WO2017066487A1 - Appareil et procédé de mesure de cinétiques de croissance ou de dissolution de particules colloïdales - Google Patents

Appareil et procédé de mesure de cinétiques de croissance ou de dissolution de particules colloïdales Download PDF

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Publication number
WO2017066487A1
WO2017066487A1 PCT/US2016/056909 US2016056909W WO2017066487A1 WO 2017066487 A1 WO2017066487 A1 WO 2017066487A1 US 2016056909 W US2016056909 W US 2016056909W WO 2017066487 A1 WO2017066487 A1 WO 2017066487A1
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Prior art keywords
sensor
electromagnetic radiation
intensity level
colloidal particles
slope
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PCT/US2016/056909
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English (en)
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WO2017066487A8 (fr
Inventor
Jan J. TATARKIEWICZ
Monette Karr
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Manta Instructions, Inc.
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Filing date
Publication date
Priority claimed from US15/018,532 external-priority patent/US9909972B2/en
Priority claimed from US15/194,823 external-priority patent/US9541490B1/en
Application filed by Manta Instructions, Inc. filed Critical Manta Instructions, Inc.
Priority to CN201680060558.6A priority Critical patent/CN108369169B/zh
Priority to JP2018539232A priority patent/JP6887599B2/ja
Publication of WO2017066487A1 publication Critical patent/WO2017066487A1/fr
Publication of WO2017066487A8 publication Critical patent/WO2017066487A8/fr

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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
    • G01N13/00—Investigating surface or boundary effects, e.g. wetting power; Investigating diffusion effects; Analysing materials by determining surface, boundary, or diffusion effects
    • G01N2013/006—Dissolution of tablets or the like
    • 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
    • G01N2015/0042—Investigating dispersion of solids
    • G01N2015/0053—Investigating dispersion of solids in liquids, e.g. trouble

Definitions

  • the present invention relates to measurement and observations of particles in liquid samples using a microscope equipped with digital video cameras.
  • Nanoparticles are ubiquitous and by far the most abundant particle-like entities in natural environments on Earth and are widespread across many applications associated with human activities. There are many types of naturally occurring nanoparticles and man-made (engineered) nanoparticles. Nanoparticles occur in air, aquatic environments, rain water, drinking water, bio-fluids, pharmaceuticals, drug delivery and therapeutic products, and a broad range of many industrial products. Nanoparticles usually occur within poly-disperse assemblages, which are characterized by co-occurrence of differently- sized particles, also those larger in diameter than 1 micron.
  • the measurements fail to account for the growth rate or dissolution rate of the particles, such that a snap-shot of a size distribution could be inaccurate a few moments later.
  • the concentration of nanoparticles of any given size, and hence the entire size distribution can be subject to unknown error.
  • the instrument to perform such an analysis typically comprises a small cell (for example a cuvette) that enables illumination of a liquid with a precisely-defined, narrow light sheet and observation of scattered light from the nanoparticles, usually (but not necessarily) at a 90 degree angle relative to the light sheet plane. It should be noted that the angle of observation need not be 90 degrees; what is important is that the scattered light is observed. Different sizes of particles can be visualized via the camera capturing light scattered by particles, with images having different sizes and intensities (various brightness of pixels) depending on the size of the particles. [0007] In U.S Patent Application No.
  • the growth/dissolution of particles can be of particular interest is various industries.
  • a pharmaceutical company may want to confirm that its drug dissolves at a particular rate such that it can be used in an effective time-release mode.
  • a dissolution may be most therapeutically effective when the particles dissolve to the nanoscale and does not re-combine to grow into larger particles.
  • Another pharmaceutical company may need to determine the time needed to crystallize new drug based on protein that can be delivered in higher doses as large crystals. So while the methods and apparatuses disclosed in Stramski and Tatarkiewicz may be helpful in obtaining a snapshot of the particle size distribution of the drug, it is not helpful in providing a dissolution rate (or conversely a growth rate).
  • a system for determining the growth/dissolution rate of colloidal particles includes multiple light sources and multiple sensors.
  • a light source is constructed to emit a beam of electromagnetic radiation at a specimen chamber that holds the colloidal particles.
  • the chamber allows a portion of the combined beam to scatter.
  • the scattered portion of the beam is directed to a sensor that detects electromagnetic radiation.
  • the sensor is connected to processor that activates the light source and obtains an image from the sensor. Multiple images may be taken at a time interval and for each image a total light intensity level (sum of all intensities registered at all pixels) is calculated and then normalized by the maximum intensity level in the sequence. Average intensity value from multiple images is obtained for each time point.
  • a formula is then calculated that fits the normalized values over time and a slope is determined from the formula. Also, instead of still images at a particular time interval, a short set of images (i.e., a video) may be taken at the time interval. An average of the sum of intensities for each video and for each time interval is calculated and then normalized by the maximum intensity level in the sequence.
  • the processor may also set a measurement window that limits how many images will be taken. That measurement window may be based on a total elapsed time or total number of images obtained. It can also be based on the slope that is calculated.
  • the processor may further set a maximum image intensity level and adjust the exposure time of the sensors when the total image intensity level exceeds the maximum intensity level.
  • the apparatus may use multiple light sources with multiple wavelengths, and multiple sensors that are biased in detecting only one of the multiple wavelengths.
  • the system may use combining structures to form the combined beam and de-combining structures (or beam splitters) before the scattered beam portion reaches the sensors.
  • the multiple light sources may be a single multi-wavelength light source.
  • the sensors may also be a single sensor that can detect multiple wavelengths.
  • FIG. 1A illustrates a system for detecting electromagnetic radiation from a cuvette using a single wavelength source.
  • FIG. IB illustrates a system for detecting electromagnetic radiation of two wavelengths.
  • FIG. 1C illustrates a system for detecting electromagnetic radiation of three wavelengths.
  • FIG. 2 is a graph showing the scattering coefficient vs. the diameter of a particle.
  • FIG. 3A is a graph showing the normalized total intensity of the particles in a colloidal solution vs. time, illustrating dissolution.
  • FIG. 3B is a graph showing the normalized total intensity of the particles in a colloidal solution vs. time, illustrating growth or crystallization.
  • FIG. 3C is a graph showing the normalized total intensity of the particles in a colloidal solution vs. time, illustrating growth or crystallization and subsequent dissolution.
  • FIG. 4 is a flowchart depicting a method for determining the growth/dissolution rate of colloidal particles.
  • connection, relationship or communication between two or more entities does not necessarily mean a direct, unimpeded connection, as a variety of other entities or processes may reside or occur between any two entities. Consequently, an indicated connection does not necessarily mean a direct, unimpeded connection unless otherwise noted.
  • a system for detecting electromagnetic radiation from a cuvette using a single wavelength 10A is shown in FIG. 1A.
  • Beam of electromagnetic radiation emitted from the light source 20 First beam of electromagnetic radiation at substantially a first wavelength 20A.
  • Second light source at a second wavelength 25 Second light source at a second wavelength 25.
  • Second beam of electromagnetic radiation at substantially a second wavelength 30.
  • Beam combining structure/dichroic mirror 35 [0039] Beam combining structure/dichroic mirror 35.
  • a second beam combining structure/dichroic mirror 37 is provided.
  • Imaging objective 60 [0046] Imaging objective 60.
  • Beam splitting structure/dichroic mirror 65 [0047] Beam splitting structure/dichroic mirror 65.
  • First sensor biased to detect electromagnetic radiation at substantially the first wavelength 75A.
  • Second sensor biased to detect electromagnetic radiation at substantially the second wavelength 85.
  • Second beam splitting structure/dichroic mirror 88 Second beam splitting structure/dichroic mirror 88.
  • a system 10A for detecting electromagnetic radiation from a cuvette includes a single light source 15 that emits at beam of electromagnetic radiation 20 at a light sheet former 45.
  • the resultant light sheet is directed at the specimen chamber/cuvette 50 that houses a colloid containing particles, i.e. nanoparticles or micron-sized particles (not shown).
  • a cuvette may be constructed according to U.S. Patent Application No. 15/194,823, filed on June 28, 2016, titled "SPECIAL PURPOSE CUVETTE ASSEMBLY AND METHOD FOR OPTICAL MICROSCOPY OF NANOPARTICLES IN LIQUIDS", the contents of which are incorporated herein by reference.
  • the scattered light exiting the imaging objective 60 reaches the sensors 75, which is connected to a processor 90.
  • FIGS IB and 1C illustrate using different wavelengths and wavelength sensors to arrive at a more robust system.
  • the benefit of using multiple wavelengths of light is that is extends the range of particles sizes that can be detected. Specifically, the intensity of scattered light depends very strongly on particle size, changing by many orders of magnitude between 10 nm and 1000 nm diameter nanoparticles, for instance.
  • a typical sensor assigns 8 bits or 256 different values to each pixel and each color, zero value corresponding to no light registered while the highest value of 255 corresponding to the maximum brightness that depends on the gain and exposure set up for the system.
  • any pixel receives more light than the maximum level corresponding to the value 255 (saturation), it is not possible to distinguish and register such a value except by lowering detector gain or shortening exposure time, thus shifting all recorded intensities into lower values. While lowering gain or shortening exposure may assist in distinguishing particles that have saturated the sensor, these adjustments also lower the sensitivity of the sensor on the bottom end of the spectrum - i.e., the smaller particles.
  • nanoparticles are comparable with the wavelength of visible light, the system is not able to distinguished details of light scattering nanoparticles but records only total intensity of light scattered with each particle projecting an image that looks like a circular blob or disc that cover several pixels in the sensor.
  • the scatter efficiency of a particle depends on the wavelength of the exposed light; thus the range of detection depends on the wavelength.
  • the operator can substantially extend the dynamic range of the system by covering broader a range of particle sizes registered.
  • Such a system 10B may include a first light source at a first wavelength 15A and a second light source at a second wavelength 25, such as two lasers with different beam colors or wavelengths. It is also possible to have a single light source that is capable of producing light at multiple wavelengths.
  • Each of these two beams is directed at a combining structure 35, such as a dichroic mirror, which combines the beams from light sources 15, 25 into a single combined beam 40 and directs the combined beam 40 to an optical system such as a light sheet former 45.
  • the light sheet former 45 may comprise a cylindrical lens together with a long working distance objective that forms a very narrow sheet of illumination.
  • the light sheet may be directed to a transparent specimen chamber 50 (such as a cuvette).
  • a portion of the combined beam that scatters 55A upon impacting the particles present in the colloid solution contained within the cuvette 50 has the same wavelengths as the illuminating light from the light sheet former 45, and can typically be observed at 90 degree angle by focusing an imaging objective 60, such as a microscope equipped with another long working distance objective. It should be noted that the angle of observation need not be at 90 degrees; what is important is that the scattered light is observed.
  • the scattered light exiting the imaging objective 60 is split into constituent wavelengths at a beam splitting structure 65 such as a second dichroic mirror, namely the separated first wavelength radiation 70A and the separated second wavelength radiation 80, that may independently reach the two sensors 75A, 85 (such as those disposed within digital grey- scale cameras), attuned to detect electromagnetic radiation at substantially the first and second wave lengths 15A, 25, respectively.
  • the two sensors can also be a single sensor that can detect electromagnetic radiation at multiple wavelengths.
  • the system can be easily extended into more wavelengths and more corresponding sensors 75A, 85 by adding more pairs of appropriate dichroic mirrors 35, 65 to combine and split more wavelengths of illuminating light sources 15, 25.
  • Such an example system IOC is shown in FIG. 1C, which illustrates a three wavelength system with a third light source at a third wavelength 32, that produces a third beam of electromagnetic radiation at substantially a third wavelength 34, and a second combining structure/dichroic mirror 37.
  • a second beam splitting structure/dichroic mirror 88 separates a third wavelength radiation 86, such that it can be detected by a third sensor biased to detect electromagnetic radiation at substantially the third wave length 87.
  • the sensors (75 A, 85 and 87) may be connected to a processor 90 that processes the images detected by the sensors (75 A, 85 and 87).
  • a sensor records intensities as a number for each pixel, and each wavelength, typically assigning an 8 bit number (corresponding to 256 different values) to each pixel and each wavelength, with a zero value corresponding to no light registered while the highest value of 255 corresponding to the maximum brightness.
  • the final image taken from the sensors consists of a matrix of numbers stored, corresponding to all pixels available on the sensors, typically more than 1 million of them. By adding all these numbers, a total brightness of the image as a single number (separately for each wavelength when more than one wavelength was used).
  • a sequence of numbers representing a time evolution of light intensity scattered by particles which in turn is proportional to the number and size of particles present in the colloid being analyzed.
  • Line 95 is a best fit for the graph, and the slope of that line is negative - indicating dissolution. Also, the slope of line 95 represents a single average growth/dissolution rate across the entire observed time.
  • a more sophisticated line 100 may fit the data which varies in slope over time - for example line 100 has a steep slope for the first minute that becomes less severe in the latter minutes. This suggests that the colloidal solution is dissolving rapidly for the first minute and less so thereafter.
  • the slope of the dissolution or growth curve is usually connected with the so called order of the process, e.g. linear time dependence of the dissolution rate (when data is plotted as the logarithm of the release or crystallized amount of drug versus time) denotes a first order process or the process where pharmaceutical dosage of released drug is proportional to the amount of drug released by unit time diminish.
  • FIG. 3B illustrates the normalized intensity plotted against time of a different colloidal solution, which indicates that the particles are growing - i.e., crystalizing or aggregating.
  • Line 105 is the best fit for this particular plot and the line 105 has an inflection point at region 110, suggesting that there is a significant amount of crystallization or aggregation during this time.
  • FIG. 3C is yet another plot of intensity against time for another colloidal solution indicating crystallization or aggregation and then dissolution after changes to the colloid (like addition of some salt that changed pH) has been introduced.
  • FIG. 4 a method 405 for determining the growth/dissolution rate of colloidal particles will be described. It should be noted that this method is described in steps, but it will be apparent to those in the art that the order of steps can be changes and still fall within the scope of the claims below.
  • a colloidal solution is inserted into the specimen chamber, e.g. the cuvette.
  • Steps 415, 420, and 425 set a number of variables for the measurements including the number of images to be taken, the time delay between the images, and the exposure time. The combination of the delay between images and the number of images to be taken defines the measurement window. This can be pre-set or as described below, it can be dynamic.
  • the method may have optional steps 430-460 that address the sensitivity of the system. Specifically, at step 430 a maximum image intensity level is set and in steps 435-445 the light sources are activated and the images are captured to determine a total image intensity level for the image at step 450. If at step 455 the total image intensity level from step 450 exceeds the maximum image intensity level, then the system will reduce the exposure time and step 460 and repeat the steps 435-455 until the total image intensity level is below the maximum at which time the system begins at step 465 to obtain the image and intensity levels from which a growth/dissolution rate will be determined. This helps prevent the large particles from over saturating the image, which tends to blind the system from the smaller particles- negatively affecting the efficiency and range of the system.
  • Steps 430-460 can be omitted as optional, and the method can proceed directly from step 425 to step 465, which activates the first and second light sources (or the single light source if a single light source apparatus setup such as that shown in FIG. 1A is used) for the exposure time (step 465), obtaining a first and second images (or a single image in a single light source apparatus setup) (steps 468 and 470). The system then delays for the preset time period between images and determines at step 480 if the number of images has been reached.
  • a total image intensity level for each image is determined and normalized (steps 485 and 490), and a formula the fits that normalize values is determine (step 95) from which a slope and be calculated (step 500).
  • the normalization process comprises of finding the largest intensity (count) of all pixels in the image and then dividing all intensities (counts) in this run by that number.
  • the method 405 may be more robust by obtaining a short video instead of a single images at steps 468 and 470. If this is done, then at step 486 an average intensity number for each of the videos in the sequence may be calculated (i.e., summed intensity of each frame/image in the video divided by the number of frames/images in the video) for each time interval, and that value is then normalized. By performing step 486, the method 405 can take images or videos at each time interval and will not unfairly weigh one in the normalization. Alternatively, if the method 405 is using only videos and each video is comprised of the same number of frames/images, then the intensity of all the pixels in all the frames/images in each video may be used and normalized; thus skipping step 486.
  • step 415 the system may not set a total number of images/videos to be reached (i.e., step 415); rather the system could set a total elapsed time, and step 480 can check if the elapsed time has been met.
  • the processor may determine the total image intensity values and the slope nearly simultaneously with taking the images (i.e., after step 470). This allows the system to have a dynamic total measurement window. Specifically, if the solution is decreasing for the first minute at a substantial rate which then stabilizes to a nearly linear function (as in FIG. 3A), the method could perform steps 485-500 nearly simultaneously with taking the images (i.e., after step 470), and step 480 could be based on a query as to whether the determined slope is changing. If it is not changing the method could stop measuring.
  • the delay between the images/vidoes may also be dynamic. For example, if the processor determines the total image intensity values and the slope nearly simultaneously with taking the images (i.e., after step 470), it can nearly simultaneously determine the slope. If that slope is large or changing rapidly (as the first part of the graph in FIG. 3A), then it might be advantageous to decrease the delay time between subsequent images/videos - in other words taking more samples images/videos when the colloidal solution is changing quickly. This would allow the system to more precisely measure the slope when the growth/dissolution rate is most volatile. When the rate begins to steady and become less volatile, then the delay between images/videos can be increased.
  • nanoparticles While the embodiments herein have referred to nanoparticles, the same methods and devices disclosed herein can also be applied to particles that are larger for example micron-sized and larger (even greater than 100 microns); thus the claims below are not to be limited to solely nanoparticles.

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  • Life Sciences & Earth Sciences (AREA)
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Abstract

L'invention concerne un système pour déterminer la vitesse de croissance/dissolution de particules colloïdales, qui comprend de multiples sources de lumière et de multiples capteurs. Une source de lumière est construite de manière à émettre un faisceau de rayonnement électromagnétique vers une chambre d'échantillon qui contient les particules colloïdales. La chambre permet à une partie du faisceau combiné de se diffuser perpendiculairement ou selon un autre angle par rapport au faisceau combiné. La partie diffusée du faisceau est dirigée vers un capteur qui détecte un rayonnement électromagnétique. Le capteur est connecté à un processeur qui active la source de lumière et obtient une image provenant du capteur. De multiples images sont capturées à un intervalle de temps et pour chaque image prise, et un niveau d'intensité d'image totale est calculé et normalisé. Une formule est ensuite calculée qui s'ajuste aux valeurs normalisées dans le temps et une pente est déterminée à partir de la formule.
PCT/US2016/056909 2015-10-14 2016-10-13 Appareil et procédé de mesure de cinétiques de croissance ou de dissolution de particules colloïdales WO2017066487A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201680060558.6A CN108369169B (zh) 2015-10-14 2016-10-13 用于测量胶体颗粒的生长或溶解动力学的装置和方法
JP2018539232A JP6887599B2 (ja) 2015-10-14 2016-10-13 コロイド粒子の成長キネティクスまたは分解キネティクスの測定のための装置および方法

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Application Number Priority Date Filing Date Title
US201562241354P 2015-10-14 2015-10-14
US62/241,354 2015-10-14
US15/018,532 US9909972B2 (en) 2016-02-08 2016-02-08 Multi-camera apparatus for observation of microscopic movements and counting of particles in colloids and its calibration
US15/018,532 2016-02-08
US15/194,823 2016-06-28
US15/194,823 US9541490B1 (en) 2015-07-01 2016-06-28 Special purpose cuvette assembly and method for optical microscopy of nanoparticles in liquids

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JP6887599B2 (ja) 2021-06-16

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