Method for observing collapsibility of collapsible solid sample and collapsibility observation system

Abstract

To execute observation of an inner structure change simultaneously with measurement of weight change of a collapsing property solid matter sample before and after a collapsing process of a solid matter sample that collapses due to contact with liquid.SOLUTION: A collapsing property observation method of a collapsing property solid matter sample can measure the weight change of a collapsing property solid matter sample 1 in the actual time by measuring the weight of the collapsing property solid matter sample by a weight measurement device 20 in a collapsing process in which the collapsing property solid matter sample 1 that collapses due to contact with liquid collapses by contacting collapsing test liquid 11 stored by an observation container 10, performs optical interference tomographic measurement by emitting the light of an infrared ray region from the outside of the observation container 10 by using an optical interference tomographic image generation device 40, performs displacement magnitude analysis of a speckle pattern by an image analysis processing device 50 for the obtained optical interference tomographic image by generating the optical interference tomographic image, and performs evaluation by quantitatively visualizing the state of inner structure change following the collapsing of the collapsing property solid matter sample 1.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a method for observing the disintegration property of a disintegrating solid sample that disintegrates upon contact with a liquid, such as a pharmaceutical tablet, a supplement tablet, or a solid food obtained by compacting raw material powder, and a disintegration property observation system.

Background Art

[0002] The disintegration property of solid pharmaceutical tablets or supplement tablets formed by adding additives to an active ingredient and compressing them into a certain shape is an important material property for effectively exerting the expected function.

[0003] The "Japanese Pharmacopoeia Explanation Book General Test Method Disintegration Test Method" describes a test in which a tablet is placed in a glass cylinder of a tester with a net bottom, and the tester is shaken by an electric motor in a test solution to confirm the time it takes for the form of an oral preparation to disintegrate in the liquid.

[0004] Patent Documents 1 and 2 disclose methods for measuring the disintegration time while applying a load to a tablet in a solution.

[0005] Further, Patent Document 3 discloses a measurement and evaluation apparatus and an evaluation method for performing various evaluations such as the liquid absorption property of a sample based on the liquid penetration rate coefficient obtained by immersing the bottom surface of a sample holder holding the sample in a liquid, reproducing the penetration of the liquid only from the lower end portion of the sample with good reproducibility, and measuring the weight change accompanying the liquid absorption.

[0006] In the disclosed technologies of the above Patent Documents 1 to 3, it is possible to measure the time it takes for a sample to disintegrate in a liquid and evaluate the liquid absorption property of the sample, but it is not possible to observe the internal structure of the sample.

[0007] Furthermore, Patent Document 4 discloses an optical coherence tomographic method for analyzing multilayer pharmaceutical tablets.

[0008] In the disclosed technology of Patent Document 4, although the layer structure of tablets and capsules can be evaluated, it is impossible to observe the internal structure change process and weight change process accompanying the disintegration of samples that disintegrate in liquid.

[0009] In addition, in the disclosed technology of Patent Document 4, as the only example, time-domain optical coherence tomography (TD-OCT) is used. Since TD-OCT is a mechanical scan, it is difficult to increase the speed, and it is said that it is not suitable for fundus examination in terms of the involuntary eye movement of fixation. Also, since the OCT probe is fixed, it cannot be used in a fused manner with different devices such as an electronic balance.

Prior Art Documents

Patent Documents

[0010]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0011] As described above, the disintegration property of solid pharmaceutical tablets or supplement tablets formed by adding additives to an active ingredient and compressing and molding them into a certain shape is an important material property for effectively exerting the expected function. In particular, for orally disintegrating tablets, which are one type of pharmaceutical tablets, it is directly related to the ease of administration for patients who have difficulty with oral administration and under water intake restrictions. That is, conventionally, more precise control has been required for pharmaceutical agents that need to accurately control the disintegration property in quality control.

[0012] However, it has been pointed out that there is a difference between the disintegration time when the tablets are actually administered and the disintegration time measured by visual determination of the appearance change using the "disintegration tester" standardized in the Japanese Pharmacopoeia.

[0013] The variation in the disintegration time of tablets is a problem caused by the fact that the quantitative design and control of the internal structure of tablets have not been accurately carried out.

[0014] Conventionally, the disintegratability of tablets has only been evaluated by measuring the disintegration time by visual determination of the appearance change using the "disintegration tester" standardized in the Japanese Pharmacopoeia. Therefore, there has been no means to understand the actual state of the disintegration phenomenon of tablets, which should be the basic information for quantitative tablet design for disintegratability control. However, with the spread of tablets that require accurate control of disintegratability, such as orally disintegrating tablets, new evaluation techniques that can directly understand the actual state of the disintegration phenomenon are being demanded.

[0015] The starting point of disintegration is the contact between the disintegrant contained in the tablet and body fluid. Therefore, if the internal structure in the tablet, which is the penetration path of body fluid, and the disintegratability can be directly related and evaluated, the basic information for quantitative tablet design can be fed back to the manufacturing process. However, with the disclosed techniques of Patent Documents 1-4 above, it is not possible to simultaneously observe in real time the process of internal structure change and weight change accompanying the disintegration of a sample that disintegrates in liquid.

[0016] Therefore, an object of the present invention is to provide a method for observing the disintegratability of a disintegratable solid sample and a disintegratability observation system that can, in situ and in real time, simultaneously observe the change in internal structure before and after the disintegration process of a solid sample that could not be observed conventionally, along with the measurement of the weight change of the disintegratable solid sample, in view of the above-mentioned conventional circumstances.

[0017] Another object of the present invention and the specific advantages obtained by the present invention will become even clearer from the description of the embodiments described below.

Means for Solving the Problems

[0018] The present invention is a method for observing the disintegration property of a disintegrating solid sample by contact with a liquid. The disintegrating solid sample is held by a sample holder suspended and supported by a weighing device, and is positioned above the surface of a disintegration test liquid stored in an observation container. By relatively displacing the height positions of the surface of the disintegrating solid sample and the surface of the disintegration test liquid, a contact control step of bringing the contact portion of the disintegrating solid sample into contact with the surface of the disintegration test liquid stored in the observation container, and in the contact control step, by bringing the contact portion of the disintegrating solid sample into contact with the surface of the disintegration test liquid stored in the observation container, the weight change of the disintegrating solid sample before and after the disintegration process in which the disintegrating solid sample is disintegrated is measured by a weighing device Weight measurement process measured in real time and, in the vicinity of the contact portion of the disintegrating solid sample that comes into contact with the surface of the disintegration test liquid stored in the observation container, light in the infrared region is irradiated from the outside of the observation container by an optical coherence tomography image generation device to perform optical coherence tomography measurement of the disintegrating solid sample and generate an optical coherence tomography image. As the optical coherence tomography image generated by the optical coherence tomography image generation device before and after the disintegration process in which the disintegrating solid sample is disintegrated, an optical coherence tomography image generation step of observing in real time the internal structure change process accompanying the disintegration due to the contact of the disintegrating solid sample with the disintegration test liquid, and using the optical coherence tomography image generated in the optical coherence tomography image generation step before and after the contact process of bringing the contact portion of the disintegrating solid sample into contact with the surface of the disintegration test liquid stored in the observation container, an image analysis step of quantitatively evaluating the internal structure change accompanying the disintegration due to the contact of the disintegrating solid sample with the disintegration test liquid by digital image correlation method-based speckle pattern displacement amount analysis. The weight change of the disintegrating solid sample before and after the contact process with the disintegration test liquid is measured in real time in the weight measurement step, and the optical coherence tomography image generated in the optical coherence tomography image generation step before and after the contact process with the disintegration test liquid is subjected to image analysis in the image analysis step, so that the internal structure change process accompanying the disintegration due to the contact of the disintegrating solid sample with the disintegration test liquid can be observed in real time.

[0019] In the method for observing the disintegration property of a disintegrating solid sample according to the present invention, in the above optical coherence tomography image generation step, an optical coherence tomography image can be obtained by wavelength-swept OCT (Swept Source Optical Coherence Tomography: SS-OCT).

[0022] The present invention is a disintegration observation system for observing the disintegration property of a disintegrating solid sample due to contact with a liquid, comprising a weight measuring device for measuring the weight of the above disintegrating solid sample, an observation container storing a disintegration test liquid for contacting the above disintegrating solid sample, and irradiating light in the infrared region from the outside of the above observation container to a region near the contact portion of the above disintegrating solid sample that contacts the surface of the above disintegration test liquid stored by the above observation container to perform optical coherence tomography measurement of the above disintegrating solid sample and generate an optical coherence tomography image. An optical coherence tomography image generation device, holding the above disintegrating solid sample by a sample holder suspended and supported by the above weight measuring device, and positioning it above the surface of the above disintegration test liquid stored by the above observation container. Contact control means for bringing the contact portion of the above disintegrating solid sample into contact with the surface of the above disintegration test liquid stored by the above observation container by relatively displacing the height positions of the above disintegrating solid sample and the surface of the above disintegration test liquid, and digital image correlation method for the optical coherence tomography image generated by the above optical coherence tomography image generation device. Image analysis processing means for performing speckle pattern displacement amount analysis, and image analysis processing for quantitatively evaluating the internal structure change accompanying the disintegration due to the contact of the above disintegrating solid sample with the above disintegration test liquid by speckle pattern displacement amount analysis. An image analysis processing device, and the Weight change of the above disintegrating solid sample before and after the contact process with the above disintegration test liquid is measured in real time by the above Weight measuring device, and the internal structure change process accompanying the disintegration due to the contact of the above disintegrating solid sample with the above disintegration test liquid can be observed in real time by the image analysis by the above image analysis processing device of the optical coherence tomography image generated by the above optical coherence tomography image generation device before and after the contact process with the above disintegration test liquid.

[0023] In the disintegration observation system for a disintegrating solid sample according to the present invention, the optical coherence tomography image generation device can be a wavelength-swept type OCT (Swept Source Optical Coherence Tomography: SS-OCT).

[0024] In the disintegration observation system for a disintegrating solid sample according to the present invention, the weight measuring device can be an electronic balance that measures the weight of the disintegrating solid sample.

[0025] The disintegration observation system for a disintegrating solid sample according to the present invention further includes means for measuring the pH and temperature of the disintegration test liquid stored in the observation container, and can be configured to simultaneously measure changes in the liquidity and temperature of the disintegration test liquid.

[0026] The disintegration observation system for a disintegrating solid sample according to the present invention further includes an imaging device that images the appearance of the disintegrating solid sample inside the observation container from outside the observation container, and can be configured to observe in real time the process of change in the appearance of the disintegrating solid sample due to disintegration accompanying contact with the liquid.

[0027] In the disintegration observation system for a disintegrating solid sample according to the present invention, the sample holder holds one end of the disintegrating solid sample without covering the periphery of the disintegrating solid sample, and the observation container can be formed with at least a wall surface made of a material that transmits light in the infrared region for performing optical coherence tomography measurement of the disintegrating solid sample by the optical coherence tomography image generation device.

[0028] In the disintegration observation system for a disintegrating solid sample according to the present invention, the contact control means can have a function of adjusting the liquid level of the disintegration test liquid stored in the observation container.

[0031] In the disintegration observation system for a disintegrating solid sample according to the present invention, the disintegration test liquid is water, and the disintegrating solid sample can be a drug that disintegrates upon contact with water.

Advantages of the Invention

[0032] According to the present invention, it is possible to observe the internal structure changes before and after the disintegration process in which a solid sample that could not be observed conventionally disintegrates, simultaneously with the measurement of the weight change of the disintegrating solid sample, in-situ and in real time.

Brief Description of the Drawings

[0033]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Embodiments for Carrying Out the Invention

[0034] Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings. For common components, common reference numerals will be given in the drawings for explanation. It goes without saying that the present invention is not limited to the following examples and can be arbitrarily changed without departing from the gist of the present invention.

[0035] The present invention is applied to a disintegration observation system 100 for a disintegrating solid sample 1 configured as shown in the block diagram of FIG. 1, for example.

[0036] The collapsibility observation system 100 for the collapsible solid sample 1 observes in real time the weight change process and the internal structure change process of the collapsible solid sample 1 accompanying the collapse due to contact with the collapse test liquid 11 stored in the observation container 10, and performs internal structure analysis. The system includes a weight measuring device 20 for measuring the weight of the collapsible solid sample 1, a sample holder 21 suspended and supported by the weight measuring device 20 for holding the collapsible solid sample 1, and a contact control means 30 for relatively displacing the height positions of the collapsible solid sample 1 and the surface of the collapse test liquid 11 so that the contact portion 1A of the collapsible solid sample 1 is positioned above the surface 11A of the collapse test liquid 11 stored in the observation container 10, thereby bringing the contact portion 1A of the collapsible solid sample 1 into contact with the surface 11A of the collapse test liquid 11 stored in the observation container 10. The system also includes an optical coherence tomography image generation device 40 for performing optical coherence tomography measurement of the collapsible solid sample 1 from outside the observation container 10 and generating an optical coherence tomography image, and an image analysis processing device 50 for quantitatively evaluating the internal structure change accompanying the collapse of the collapsible solid sample 1 due to contact with the collapse test liquid 11 based on the optical coherence tomography image of the collapsible solid sample 1 obtained by the optical coherence tomography image generation device 40, etc.

[0037] In this collapsibility observation system 100, the contact control means 30 changes the relative distance between the contact portion 1A of the collapsible solid sample 1 and the surface 11A of the collapse test liquid 11. For example, the liquid level of the collapse test liquid 11 can be easily adjusted to an arbitrary initial height, and there is no vibration due to mechanical operation. For example, it consists of a liquid level adjustment mechanism using a tube pump.

[0038] Also, the weight measuring device 20 measures the weight change accompanying the collapse of the collapsible solid sample 1 due to contact with the collapse test liquid 11, and an electronic balance that automatically measures minute weight changes with high precision in units of 1 second is used.

[0039] In addition, the optical coherence tomography image generation device 40 in this disintegration observation system 100 includes, for example, as shown in the schematic diagram of FIG. 2, a light source 41, a half mirror 42, a reference mirror 43, and a detector 44, and includes a camera head unit 45 including an optical interference system constituted by the half mirror 42 and the reference mirror 43, and an optical coherence tomography image generation unit 47 including the light source 41, the detector 44, and an information processing unit 46.

[0040] In this disintegration observation system 100, the sample 1 is a disintegrating solid that is disintegrated by contacting the surface of the disintegration test liquid 11 stored in the observation container 10.

[0041] The sample holder 41 holds one end of the disintegrating solid sample 1 without covering the periphery of the disintegrating solid sample 1 while being suspended and supported by the weighing device 20.

[0042] The light source 41 of the optical coherence tomography image generation device 40 is for irradiating light in the infrared region reflected by the disintegrating solid sample 1 from outside the observation container 10. The light reflected by the disintegrating solid is, for example, light that is not absorbed by the disintegrating solid.

[0043] The observation container 10 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 disintegrating solid sample 1 by the optical coherence tomography image generation device 40.

[0044] The half mirror 42 is provided on the optical path of the light emitted from the light source 41. Further, the half mirror 42 is arranged such that the surface 42a on the light source 41 side is inclined at an angle of 45° with respect to the optical path on the light source 41 side.

[0045] The half mirror 42 divides the light emitted from the light source 41 into irradiation light that irradiates the disintegrating solid sample 1 and reference light that enters the reference mirror 43. Then, the half mirror 42 reflects the divided irradiation light and makes it enter the disintegrating solid sample 1. The half mirror 42 also transmits the divided reference light and makes it enter the reference mirror 43.

[0046] The reference mirror 43 is provided on the optical path of the light emitted from the light source 41.

[0047] The reference mirror 43 reflects the reference light transmitted through the half mirror 42 and returns the reflected light to the half mirror 42. For this purpose, the reference mirror 43 is provided so as to face the half mirror 42.

[0048] Also, the reference mirror 23 is movable along the optical path direction of the light emitted from the light source 41. That is, the reference mirror 43 can adjust the distance from the half mirror 42. Instead of making the reference mirror 43 movable, a wavelength tunable light source may be used to achieve a similar function.

[0049] The detector 44 is provided on the optical path of the return light obtained by irradiating the light-disintegrating 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, returns to the half mirror 42, and is further reflected by the half mirror 42.

[0050] An interference optical system is constituted by the half mirror 22 and the reference mirror 43 of the optical coherence tomography image generation apparatus 40.

[0051] The detector 44 is for observing the interference light between the return light and the reference light described above.

[0052] Here, in this disintegration observation system 100, using the optical coherence tomography image generation apparatus 40, the internal structure change process accompanying the disintegration of the light-disintegrating solid sample 1 is non-destructively and dynamically observed in real time. For dynamic observation, in terms of time resolution, Fourier domain OCT (FD-OCT) which is faster than TD-OCT is desirable, and among them, wavelength swept OCT (SS-OCT) which is even faster is more desirable.

[0053] In the optical coherence tomography (OCT) image generation device 40 of this collapse observation system 100, depth measurement is performed by sweeping the wavelength of the light source 41 (A-scan), and a two-dimensional tomographic image is generated by sliding the laser beam horizontally (B-scan). A wavelength-swept OCT (Swept Source Optical Coherence Tomography: SS-OCT) is adopted.

[0054] In this optical coherence tomography image generation device 40, as the light source 41, a wavelength-tunable light source with a central wavelength of 1700 nm and a light source frequency of 90 kHz is used.

[0055] The generation time of the SS-OCT optical coherence tomography image is determined by the speed of the depth scan (A-scan) and the number of A-scans repeated in the plane (B-scan). For example, for 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) within 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 (frames per second; a unit of frame rate indicating the number of frames processed per unit time), enabling real-time dynamic observation. Note that the frame rate (fps) that can be acquired as data varies depending on the specifications of the hardware and software of a personal computer (PC).

[0056] By repeating the depth scan (A-scan) of the SS-OCT spatially (C-scan), three-dimensional measurement can also be acquired at high speed. For example, when the A-scan is repeated 100 times within a range of 1 mm in the horizontal direction (B-scan) and further repeated 100 times within a range of 1 mm in the depth direction (C-scan) using a 90 kHz light source, the three-dimensional measurement time is computationally 0.11 s. The horizontal and depth resolutions of the three-dimensional image generated thereby are 10 μm / pixel. The depth resolution varies depending on the refractive index of the sample, the wavelength of the light source, and the wavelength sweep range.

[0057] In this disintegration observation system 100, the optical coherence tomography image generation device 40 observes the disintegration state of the disintegrating solid sample 1 from outside the observation container 10 in which the disintegration test liquid 11 is stored. Therefore, by setting the wall surface position of the observation container 10 at a location where the interference distance in the optical coherence tomography image generation device 40 is also short, noise caused by reflection from the wall surface of the observation container 10 is reduced as much as possible.

[0058] Also, in order to reduce noise caused by strong reflection from the surface of the disintegrating solid sample 1, at a position where the contact between the end face of the disintegrating solid sample 1 and the liquid surface can be observed, and by adjusting to an arbitrary angle with little influence of specular reflection, a desired region is observed with low noise.

[0059] With the optical axis of the light in the infrared region irradiated from the camera head unit 45 of the optical coherence tomography image generation device 40 inclined 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 disintegrating solid sample 1, the optical coherence tomography image generation device 40 generates an optical coherence tomography image. Here, the holding posture of the camera head unit 45 is variably adjustable, but even if the holding posture of the disintegrating solid sample 1 by the sample holder 21 is variably adjustable, the optical axis of the light in the infrared region irradiated to the disintegrating solid sample 1 can be inclined with respect to the normal direction of the observation surface of the disintegrating solid sample 1.

[0060] That is, the half mirror 42 divides the light in the infrared region emitted from the light source 41 into irradiation light that irradiates the disintegrating solid sample 1 and reference light that enters the reference mirror 43. The half mirror 42 reflects the divided irradiation light and makes it incident on the disintegrating solid sample 1. Also, the half mirror 42 transmits the divided reference light and makes it incident on the reference mirror 43. That is, the irradiation light divided by the half mirror 42 is irradiated to the disintegrating solid sample 1 in the observation container 10 from outside the observation container 10 through at least a wall surface of the observation container 10 that is transparent to light in the infrared region.

[0061] The irradiation light incident on the collapsible solid sample 1 is reflected at an interface with a refractive index difference, such as the surface or internal structure of the collapsible solid sample 1, and exits from the surface of the contact portion 1A of the collapsible solid sample 1, that is, the observation surface, as the return light. Then, the return light exiting from the observation surface is incident on the half mirror 42 of the optical interference tomography image generation device 40 through the transparent wall surface of the observation container 10.

[0062] The return light obtained by irradiating the collapsible solid sample 1 with the irradiation light and the reference light reflected by the reference mirror 44 and returned are overlapped again on the half mirror 42. At this time, if the distances traveled by the return light from the collapsible solid sample 1 and the reference light from the reference mirror 44 are equal, the two lights reinforce each other. On the other hand, if there is a deviation in the distances traveled by the return light from the collapsible solid sample 1 and the reference light from the reference mirror 44 and the phases of the lights are reversed, the two lights cancel each other out.

[0063] Here, the reference mirror 44 constituting the optical interference system is moved to adjust the distance between the reference mirror 44 and the half mirror 42, and the position where the two lights interfere and reinforce each other is observed on the detector 44. By this observation, it is possible to know at what depth there is a reflecting surface in the collapsible solid sample 1. That is, the distribution of the signal intensity in the depth direction reflecting the internal structure information of the collapsible solid sample 1 can be obtained. Further, by imaging the distribution of the signal intensity in the depth direction continuous in the horizontal direction, the internal structure of the collapsible solid sample 1 can be visualized.

[0064] That is, the optical coherence tomography (OCT) image generation device 40 irradiates the disintegrating solid sample 1 in the observation container 10 with light in the infrared region emitted from the light source 41 of the OCT image generation unit 47 through the optical interference system in the camera head unit 45, and the detector 44 of the OCT image generation unit 47 detects the interference light between the return light from the disintegrating solid sample 1 obtained by the optical interference system included in the camera head unit 45 and the reference light, thereby performing OCT measurement on the disintegrating solid sample 1. An OCT image is generated from the distance image information obtained from the interference light as the detection output by the detector 44 by an information processing unit 46 using, for example, a personal computer (PC). As a method for the OCT image generation unit 47 of the OCT image generation device 40 to generate a tomographic image, a tomographic image generation method in OCT measurement can be used.

[0065] In this OCT image generation device 40, by adopting wavelength-swept OCT (SS-OCT) capable of generating a two-dimensional tomographic image at high speed, the internal structure of the disintegrating solid sample 1 that is disintegrated by contacting the surface of the disintegration test liquid 11 in the observation container 10 can be observed during the disintegration process of the disintegrating solid sample 1, and the internal structure change process of the disintegrating solid sample 1 can be observed in real time by generating the internal structure of the disintegrating solid sample 1 as a two-dimensional tomographic image at high speed during the disintegration process.

[0066] Note that the orientation of the tomographic image generated by the OCT image generation unit 47 is not limited to a specific orientation. For example, the OCT image generation device 40 may scan the disintegrating solid sample 1 three-dimensionally, and the information processing unit 46 of the OCT image generation unit 47 may generate a three-dimensional image of the disintegrating solid sample 1. Thereby, the OCT image generation unit 47 can generate tomographic images at any position and in any orientation within the scan range of the disintegrating solid sample 1.

[0067] Here, FIG. 3 is a process diagram showing the execution procedure of the method for observing the disintegratability of the disintegratable solid sample 1 according to the present invention.

[0068] In this disintegratability observation system 100, the method for observing the disintegratability of the disintegratable solid sample 1 is executed according to the procedure shown in the process diagram of FIG. 3.

[0069] That is, in the disintegratability observation system 100, when starting the observation of the disintegratability of the disintegratable solid sample 1, after starting the operations of the weight measurement step (S1) and the optical coherence tomography image generation step (S2), the operation of the contact control step (S3) is started.

[0070] In the weight measurement step (S1), the weight of the disintegratable solid sample 1 held by the sample holder 21 suspended and supported by the weight measuring device 20 is measured. In this weight measurement step (S1), the weight of the disintegratable solid sample 1 is repeatedly measured, for example, every 1 second, by the weight measuring device 20 using an electronic balance. The weight measurement in this weight measurement step (S1) is repeatedly performed until the determination process (S4) of whether to end the weight measurement is performed and the weight measurement ends.

[0071] Also, in the optical coherence tomography image generation step (S2), infrared light in the infrared region is irradiated from the outside of the observation container 10 by the optical coherence tomography image generation device 40 to the vicinity of the contact portion 1A of the disintegratable solid sample 1 that is brought into contact with the surface of the disintegration test liquid 11 stored by the observation container 10, and the optical coherence tomography measurement of the disintegratable solid sample 1 is performed, for example, at 75 fps, to generate an optical coherence tomography image.

[0072] Then, while simultaneously performing the weight measurement by the weight measurement step (S1) and the generation of the optical coherence tomography image by the optical coherence tomography 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 disintegratable solid sample 1 and the surface 11A of the disintegration test liquid 11 is changed by the contact control means 30 composed of a liquid level adjustment mechanism by a tube pump, so that the contact portion 1A of the disintegratable solid sample 1 and the surface 11A of the disintegration test liquid 11 are brought into contact.

[0073] In this contact control step (S3), for example, control is performed to inject the disintegration test liquid 11 into the observation container 10 by a tube pump to raise the liquid level 11A, and the liquid supply by the tube pump is stopped at the stage where the contact between the disintegrating solid sample 1 and the disintegration test liquid 11 is confirmed on the optical coherence tomography image obtained by the optical coherence tomography image generation device 40.

[0074] In the optical coherence tomography image generation step (S2), the optical coherence tomography image obtained by the optical coherence tomography image generation device 40 is subjected to displacement amount analysis processing of the speckle pattern in the next image analysis step (S5) by the image analysis processing device 50.

[0075] In the image analysis processing device 50, by performing displacement amount analysis processing of the speckle pattern by the digital image correlation method in the image analysis step (S5), the internal structure change accompanying the disintegration of the disintegrating solid sample 1 due to contact with the disintegration test liquid 11 is quantitatively evaluated.

[0076] The processes of the optical coherence tomography image generation step (S2) and the image analysis step (S5) are repeatedly performed until the determination process (S6) of whether to end the image analysis is performed and the image analysis ends.

[0077] In this image analysis step (S5), the image analysis apparatus 50 compares the optical coherence tomography images before and after the internal structure change of the collapsible solid sample 1 that collapses when the collapsible solid sample 1 comes into contact with the collapse test liquid 11, that is, in the frame at time t0 before the time t1 which is the starting point of the collapse as described later, and the optical coherence tomography image obtained at the time of the frame after time t1, and performs image analysis processing for analyzing the displacement amount of the speckle pattern. That is, in the image analysis apparatus 50, for example, by the digital image correlation method (a method of comparing images including random patterns such as a speckle pattern and examining the displacement amount of the pattern), as shown in FIG. 4, the optical coherence tomography image in the frame at time t0 is divided into minute regions called subsets including feature points, and a region (subset) that becomes the optimal value of the normalized correlation coefficient is searched for from the optical coherence tomography image in the frame at time t1 after displacement, whereby a displacement vector indicating the displacement amount of the subset can be obtained. By repeating this process for all small regions, a displacement vector indicating the displacement amount of the subsets in the entire field of view can be obtained.

[0078] As described above, the depth direction scan (A-scan) speed of SS-OCT is, for example, 90,000 times per second for a 90 kHz light source. By repeating this in a planar (B-scan) or spatial (C-scan) manner, a two-dimensional image or a three-dimensional image can be acquired. In the observation of the internal structure of scatterers such as pharmaceutical tablets, supplement tablets, and solid foods formed by compacting raw material powders, the random granular pattern (speckle pattern) due to the interference of reflected lights is noise, but since the speckle pattern is sensitive to structural changes, in the collapsibility observation system 100, regarding the optical coherence tomography image obtained by the optical coherence tomography image generation apparatus 40, by analyzing the displacement amount of the speckle pattern, the internal structure change state accompanying the collapse due to the contact of the collapsible solid sample 1 with the collapse test liquid 11 can be quantitatively visualized by the image analysis apparatus 50.

[0079] Note that the above image analysis processing apparatus 50 is an information processing apparatus using a personal computer (PC). A weight measurement apparatus 20 using the above electronic balance, a contact control means 30 including a liquid level adjustment mechanism by a tube pump, an optical coherence tomography image generation apparatus 40, etc. are connected by USB, for example, and their operation control is performed.

[0080] Here, a commercially available United States Pharmacopeia (USP) prednisone standard tablet was used as the disintegrating solid sample 1 for observation, and water was used as the disintegration test liquid 11. When disintegration observation was performed by the disintegration observation system 100, measurement results of the weight change rate as shown in FIG. 5 were obtained, and optical coherence tomography images in the disintegration process as shown in FIG. 7 were obtained. Furthermore, analysis results by the digital image correlation method as shown in FIG. 8 were obtained.

[0081] The central wavelength of the SS-OCT apparatus (IVS-4000, manufactured by Santec Co., Ltd.) used as the optical coherence tomography image generation apparatus 40 serving as the observation axis is 1700 nm, and the light source frequency is 90 kHz. The axial resolution is 9.4 μm (when n = 1 (refractive index)), and the lateral resolution is 11.8 μm.

[0082] The weight change was recorded every second by connecting an electronic balance (AP125WD, manufactured by Shimadzu Corporation) with a minimum display of 0.01 mg as the weight measurement apparatus 20 to the PC. The tablet was fixed with double-sided tape to the specific gravity measurement jig of the electronic balance as the disintegrating solid sample 1, and the height and angle of the camera head portion 45 of the optical coherence tomography image generation apparatus 40 were adjusted so that the end of the tablet in contact with water, which is the disintegration test liquid 11, could be observed. The water level was controlled by a tube pump, generation was started at 75 fps simultaneously with weight measurement, and water supply by the tube pump was stopped at the stage when contact between the tablet and water was confirmed on the optical coherence tomography image. Recording was continued until the tablet was completely disintegrated, contact with water was lost, and a rapid weight loss was observed. The displacement amount analysis of the speckle pattern was performed using commercially available digital image correlation method (DIC) software (sDIC, manufactured by Nissha Digital Image Co., Ltd.).

[0083] Figure 5 shows the weight change rate before and after contact between a tablet, which is the disintegrating solid sample 1 measured by the weight measuring device 20, and water. The horizontal axis represents the measurement time s, and the vertical axis represents the weight change rate %.

[0084] The weight change before and after contact between the tablet and water is roughly 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. The weight change rate is not constant and is maximum in region A. This is considered to reflect the process of weight increase due to water absorption (or water conduction) starting from the contact between the tablet and water (time t1), in addition to the process of weight decrease from swelling to disintegration. The weight decrease in the region after time t4 when region C ends is due to the fact that the tablet has disintegrated and lost contact with water.

[0085] As shown in FIG. 6, FIG. 7 is an optical coherence tomography image at each time before and after contact between a tablet and water, with the contact portion 1A between the disintegrating solid sample 1 (i.e., the tablet) and the disintegration test liquid 11 (i.e., water) as the observation region, generated by the optical coherence tomography image generation device 40. The incident light is irradiated from the A-scan direction.

[0086] (A) in FIG. 7 is an optical coherence tomography image at the time (t0) before contact between the tablet and water, and the inside of the broken line is the tablet.

[0087] In the optical coherence tomography image shown in FIG. 7(A), the high-intensity region is mainly due to reflection at the interface between the constituent particles and air. Since a powder material such as a tablet contains a large number of optical inhomogeneous structures, the signal intensity attenuates in the depth direction (A-scan direction) due to light scattering by these structures. Also, due to the influence of water supply from the tube pump, the liquid level before contact with the tablet appears to be a curved surface.

[0088] (B) in FIG. 7 is an optical coherence tomography image at the time when contact between the tablet and water is observed. This coincides with time t1 when the weight starts to increase in the above region A.

[0089] Figures (C) and (D) in Fig. 7 are each an optical coherence tomography image of the above region A. (C) is the optical coherence tomography image at the time point 1 second after the above time t1, and (D) is the optical coherence tomography image at the time point 3 seconds after the above time t1.

[0090] The contact interfaces with water at the positions indicated by the arrow "→" in (B), (C), and (D) of Fig. 7 rise toward the tablet side, and the region where a fluid change in the speckle pattern is observed gradually expands from near the interface.

[0091] At this time, since there is no change in the outer shape of the tablet, it is considered that water absorption due to the capillary force of the tablet occurs in region A.

[0092] Also, in the optical coherence tomography image shown in (E) of Fig. 7 corresponding to region B at the time point 12 seconds after the above time t1, it was observed that small-scale masses spread in a string-of-beads manner from the end of the tablet toward the outside.

[0093] Furthermore, in the optical coherence tomography image shown in (F) of Fig. 7 corresponding to region C at the time point 30 seconds after the above time t1, significant structural changes such as the generation and separation of larger masses were observed.

[0094] From these results, it is considered that swelling and disintegration due to water absorption occur from region B to region C. The reason why the weight continues to increase even in region C where disintegration has already occurred is that the contact between the tablet remaining on the jig and the liquid surface is not lost, and a similar process is proceeding outside the observation range.

[0095] In this way, in this disintegration observation system 100, taking the contact portion 1A of the disintegration solid sample 1, i.e., the tablet, which is in contact with the disintegration test liquid 11, i.e., water, as the observation region, by bringing the contact portion 1A of the disintegration solid sample 1, i.e., the tablet, into contact with the surface of the disintegration test liquid 11, i.e., water, stored in the above observation container 10, it is possible to simultaneously observe in real time the internal structural changes of the above tablet before and after the disintegration process in which the above tablet disintegrates, while measuring the weight change of the above tablet before and after the disintegration process.

[0096] Next, FIG. 8 is a diagram in which, based on the optical coherence tomography image at the time (t0) before the tablet shown in FIG. 7(A) contacts water by the above-described image analysis processing apparatus 50, displacement amount analysis of the speckle pattern is performed on the optical coherence tomography image corresponding to region A after the start of contact between the tablet and water (time t1), and the displacement amount of the speckle pattern is visualized by the displacement vector length. The result of the displacement amount analysis of the speckle pattern of the optical coherence tomography image at the time point when 0.01 seconds have elapsed from time t1 is shown, and (B) shows the result of the displacement amount analysis of the speckle pattern of the optical coherence tomography image at the time point when 1 second has elapsed from time t1.

[0097] The lower end of the image is the contact interface with water. Although it is difficult to distinguish in grayscale, a region that is darker than the surface and is shown inside can be seen. This suggests a planar structural change within the scale. On the other hand, there was no shading corresponding to the scale inside the broken line. This is because the pattern correlation could not be obtained, suggesting that a significant structural change occurred spatially. The reason for the small change near the surface is considered to be due to the difference in density inside the tablet caused by the coating agent and the pressure distribution during compression molding.

[0098] As described above, in the disintegration observation system 100, regarding the optical coherence tomography image obtained by the optical coherence tomography image generation apparatus 40, by analyzing the displacement amount of the speckle pattern by the above-described image analysis processing apparatus 50, it is possible to quantitatively visualize and evaluate the state of the internal structural change accompanying the disintegration due to the contact between the disintegrating solid sample 1 and the disintegration test liquid 11.

[0099] That is, in this disintegration observation system 100, a wavelength-swept type OCT (Swept Source Optical Coherence Tomography: SS-OCT) capable of high-speed observation and an electronic balance capable of high-speed measurement are integrated. Furthermore, by devising the position of the OCT probe, the fixing method of the disintegrating solid sample, the liquid level control method, the image processing of the optical coherence tomography image, and the analysis method, it is possible to observe the internal structure changes before and after the disintegration process in which the solid sample that could not be observed conventionally disintegrates, simultaneously with the measurement of the weight change of the above-mentioned disintegrating solid sample, in-situ and in real time.

[0100] Here, the disintegration observation system 100 can perform disintegration observation on various disintegrating solid substances such as supplement tablets other than pharmaceutical tablets and solid foods formed by compacting raw material powders as the disintegrating solid sample 1 that disintegrates upon contact with a liquid.

[0101] Also, the disintegration test liquid 11 is not limited to water, and may be a first disintegration test liquid whose composition resembles gastric juice, a second disintegration test liquid whose composition resembles intestinal juice, etc., and a disintegration test liquid corresponding to the use of the disintegrating solid sample 1 can be used.

[0102] Also, as shown in FIG. 9, the disintegration observation system 100 for the above-mentioned disintegrating solid sample 1 further includes a pH meter 60 for measuring the pH of the disintegration test liquid 11 stored in the observation container 10 and a thermometer 70 such as a thermocouple for measuring the temperature, so that changes in the liquid properties and temperature of the disintegration test liquid 11 can also be measured simultaneously. Furthermore, by providing an imaging device 80 such as a CCD camera for imaging the appearance of the disintegrating solid sample 1 inside the observation container 10 from outside the observation container 10, it is also possible to observe in real time the change process of the appearance of the disintegrating solid sample 1 due to disintegration upon contact with the disintegration test liquid 11 of the disintegrating solid sample 1.

Explanation of symbols

[0103] 1 Disintegrating solid sample, 1A Contact portion of the disintegrating solid sample, 10 Observation container, 11 Disintegration test liquid, 11A Surface of the disintegration test liquid, 20 Weight measuring device, 21 Sample holder, 30 Contact control means, 40 Optical coherence tomography image generation device, 41 Light source, 42 Half mirror, 43 Reference mirror, 44 Detector, 45 Camera head unit, 46 Information processing unit, 47 Optical coherence tomography image generation unit, 50 Image analysis processing device, 60 pH meter, 70 Temperature measuring means, 80 Imaging device

Claims

1. A method for observing the collapsibility of a collapsible solid sample by observing the collapsibility upon contact with a liquid, holding the collapsible solid sample with a sample holder suspended and supported by a weighing device, and positioning it above the surface of a collapse test liquid stored in an observation container, and relatively displacing the height positions of the collapsible solid sample and the surface of the collapse test liquid to bring the contact portion of the collapsible solid sample into contact with the surface of the collapse test liquid stored in the observation container, a contact control step; in the contact control step, measuring in real time with a weighing device the change in weight of the collapsible solid sample before and after the collapse process in which the collapsible solid sample collapses by bringing the contact portion of the collapsible solid sample into contact with the surface of the collapse test liquid stored in the observation container, a weight measurement step; irradiating light in the infrared region from outside the observation container with a light interference tomography image generation device to the vicinity region of the contact portion of the collapsible solid sample that is brought into contact with the surface of the collapse test liquid stored in the observation container, performing light interference tomography measurement of the collapsible solid sample to generate a light interference tomography image, and observing in real time the internal structure change process accompanying the collapse due to the contact of the collapsible solid sample with the collapse test liquid as the light interference tomography image generated by the light interference tomography image generation device before and after the collapse process in which the collapsible solid sample collapses, a light interference tomography image generation step; using the light interference tomography image generated in the light interference tomography image generation step before and after the contact process of bringing the contact portion of the collapsible solid sample into contact with the surface of the collapse test liquid stored in the observation container, performing speckle pattern displacement amount analysis by digital image correlation method to quantitatively evaluate the internal structure change accompanying the collapse due to the contact of the collapsible solid sample with the collapse test liquid, an image analysis step characterized in that the change in weight of the collapsible solid sample before and after the contact process with the collapse test liquid is measured in real time in the weight measurement step, and the light interference tomography image generated in the light interference tomography image generation step before and after the contact process with the collapse test liquid is subjected to image analysis in the image analysis step, whereby the internal structure change process accompanying the collapse due to the contact of the collapsible solid sample with the collapse test liquid can be observed in real time. A method for observing the collapsibility of a collapsible solid sample.

2. The method for observing the disintegration property of a disintegrating solid sample according to claim 1, wherein in the optical coherence tomography image generation step, an optical coherence tomography image is obtained by a wavelength-swept OCT (Swept Source Optical Coherence Tomography: SS-OCT).

3. A disintegration observation system for observing the disintegration property of a disintegrating solid sample due to contact with a liquid, a weight measuring device for measuring the weight of the disintegrating solid sample, an observation container storing a disintegration test liquid for contacting the disintegrating solid sample, an optical coherence tomography image generation device that irradiates light in the infrared region from outside the observation container to a region near the contact portion of the disintegrating solid sample that contacts the surface of the disintegration test liquid stored in the observation container, performs optical coherence tomography measurement of the disintegrating solid sample, and generates an optical coherence tomography image, contact control means for holding the disintegrating solid sample by a sample holder suspended and supported by the weight measuring device, and relatively displacing the height positions of the disintegrating solid sample and the surface of the disintegration test liquid in a state where the disintegrating solid sample is positioned above the surface of the disintegration test liquid stored in the observation container, so that the contact portion of the disintegrating solid sample contacts the surface of the disintegration test liquid stored in the observation container, an image analysis processing means for performing speckle pattern displacement amount analysis on the optical coherence tomography image generated by the optical coherence tomography image generation device by the digital image correlation method, and performing image analysis for quantitatively evaluating the internal structure change accompanying the disintegration of the disintegrating solid sample due to contact with the disintegration test liquid by the speckle pattern displacement amount analysis, and an image analysis processing device comprising measuring in real time the weight change of the disintegrating solid sample before and after the contact process with the disintegration test liquid by the weight measuring device, and observing in real time the internal structure change process accompanying the disintegration of the disintegrating solid sample due to contact with the disintegration test liquid by image analysis of the optical coherence tomography image generated by the optical coherence tomography image generation device by the image analysis processing device before and after the contact process with the disintegration test liquid. A disintegration observation system for a disintegrating solid sample, characterized in that it is possible to do so.

4. The optical coherence tomography image generation device is a wavelength-swept OCT (Swept Source Optical Coherence Tomography: SS-OCT), and the disintegration observation system for a disintegrating solid sample according to claim 3 is characterized in that.

5. The collapsible solid sample disintegration observation system according to claim 3 or claim 4, wherein the weight measuring device is an electronic balance for measuring the weight of the collapsible solid sample.

6. Furthermore, it is provided with means for measuring the pH and temperature of the disintegration test liquid stored in the observation container, The collapsible solid sample disintegration observation system according to any one of claims 3 to 5, characterized in that changes in the liquidity and temperature of the disintegration test liquid can also be measured simultaneously.

7. Furthermore, it is provided with an imaging device for imaging the appearance of the collapsible solid sample inside the observation container from outside the observation container, and the change process of the appearance of the collapsible solid sample due to the disintegration accompanying the contact of the collapsible solid sample with the liquid can be observed in real time. The collapsible solid sample disintegration observation system according to any one of claims 3 to 6.

8. The sample holder holds one end of the collapsible solid sample without covering the periphery of the collapsible solid sample, The observation container is characterized in that at least the wall surface 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 generation device. The collapsible solid sample disintegration observation system according to any one of claims 3 to 7.

9. The contact control means has a function of adjusting the liquid level of the disintegration test liquid stored in the observation container. The collapsible solid sample disintegration observation system according to any one of claims 3 to 8.

10. The disintegration test liquid is water, and the collapsible solid sample is a drug that disintegrates upon contact with water. The collapsible solid sample disintegration observation system according to any one of claims 3 to 9.

Images