Method for manufacturing porous silicon nanoparticles by means of ultrasonic treatment

Abstract

The present invention relates to a method for manufacturing porous silicon nanoparticles by means of ultrasonic treatment. A novel ultrasonic treatment apparatus using a duty cycle scheme was fabricated, and physical properties such as optimized conditions of the apparatus, yield, size, size distribution, surface state, shape, pore size, and drug delivery capacity of the porous silicon nanoparticles manufactured by the duty cycle scheme were analyzed. The duty cycle scheme was confirmed to exhibit a significantly higher yield of porous silicon nanoparticles compared to conventional schemes, and the porous silicon nanoparticles manufactured by the duty cycle scheme exhibited similar physical properties to those of porous silicon nanoparticles manufactured by the conventional schemes. Therefore, it was confirmed that the method for manufacturing porous silicon nanoparticles by means of ultrasonic treatment using the duty cycle scheme of the present invention is suitable for mass production.

Description

Method for manufacturing porous silicon nanoparticles using ultrasonic treatment

[0001] The present invention relates to a method for manufacturing porous silicon nanoparticles using ultrasonic treatment.

[0002] Porous silicon nanoparticles are currently being utilized in various biological fields, such as drug delivery systems, bioimaging, and sensing. This is because the utility of porous silicon nanoparticles has increased as various methods, such as surface chemistries, drug- or imaging-material-loading strategies into the internal space of porous nanoparticles, and particle size control methods, have been continuously developed. Currently, porous silicon nanoparticles are most commonly manufactured by ultrasonic fragmentation of the porous film created after electrochemical anodization of silicon wafers. The nanoparticles thus manufactured can have precisely controlled nanostructures, and much research is currently being conducted on porous silicon nanoparticles.

[0003] However, despite extensive research on this material, the high production cost of porous silicon nanoparticles remains a significant challenge. While commercial production of porous silicon nanoparticles is currently underway, mass production and highly reproducible manufacturing methods remain elusive.

[0004] Porous silicon nanoparticles are manufactured from conventional silicon wafers through two main processes: electrochemical anodization of the silicon wafer to create a porous silicon film, and fracture of the produced porous silicon film to produce porous silicon nanoparticles of the desired size. Various porous silicon film fracture processes have been developed to date, including physical grinding, ball milling, lithography, sonication, and microfluidization. All of these methods aim to increase the yield and reproducibility of porous silicon nanoparticles and to produce large quantities. Furthermore, extensive research has been conducted to tailor the properties of the manufactured nanoparticles to their intended use, including size and size distribution, porosity, surface chemistry, and intra-particle molecular capture and release. Currently, the most widely used method is sonication, as it utilizes widely available ultrasonic cleaners without requiring expensive equipment. However, this method is difficult to mass-produce and requires ultrasonic treatment for 16-24 hours to reach the desired size. This ultrasonic treatment generates heat, which can cause oxidation and dissolution of the silicon. Furthermore, the uneven supply of ultrasonic waves leads to incomplete fracture of the porous silicon film during the fracture process, resulting in a low yield due to the small amount of film that reaches the desired size.

[0005] The process of crushing porous silicon films using existing ultrasonic cleaners has limitations in terms of yield and reproducibility improvement and mass production due to uneven ultrasonic supply, rise in water temperature in the ultrasonic bath during the crushing process, and limited mass of film that can be processed in a single ultrasonic crushing process. Therefore, the need for the introduction of new ultrasonic processing equipment has been increasing.

[0006] Accordingly, the inventors of the present invention have developed a technology for manufacturing a large quantity of porous silicon nanoparticles having the same physical properties as porous silicon nanoparticles manufactured by conventional ultrasonic treatment, as well as high yield and reproducibility. In this way, they introduced a new duty cycle type ultrasonic treatment equipment into the porous silicon film crushing process, and by utilizing this, they developed a porous silicon nanoparticle manufacturing method and optimized it, and developed a porous silicon nanoparticle manufacturing technology.

[0007] The purpose of the present invention is to provide a method for producing porous silicon nanoparticles, comprising the steps of: 1) adding a solvent and a porous silicon film to a reactor; and 2) crushing the porous silicon film by ultrasonic treatment in a duty cycle manner.

[0008] Another object of the present invention is to provide porous silicon nanoparticles manufactured by the above method.

[0009] Another object of the present invention is to provide a method for manufacturing a drug delivery system, including a step of loading a drug into the porous silicon nanoparticles.

[0010] To achieve the above purpose, a method for producing porous silicon nanoparticles is provided, comprising: 1) a step of adding a solvent and a porous silicon film to a reactor; and 2) a step of crushing the porous silicon film by ultrasonic treatment in a duty cycle manner.

[0011] In addition, the present invention provides porous silicon nanoparticles manufactured by the above method.

[0012] In addition, the present invention provides a method for manufacturing a drug delivery system, including a step of loading a drug into the porous silicon nanoparticles.

[0013] The present invention relates to a method for manufacturing porous silicon nanoparticles using ultrasonic treatment, and by manufacturing a novel ultrasonic treatment device of a duty cycle type, and analyzing the optimized conditions of the device, the yield, size, size distribution, surface state, shape, pore size, drug delivery capability, and other physical properties of porous silicon nanoparticles manufactured by the duty cycle type, it was confirmed that the duty cycle type exhibits a significantly higher yield of manufacturing porous silicon nanoparticles than the conventional method, and that the porous silicon nanoparticles manufactured by the duty cycle type exhibit similar physical properties to the porous silicon nanoparticles manufactured by the conventional method, and thus the present invention can be usefully utilized in related industries.

[0014] Figure 1 is a diagram showing the structure of a duty cycle type ultrasonic treatment equipment and the process of manufacturing porous silicon nanoparticles through duty cycle type ultrasonic treatment.

[0015] Figure 2 is a diagram showing the optimization process of a technology for manufacturing porous silicon nanoparticles using a duty cycle type ultrasonic processing equipment.

[0016] Figures 3 to 5 are diagrams showing the results of a process for optimizing the technology for manufacturing porous silicon nanoparticles by setting the mass of the porous silicon film in the reactor, the volume of the solvent, and the number of repetitions of ultrasonic treatment as parameters.

[0017] Figure 6 is a diagram showing the properties of porous silicon nanoparticles obtained by changing only the mass of the porous silicon film in the reactor while fixing other parameters during the optimization process of the manufacturing technology.

[0018] Figure 7 is a diagram showing the properties of porous silicon nanoparticles obtained by changing only the volume of solvent in the reactor while fixing other parameters during the optimization process of the manufacturing technology.

[0019] Figure 8 is a diagram showing the properties of porous silicon nanoparticles obtained by changing only the number of repetitions of ultrasonic treatment while fixing other parameters during the optimization process of manufacturing technology.

[0020] Figure 9 is a diagram showing a process for manufacturing porous silicon nanoparticles using a conventional ultrasonic treatment (ultrasonic cleaner) method and a duty cycle ultrasonic treatment method.

[0021] Figures 10 to 14 are diagrams comparing the properties of porous silicon nanoparticles obtained after conventional ultrasonic treatment (ultrasonic cleaner) and duty cycle ultrasonic treatment.

[0022] Figures 15 to 21 are diagrams comparing the drug delivery effects of porous silicon nanoparticles obtained after conventional ultrasonic treatment (ultrasonic cleaner) and duty cycle ultrasonic treatment.

[0023] The terminology used in this specification is intended to appropriately express preferred embodiments of the present invention, and may vary depending on the intent of the user or operator, or the customs of the field to which the present invention pertains. Therefore, the definitions of these terms should be determined based on the contents of this specification as a whole. Throughout this specification, when a part is said to "include" a certain component, unless specifically stated otherwise, this does not mean that other components are excluded, but rather that other components may be included.

[0024] Throughout this specification, '%' used to indicate the concentration of a particular substance is (w / w) % for solid / solid, (w / v) % for solid / liquid, and (v / v) % for liquid / liquid, unless otherwise stated.

[0025]

[0026] The present invention provides a method for producing porous silicon nanoparticles, comprising the steps of: 1) adding a solvent and a porous silicon film to a reactor; and 2) crushing the porous silicon film by ultrasonic treatment in a duty cycle manner.

[0027] In the present invention, equipment for performing duty cycle type ultrasonic treatment may be characterized by comprising an ultrasonic supply device, a multi-sample holding device / rotary plate, and a water cooling circulation device.

[0028] The above ultrasonic supply device used was a Diagenode Bioruptor® Pico sonication device (model B01080010), but is not limited thereto, and an ultrasonic supply device with similar specifications may be used. In addition, a step of crushing the porous silicon film is performed by combining a reactor containing the porous silicon film as a sample with the multi-sample holder / rotary plate.

[0029] The reactor is not limited to a specific form, and refers to a configuration capable of performing a step of adding a porous silicon film as a sample and crushing the porous silicon film. For the basic form and configuration of the ultrasonic treatment device, refer to Ultrasonics Sonochemistry Volume 90, November 2022, 106181.

[0030] In one embodiment of the present invention, the reactor of step 1) has a volume of 10 to 20 mL and may be composed of six reactors, but is not limited thereto.

[0031] In one embodiment of the present invention, the solvent in step 1) may be ethanol, and may be included in a volume of 180 to 280 μL per reactor, but is not limited thereto.

[0032] In one embodiment of the present invention, the porous silicon film of step 1) may be added in a mass of 15 to 30 mg, but is not limited thereto.

[0033] In one embodiment of the present invention, step 2) may be characterized in that it is performed while maintaining a temperature of 4 to 8°C, but is not limited thereto.

[0034] In one embodiment of the present invention, the duty cycle method of step 2) may be to process ultrasonic waves for 2 to 6 cycles by repeating ON / OFF for 30 seconds each, 30 times, as one cycle, but is not limited thereto.

[0035] In the present invention, the duty cycle is expressed as a percentage of the time that the signal is on in one cycle of the signal, and in the present invention, it means that the ratio of the ultrasonic waves being turned on / off is 50%.

[0036] In one embodiment of the present invention, the ultrasonic treatment in step 2) may be ultrasonic treatment having an intensity of 150 watts or more and a frequency of 40 kHz or more, but is not limited thereto.

[0037] In the present invention, ultrasonic treatment was performed using a Diagenode Bioruptor® Pico sonication device (model B01080010), but is not limited thereto and may be performed by an ultrasonic treatment device with similar specifications.

[0038] In addition, the present invention provides porous silicon nanoparticles manufactured by the above method.

[0039]

[0040] In addition, the present invention provides a method for manufacturing a drug delivery system, including a step of loading a drug into the porous silicon nanoparticles.

[0041] In one embodiment of the present invention, the drug may be doxorubicin, but is not limited thereto.

[0042] The present invention is described in more detail through the following examples. However, the following examples are intended only to concretize the content of the present invention and are not intended to limit the present invention.

[0043]

[0044] <Example 1> Development and optimization of a method for manufacturing porous silicon nanoparticles using duty-cycle ultrasonic treatment.

[0045] 1-1. Development of new ultrasonic processing equipment

[0046] In order to mass-produce porous silicon nanoparticles with high yield and reproducibility while having the same properties as porous silicon nanoparticles manufactured by existing ultrasonic processing devices, a novel ultrasonic processing device was manufactured. Unlike existing ultrasonic cleaners that have continuous ultrasonic processing conditions of power: 48 Watts, frequency: 35 kHz, and ultrasonic processing time: 16-24 hours, the novel ultrasonic processing device exhibits an ultrasonic intensity of 150 Watts, which is stronger than existing ultrasonic cleaners, and can process a higher frequency of 40 kHz than existing ultrasonic cleaners. In addition, the porous silicon fragmentation process can be performed by ultrasonic treatment in a duty cycle (ON / OFF) mode ((50% duty cycle, ON / OFF cycle: 30s / 30s, on-off cycle: 30 times (total 30 minutes) for 1 ultrasonic treatment, ultrasonic treatment equipment is used for 30 minutes, then the equipment is rested for 30 minutes (ultrasonic treatment: 1 time)). The structure of the duty cycle ultrasonic treatment equipment and the process of manufacturing porous silicon nanoparticles through the duty cycle ultrasonic treatment are shown in Fig. 1, and the characteristics of the novel ultrasonic treatment equipment are shown in Table 1 below.

[0047] PropertiesStatic bath asonicationAdaptive cavitation sonicationPower (Frequency)48 Watts (~35 kHz)150 Watts (~40 kHz)Sonication typeContinuous50% duty cycle (ON / OFF)Number of vessels used in the reactor at one time16Temperature control and rangeNone (25~65 °C)Active(4~8°C) (cooler / circulator)Processing time per single porous Si film sample>24 hr2~6 hrSolvent used (volume)EtOH (~6 mL)EtOH (≤ 2 mL)Reactor material (volume)Glass vial (~20 mL)polypropylene tube (15 mL)Volume of water in sonication bath~1900 mL700 mLNanoparticle yield (from 30 mg of pSi film)34.5 % ± 1.6450.3 % ± 0.82 - 58.6% ± 1.33

[0048]

[0049] 1-2. Optimization of a Manufacturing Method for Porous Silicon Nanoparticles Based on Duty-Cycling Ultrasonic Treatment

[0050] Figure 2 shows the optimization process of the porous silicon nanoparticle manufacturing technology.

[0051] The yields were compared based on the mass of porous silicon nanoparticles produced under the same conditions for operating the ultrasonic treatment equipment, with the mass of the porous silicon film, the volume of the solvent, and the number of repetitions of the ultrasonic treatment set as parameters. The yields of the porous silicon nanoparticles obtained through optimization are shown in Figures 3 to 5.

[0052] In order to confirm the effect of the mass of the porous silicon film, the solvent volume (ethanol, 230 μL) and the number of sonication repetitions (4 times) in one reactor were fixed at constant values, and the mass of the porous silicon film in one reactor was changed to 7.5 mg, 15 mg, and 30 mg, respectively, and the yields of the produced porous silicon nanoparticles were compared. The yields were 57, 50, and 54%, respectively, and the change in yield due to the mass difference did not show a tendency. Considering the above results, the mass of the porous silicon film was set to the largest value, 30 mg, because a larger amount of porous silicon nanoparticles can be produced as the mass of the porous silicon film increases.

[0053] In order to confirm the effect of the volume of the solvent (ethanol) in the reactor, the mass of the porous silicon film (30 mg) in one reactor and the number of sonication repetitions (4 times) were fixed at constant values, and the yields of the porous silicon nanoparticles manufactured by varying the volume of the solvent (ethanol) in the reactor to 230 μL, 700 μL, and 2000 μL were compared. As the volume of the solvent in the reactor increased, the yields of the manufactured porous silicon nanoparticles gradually decreased to 55, 47, and 31%, respectively. Considering the above results, the solvent volume in the reactor was set to 230 uL for the optimal yield.

[0054] In order to examine the effect of the number of sonication repetitions, the mass of the porous silicon film (30 mg) in one reactor and the volume of the solvent in the reactor (ethanol, 230 μL) were fixed at constant values, and the number of sonication repetitions was varied to 2, 4, and 6, and the yields of the porous silicon nanoparticles manufactured by sonication were compared. When the number of repetitions was 2, it reached 50%, and as the number of repetitions increased, the yield also showed a trend of increasing; however, the rate of increase decreased as the number of repetitions increased. Considering the above results, the number of repetitions was set to 2 to maximize efficiency.

[0055] Considering the above results comprehensively, the optimal conditions for manufacturing porous silicon nanoparticles were set as follows: the mass of the porous silicon film in the reactor was 30 mg, the solvent volume in the reactor was ethanol, 230 μL, and the number of sonication cycles was 2.

[0056]

[0057] In order to confirm the reproducibility of porous silicon nanoparticles manufactured under the established optimal conditions, the physical properties such as size, size distribution, and surface state of the manufactured porous silicon nanoparticles were confirmed by using transmission electron microscopy (TEM), atomic force transducer-four-wave infrared spectroscopy (ATR-FTIR), dynamic light scattering (DLS), and zeta potential analysis according to changes in (a) the mass of the porous silicon film in the reactor, (b) the volume of the solvent, and (c) the number of sonication repetitions. The analysis results are shown in Figures 6 to 8.

[0058] Looking at Figures 6 to 8, it can be seen that the size, size distribution, and surface condition of the manufactured porous silicon nanoparticles are constant without significant difference even when the mass of the porous silicon film, solvent volume, and number of repetitions of ultrasonic treatment are changed, confirming that the porous silicon nanoparticles manufactured according to the above optimal conditions exhibit high reproducibility.

[0059]

[0060] <Example 2> Porous silicon nanoparticles based on duty cycle ultrasonic treatment and comparison with conventional porous silicon nanoparticles based on ultrasonic treatment

[0061] Porous silicon nanoparticles manufactured using duty-cycle sonication were compared with those manufactured using conventional sonication in an ultrasonic cleaner. Figure 9 illustrates the process of manufacturing porous silicon nanoparticles using the two methods. Furthermore, the physical properties of the porous silicon nanoparticles manufactured using the two methods are shown in Figures 10 to 14.

[0062] Looking at Figures 10 to 14, the yield when using a conventional ultrasonic cleaner was 34.5%, and the yield when using duty cycle ultrasonic treatment was 50.3%, confirming that the duty cycle method showed a higher yield than when using a conventional ultrasonic cleaner. Other than the yield, there was no significant difference in the size and size distribution of the nanoparticles, surface condition, nanoparticle shape, and pore size. In other words, it can be confirmed that the porous silicon nanoparticles manufactured based on duty cycle ultrasonic treatment and the conventional porous silicon nanoparticles are the same material, and the duty cycle method showed a higher yield than the conventional ultrasonic cleaner.

[0063] In addition, when looking at the total amount of nanoparticles produced within 24 hours, 10.35 mg was obtained when using a conventional ultrasonic cleaner, and 1072.8 mg was obtained when using the duty cycle method, showing that the duty cycle method can obtain nanoparticles 100 times more than the conventional method, confirming that the duty cycle method is a method suitable for mass production compared to the conventional method.

[0064] Through the above results, it was confirmed that the novel ultrasonic treatment method exhibits higher yield and reproducibility than the existing ultrasonic treatment method, and is a suitable method for producing a large quantity of porous silicon nanoparticles.

[0065]

[0066] <Example 3> Comparison of drug delivery capabilities of porous silicon nanoparticles

[0067] In order to confirm whether the porous silicon nanoparticles manufactured by the novel ultrasonic treatment method have the same drug delivery capability as the porous silicon nanoparticles manufactured by the conventional ultrasonic treatment, the porous silicon nanoparticles manufactured by the two methods were loaded with doxorubicin and used as a drug delivery system, and their physical properties were confirmed. Figures 15 to 21 show the measured physical properties, such as particle size before and after drug loading, surface state, particle shape after drug loading, degree of drug loading, and drug release kinetics. As shown in Figures 15 to 21, when the porous silicon nanoparticles manufactured by the two methods were used, there was no significant difference in particle size before and after drug loading, surface state, particle shape after drug loading, degree of drug loading, and drug release kinetics.

[0068] Through the above results, it was confirmed that porous silicon nanoparticles manufactured by a novel ultrasonic treatment method can be used as a drug delivery vehicle, as they exhibit the same physical properties as porous silicon nanoparticles manufactured by conventional ultrasonic treatment even when ultrasonic treatment is performed in a duty cycle manner, and there is no difference in activity as a drug delivery vehicle.

Claims

1. 1) Adding a solvent and a porous silicon film to the reactor; and 2) A method for producing porous silicon nanoparticles, comprising the step of crushing a porous silicon film by ultrasonic treatment in a duty cycle manner.

2. In paragraph 1, A manufacturing method, wherein the reactor of step 1) above has a volume of 10 to 20 mL and is composed of six reactors.

3. In paragraph 1, A manufacturing method wherein the solvent of step 1) above is ethanol and is contained in a volume of 180 to 280 μL per reactor.

4. In paragraph 1, A manufacturing method wherein the porous silicon film of step 1) is added in a mass of 15 to 30 mg.

5. In paragraph 1, A manufacturing method characterized in that the above step 2) is performed while maintaining a temperature of 4 to 8°C.

6. In paragraph 1, The duty cycle method of step 2) above is a manufacturing method in which the ultrasonic waves are processed for 2 to 6 cycles by repeating ON / OFF for 30 seconds each, 30 times as one cycle.

7. In paragraph 1, A manufacturing method wherein the ultrasonic treatment in step 2) above is performed using ultrasonic waves having an intensity of 150 watts or more and a frequency of 20 to 40 kHz.

8. Porous silicon nanoparticles manufactured by the method of paragraph 1.

9. A method for manufacturing a drug delivery system, comprising the step of loading a drug into the porous silicon nanoparticles of clause 8.

10. In paragraph 9, A manufacturing method wherein the above drug is doxorubicin.

Images