particle size and PSD analysis method
In embodiments, the diluent is water comprising one or more additives, wherein the additives are at least one of a salt, a buffer substance and a surfactant, wherein the method comprises at least one of the steps of: - adding the salt to the water to control ionicity of the diluted fluid flow; - adding the buffer substance to the water to control the pH of the diluted fluid flow; and - adding the surfactant to the water to control and/or prevent agglomeration of particles in the diluted fluid flow.
The additives allow the diluted fluid flow to remain stable and may allow for improved measurements of the particle size and/or particle size distribution.
In embodiments, the sample flow rate is between 1 and 100 uL/min. It was found that for many flowing nanosuspension, e.g. in industrial processes, a sample flow rate between 1 and 100 pyL/min minimally impacts the process.
In embodiments, the mixer comprises a micro-scale static mixer comprising obstacles provided in the device channel. A micro-scale static mixer is an example of a static mixer using static components to mix the fluid flows. The micro-scale static mixer may mix the fluid flows by providing one or more obstacles in the fluid flow path and to create collisions in the fluid flow which leads to chaotic movements in the fluid flow which increases the mixing of the fluid flows. For example, the obstacle may be formed by a varying diameter of the device channel. Static micromixing may depend on varies mechanisms, for example on chaotic advection, inertial force mixing, split and recombine mixing, or multi-lamination mixing. In embodiments, the typical internal volume of a static micromixer required to achieve a sufficiently homogeneously mixed is between 5 and 150 microliters.
In embodiments, the diluent flow rate is between 0.1 and 10 mL/min, preferably between 0.1 and 1 mL/min, e.g. wherein the diluent flow rate is controlled by a diluent flow pump, e.g. a micro-gear pump.
Various features of the microdilution device may be connected to a processor that is configured to perform, steps of, the method. For example, the processor may be connected to the diluent flow pump, the pressure controller, the flow control systems, and/or the particle size detection device.
In embodiments, the method further comprises, after measuring the particle size or particle size distribution: - draining the diluted sample flow from the device channel to a drain channel for reclaiming or discarding the diluted sample flow. - Cleaning the sample flow, diluent flow and dilute sample flow channels.
In embodiments, the device channel has an inner diameter between 0.1mm and 1.5mm.
The method of the invention may advantageously be used in processes that require a sterile environment. An aspect of the invention relates to a method, wherein the suspension flow is a sterile nanosuspension flow, wherein the microdilution device further comprises a perforated filter having perforations with a diameter smaller than 0.22 micrometres for filtering the diluent. The perforated filter allows the diluent to be filtered before being mixed with the sample flow, so that the sample flow is not contaminated by the diluent.
In further embodiments of the sterile process, the particle size detection device comprises a removable flow cell, wherein the method comprises: - sterilizing the removable flow cell; - providing the removable flow cell in the particle size detection device;
- allowing diluted fluid flow to flow through the removable flow cell for measuring particle size or particle size distribution thereof, wherein preferably, the method further comprises: - sterilizing the flow cell, device channel, the connector, the pressure controller, the mixer and the second flow sensor; - removing the flow cell, device channel, the connector, the pressure controller, the mixer and the second flow sensor after measuring the particle size and/or particle size distribution.
For example, the flow cell is removable from the particle size detection device and may form apart of the device channel. Similarly, in embodiments comprising the flow control system, the second flow sensor may comprise a removable flow cell through which the diluted fluid may flow. The removable flow cell allows the particle size detection device, or the flow control system, that is in contact with the fluid flow to be easily sterilized so that the method does not contaminate the sterile nanosuspension, or the related process.
The flow cell, device channel, the connector, the pressure controller, the mixer and/or the second flow sensor, or the flow control system, may be provided sterilized, to allow for sterile measurements, and connected with the diluent channel, the nanosuspension flow and the particle size detection device. For example these parts may be provided sterile by the manufacturer or sterilized by the user. The flow cell, device channel, the connector, the pressure controller, the mixer and/or the second flow sensor, or the flow control system may be removed after measuring and subsequently thrown away or cleaned, reassembled and sterilized to be used for another measurement.
The invention is further related to a microdilution device for determining a particle size or a particle size distribution in a flowing suspension, comprising: - a device channel that is connected or connectable to the suspension flow, e.g. to a process channel containing the suspension flow, via a connector for extracting a sample flow of the suspension flow; - a pressure controller for controlling a pressure difference between the device channel and the suspension flow; - a diluent channel which is connected to the device channel for providing a diluent to the device channel; - a mixer provided for mixing the diluent with the sample flow downstream from the diluent channel in the device channel; - a particle size detection device for measuring particle size or a particle size distribution in the diluted fluid flow downstream from the mixer,
wherein the microdilution device is arranged to: - operate the pressure controller to create an underpressure in the device channel over the connector, creating a sample flow of suspension fluid through the connector to the device channel with a flow rate below 1 mL/min; - provide a diluent to the sample flow from the diluent channel, diluting the sample flow with the diluent by a dilution factor; - use the mixer to mix the sample flow with the diluent flow; - operate the particle size detection device to measure a particle size or particle size distribution of the diluted fluid flow.
For example, the device channel may comprise a flow cell that allows the dilute suspension flow to be measured by the particle size detection device. This can be done e.g. through measuring through a sight glass.
In embodiments, the microdilution device is further arranged to, for determining the dilution factor:
D measure particle sizes, e.g. of the nanosuspension flow, for a range of test dilution factors; and
O set the dilution factor in a subrange of the range of test dilution factors, in which subrange the measured particle sizes are independent of the test dilution factor.
It was found that the measured particle sizes may depend on the dilution factor that was used, particularly when the dilution factor is too big or too small. In order to ensure that the correct, e.g. actual, particle size is measured the dilution factor that us used in the method of claim 1 is determined by performing multiple measurements of the particle sizes for a range of test dilution factors, e.g. wherein for each measurement the dilution factor is increased slightly, and then choosing the dilution factor for use in measuring the particle size in the nanosuspension flow in a subrange of the range of test dilution factors, in which subrange the measured particle sizes are independent of the dilution factor.
In embodiments of the microdilution device the connector is a Luer connector comprising a male connector part and a mating female connector part, for example wherein the female connector part is provided on the process channel and wherein the male connector part is provided on the device channel, for example wherein the female connector part comprises a needle that can be inserted into the process through a resealable membrane for closing the process when the needle is not inserted.
In embodiments of the microdilution device, the pressure controller comprises a micro- peristaltic pump, a vacuum pump, osmotic pump, dispensing pump, a syringe pump, a positive displacement pump, or a piezo pump, that is provided on the device channel between the connector and the diluent channel.
In embodiments of the microdilution device the microdilution device comprises a flow measurement and control system, for example based on a Proportional Integral Derivative (PID) control system, comprising a first flow sensor provided in the diluent channel and a second flow sensor provided between the mixer and the particle size detection device, wherein microdilution device is further arranged to: - measure a flow rate of the diluent through the diluent flow channel with the first flow sensor; - measuring a flow rate of the diluted fluid flow with the second flow sensor; - determine the flow rate of the sample flow through the connector based on the measured diluent flow rate and the measured diluted fluid flow rate; and - operate the pressure controller to control the sample flow rate based on the determined sample flow rate, e.g. by changing the pressure if the determined sample flow rate deviates from a predetermined sample flow rate.
In embodiments of the microdilution device the diluent comprises one or more additives wherein the additives are at least one of a salt, a buffer substance and a surfactant, wherein the microdilution device is further arranged to: - add the salt to the water to control ionicity of the diluted fluid flow; - add the buffer substance to the water to control the pH of the diluted fluid flow; and - add the surfactant to the water to control and/or prevent agglomeration of particles in the diluted fluid flow.
In embodiments of the microdilution device the sample flow rate is between 1 and 100
HL/min.
In embodiments of the microdilution device the mixer comprises a micro-scale static mixer, for example comprising an obstacle provided in the device channel.
In embodiments of the microdilution device the diluent flow rate is between 8.1 and 10 ml/min, for example between 0.1 and 1 mL/min, e.g. wherein the diluent flow rate is controlled by a diluent flow pump.
In embodiments of the microdilution device, the microdilution device further comprises a drain channel and wherein the microdilution device is further arranged to, after measuring the particle size or particle size distribution: - drain the diluted sample flow from the device channel to a drain channel for reclaiming or discarding the diluted sample flow.
In embodiments of the microdilution device the device channel has an inner diameter between 0.1mm and 1.5mm.
In embodiments of the microdilution device the nanosuspension flow is a sterile nanosuspension flow, wherein the microdilution device further comprises a perforated filter having perforations with a diameter smaller than 0.3 micrometres for filtering the diluent.
In embodiments of the microdilution device, the particle size detection device comprises a removable flow cell, wherein the microdilution device is arranged to: - sterilize the removable flow cell; - provide the removable flow cell in the particle size detection device; - allow diluted fluid flow to flow through the removable flow cell for measuring particle size or particle size distribution thereof, wherein preferably, the microdilution device is further arranged to: - sterilize the device channel, the connector, the pressure controller, the mixer and the second flow sensor; - remove the device channel, the connector, the pressure controller, the mixer and the second flow sensor after measuring the particle size and/or particle size distribution.
The invention will be explained below with reference to the drawing, in which: - Fig. 1 schematically shows a diagram of the method; and - Fig. 2 schematically shows a microdilution device of the invention.
Figure 1 schematically shows a diagram of the method, wherein the first step 100 is connecting the microdilution device 1, via the connector 3 to the suspension flow. For example, the connector 3 may be a Luer type connector which may be connected to a process channel comprising the suspension flow.
Once the microdilution device 1 is connected to the suspension flow, the pressure controller 4 is operated 101 to create an underpressure in the device channel 2 over the connector 3, i.e. the pressure in the device channel 2 is lower than the pressure in the nanosuspension flow,
so that a sample flow of nanosuspension fluid through the connector 3 to the device channel 2 is created with a flow rate below 1 mL/min.
The so created sample flow in the device channel 2 is diluted with a diluent by a dilution factor by providing 102 a diluent to the sample flow. The diluent may be water or other suitable diluents such as organic solvents. Additives may be added to the water to control properties of the diluted liquid such as its ionicity, its pH, or the agglomeration of particles. The amount of diluent, and thus the dilution factor which is a measure for how much the sample is diluted with the diluent, may depend on a minimal flow rate for which the sample flow and diluent flow may be mixed by the mixer 6. The dilution factor may be based on a previous measurement of a particle size and/or a particle size distribution in the suspension flow, e.g. as measured in the device channel by the particle size detection device 7 or by other means. Preferably, the dilution factor is a dilution factor for which the previous measurement of particle size and/or particle size distribution resulted in an error-free correct measured particle size and/or particle size distribution. For example, it may be found in previous measurements that the determined particle size is higher for dilution factors higher than 80 or lower than 40, so that the dilution factor used for determining the actual particle size lies between 40 and 80.
After the sample flow has been diluted, the mixer 6 is used 103 to mix the sample flow with the diluent flow such that the sample flow and diluent flow are mixed and a uniform diluted sample flow is present downstream of the mixer 6. As described, various embodiments of the mixer 6 may be used, such as an active mixer 6 or a passive mixer 6.
The particle size or particle size distribution is measured in the diluted sample flow by operating 104 the particle size detection device 7 which is provided downstream from the mixer 6.
Figure 2 schematically shows a microdilution device 1 arranged to be use for the method. The microdilution device 1 may be used for determining a particle size or a particle size distribution in a flowing suspension and comprises a device channel 2, which may have an inner diameter between 0.1mm and 1.5mm, for example depending on the desired flow rate or viscosity of the sample flow. The inner diameter may not be constant, e.g. the inner diameter may be larger downstream of the diluent channel 5.
The device channel 2 is connected or connectable to the suspension flow via a connector 3 which is provided on one end of the device channel 2. The connector 3 may be a Luer connector comprising a male connector part provided on the device channel 2. A mating female connector part may then be provided on the process channel or on a needle. If the device channel 2 is connected to the suspension flow a sample flow of the suspension flow may be extracted.
The pressure control 4 is arranged to control a pressure difference between the device channel 2 and the suspension flow, such that an underpressure in the device channel 2, relative to the suspension flow, may be created. By controlling the underpressure, a flow rate of the sample flow may be controlled, such that the sample flow rate is below 1 mL/min. The pressure controller 4 may comprise a pump and/or a pressure measuring device for measuring the pressure in the device channel 2. The pump may be a micro-peristaltic pump, a vacuum pump, a venturi pump, or a piezo pump that is provided on the device channel between the connector and the diluent channel 2.
Downstream of the pressure controller 4 a diluent channel 5 is connected to the device channel 2, for providing the diluent to the device channel 2. In embodiments, a diluent pump may be provided for controlling the diluent flow rate.
Figure 2 further shows that the diluent channel 5, in this embodiment, comprises a perforated filter 10 having perforations with a diameter smaller than 0.22 micrometres for filtering the diluent. This may prevent the diluent from contaminating the sample flow, which may be advantageous in sterile suspension flows.
The diluent channel 5 shown in figure 2 further comprises a first flow sensor 8 for measuring a flow rate of the diluent through the diluent flow channel 5. The first flow sensor 8 is part of a flow control system, for example a PID control system, for determining the flow rate of the sample flow through the connector 3. In combination with the second flow sensor 9, which is provided on the device channel 2 downstream from where the diluent channel 5 is connected to the device channel 2, this allows the flow control system to determine the flow rate of the sample flow, i.e. by measuring both the diluted flow rate and the diluent sample flow rate and subtracting the two flow rates. For example, if the flow control system is a PID control system, the sample flow rate may be controlled based on the proportional, integral or derivative of the determined sample flow rate.
The microdilution device further comprises a mixer 6 for mixing the diluent with the sample flow rate downstream from the diluent channel 5 in the device channel 2. In embodiments, the mixer 6 comprises a micro-scale static mixer comprising obstacles provided in the device channel 2. In other embodiments, the mixer 6 may comprise an active mixer component for actively mixing the diluent flow with the sample flow such that a uniform diluted flow is created downstream of the mixer 6.
Downstream of the mixer 6, the particle size detection device 7 for measuring particle size or a particle size distribution in the diluted fluid flow is provided. The particle size detection device 7 may measure particle sizes or particle size distribution based on a mean free path length of a light, e.g. a laser light, radiated through the diluted sample flow. The particle size detection device 7 may further comprise a removable flow cell which may be sterilized. The flow cell may be provided in the device channel 2, such that the diluted flow flows through the removable flow cell, where the particle size detection device 7 measures the particle size or particle size distribution.
Claims (20)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL2032163A NL2032163B1 (en) | 2022-06-14 | 2022-06-14 | Method for diluting a suspension and for determining a particle size or a particle size distribution therein |
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| Application Number | Priority Date | Filing Date | Title |
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| NL2032163A NL2032163B1 (en) | 2022-06-14 | 2022-06-14 | Method for diluting a suspension and for determining a particle size or a particle size distribution therein |
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| NL2032163B1 true NL2032163B1 (en) | 2023-12-21 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6947126B2 (en) * | 2002-03-13 | 2005-09-20 | The Boc Group, Inc. | Dilution apparatus and method of diluting a liquid sample |
| US7716969B2 (en) * | 2006-09-29 | 2010-05-18 | The Administrators Of The Tulane Educational Fund | Methods and devices for simultaneously monitoring colloid particles and soluble components during reactions |
| US20120287435A1 (en) * | 2011-05-12 | 2012-11-15 | Jmar Llc | Automatic dilution for multiple angle light scattering (mals) instrument |
| US20170234842A1 (en) * | 2014-10-13 | 2017-08-17 | Administrators Of The Tulane Educational Fund | Device and method for changing solution conditions in serial flow |
| WO2019125155A1 (en) | 2017-12-20 | 2019-06-27 | Inprocess Ip B.V. | Method and apparatus for in-process particle size determination of nanosuspensions under flow |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6947126B2 (en) * | 2002-03-13 | 2005-09-20 | The Boc Group, Inc. | Dilution apparatus and method of diluting a liquid sample |
| US7716969B2 (en) * | 2006-09-29 | 2010-05-18 | The Administrators Of The Tulane Educational Fund | Methods and devices for simultaneously monitoring colloid particles and soluble components during reactions |
| US20120287435A1 (en) * | 2011-05-12 | 2012-11-15 | Jmar Llc | Automatic dilution for multiple angle light scattering (mals) instrument |
| US20170234842A1 (en) * | 2014-10-13 | 2017-08-17 | Administrators Of The Tulane Educational Fund | Device and method for changing solution conditions in serial flow |
| WO2019125155A1 (en) | 2017-12-20 | 2019-06-27 | Inprocess Ip B.V. | Method and apparatus for in-process particle size determination of nanosuspensions under flow |
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