JP7708380B2 - Method and system for observing the disintegration properties of disintegrating solid samples - Google Patents

Description

The present invention relates to a method and system for observing the disintegration properties of disintegrative solid samples that disintegrate when in contact with liquid, such as pharmaceutical tablets, supplement tablets, and solid foods made by compacting raw material powders.

The disintegration property of solid pharmaceutical tablets or supplement tablets, which are made by adding additives to active ingredients and compressing them into a certain shape, is an important material property for ensuring that the desired functions are effective.

The "Japanese Pharmacopoeia Commentary: General Test Methods: Disintegration Test" describes a test in which a tablet is placed in a glass tube with a mesh bottom, the tester is shook in a test liquid by an electric motor, and the time it takes for the oral dosage form to disintegrate in the liquid is confirmed.

Patent documents 1 and 2 disclose a method for measuring the disintegration time while applying a load to a tablet in a solution.

Patent document 3 discloses a measurement and evaluation device and method in which the bottom surface of a sample holder holding a sample is immersed in liquid, the liquid is caused to penetrate reproducibly only from the lower end of the sample, and various evaluations such as the liquid absorption of the sample are performed based on the penetration rate coefficient obtained by measuring the weight change associated with the liquid absorption.

The techniques disclosed in Patent Documents 1 to 3 above make it possible to measure the time it takes for a sample to disintegrate in liquid and to evaluate the sample's liquid absorption, but they do not allow for observation of the internal structure of the sample.

Furthermore, Patent Document 4 discloses an optical coherence tomographic method for analyzing multi-layer pharmaceutical tablets.

The technology disclosed in Patent Document 4 can evaluate the layer structure of tablets and capsules, but it cannot observe the process of internal structure or weight change that accompanies the disintegration of a sample that disintegrates in liquid.

The technology disclosed in Patent Document 4 uses time-domain optical coherence tomography (TD-OCT) as the only example. TD-OCT is difficult to speed up because it is a mechanical scan, and is said to be unsuitable for fundus examinations due to the eye's fixational micromovements. In addition, because the OCT probe is fixed, it cannot be used in conjunction with other types of devices such as an electronic balance.

JP 2001-141718 A Patent No. 3965372 JP 2020-51997 A Special Publication No. 2010-536039

As mentioned above, the disintegration property of solid pharmaceutical tablets or supplement tablets, which are made by adding additives to active ingredients and compressing them into a certain shape, is an important material property for effectively performing the expected functions. In particular, for orally disintegrating tablets, which are a type of pharmaceutical tablet, this directly relates to the ease of administration to patients who have difficulty with oral administration or who are under water intake restrictions. In other words, more strict control is required for pharmaceutical agents, which have traditionally required precise quality control of disintegration property.

However, it has been pointed out that the disintegration time when the tablet is actually administered differs from the disintegration time measured by visually inspecting the appearance change using a "disintegration tester" standardized by the Japanese Pharmacopoeia.

The variability in tablet disintegration time is a problem caused by the lack of quantitative design and control of the internal structure of the tablet.

Conventionally, tablet disintegration was only evaluated by measuring the disintegration time through visual inspection of changes in appearance using a "disintegration tester" standardized by the Japanese Pharmacopoeia, so there was no way to understand the actual state of tablet disintegration, which should be the basis for quantitative tablet design to control disintegration. However, with the spread of tablets that require precise control of disintegration, such as orally disintegrating tablets, there is a demand for new evaluation techniques that can directly understand the actual state of the disintegration phenomenon.

Disintegration begins when the disintegrant contained in the tablet comes into contact with bodily fluids. Therefore, if it were possible to directly correlate and evaluate disintegration properties with the internal structure of the tablet, which serves as a route for bodily fluids to penetrate, basic information for quantitative tablet design could be fed back to the manufacturing process. However, the technologies disclosed in Patent Documents 1-4 above do not allow for simultaneous, real-time observation of the process of changes in internal structure or weight that accompany the disintegration of a sample that disintegrates in liquid.

In view of the above-mentioned conventional situation, the object of the present invention is to provide a method and system for observing the disintegration properties of a disintegration solid sample, which allows observation of changes in the internal structure of a solid sample before and after the disintegration process, which could not be observed in the past, to be performed in situ and in real time, while simultaneously measuring the weight change of the disintegration solid sample.

Other objects of the present invention and specific advantages obtained by the present invention will become more apparent from the description of the embodiments described below.

The present invention relates to a disintegration observation method for observing the disintegration of a disintegrable solid sample due to contact with a liquid, the method comprising: a contact control step of holding the disintegrable solid sample by a sample holder supported by hanging from a weight measuring device, and positioning the disintegrable solid sample above the surface of a disintegration test liquid stored in an observation vessel, and relatively displacing the height positions of the disintegrable solid sample and the surface of the disintegration test liquid to bring a contact portion of the disintegrable solid sample into contact with the surface of the disintegration test liquid stored in the observation vessel; and a contact control step of controlling the contact of the disintegrable solid sample with the surface of the disintegration test liquid stored in the observation vessel. a weight measuring step of measuring in real time a weight change of the disintegrable solid sample before and after a disintegration process in which the disintegrable solid sample is disintegrated by contacting a portion of the disintegrable solid sample with a surface of the disintegration test liquid stored in the observation container, using a weight measuring device; and a step of irradiating an area near the contact portion of the disintegrable solid sample that is brought into contact with the surface of the disintegration test liquid stored in the observation container with infrared light from outside the observation container using an optical coherence tomography image generating device to perform optical coherence tomography measurement of the disintegrable solid sample and generate an optical coherence tomography image of the disintegrable solid sample. and an image analysis step of quantitatively evaluating the internal structure change caused by the disintegration of the disintegrable solid sample due to contact with the disintegration test liquid by speckle pattern displacement analysis by a digital image correlation method using the optical coherence tomography images generated in the optical coherence tomography image generation step before and after a contact process in which a contact portion of the disintegrable solid sample is brought into contact with a surface of the disintegration test liquid stored in the observation container, the optical coherence tomography images being generated by the optical coherence tomography image generation device before and after a disintegration process in which the disintegrable solid sample is disintegrated. The method is characterized in that the internal structure change process caused by the disintegration of the disintegrable solid sample due to contact with the disintegration test liquid is observed in real time by measuring a weight change of the disintegrable solid sample before and after the contact process with the disintegration test liquid in the weight measurement step in real time and by image analyzing the optical coherence tomography images generated in the optical coherence tomography image generation step before and after the contact process with the disintegration test liquid in the image analysis step.

In the method for observing the disintegration of a disintegrating solid sample according to the present invention, the optical coherence tomography image generating step may be performed by swept source optical coherence tomography (SS-OCT).

The present invention is a disintegration observation system for observing the disintegration of a disintegrable solid sample due to contact with a liquid, comprising: a weight measuring device for measuring the weight of the disintegrable solid sample; an observation vessel storing a disintegration test liquid with which the disintegrable solid sample will come into contact; an optical coherence tomography image generating device for irradiating an area near the contact portion of the disintegrable solid sample that will come into contact with the surface of the disintegration test liquid stored in the observation vessel with light in the infrared region from outside the observation vessel, thereby performing optical coherence tomography measurement of the disintegrable solid sample and generating an optical coherence tomography image; and a sample holder supported by hanging on the weight measuring device for holding the disintegrable solid sample and positioning the disintegrable solid sample above the surface of the disintegration test liquid stored in the observation vessel, thereby relatively displacing the height positions of the surfaces of the disintegration test liquid and the disintegration test liquid to measure the contact portion of the disintegrable solid sample stored in the observation vessel. and an image analysis processing device which performs image analysis to quantitatively evaluate an internal structural change accompanying disintegration of the disintegrable solid sample due to disintegration due to contact with the disintegration test liquid by the speckle pattern displacement analysis, wherein the weight measurement device measures in real time the weight change of the disintegrable solid sample before and after the contact process with the disintegration test liquid, and the image analysis processing device analyzes the optical coherence tomographic images generated by the optical coherence tomographic image generating device before and after the contact process with the disintegration test liquid, thereby making it possible to observe in real time the internal structural change process of the disintegrable solid sample accompanying disintegration due to contact with the disintegration test liquid.

In the disintegration observation system for disintegrating solid samples according to the present invention, the optical coherence tomography image generating device may be a swept source optical coherence tomography (SS-OCT).

In the disintegration observation system for disintegrable solid samples according to the present invention, the weight measuring device may be an electronic balance that measures the weight of the disintegrable solid sample.

The disintegration observation system for disintegration solid samples according to the present invention may further include a means for measuring the pH and temperature of the disintegration test liquid stored in the observation container, making it possible to simultaneously measure changes in the liquid properties and temperature of the disintegration test liquid.

The disintegration observation system for disintegration solid samples according to the present invention may further include an imaging device that images the appearance of the disintegration solid sample in the observation container from outside the observation container, making it possible to observe in real time the process of change in the appearance of the disintegration solid sample as it disintegrates due to contact with the liquid.

In the collapsibility observation system for a collapsible solid sample according to the present invention, the sample holder holds one end of the collapsible solid sample without covering the periphery of the collapsible solid sample, and the observation container has at least a wall surface formed of a material that transmits light in the infrared region for performing optical coherence tomography measurement of the collapsible solid sample by the optical coherence tomography image generating device.

In the disintegration observation system for disintegration solid samples according to the present invention, the contact control means may have a function of adjusting the liquid level of the disintegration test liquid stored in the observation container.

In the disintegration observation system for disintegrating solid samples according to the present invention, the disintegration test liquid may be water, and the disintegrating solid sample may be a drug that disintegrates upon contact with water.

According to the present invention, it is possible to observe the internal structural changes before and after the disintegration process of a solid sample, which was previously impossible to observe, in situ and in real time, while simultaneously measuring the weight change of the disintegrable solid sample.

FIG. 1 is a block diagram showing the configuration of a system for observing the collapsibility of a collapsible solid sample to which the present invention is applied. FIG. 2 is a schematic diagram showing a configuration of an optical coherence tomographic image generating device in the collapse observation system. FIG. 2 is a process diagram showing the procedure of a method for observing the collapsibility of a collapsible solid sample carried out in the above-mentioned collapsibility observation system. 11 is a diagram for explaining the displacement amount analysis process of a subset including image analysis feature points, which is executed by the image analysis processing device of the above-mentioned collapse observation system. FIG. FIG. 2 is a graph showing the results of weight change measurement obtained by observing the disintegration properties of commercially available United States Pharmacopoeia (USP) standard tablets for prednisone using the disintegration property observation system. FIG. 2 is a schematic diagram showing observation areas in the disintegration observation of the above-mentioned prednisone standard tablet. FIG. 1 shows optical coherence tomography images generated by the optical coherence tomography image generating device at each time before and after contact of a standard prednisone tablet with water, in which (A) is an optical coherence tomography image at time t0 before the tablet comes into contact with water, (B) is an optical coherence tomography image at time t1 when contact of the tablet with water is observed, (C) is an optical coherence tomography image 1 second after the time t1, (D) is an optical coherence tomography image 3 seconds after the time t1, (E) is an optical coherence tomography image 12 seconds after the time t1, and (F) is an optical coherence tomography image 30 seconds after the time t1. The optical coherence tomography images generated by the optical coherence tomography image generating device were subjected to a displacement analysis of the speckle pattern at each time point before and after contact between a standard prednisone tablet and water, and the displacement of the speckle pattern was visualized by the displacement vector length, where (A) shows the result of the displacement analysis of the speckle pattern of the optical coherence tomography image 0.01 seconds after contact, and (B) shows the result of the displacement analysis of the speckle pattern of the optical coherence tomography image 1 second after contact. FIG. 1 is a block diagram showing the configuration of a disintegration observation system for a disintegration solid sample that is capable of simultaneously measuring the properties of the disintegration test liquid and changes in temperature.

The following describes in detail the embodiments of the present invention with reference to the drawings. Common components are described with common reference numerals in the drawings. Furthermore, the present invention is not limited to the following examples, and can be modified as desired without departing from the spirit of the present invention.

The present invention is applied to, for example, a disintegration observation system 100 for a disintegration solid sample 1 having a configuration as shown in the block diagram of Figure 1.

This disintegration observation system 100 for a disintegration solid sample 1 observes in real time the weight change process and internal structure change process of the disintegration solid sample 1 accompanying disintegration due to contact with the disintegration test liquid 11 stored in the observation container 10, and performs internal structure analysis. The disintegration solid sample 1 is held by a weight measuring device 20 that measures the weight of the disintegration solid sample 1, and a sample holder 21 suspended and supported by the weight measuring device 20, and the disintegration solid sample 1 is positioned above the surface of the disintegration test liquid 11 stored in the observation container 10, and the relative height positions of the surfaces of the disintegration solid sample 1 and the disintegration test liquid 11 are measured. The apparatus includes a contact control means 30 that brings the contact portion 1A of the disintegrable solid sample 1 into contact with the surface 11A of the disintegration test liquid 11 stored in the observation container 10 by mechanically displacing the disintegrable solid sample 1, an optical coherence tomography image generating device 40 that performs optical coherence tomography measurement of the disintegrable solid sample 1 from outside the observation container 10 and generates an optical coherence tomography image, and an image analysis processing device 50 that quantitatively evaluates the internal structural change accompanying the disintegration of the disintegrable solid sample 1 due to contact with the disintegration test liquid 11 based on the optical coherence tomography image of the disintegrable solid sample 1 obtained by the optical coherence tomography image generating device 40.

In this disintegration observation system 100, the contact control means 30 changes the relative distance between the contact portion 1A of the disintegration solid sample 1 and the surface 11A of the disintegration test liquid 11, and is, for example, a liquid level adjustment mechanism using a tube pump that can easily adjust the liquid level of the disintegration test liquid 11 to any initial height and does not vibrate due to mechanical operation.

The weight measuring device 20 measures the change in weight associated with the disintegration of the disintegrable solid sample 1 upon contact with the disintegration test liquid 11, and uses an electronic balance that automatically measures minute weight changes with high precision and in units of one second.

The optical coherence tomographic image generating device 40 in this collapse observation system 100 includes a light source 41, a half mirror 42, a reference mirror 43, and a detector 44, as shown in the schematic diagram of FIG. 2, and is made up of a camera head unit 45 including an optical interference system composed of the half mirror 42 and the reference mirror 43, and an optical coherence tomographic image generating unit 47 including the light source 41, the detector 44, and an information processing unit 46.

In this disintegration observation system 100, the sample 1 is a disintegrating solid that disintegrates upon contact with the surface of the disintegration test liquid 11 stored in the observation container 10.

The sample holder 41 is suspended and supported by the weight measuring device 20 and holds one end of the collapsible solid sample 1 without covering the periphery of the collapsible solid sample 1.

The light source 41 of the optical coherence tomography image generating device 40 is for irradiating the observation container 10 with light in the infrared region that is reflected by the collapsible solid sample 1 from outside the observation container 10. The light reflected by the collapsible solid is, for example, light that is not absorbed by the collapsible solid.

At least the wall surface of the observation container 10 is made of a material that transmits light in the infrared range so that the optical coherence tomography measurement of the disintegrable solid sample 1 can be performed by the optical coherence tomography image generating device 40.

The half mirror 42 is provided on the optical path of the light emitted from the light source 41. The half mirror 42 is also arranged so that its surface 42a on the light source 41 side is inclined at an angle of 45° toward the light source 41 with respect to the optical path.

The half mirror 42 splits the light emitted from the light source 41 into irradiation light that is irradiated onto the collapsible solid sample 1 and reference light that is incident on the reference mirror 43. The half mirror 42 then reflects the split irradiation light so that it is incident on the collapsible solid sample 1. The half mirror 42 also transmits the split reference light so that it is incident on the reference mirror 43.

The reference mirror 43 is provided on the optical path of the light emitted from the light source 41.

The reference mirror 43 reflects the reference light that has passed through the half mirror 42 and returns the reflected light to the half mirror 42. For this reason, the reference mirror 43 is disposed opposite the half mirror 42.

The reference mirror 23 is also movable along the optical path direction of the light emitted from the light source 41. In other words, the reference mirror 43 is capable of adjusting the distance between it and the half mirror 42. Instead of making the reference mirror 43 movable, a wavelength-variable light source may be used to achieve the same function.

The detector 44 is provided on the optical path of the return light obtained by irradiating the disintegrable solid sample 1 with the irradiation light, and on the optical path of the reference light. The reference light is reflected by the reference mirror 43 and returns to the half mirror 42, and is further reflected by the half mirror 42.

The half mirror 22 and the reference mirror 43 of the optical coherence tomographic image generating device 40 constitute an interference optical system.

The detector 44 is used to observe the interference light between the return light and the reference light.

Here, in this disintegration observation system 100, the optical coherence tomographic image generating device 40 is used to perform non-destructive, real-time dynamic observation of the process of internal structural changes accompanying the disintegration of the disintegration solid sample 1. For dynamic observation, in terms of time resolution, a faster Fourier domain OCT (FD-OCT) is preferable to a TD-OCT, and among these, a faster swept wavelength OCT (SS-OCT) is even more preferable.

The optical coherence tomography image generating device 40 in this collapse observation system 100 employs swept source optical coherence tomography (SS-OCT), which measures the depth direction by sweeping the wavelength of the light source 41 (A-scan) and generates a two-dimensional tomographic image by sliding the laser light laterally (B-scan).

In this optical coherence tomographic image generating device 40, a tunable light source with a central wavelength of 1700 nm and a light source frequency of 90 kHz is used as the light source 41.

The time it takes to generate an optical coherence tomographic image using SS-OCT is determined by the speed of the depth scan (A-scan) and the number of times the A-scan is repeated in the plane (B-scan). For example, with a 90 kHz light source, the depth scan (A-scan) is 90,000 times per second. If this is repeated 100 times in the plane (B-scan) over a range of 1 mm, a two-dimensional image with a horizontal resolution of 10 μm/pixel can be displayed at 900 frames per second (fps; a unit of frame rate indicating the number of frames processed per unit time), making dynamic observation in real time possible. The frame rate (fps) at which data can be obtained varies depending on the hardware and software specifications of the personal computer (PC).

Three-dimensional measurements can also be obtained quickly by spatially repeating the SS-OCT depth scan (A-scan). For example, if an A-scan is repeated 100 times in a range of 1 mm in the horizontal direction (B-scan) with a 90 kHz light source, and then 100 times in a range of 1 mm in the depth direction (C-scan), the calculated three-dimensional measurement time is 0.11 seconds. The horizontal and depth resolutions of the three-dimensional image generated in this way are 10 μm/pixel. The depth resolution varies depending on the refractive index of the sample, and the wavelength and wavelength sweep width of the light source.

In this disintegration observation system 100, the optical coherence tomographic image generating device 40 observes the disintegration state of the disintegration solid sample 1 from outside the observation container 10 in which the disintegration test liquid 11 is stored. Therefore, by setting the wall position of the observation container 10 at a location where the interference distance in the optical coherence tomographic image generating device 40 is also short, noise due to reflection from the wall of the observation container 10 is reduced as much as possible.

In addition, to reduce noise caused by strong reflection from the surface of the collapsible solid sample 1, the desired area can be observed with low noise by adjusting the position to an arbitrary angle where the influence of specular reflection is minimal and where it is possible to observe before and after contact between the end face of the collapsible solid sample 1 and the liquid surface.

The optical coherence tomographic image generating device 40 generates an optical coherence tomographic image in a state where the optical axis of the light in the infrared region irradiated from the camera head unit 45 of the optical coherence tomographic image generating device 40 to the collapsible solid sample 1 is tilted at a predetermined angle θ within an angle range of 1 to 10° with respect to the normal direction of the observation surface of the collapsible solid sample 1. Here, the holding attitude of the camera head unit 45 is freely adjustable, but even if the holding attitude of the collapsible solid sample 1 by the sample holder 21 is freely adjustable, the optical axis of the light in the infrared region irradiated to the collapsible solid sample 1 can be tilted with respect to the normal direction of the observation surface of the collapsible solid sample 1.

That is, the light in the infrared region emitted from the light source 41 is split by the half mirror 42 into irradiation light that is irradiated onto the collapsible solid sample 1 and reference light that is incident on the reference mirror 43. The half mirror 42 reflects the split irradiation light and makes it incident on the collapsible solid sample 1. The half mirror 42 also transmits the split reference light and makes it incident on the reference mirror 43. That is, the irradiation light split by the half mirror 42 is irradiated onto the collapsible solid sample 1 in the observation container 10 from outside the observation container 10 through a wall surface of the observation container 10 that is transparent to at least light in the infrared region.

The irradiated light incident on the collapsible solid sample 1 is reflected at interfaces with different refractive indices, such as the surface and internal structure of the collapsible solid sample 1, and is emitted as return light from the surface of the contact portion 1A of the collapsible solid sample 1, i.e., the observation surface. The return light emitted from the observation surface is then incident on the half mirror 42 of the optical coherence tomography image generating device 40 via the transparent wall surface of the observation container 10.

The return light obtained by irradiating the disintegrable solid sample 1 with the irradiation light and the reference light reflected back by the reference mirror 44 are superimposed again on the half mirror 42. At this time, if the distance traveled by the return light from the disintegrable solid sample 1 and the reference light from the reference mirror 44 is equal, the two lights will reinforce each other. On the other hand, if there is a difference in the distance traveled by the return light from the disintegrable solid sample 1 and the reference light from the reference mirror 44, and the phases of the lights are reversed, the two lights will cancel each other out.

The reference mirror 44 that constitutes the optical interference system is then moved to adjust the distance between the reference mirror 44 and the half mirror 42, and the position on the detector 44 where the two lights interfere and reinforce each other is observed. This observation makes it possible to determine at what depth within the collapsible solid sample 1 the reflective surface is located. In other words, it is possible to obtain a distribution of signal intensity in the depth direction that reflects information on the internal structure of the collapsible solid sample 1. In addition, by imaging the horizontally continuous distribution of signal intensity in the depth direction, it is possible to visualize the internal structure of the collapsible solid sample 1.

That is, the optical coherence tomography image generating device 40 performs optical coherence tomography measurement of the collapsible solid sample 1 by irradiating the light in the infrared region emitted from the light source 41 of the optical coherence tomography image generating unit 47 through the optical interference system in the camera head unit 45 to the collapsible solid sample 1 in the observation container 10, and detecting the interference light between the return light from the collapsible solid sample 1 and the reference light obtained by the optical interference system included in the camera head unit 45 with the detector 44 of the optical coherence tomography image generating unit 47. An optical coherence tomography image is generated by an information processing unit 46 using, for example, a personal computer (PC) from the distance image information by the interference light obtained as the detection output by the detector 44. As a method for the optical coherence tomography image generating unit 47 of the optical coherence tomography image generating device 40 to generate a tomography image, a tomography image generating method in optical coherence tomography measurement can be used.

This optical coherence tomography image generating device 40 employs swept source optical coherence tomography (SS-OCT), which can generate two-dimensional tomographic images at high speed, making it possible to observe the internal structure of the disintegrable solid sample 1 during the disintegration process of the disintegrable solid sample 1, which disintegrates upon contact with the surface of the disintegration test liquid 11 in the observation container 10, and by generating the internal structure of the disintegrable solid sample 1 during the disintegration process at high speed as a two-dimensional tomographic image, it is possible to observe the process of change in the internal structure of the disintegrable solid sample 1 in real time.

The orientation of the tomographic image generated by the optical coherence tomographic image generating unit 47 is not limited to a specific orientation. For example, the optical coherence tomographic image generating device 40 may scan the collapsible solid sample 1 three-dimensionally, and the information processing unit 46 of the optical coherence tomographic image generating unit 47 may generate a three-dimensional image of the collapsible solid sample 1. This allows the optical coherence tomographic image generating unit 47 to generate a tomographic image at any position and in any orientation within the scanning range of the collapsible solid sample 1.

Here, FIG. 3 is a process diagram showing the procedure for carrying out the method for observing the disintegration of a disintegrable solid sample 1 according to the present invention.

In this collapsibility observation system 100, the collapsibility observation method for the collapsible solid sample 1 is carried out according to the procedure shown in the process diagram of Figure 3.

In other words, in the collapsibility observation system 100, when collapsibility observation of the collapsible solid sample 1 is started, the weight measurement process (S1) and the optical coherence tomographic image generation process (S2) are started, and then the contact control process (S3) is started.

In the weight measurement step (S1), the weight of the disintegrable solid sample 1 held by the sample holder 21 suspended and supported by the weight measurement device 20 is measured. In this weight measurement step (S1), the weight of the disintegrable solid sample 1 is repeatedly measured, for example, every second, by the weight measurement device 20 using an electronic balance. The weight measurement in this weight measurement step (S1) is repeated until a determination process (S4) is performed as to whether or not to end the weight measurement, and the weight measurement is ended.

In addition, in the optical coherence tomography image generating step (S2), an optical coherence tomography image generating device 40 irradiates infrared light from outside the observation container 10 to an area near the contact portion 1A of the disintegrative solid sample 1 that is brought into contact with the surface of the disintegration test liquid 11 stored in the observation container 10, and performs optical coherence tomography measurement of the disintegrative solid sample 1 at, for example, 75 fps to generate an optical coherence tomography image.

Then, while simultaneously performing the weight measurement in the weight measurement step (S1) and the generation of the optical coherence tomographic image in the optical coherence tomographic image generation step (S2), the operation of the contact control step (S3) is started, and the relative distance between the contact portion 1A of the disintegrable solid sample 1 and the surface 11A of the disintegration test liquid 11 is changed by the contact control means 30 consisting of a liquid level adjustment mechanism using a tube pump, so that the contact portion 1A of the disintegrable solid sample 1 and the surface 11A of the disintegration test liquid 11 are brought into contact with each other.

In this contact control step (S3), for example, a tube pump is used to inject the disintegration test liquid 11 into the observation container 10 to control the liquid level 11A to rise, and when contact between the disintegration solid sample 1 and the disintegration test liquid 11 is confirmed on the optical coherence tomography image obtained by the optical coherence tomography image generating device 40, the supply of liquid by the tube pump is stopped.

The optical coherence tomographic image obtained by the optical coherence tomographic image generating device 40 in the optical coherence tomographic image generating step (S2) is subjected to a speckle pattern displacement analysis process by the image analysis processing device 50 in the next image analysis step (S5).

In the image analysis process (S5), the image analysis processing device 50 performs a displacement analysis process of the speckle pattern using a digital image correlation method to quantitatively evaluate the internal structural change accompanying the disintegration of the disintegrable solid sample 1 due to contact with the disintegration test liquid 11.

The optical coherence tomographic image generation process (S2) and image analysis process (S5) are repeated until a determination process (S6) is performed as to whether or not to end the image analysis, and the image analysis is completed.

In this image analysis step (S5), the image analysis processing device 50 performs image analysis processing to analyze the displacement amount of the speckle pattern by comparing an optical coherence tomography image in a frame at time t0 before the internal structure change of the disintegrable solid sample 1 that disintegrates due to contact between the disintegrable solid sample 1 and the disintegration test liquid 11, that is, an optical coherence tomography image obtained in a frame at time t1 after time t1, before and after the change in the internal structure of the disintegrable solid sample 1, as described below. That is, the image analysis processing device 50 performs image analysis processing to analyze the displacement amount of the speckle pattern by, for example, dividing the optical coherence tomography image in the frame at time t0 into minute regions called subsets containing characteristic points as shown in FIG. 4 by using a digital image correlation method (a method of comparing images containing random patterns such as speckle patterns and examining the displacement amount of the pattern), and finding a region (subset) that has an optimal value of the normalized correlation coefficient from the optical coherence tomography image in the frame at time t1 after the displacement. A displacement vector indicating the displacement amount of the subset can be obtained by repeating this process for all small regions.

As described above, the depth direction scan (A-scan) speed of SS-OCT is, for example, 90,000 times per second with a 90 kHz light source. By repeating this planar (B-scan) or spatial (C-scan), two-dimensional and three-dimensional images can be obtained. In observing the internal structure of scattering bodies such as pharmaceutical tablets, supplement tablets, solid foods made of powdered raw materials, etc., random granular patterns (speckle patterns) caused by interference between reflected lights are noise, but the speckle patterns are sensitive to structural changes. Therefore, in the disintegration observation system 100, the amount of displacement of the speckle pattern is analyzed for the optical coherence tomography image obtained by the optical coherence tomography image generating device 40, and the image analysis processing device 50 can quantitatively visualize the state of internal structural changes that occur due to disintegration of the disintegration solid sample 1 due to contact with the disintegration test liquid 11.

The image analysis processing device 50 is an information processing device using a personal computer (PC), and is connected, for example via USB, to a weight measuring device 20 using the electronic balance, a contact control means 30 consisting of a liquid level adjustment mechanism using a tube pump, an optical coherence tomographic image generating device 40, etc., and controls their operation.

Here, a commercially available United States Pharmacopeia (USP) prednisone standard tablet was used as the disintegration solid sample 1 to be observed, and water was used as the disintegration test liquid 11. Disintegration observation was performed using the disintegration observation system 100, and the weight change rate measurement results shown in Figure 5 were obtained. In addition, optical coherence tomography images of the disintegration process were obtained as shown in Figure 7. Furthermore, analysis results using the digital image correlation method were obtained as shown in Figure 8.

The SS-OCT device (IVS-4000, Santec Co., Ltd.) used as the optical coherence tomography image generating device 40, which is the basis of the observation, has a central wavelength of 1700 nm and a light source frequency of 90 kHz. The axial resolution is 9.4 μm (when n = 1 (refractive index)) and the lateral resolution is 11.8 μm.

The weight change was recorded every second using an electronic balance (AP125WD, Shimadzu Corporation) with a minimum display of 0.01 mg as the weight measuring device 20, which was connected to a PC. As the disintegrating solid sample 1, a tablet was fixed to the specific gravity measuring tool of the electronic balance with double-sided tape, and the height and angle of the camera head 45 of the optical coherence tomography image generating device 40 were adjusted so that the end of the tablet in contact with the water, which was the disintegration test liquid 11, could be observed. The water level was controlled by a tube pump, and generation was started at 75 fps simultaneously with the weight measurement, and water supply by the tube pump was stopped when contact between the tablet and water was confirmed on the optical coherence tomography image. Recording was continued until the tablet completely disintegrated, lost contact with the water, and a rapid weight loss was observed. The displacement amount analysis of the speckle pattern was performed using commercially available digital image correlation (DIC) software (sDIC, Seika Digital Image Co., Ltd.).

Figure 5 shows the weight change rate obtained by measuring the weight of the disintegrative solid sample 1, i.e., the tablet, before and after contact with water using the weight measuring device 20. The horizontal axis is the measurement time s, and the vertical axis is the weight change rate %.

The weight change before and after the tablet comes into contact with water can be broadly divided into region A from time t1 to time t2, region B from time t2 to time t3, and region C from time t3 to time t4, and the rate of weight change was not constant, being greatest in region A. This is thought to reflect the process of weight loss from swelling to disintegration, in addition to the weight increase due to water absorption (or water conduction) starting from the contact of the tablet with water (time t1). The weight loss in the region after time t4, where region C ends, is due to the tablet disintegrating and losing contact with water.

Figure 7 shows optical coherence tomographic images generated by the optical coherence tomographic image generating device 40 at various times before and after the tablet comes into contact with water, with the disintegration solid sample 1, i.e., the contact portion 1A of the tablet, being the observation area that comes into contact with the disintegration test liquid 11, i.e., water, as shown in Figure 6, and the incident light is irradiated from the A-scan direction.

Figure 7 (A) is an optical coherence tomography image taken at a time (t0) before the tablet comes into contact with water, with the tablet inside the dashed line.

In the optical coherence tomography image shown in Figure 7 (A), the high brightness areas are mainly due to reflection at the interface between the constituent particles and the air. Powder materials such as tablets contain many optically inhomogeneous structures, and the signal intensity attenuates in the depth direction (A-scan direction) due to light scattering caused by these. In addition, due to the influence of the water supply from the tube pump, the liquid surface before it comes into contact with the tablet appears curved.

Figure 7 (B) is an optical coherence tomography image at the time when contact between the tablet and water was observed. This coincides with time t1 when the weight began to increase in the above-mentioned region A.

(C) and (D) in FIG. 7 are optical coherence tomographic images of the above-mentioned region A, where (C) is an optical coherence tomographic image taken 1 second after time t1, and (D) is an optical coherence tomographic image taken 3 seconds after time t1.

The contact interface with water at the position indicated by the arrow "→" in Figures 7(B), (C), and (D) rises toward the tablet, and the area in which a fluid change in the speckle pattern can be observed gradually expands from near the interface.

At this time, since there is no change in the external shape of the tablet, it is believed that water absorption is occurring in region A due to the tablet's capillary force.

In addition, in the optical coherence tomography image shown in FIG. 7(E) corresponding to region B taken 12 seconds after time t1, small lumps were observed spreading outward from the end of the tablet in a chain-like pattern.

Furthermore, in the optical coherence tomography image shown in FIG. 7(F) corresponding to region C taken 30 seconds after time t1, significant structural changes such as the formation and separation of larger agglomerates were observed.

From these results, it is believed that swelling and collapse due to water absorption are occurring from region B to region C. The reason that the weight continues to increase even in region C, where collapse has already occurred, is because the tablet remaining in the jig has not lost contact with the liquid surface, and a similar process is occurring outside the observation range.

In this manner, in this disintegration observation system 100, the disintegration solid sample 1, i.e., the contact portion 1A of the tablet that comes into contact with the disintegration test liquid 11, i.e., water, is used as the observation area, and the disintegration solid sample 1, i.e., the contact portion 1A of the tablet is brought into contact with the surface of the disintegration test liquid 11, i.e., water, stored in the observation container 10, thereby measuring the weight change of the tablet before and after the disintegration process in which the tablet disintegrates, and at the same time, the internal structural change of the tablet before and after the disintegration process can be simultaneously observed in real time.

Next, FIG. 8 shows the image analysis processing device 50 performing a displacement analysis of the speckle pattern for the optical coherence tomography image corresponding to region A after the contact between the tablet and water (time t1) using the optical coherence tomography image at time (t0) before the tablet comes into contact with the water shown in FIG. 7 (A) as a reference, and visualizing the displacement of the speckle pattern by the displacement vector length. The figure shows the result of the displacement analysis of the speckle pattern of the optical coherence tomography image 0.01 seconds after time t1, and FIG. 8 shows the result of the displacement analysis of the speckle pattern of the optical coherence tomography image 1 second after time t1.

The bottom edge of the image is the contact interface with water. Although it is difficult to distinguish in grayscale, it is possible to see areas that appear darker inside than on the surface. This suggests a planar structural change within the scale. On the other hand, within the dashed line, there was no shading that corresponded to the scale. This is because it was not possible to obtain correlation between the patterns, suggesting that a significant structural change occurred spatially. The reason for the small change near the surface is thought to be due to differences in density inside the tablet caused by the coating agent and the pressure distribution during compression molding.

In this way, in the disintegration observation system 100, the image analysis processing device 50 analyzes the displacement amount of the speckle pattern of the optical coherence tomography image obtained by the optical coherence tomography image generating device 40, and the state of the internal structure change accompanying the disintegration of the disintegrable solid sample 1 due to contact with the disintegration test liquid 11 can be quantitatively visualized and evaluated.

In other words, this disintegration observation system 100 combines swept source optical coherence tomography (SS-OCT), which enables high-speed observation, with an electronic balance, which enables high-speed measurement. By further improving the position of the OCT probe, the method of fixing the disintegrating solid sample, the liquid level control method, and the image processing and analysis method of the optical coherence tomographic images, it is possible to observe the internal structural changes before and after the disintegration process of the solid sample, which was previously impossible to observe, in situ and in real time, while simultaneously measuring the weight change of the disintegrating solid sample.

The disintegration observation system 100 can perform disintegration observations on various disintegrating solids, such as supplement tablets other than pharmaceutical tablets and solid foods made by solidifying raw material powders, as the disintegrating solid sample 1 that disintegrates upon contact with liquid.

The disintegration test liquid 11 is not limited to water, but may be a disintegration test liquid 1 having a composition similar to gastric fluid, a disintegration test liquid 2 having a composition similar to intestinal fluid, etc., and a disintegration test liquid can be used according to the application of the disintegratable solid sample 1.

As shown in FIG. 9, the disintegration observation system 100 for the disintegration test liquid 11 may further include a pH meter 60 for measuring the pH of the disintegration test liquid 11 stored in the observation container 10 and a temperature measuring means 70 such as a thermocouple for measuring the temperature, thereby making it possible to simultaneously measure the changes in the liquid properties and temperature of the disintegration test liquid 11. Furthermore, the system may include an imaging device 80 such as a CCD camera for imaging the appearance of the disintegration test liquid 11 in the observation container 10 from outside the observation container 10, thereby making it possible to observe in real time the change in the appearance of the disintegration test liquid 11 caused by the disintegration of the disintegration test liquid 11 due to contact with the disintegration test liquid 11.

1 Disintegrable solid sample, 1A Contact portion of disintegrable solid sample, 10 Observation container, 11 Disintegration test liquid, 11A Surface of disintegration test liquid, 20 Weight measuring device, 21 Sample holder, 30 Contact control means, 40 Optical coherence tomography image generating device, 41 Light source, 42 Half mirror, 43 Reference mirror, 44 Detector, 45 Camera head, 46 Information processing unit, 47 Optical coherence tomography image generating unit, 50 Image analysis processing device, 60 pH meter, 70 Temperature measuring means, 80 Imaging device

Claims (10)

A method for observing the disintegration of a disintegrable solid sample due to contact with a liquid, comprising the steps of:
a contact control step of holding the disintegrable solid sample by a sample holder suspended and supported by a weight measuring device, and positioning the disintegrable solid sample above the surface of the disintegration test liquid stored in an observation vessel, and relatively displacing the height positions of the disintegrable solid sample and the surface of the disintegration test liquid, thereby bringing the contact portion of the disintegrable solid sample into contact with the surface of the disintegration test liquid stored in the observation vessel;
a weight measuring step of measuring in real time a change in weight of the disintegrable solid sample before and after a disintegration process in which the disintegrable solid sample is disintegrated by contacting a contact portion of the disintegrable solid sample with a surface of the disintegration test liquid stored in the observation container in the contact control step, using a weight measuring device;
an optical coherence tomography image generating step of irradiating an area near a contact portion of the disintegrative solid sample, which is brought into contact with the surface of the disintegration test liquid stored in the observation container, with infrared light from the outside of the observation container by an optical coherence tomography image generating device, performing optical coherence tomography measurement of the disintegrative solid sample, and generating an optical coherence tomography image, and observing in real time an internal structure change process accompanying disintegration of the disintegrative solid sample due to contact with the disintegration test liquid as optical coherence tomography images generated by the optical coherence tomography image generating device before and after the disintegration process in which the disintegrative solid sample is disintegrated;
and an image analysis step of quantitatively evaluating an internal structural change associated with disintegration of the disintegrable solid sample due to contact with the disintegration test liquid by speckle pattern displacement analysis by a digital image correlation method using optical coherence tomographic images generated in the optical coherence tomographic image generating step before and after a contact process in which the contact portion of the disintegrable solid sample is brought into contact with the surface of the disintegration test liquid stored in the observation container,
A method for observing the disintegration properties of a disintegrable solid sample, characterized in that the change in weight of the disintegrable solid sample before and after the contact process with the disintegration test liquid is measured in real time in the weight measuring step, and the optical coherence tomographic images generated in the optical coherence tomographic image generating step before and after the contact process with the disintegration test liquid are image analyzed in the image analysis step, thereby making it possible to observe in real time the process of changes in the internal structure of the disintegrable solid sample accompanying disintegration due to contact with the disintegration test liquid. The method for observing the disintegration of a disintegrating solid sample according to claim 1, characterized in that in the optical coherence tomography image generating step, the optical coherence tomography image is obtained by swept source optical coherence tomography (SS-OCT). A disintegration observation system for observing disintegration of a disintegrable solid sample due to contact with a liquid, comprising:
A weight measuring device for measuring the weight of the disintegrable solid sample;
an observation vessel containing a disintegration test liquid with which the disintegrative solid sample is to be brought into contact;
an optical coherence tomography image generating device for irradiating an area near a contact portion of the disintegrative solid sample, which is brought into contact with a surface of the disintegration test liquid stored in the observation container, with infrared light from outside the observation container, thereby performing optical coherence tomography measurement of the disintegrative solid sample and generating an optical coherence tomography image;
a contact control means for holding the disintegrable solid sample using a sample holder suspended and supported by the weight measuring device, and positioning the disintegrable solid sample above the surface of the disintegration test liquid stored in the observation vessel, and relatively displacing the height positions of the disintegrable solid sample and the surface of the disintegration test liquid, thereby bringing the contact portion of the disintegrable solid sample into contact with the surface of the disintegration test liquid stored in the observation vessel;
an image analysis processing device that performs image analysis to quantitatively evaluate an internal structural change accompanying disintegration of the disintegrable solid sample due to contact with the disintegration test liquid by using the speckle pattern displacement analysis of the optical coherence tomographic image generated by the optical coherence tomographic image generating device,
a weight measuring device for measuring in real time the weight change of the disintegratable solid sample before and after the contact process with the disintegration test liquid, and an image analysis processing device for analyzing optical coherence tomographic images generated by the optical coherence tomographic image generating device before and after the contact process with the disintegration test liquid, thereby making it possible to observe in real time the process of changes in the internal structure of the disintegratable solid sample accompanying disintegration due to contact with the disintegration test liquid. The collapsibility observation system for collapsible solid samples according to claim 3, characterized in that the optical coherence tomography image generating device is a swept source optical coherence tomography (SS-OCT). The system for observing the disintegration of a disintegrable solid sample according to claim 3 or 4, characterized in that the weight measuring device is an electronic balance for measuring the weight of the disintegrable solid sample. Further, a means for measuring the pH and temperature of the disintegration test liquid stored in the observation container is provided,
6. The system for observing the disintegration properties of a disintegrable solid sample according to claim 3, further comprising a means for simultaneously measuring changes in the properties and temperature of the disintegration test liquid. The collapsibility observation system for collapsible solid samples according to any one of claims 3 to 6, further comprising an imaging device for imaging the appearance of the collapsible solid sample in the observation container from outside the observation container, making it possible to observe in real time the process of change in the appearance of the collapsible solid sample accompanying the collapse of the collapsible solid sample due to contact with the liquid. the sample holder holds one end of the collapsible solid sample without covering the periphery of the collapsible solid sample;
8. The collapsibility observation system for a collapsible solid sample according to claim 3, wherein at least a wall surface of the observation container is formed of a material that transmits light in the infrared region for performing optical coherence tomography measurement of the collapsible solid sample by the optical coherence tomography image generating device. The disintegration observation system for disintegrating solid samples according to any one of claims 3 to 8, characterized in that the contact control means has a function of adjusting the liquid level of the disintegration test liquid stored in the observation container. The disintegration observation system for disintegrable solid samples according to any one of claims 3 to 9, characterized in that the disintegration test liquid is water, and the disintegrable solid sample is a drug that disintegrates upon contact with water.