Thermal compensation

Abstract

A temperature verification device for checking the accuracy of a temperature sensor of a dynamic light scattering instrument, the temperature verification device comprising: a body configured to be received in a sample cell holder; and the calibration temperature sensor is positioned in the main body at a position corresponding to the scattering volume of the dynamic light scattering instrument.

Description

Technical Field

[0001] The present invention relates to a method and apparatus for particle characterization, and more particularly, to temperature control in particle characterization. Background Art

[0002] There are various techniques for particle characterization, in which the motion of particles suspended in a dilute fluid is utilized to infer the particle size or the particle size distribution of particles in a sample. The Brownian motion of particles is affected by the particle size. Therefore, the relationship between the diffusion coefficient and the particle size is expressed by the following Stokes-Einstein equation.

[0003]

[0004] Where D is the diffusion coefficient of the particles in the dispersant, k B is the Boltzmann constant, T is the absolute temperature of the dispersant, η is the dynamic viscosity of the dispersant, and γ is the hydrodynamic radius of the particles.

[0005] If the composition of the dispersant is known (which is usually the case), then the relationship between its viscosity and temperature is also known. Given a known temperature, the particle size can be determined from the diffusion coefficient. If the temperature is uncertain, then the particle size will also be uncertain.

[0006] In addition, besides temperature being a necessary parameter for particle characterization based on particle diffusion, the properties of particles may also depend on temperature. For example, the aggregation properties of certain proteins may be relevant to their pharmaceutical applications, and these properties may strongly depend on temperature. Understanding the stability of proteins in suspension at very specific temperatures (such as refrigeration temperature and body temperature) may be important.

[0007] Dynamic light scattering (DLS), sometimes also referred to as photon correlation spectroscopy (PCS), is a technique for detecting the Brownian motion of particles and determining particle properties. In DLS, a light source is used to irradiate a sample containing particles suspended in a dilute fluid. The light scattered by the particles is detected. Due to the Brownian motion of the irradiated particles, the intensity of the scattered light changes over time. The autocorrelation function can be determined based on the time course of the scattered intensity. Given a known scattering vector (usually denoted by q), the diffusion coefficient D can be determined from the autocorrelation function. For example, it can be shown that for a dilute solution of monodisperse nanoparticles, the normalized autocorrelation function g (1) (t) is related to the scattering vector q and the diffusion coefficient as follows:

[0008] g (1) (t) = exp(-q 2 Dt) (2)

[0009] The relationship between the diffusion coefficient and the particle size can be expressed by the Stokes-Einstein equation (1).

[0010] Any technique that relies on characterizing the Brownian motion of particles through the Stokes-Einstein equation to determine particle properties is temperature-sensitive. Generally, a DLS instrument package has a temperature control system that ensures the sample has a specific and known temperature so that temperature does not cause errors in particle characterization.

[0011] Although great progress has been made in improving the accuracy of temperature control, there is still room for improvement. Minimizing temperature-related errors in particle characterization is desirable. Summary of the Invention

[0012] According to a first aspect, there is provided a system comprising:

[0013] An instrument for performing particle analysis by dynamic light scattering, the instrument comprising:

[0014] A sample cell holder configured to receive a sample cell for containing a sample comprising particles suspended in a diluting fluid;

[0015] A light source configured to irradiate the sample with a light beam so as to generate scattered light through the interaction of the light beam with the particles in a scattering region;

[0016] A light detector configured to detect the scattered light from the scattering region and output scattered data;

[0017] A temperature sensor configured to measure the temperature of the sample cell holder;

[0018] A processor configured to receive the scattered data and the temperature measurement of the sample cell holder and determine the particle size by performing dynamic light scattering analysis on the scattered data;

[0019] The system further comprises a temperature verification device, the temperature verification device comprising:

[0020] A body configured to be received in the sample cell holder;

[0021] A calibration temperature sensor located within the body and set to measure the temperature of the scattering volume.

[0022] According to a second aspect, there is provided a temperature verification device for checking the accuracy of a temperature sensor of a dynamic light scattering instrument, the temperature verification device comprising:

[0023] A body configured to be received in a sample cell holder;

[0024] A calibrated temperature sensor located within the body at a position corresponding to the scattering volume of the dynamic light scattering instrument.

[0025] Placing the temperature sensor within the body at a position corresponding to the scattering volume of the dynamic light scattering instrument enables a more representative calibration of the dynamic light scattering instrument.

[0026] The dynamic light scattering instrument may include a thermal regulator, the thermal regulator including a heating system and / or a cooling system for controlling the temperature of the sample cell holder (and thus the temperature of the sample).

[0027] The thermal regulator may include a thermoelectric device. The thermal regulator may be controlled by the processor. The thermal regulator may further include at least one heat sink for dissipating heat from the thermal regulator away from the sample cell holder. The thermal regulator may include a heat transfer fin between the thermoelectric device and the sample cell holder.

[0028] Each of the following features may apply to the first or second aspect above.

[0029] The calibrated temperature sensor may include a thermocouple or a PT100 sensor. The PT100 sensor may include a thin film PT00 sensor.

[0030] The device may further include a printed circuit board including a plurality of conductive traces for connecting the calibrated temperature sensor to a connector located outside the body.

[0031] The body may include a cuboid internal space. The printed circuit board may be disposed diagonally within the cuboid internal space. The position of the calibrated temperature sensor may be within the cuboid internal space. The position of the calibrated temperature sensor may be between 0.5 mm and 20 mm (or between 5 mm and 15 mm) from the bottom surface of the cuboid internal space.

[0032] The plurality of traces may include four traces for performing a four-wire measurement of the resistance of the temperature sensor. A first pair of traces may be connected to a first end of the temperature sensor, and a second pair of traces are connected to a second end of the temperature sensor.

[0033] The printed circuit board may include a U-shaped portion including a first vertical leg, a second vertical leg, and a horizontal crossbar located between the first vertical leg and the second vertical leg.

[0034] The first vertical leg may include the first pair of traces, with a first trace of the first pair of traces disposed on a first side of the first vertical leg and a second trace of the first pair of traces disposed on an opposite second side of the first vertical leg. The second vertical leg may include the second pair of traces, with a first trace of the second pair of traces disposed on a first side of the second vertical leg and a second trace of the second pair of traces disposed on an opposite second side of the second vertical leg.

[0035] Each vertical leg may be disposed at a corner of an internal space of the body.

[0036] The printed circuit board may include an H-shaped portion, an upper region of the H-shaped portion including the U-shaped portion, and lower legs of the H-shaped portion being in contact with a bottom surface of the body.

[0037] The body may include the same type of sample cell that can be used for performing dynamic light scattering analysis.

[0038] The body may be a cuvette.

[0039] The body may be a cuvette having a square cross-section with a side length of 12.5 mm, or a cuvette having a square cross-section with a side length of 10 mm, or a cuvette having any other shape or size.

[0040] The cuvette may be a glass cuvette or a polystyrene cuvette (or any other suitable transparent cuvette material suitable for dynamic light scattering measurements).

[0041] The device may include a sample mimic, with the calibration temperature sensor embedded therein.

[0042] The volume of the sample mimic may be between 0.5 ml and 2 ml.

[0043] The sample mimic may be selected to match a typical sample volume used for analysis by dynamic light scattering in a dynamic light scattering instrument.

[0044] The sample mimic may be a liquid. A liquid sample mimic may make the operation of the device more difficult and may introduce errors if the liquid is displaced. The sample mimic may include a solid-phase polymer material. The material may also be non-polymeric provided that it has suitable elastic and thermal properties. For example, a certain form of wax or the like. However, a polymer silicone material has the advantages of being stable, easy to handle, non-toxic, inexpensive, and having appropriate compatibility.

[0045] The elastic modulus of the sample mimic material may be less than 5 GPa. The Shore A hardness of the sample mimic material may be less than 50, or less than 30.

[0046] The sample mimic includes silicone (or some other solid-phase polymer material).

[0047] The thermal conductivity of the sample mimic at 25 °C can be between 0.1 W / m·K and 2 W / m·K. The thermal conductivity of the sample mimic at 25 °C can be between 0.1 W / m·K and 0.5 W / m·K.

[0048] The temperature verification device may further include a heat insulation cover, and the main body is attached to the heat insulation cover.

[0049] According to a third aspect, there is provided a method for verifying the temperature measurement value of a dynamic light scattering instrument, including:

[0050] Placing the temperature verification device in the sample cell holder;

[0051] Comparing the temperature measured by the temperature verification device with the temperature measured by the dynamic light scattering instrument;

[0052] Verifying that the temperature measured by the dynamic light scattering instrument can characterize the temperature measured by the temperature verification device.

[0053] The temperature verification device may be the device according to the second aspect. The dynamic light scattering instrument and the temperature verification device may jointly form the system according to the first aspect.

[0054] The method may further include adjusting the temperature reading of the dynamic light scattering instrument until the sample temperature measured by the dynamic light scattering instrument is within a predetermined tolerance range of the temperature measured by the temperature verification device.

[0055] The method may include repeating the measurement process at a plurality of different temperatures corresponding to the specified temperature control range of the dynamic light scattering instrument.

[0056] The method features described in the summary of the invention or the specific implementation here may be applicable to the systems or devices of the first and / or second aspects. For example, the dynamic light scattering instrument may include instructions for causing the dynamic light scattering instrument and / or the temperature verification device to perform any of the method steps described in this specification. Detailed Description

[0057] Exemplary embodiments will be described with reference to the accompanying drawings by way of example only, where:

[0058] Figure 1 is a schematic diagram of a dynamic light scattering instrument;

[0059] Figure 2 is a schematic diagram of a system according to an embodiment, including Figure 1a dynamic light scattering instrument, and a temperature verification device is placed in the sample holder;

[0060] Figure 3 is a diagram of a temperature verification device according to an embodiment; and

[0061] Figure 4 is a flowchart illustrating the steps of a method according to an embodiment.

[0062] Reference Figure 1 , shows a dynamic light scattering instrument 200, which includes a light source 201, a light detector 203, a sample cell 206, a processor 205, a temperature sensor 207, and a temperature controller 220.

[0063] The light source 201 may include a laser or a light emitting diode, and irradiates the sample 204 in the sample cell 206 with an irradiation beam 208 through a focusing lens 222 (which is movable to adjust the position of the focusing region within the sample cell). An irradiation optical fiber 231 and an optical fiber coupling lens 221 (such as a gradient index (GRIN) lens) may be provided between the light source 201 and the focusing lens 222. In other embodiments, the light source 201 may be coupled to the focusing lens 222 in free space (such as using any suitable optical elements, including mirrors, prisms, lenses, etc.). The sample 204 includes particles suspended in a diluent, and the irradiation beam 208 generates scattered light by interacting with the particles in the sample 204. The backscattered light is detected by the light detector 203 through a detection optical path 209, and the detection optical path 209 reaches the light detector 203 through the focusing lens 222, the coupling lens 223, and the detection optical fiber 233. The overlapping region between the detection optical path 209 and the irradiation beam 208 defines a scattering region, and the light detector 203 detects the scattered light from this scattering region. In some embodiments, multiple detection optical paths (for multi-angle dynamic light scattering) may be included.

[0064] The sample cell 206 is received in a sample cell holder 210. The sample cell 206 may be a cuvette. The cuvette may be made of a transparent glass material or a polymer material. The cuvette may have a square cross-section (such as 12.5 mm × 12.5 mm, or 10 mm × 10 mm, or 8 mm × 8 mm). The internal dimensions of a 12.5 mm cuvette may be 10 mm × 10 mm (such as a wall thickness of 1.25 mm on each side). The sample cell holder 210 may include a cuvette holder configured to receive the cuvette. The sample cell holder 210 may include an elastic element (not shown) configured to urge the sample cell 206 to have good thermal contact with the sample cell holder 210.

[0065] For DLS, more complex detection devices can also be used (for example, for multi-angle DLS, multiple detection optical paths at different angles are used). In some embodiments, detectors for receiving lateral scattered light and / or forward scattered light can be provided.

[0066] The photodetector 203 can be a photon counting detector, such as an avalanche photodiode. As already discussed in the background art, the output of the detector 201 can be processed by the processor 205 to determine the properties of the particles, such as the intensity-weighted average particle size (Z average), polydispersity, and / or the particle size distribution. Such processing can include determining the autocorrelation function based on the time course of the scattering intensity, determining the diffusion coefficient based on the autocorrelation function, and then using the Stokes-Einstein equation (which requires the temperature of the sample as an input) to determine the particle size.

[0067] The thermal regulator 220 is configured to control the temperature of the sample by heating or cooling the sample cell holder 210 (e.g., in response to a control signal from the processor 205). The thermal regulator 220 can include a heat sink, a thermoelectric device, and a heat transfer fin. The thermoelectric device is operable to heat or cool using the thermoelectric effect (also known as the Peltier effect). The heat sink dissipates the heat generated by the thermoelectric device and can include heat transfer fins to ensure that the heat flow to and from the thermoelectric device is evenly applied to the sample cell holder 210. The heat transfer fins can include aluminum or any other material with high thermal conductivity. Thermal paste or solid-phase thermal pads (such as graphite) can be used between the components of the thermal regulator 220 and between the thermal regulator 220 and the sample cell holder 210.

[0068] As referenced Figure 1 As described, the dynamic light scattering instrument 200 can include an ambient temperature sensor 228 that measures the ambient temperature near the sample cell 206.

[0069] In some cases, the desired temperature of the sample 204 may be different from the ambient air temperature around the sample cell 206. In such cases, there may be a temperature gradient between the sample 204 and the temperature sensor 207 because the thermal regulator 220 may cause heat to flow between the sample and the thermoelectric device to maintain the desired temperature. The greater the temperature difference between the sample 204 and the ambient air, the greater this temperature gradient tends to be. This temperature gradient may cause an error between the temperature reported by the temperature sensor 207 and the temperature of the sample 204. To correct for this, an ambient temperature sensor 228 may be provided to measure the ambient air temperature in the region of the sample cell 206. The processor 205 may use the ambient air temperature to correct for errors in the apparent sample temperature measured by the temperature sensor 207, for example using a look-up table or a mathematical function that models the correction. Additionally, or alternatively, the ambient air temperature may enable the temperature of the sample to be set to match the temperature of the ambient air, thereby minimizing any heat flow.

[0070] The instrument 200 may operate in two modes: i) ambient-corrected temperature mode; ii) temperature control mode. In the ambient-corrected temperature mode, the thermal regulator 220 is set to maintain the temperature of the sample 204 at the same temperature as that measured by the ambient temperature sensor 228. Maintaining the temperature of the sample at the ambient temperature can minimize any heat flow between the sample 204 and the surrounding environment, thereby minimizing any temperature gradient that causes an error between the temperature measured by the temperature sensor 207 and the true temperature of the sample 204. In the temperature control mode, the thermal regulator 220 may be used to set any desired temperature for the sample 204, and the processor may correct for temperature errors in the manner described above. In either mode, a predetermined tolerance (e.g., 0.5 K) may be defined for the control loop that controls the thermal regulator. In other embodiments, a control loop that incorporates at least one of proportional, integral, and derivative temperature errors may be employed to track the target temperature as closely as possible.

[0071] The temperature sensor 207 may have a low thermal conductivity path to the sample 204 through the material of the sample cell holder 210 (which may include aluminum, for example) and the material of the wall of the sample cell 206 (which may be composed of glass and have a thickness of approximately 1.25 mm, for example, a thickness between 0.5 mm and 2 mm).

[0072] For accurate temperature control of the sample 204, the accuracy of the temperature sensor 207 (and, in embodiments that include an ambient temperature sensor 228, the accuracy of the ambient temperature sensor 228) is important.

[0073] Reference Figure 2 again illustrates Figure 1The dynamic light scattering instrument 200 shown in [figure], but the temperature verification device 100 replaces the sample cell 206 in the sample cell holder 210. The temperature verification device 100 can be used to verify whether the temperature reading measured by the instrument accurately reflects the temperature of the sample in the scattering volume. In some embodiments, the temperature verification device 100 can be used to calibrate the sample temperature determined by the instrument 200 (depending on the reading of the temperature sensor 207 and optionally also on the reading of the ambient temperature sensor 228). This can be done with the light source turned off to avoid direct heating of the sensor 107 by the light source. It can also be done with the light source on but focused at a location away from the sample position to measure the heating effect of the laser on the sample mimic.

[0074] The temperature verification device 100 includes: a sample mimic 104, a body 106, a lid 110, a printed circuit board 108, a calibrated temperature sensor 107, and wires 150. An example of the temperature verification device 100 is shown in Figure 3 more detail.

[0075] The body 106 can be substantially the same as the sample cell 206 used in the dynamic light scattering instrument 200 during particle characterization, or at least be thermally representative of the sample cell 206. For example, the body 106 can include a standard cuvette made of the same material as the cuvette used for dynamic light scattering measurements (e.g., silica glass, polystyrene, or any other suitable transparent material). Making the body 106 have a geometry, wall thickness, and material similar to that of a standard cuvette for light scattering analysis can provide a more representative thermal arrangement in temperature verification.

[0076] A lid 110 can be provided, and the body 106 is attached to the lid 110. The lid 110 can represent the thermal insulation lid used in the DLS instrument to limit heat loss from the sample cell 206, and including it in the temperature verification device 100 can improve the fidelity of the temperature verification device 100 in simulating the sample cell 206 and the sample 204 under measurement conditions. As can be seen most clearly from Figure 3 it, the bottom surface of the body 106 and the top surface of the lid 110 are not necessarily parallel to each other. This is a result of the orientation of the sample cell 206 in the instrument 200 in use, where the sample cell 206 is angled so that the vertical wall of the sample cell 206 makes a small angle with the laser, causing the scattering plane in the sample to make a small angle with the bottom of the sample cell 206. This ensures that any reflection of the irradiated beam from the outer surface of the sample cell 206 can be absorbed, thus minimizing optical noise in the measurement.

[0077] The body 106 defines the internal space of the temperature verification device 100, and the sample simulant 104 is disposed within this internal space. The sample simulant 104 may include a material that provides the temperature verification device 100 with thermal characteristics that are representative of the sample 204 in the sample cell 206 under normal measurement conditions. For example, the sample simulant 104 may include a material with a thermal conductivity less than that of water to at least partially compensate for the conductive heat path provided by the PCB 108. Simulation of the steady-state thermal characteristics of the system may be of utmost importance because the instrument will typically be configured to wait for the temperature to stabilize for at least a predetermined period of time before performing dynamic light scattering measurements. Thus, the heat capacity of the sample simulant 104 is less important than its thermal conductivity (since heat capacity does not affect the steady-state heat distribution). In normal dynamic light scattering measurements, the sample cell 206 will contain an aqueous dilution, and there will be nothing in the sample cell 206 other than the sample 204. The PCB 108 will affect the thermal characteristics of the device 200 by providing a heat conduction path from the scattering region to the sidewall of the body 106 and to the lid 110. Accordingly, a sample simulant 104 with a thermal conductivity lower than that of water can be selected. The thermal conductivity of water at room temperature is approximately 0.6 W / m·K. The thermal conductivity of the sample simulant 104 at 25 °C can be between 0.1 W / m·K and 0.5 W / m·K. In one exemplary embodiment, the sample simulant 104 may include Corning Silicone 732 (which has a thermal conductivity of approximately 0.2 W / m·K), but other materials may also be used. The sample simulant 104 preferably includes a solid-phase material (although this is not required).

[0078] In some embodiments, the sample simulant 104 may include or be composed of at least a translucent material so that the user can visually inspect whether the position of the calibration temperature sensor 107 coincides with (or is at least close to) the scattering region 216. The volume of the sample simulant 104 in the sample may correspond to the recommended sample volume for analysis in the sample cell 206. For example, the volume of the sample simulant 104 may be approximately 1 ml, or between 0.2 ml and 2 ml. In some embodiments, cuvettes with dimensions smaller (or larger) than approximately 1 cm may be used, so smaller volumes may also be suitable.

[0079] The printed circuit board 108 is configured to support the calibration temperature sensor 107 in a suitable position within the body 106 such that the temperature read by the calibration temperature sensor 107 corresponds to the temperature in the scattering region. In some embodiments, the calibration temperature sensor 107 may be positioned at the scattering volume. The calibration temperature sensor 107 does not necessarily have to be precisely located at the position of the scattering volume, but preferably the calibration temperature sensor 107 is at a distance of 2 mm or less (or 3 mm or less) from the scattering volume. Positioning the calibration temperature sensor at or near the scattering volume ensures that the temperature monitored by the calibration temperature sensor can characterize the temperature at the scattering volume during dynamic light scattering measurements of the sample.

[0080] The printed circuit board 108 may include a U-shaped portion that includes a first vertical leg 121, a second vertical leg 122, and a horizontal crossbar 125 located between the first vertical leg 121 and the second vertical leg 122. The first vertical leg 121 and the second vertical leg 122 may each be disposed at diagonally opposite corners of the internal space of the body 106 of the temperature verification device. This positions the PCB 108 relative to the body 106 in a position that lies in a horizontal plane. To assist in positioning the calibration temperature sensor 107 at the correct height so that the temperature it measures can characterize the temperature at the scattering volume 216, the printed circuit board may include an H-shaped region. The H-shaped region may include the aforementioned U-shaped region as its upper portion and include additional lower legs 123, 124 that are continuations of the aforementioned vertical legs 121, 122 extending beyond the horizontal crossbar 125 to contact the bottom of the internal space of the body 106 (thereby positioning the calibration temperature sensor 107 at a suitable height within the body 106 in the vertical direction). The lower legs include a first lower leg 123 that is a continuation of the vertical leg 121 (i.e., coaxial or at least parallel to the vertical leg 121), and a second lower leg 124 that is a continuation of the second vertical leg 122.

[0081] The calibration temperature sensor 107 may be a PT100 temperature sensor that includes a platinum wire configured to have a nominal resistance of 100 ohms (e.g., at 0 degrees Celsius). Platinum has a well-known thermal resistivity coefficient, and the change in resistance with temperature is relatively linear over the temperature range of interest. The calibration temperature sensor 107 may include a thin-film PT100 sensor or a wire-wound PT100 sensor.

[0082] For dynamic light scattering, most measurements will be made at temperatures between 0 °C and 100 °C (since the diluent is typically aqueous), and more specifically, most measurements may be made at room temperature (e.g., 25 °C), refrigerated temperature (e.g., 4 °C), or body temperature (e.g., 37 °C). To accommodate a wider range of measurement temperatures, some DLS instruments may operate at temperatures below 0 °C (e.g., -10 °C or -20 °C) and above 100 °C (e.g., 120 °C), which may be useful when the diluent is not water. To accommodate a potentially relatively wide range of temperature control specifications, it may be necessary for the sample analog 104 to be thermally stable over a temperature range of -20 °C to 120 °C.

[0083] The calibration temperature sensor 107 may have calibration attributes traceable to national calibration standards (e.g., traceable to standards of the National Institute of Standards and Technology (NIST) in the United States, and / or compliant with ISO / IEC 17025 standards).

[0084] To obtain a measurement from a PT100 temperature sensor, it is necessary to determine the resistance of the platinum wire of the sensor. The most accurate resistance measurement can be achieved using four leads. A first pair of leads can be used to drive current through the PT100 resistor, and a second pair of leads can be used to measure the voltage across the PT100 resistor. The current required to determine the voltage can be negligible, so the voltage drop across the PT100 resistor can be measured with high precision. In a two-lead measurement, parasitic resistance (i.e., resistance other than that of the PT100 resistor) may cause a voltage drop, which interferes with the accurate measurement of the voltage drop across the PT100 resistor. The resistance value of the PT100 resistor can be inferred according to Ohm's law.

[0085] For the four-lead connection of the PT100 resistor, it is necessary to connect two leads to each end of the PT100 resistor respectively. In an exemplary embodiment, the first lead and the second lead are connected to the first end of the PT100 resistor, and the third lead and the fourth lead are connected to the second end of the PT100 resistor. These four leads can be disposed on the first side and the second side of the PCB 108 respectively. The first lead is formed by conductive traces on the first side of the first vertical leg 121 and the first side of the horizontal crossbar 125. The second lead is formed by conductive traces on the second side of the first vertical leg 121 and the second side of the horizontal crossbar 125. The third lead is formed by conductive traces on the first side of the second vertical leg 122 and the first side of the horizontal crossbar 125. The fourth lead is formed by conductive traces on the second side of the second vertical leg 122 and the second side of the horizontal crossbar 125. This lead arrangement allows for the use of a PCB with a minimum width for the legs 121, 122, and the bar 125, thus minimizing the interference with thermal characteristics caused by the PCB 108.

[0086] The arrangement of the leads is not necessary, and other embodiments may employ a single-sided PCB 108 (the PCB 108 has conductors only on one side), or some other lead arrangement. The H-shaped arrangement of the printed circuit board 108 is not necessary, and in other embodiments, the PCB 108 may be configured as a central "bar" structure that is supported at its root in the lid 110 and does not contact any inner surface of the body 106. Using the printed circuit board 108 as a carrier for the calibration temperature sensor 107 is not necessary - in some embodiments, the calibration temperature sensor 107 may be supported only by the sample mock-up 104, and / or by means of suspension wires that are also used for electrical contact with the calibration temperature sensor 107.

[0087] The printed circuit board 108 may be connected to the leads 150 in the lid 110. The leads 150 lead out the above four leads from the temperature verification device 100 for connection to an external readout circuit. The external readout circuit is configured to read the temperature from the calibration temperature sensor 107. In some embodiments, the readout circuit for the temperature verification device may be a separate readout device 160 from the dynamic light scattering instrument 200. In other embodiments, the readout circuit for the temperature verification device may be part of the dynamic light scattering instrument 200 (e.g., integrated in the processor 205).

[0088] As Figure 4 shown, the verification of the temperature control and temperature reading of the dynamic light scattering instrument 200 may be carried out as follows:

[0089] i) Insert the temperature verification device into the sample cell holder, step 301.

[0090] ii) Set the target temperature for the sample, step 302.

[0091] iii) Wait for the dynamic light scattering instrument to indicate that the target temperature has been reached, step 303, and optionally wait for an appropriate time for the temperature of the temperature verification device to stabilize (the temperature indicated by the instrument may stabilize before the temperature of the temperature verification device stabilizes).

[0092] iv) Compare the temperature indicated by the DLS instrument (if the temperature reading is not available, the target temperature) with the temperature indicated by the temperature verification device, step 304.

[0093] v) Repeat steps ii) to iv) until a sufficient range of temperature values (e.g., within the range indicated in the instrument specifications) has been verified.

[0094] And optionally:

[0095] vi) If the temperature indicated by the DLS instrument does not match the temperature indicated by the temperature verification device (outside the predetermined tolerance range, e.g., a tolerance range of 0.5 K), then adjust the temperature control system and / or the temperature reading of the dynamic light scattering instrument to correct this problem, step 305.

[0096] Once any necessary adjustments (if any) have been made, it can be said that the dynamic light scattering instrument 200 has been calibrated (calibrated against a standard, since the temperature verification device 100 has also been calibrated). The users of the dynamic light scattering instrument 200 and the temperature verification device 100 can thus verify that the temperature of the instrument 200 is operating within the specifications through a transparent and representative test traceable to the national calibration standard. Such traceable calibration and verification may be important in some cases, for example, in drug development.

[0097] In some embodiments, the above method steps may be at least partially automated. For example, when the reading of the temperature of the temperature verification device 100 is performed by the dynamic light scattering instrument, the processor of the dynamic light scattering instrument 200 may use the temperature verification device 100 to control the automatic calibration of its temperature control system. In other embodiments, a technician may compare the set / measured temperature of the instrument 200 with the temperature of the temperature verification device 100 and optionally make any adjustments to the instrument 200 manually.

[0098] Although the exemplary embodiments have been described in detail, there may still be other variant embodiments, and the scope of the present invention should be determined with reference to the appended claims.

Claims

1. A system, comprising: An instrument for performing particle analysis by dynamic light scattering, the instrument comprising: A sample cell holder configured to receive a sample cell for holding a sample containing particles suspended in a dilution fluid; A light source configured to irradiate the sample with a light beam, thereby generating scattered light through the interaction of the light beam with the particles in a scattering region; A light detector configured to detect the scattered light from the scattering region and output scattered data; A temperature sensor configured to measure the temperature of the sample cell holder; A processor configured to receive the scattered data and the temperature measurement of the sample cell holder and determine the particle size by performing dynamic light scattering analysis on the scattered data; The system further comprises a temperature verification device, the temperature verification device comprising: A body configured to be received in the sample cell holder; A calibrated temperature sensor located within the body and set to measure the temperature of the scattering volume.

2. A temperature verification device for checking the accuracy of a temperature sensor of a dynamic light scattering instrument, the temperature verification device comprising: A body configured to be received in a sample cell holder; A calibrated temperature sensor located within the body at a position corresponding to the scattering volume of the dynamic light scattering instrument.

3. The system according to claim 1, or the device according to claim 2, wherein the calibrated temperature sensor comprises a thin film PT100 sensor.

4. The system according to any one of the preceding system claims, or the device according to any one of the preceding device claims, wherein the device further comprises a printed circuit board comprising a plurality of conductive traces for connecting the calibrated temperature sensor to a connector located outside the body.

5. The system or device according to claim 4, wherein the body comprises a rectangular parallelepiped internal space, and the printed circuit board is disposed in the rectangular parallelepiped internal space in a diagonal manner.

6. The system or device according to claim 4 or 5, wherein the plurality of traces comprises four traces for performing a four-wire measurement of the resistance of the temperature sensor, a first pair of traces being connected to a first end of the temperature sensor, and a second pair of traces being connected to a second end of the temperature sensor.

7. The system or device according to any one of claims 4 to 6, wherein the printed circuit board comprises a U-shaped portion comprising a first vertical leg, a second vertical leg, and a horizontal crossbar located between the first vertical leg and the second vertical leg.

8. The system or device according to claim 7, wherein the first vertical leg includes the first pair of traces, a first trace of the first pair of traces is disposed on a first side of the first vertical leg, a second trace of the first pair of traces is disposed on a second opposite side of the first vertical leg, and the second vertical leg includes the second pair of traces, a first trace of the second pair of traces is disposed on a first side of the second vertical leg, and a second trace of the second pair of traces is disposed on a second opposite side of the second vertical leg.

9. The system or device according to claim 7 or 8, wherein the printed circuit board includes an H-shaped portion, an upper region of the H-shaped portion includes the U-shaped portion, and lower legs of the H-shaped portion are in contact with a bottom surface of the main body.

10. The system or device according to any one of the preceding claims, wherein the main body includes a sample cell of the same type that can be used for dynamic light scattering analysis.

11. The system or device according to any one of the preceding claims, wherein the main body is a cuvette.

12. The system or device according to any one of the preceding claims, wherein the main body is a cuvette having a square cross-section with a side length of 12.5 mm.

13. The system or device according to claim 11 or 12, wherein the cuvette is a glass cuvette or a polystyrene cuvette.

14. The system or device according to any one of the preceding claims, wherein the device includes a sample simulant, and the calibration temperature sensor is embedded in the sample simulant.

15. The system or device according to claim 14, wherein the volume of the sample simulant is between 0.5 ml and 2 ml.

16. The system or device according to claim 14 or 15, wherein the sample simulant includes a solid-phase polymer material.

17. The system or device according to claim 16, wherein the sample simulant includes silicone.

18. The system or device according to any one of claims 14 to 17, wherein the thermal conductivity of the sample simulant at 25 °C is between 0.1 W / m·K and 2 W / m·K.

19. The system or device according to any one of the preceding claims, wherein the temperature verification device further includes a heat-insulating cover, and the main body is attached to the heat-insulating cover.

20. A method for verifying temperature measurement values of a dynamic light scattering instrument, comprising: placing the temperature verification device in a sample cell holder; comparing the temperature measured by the temperature verification device with the temperature measured by the dynamic light scattering instrument; verifying that the temperature measured by the dynamic light scattering instrument can characterize the temperature measured by the temperature verification device.

21. The method according to claim 20, wherein the temperature verification device is the temperature verification device according to any one of the preceding temperature verification device claims, or the dynamic light scattering instrument and the temperature verification device together form the system according to any one of the preceding system claims.

22. The method according to claim 20 or 21 further comprises adjusting the temperature reading of the dynamic light scattering instrument until the sample temperature measured by the dynamic light scattering instrument is within a predetermined tolerance of the temperature measured by the temperature verification device.

23. The method according to any one of claims 21 to 22 comprises repeating the measurement process at a plurality of different temperatures corresponding to a specified temperature control range of the dynamic light scattering instrument.

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