Pellet and method for manufacturing the same

Abstract

To provide pellets for various fields such as pharmaceuticals, foods, and electronic components at low cost with stable quality.SOLUTION: In a pellet such as a tablet, a tab, or a chip including a core composed of a powder-molded body and a coating film covering the surface of the core, the coating film contains an aggregate that is a self-assembled body of noble metal nanoparticles made of gold, silver, or platinum-group metals having an average diameter of 100 nm or less, and a Raman-active chemical substance such as adenine that exhibits SERS, and is characterized in that the manufacturing process is controlled by measuring the Raman scattering intensity of the chemical substance.SELECTED DRAWING: Figure 4

Description

[Technical Field]

[0001] The present invention relates to pellets, also called pills, tablets or chips, which are used in the fields of medicine, food, electronic parts and the like, and to a method for producing the same. [Background technology]

[0002] In recent years, in order to meet the demand for stable quality at each stage of the manufacturing process, mainly for pharmaceuticals, the introduction of process analytical technology (hereinafter abbreviated as PAT) to control the quality of intermediate products has been promoted. For example, Non-Patent Document 1 describes a method of controlling the amount of coating in the coating process of tablets, i.e., pellets, while irradiating them with a laser in real time using near-infrared spectroscopy. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] WO2020 / 171010 "Method for expressing numerical information" [Non-patent literature]

[0004] [Non-Patent Document 1] Takashi Nishii, Katsuhiro Matsuzaki, Shigeaki Morita, Journal of Pharmaceutical Machinery and Technology, 28,5,24-28(2019) [Non-patent document 2] T. Fukuoka, A. Yamaguchi, R. Hara, T. Matsumoto, Y. Utsumi, Y. Mori, 2015 International Conference on Electronics Packaging and iMAPS All Asia Conference (ICEP-IAAC 2015) Proceedings, 432-435, 2015. Summary of the Invention [Problem to be solved by the invention]

[0005] However, the method described in Non-Patent Document 1 utilizes the correlation between the attenuation of the absorption spectrum specific to the main ingredient contained in the pellet core, i.e., the uncoated tablet, and the amount of coating. Therefore, every time the main ingredient is changed, it is necessary to obtain the correlation between the attenuation of the absorption spectrum and the amount of coating through complex multivariate analysis (so-called validation), which requires a lot of time and cost for production management. Therefore, an object of the present invention is to provide pellets for various fields with stable quality at low cost. [Means for solving the problem]

[0006] To solve this problem, the pellets of this invention are: A pellet having a core made of a powder molding and a coating covering the surface of the core, The coating is characterized by containing aggregates of noble metal nanoparticles and a Raman-active chemical substance that exhibits SERS. The pellets of this invention may be pharmaceuticals, food products, or electronic components, and are called tablets in the pharmaceutical industry, tablets in the food industry, and chips in the electronic component industry. Cores are called plain tablets in the pharmaceutical industry. Precious metal nanoparticles are particles made of precious metals such as gold, silver, and platinum group metals, with an average diameter of 100 nm or less. The aggregates and the chemical substances are in close proximity to each other and function as tags for measuring various physical properties in the coating during the manufacturing process and quality control after manufacturing. "Raman activity that exhibits SERS" refers to the phenomenon in which the Raman scattering intensity of a substance increases when the substance is in close proximity to a precious metal nanoparticle.

[0007] One suitable method for producing the pellets of the present invention comprises: A method comprising: a preparation step of preparing a core made of a powder molding; and a coating step of covering a surface of the core with a coating, the coating contains aggregates of noble metal nanoparticles and a Raman-active chemical substance that exhibits SERS; During the coating process, the Raman scattering intensity of the chemical substance is measured.

[0008] The Raman scattering intensity is proportional to the amount of the chemical substance present in the area where the incident light strikes. Therefore, this method allows the thickness or coating rate of the coating to be obtained based on the measured Raman scattering intensity. Furthermore, because the measured Raman scattering intensity does not depend on the type of component in the core, this method does not require validation, and the same correlation data can be applied to other pellets with different core components. The Raman scattering intensity can be measured in real time during the coating process, which allows the thickness of the coating to be controlled with high precision and high production efficiency. The Raman scattering intensity can also be measured by sampling the core during the coating process and measuring the sampled core. This means that the container, such as a pan in which the core is rolled during the coating process, does not need to have a transparent window for inserting a probe, and the thickness of the coating can be managed inexpensively. [Effects of the Invention]

[0009] As described above, the pellets of the present invention have the above-mentioned tag in the coating, and therefore various management such as the coating thickness and number can be easily performed with high precision. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 is a configuration diagram of a coating device used in the manufacturing method of Example 1. [Figure 2] 1 shows the SERS spectrum of the Raman-active chemical substance used in Example 1, with the vertical axis representing intensity and the horizontal axis representing Raman shift. [Figure 3] 1 is a graph showing the correlation between spray time and coating level in Example 1, with the vertical axis representing coating level and the horizontal axis representing time. [Figure 4]1 is a graph showing the correlation between spraying time and peak height in Example 2. [Example]

[0011] Example 1 The coating apparatus used in this example is for spraying coating liquid 1 onto uncoated tablets 3 as shown in FIG. 1 and includes a hollow, porous, disk-shaped coating pan 2, a Peristaltic (registered trademark) pump 6, a compressor 7, a two-fluid nozzle 8, a Raman spectroscopic probe 9, a Raman spectrometer 11, and a personal computer 12. The pan 2 is tilted to increase the spray area. The nozzle 8 is attached to the first main surface of the pan 2 at approximately the center thereof so that its tip is located within the pan 2, and its rear end is connected to piping from the pump 6 and the compressor 7. The compressor 7 atomizes the liquid delivered from the pump 6 using compressed air. The probe 9 is attached to the second main surface of the pan 2 at approximately the center thereof so that its tip is located within the pan 2, and its rear end is connected to the Raman spectrometer 11 via an optical fiber 10. The second main surface of the pan 2 is provided with an air vent 4 on one side and an air vent 5 on the other side, with the probe 9 in between.

[0012] A placebo tablet with a diameter of 8 mm, mainly composed of lactose and hydroxypropyl cellulose, was prepared as an uncoated tablet. This uncoated tablet was irradiated with a 785 nm laser at 77 mW for 60 minutes from the probe 9, and the Raman scattering was measured with the Raman spectrometer 11. -1 No peak was observed at this position.

[0013] A 100 μM adenine and 50 mM sodium chloride solution were added to a 0.3 mM chloroauric acid colloidal solution of gold nanoparticles with an average diameter of 60 nm, and the gold nanoparticles were self-aggregated by stirring to obtain a nanotag dispersion. The nanotag dispersion and coating solution (2% hydroxypropyl cellulose, 98% purified water) were mixed with a stirrer to obtain nanotag-containing coating solution 1.

[0014] The uncoated tablets were placed in a coating pan 2, and the coating pan 2 was rotated to roll the uncoated tablets 3, and hot air was blown in through a vent 4 and exhausted through a vent 5. While this rolling, blowing, and exhausting were taking place, nanotag-containing coating solution 1 was sent from a pump 6 to a two-fluid nozzle 8 simultaneously with air compressed by a compressor 7, and the nanotag-containing coating solution 1 was sprayed onto the uncoated tablets 3. The sprayed coating solution 1 was dried almost instantly by the hot air, forming a film. During spraying, a 785 nm laser was irradiated from a probe 9 at 77 mW for 60 minutes, and Raman scattering was detected every 4 seconds with a Raman spectrometer 11. Unlike the observation results for the uncoated tablets, where no specific peak was observed, a peak at 735 cm was observed at each detection, as shown in Figure 2. -1 A spectrum with a high peak specific to adenine was observed at the position of 735 cm in the spectrum 60 minutes after the start of spraying. -1 The peak height was set as a coating level of 1% in terms of mass percentage of the coating relative to the entire pellet, and the coating level was calculated every 4 seconds from the start of spraying by the personal computer 12 and plotted as shown in FIG.

[0015] As shown in Figure 3, the coating level increased over time, which correlated with the mass of the film formed by spraying.

[0016] Example 2 Instead of the coating device of Example 1, a Freund Corporation HC-FZ-LABO20 coating machine was used to spray the same uncoated tablets as in Example 1 with a nanotag-containing coating solution of the same composition as in Example 1, to produce tablets. After a predetermined time of spraying, the machine was stopped, five tablets were sampled, and a laser (785 nm, 40 mW) was irradiated for 1 second using a Lambda Vision RAMmini785 Raman spectrometer to measure the 735 cm specific to adenine. -1 The SERS peak around 735 cm was recorded. The horizontal axis represents the coating time (5, 10, 18, and 20 minutes), and the text data of the measured SERS spectrum was used to determine the peak around 735 cm. -1The peak heights were calculated, five values ​​were averaged, and plotted with error bars for the peak heights as shown in Figure 4. The peak heights increased over time, demonstrating that sampling can also be used to monitor the progress of coatings sprayed using the method of the present invention.

Claims

1. A pellet having a core made of a powder molding and a coating covering the surface of the core, A pellet, wherein the coating contains aggregates of noble metal nanoparticles and a Raman-active chemical substance that exhibits SERS.

2. The pellet according to claim 1, which is any one of a medicine, a food product, and an electronic part.

3. A method comprising: a preparation step of preparing a core made of a powder molding; and a coating step of covering the surface of the core with a coating, the coating contains aggregates of noble metal nanoparticles and a Raman-active chemical substance that exhibits SERS; A method for producing pellets, characterized in that the Raman scattering intensity of the chemical substance is measured during the coating process.

4. The method of claim 3 , wherein the Raman scattering intensity is measured in real time during the coating process.

5. The method of claim 3 , wherein the core is sampled during the coating process and the Raman scattering intensity is measured on the sampled core.

6. The method of claim 3 , wherein the aggregates are self-assemblies and the chemical is adenine.

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