Automatically weighed chemical reagent, preparation method and application thereof

Abstract

The invention discloses an automatic weighing chemical reagent as well as a preparation method and application thereof, and belongs to the field of precise weighing. Aiming at the problems of poor weighing fluidity and limited weighing precision of the existing high-viscosity chemical reagent, the invention provides the preparation method of the automatic weighing chemical reagent, which comprises the following steps: mixing the chemical reagent with an inert carrier to obtain a mixture; performing mechanical impact on the mixture, crushing the chemical reagent in the mixture into powder by utilizing the mechanical impact force, and wrapping the surface of the inert carrier with the powder to obtain composite powder, namely the automatically weighed chemical reagent; the inert carrier is a spherical carrier which cannot be broken during mechanical impact and does not influence the subsequent reaction of the chemical reagent, and the particle size unit of the inert carrier is micron. The fluidity of the whole method is remarkably improved (the Karl index is reduced by more than or equal to 20%, and the repose angle is less than or equal to 40 degrees), the adhesion and caking problems are thoroughly solved, the requirements of a high-flux automatic parallel reaction system are met, and the method is suitable for automatic synthesis platforms in the fields of medicine, material chemistry and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical reagent processing and precise distribution, and more specifically, relates to an automatically weighed chemical reagent, a preparation method and an application thereof. Background Art

[0002] In the fields of drug discovery, catalytic screening, and materials science, high-throughput experiments (HTE) have become an important means of rapidly evaluating multivariate reaction conditions. However, the automated transfer of solid or viscous liquid reagents still faces significant bottlenecks: 1. Most solid reagents have uneven particle sizes and irregular morphologies (such as sharp edges and cracks), which lead to enhanced van der Waals and electrostatic interactions between particles, easy agglomeration, and poor fluidity; 2. High-viscosity reagents have serious residues in sampling devices or pipelines, affecting distribution accuracy; 3. Manual weighing errors of >10% at the microgram to milligram level make it difficult to meet the HTE requirements for repeatability and material conservation. In other words, with the rapid development of high-throughput technology, it is difficult to achieve accurate weighing of solid / semi-solid / high-viscosity liquid chemical reagents that are prone to adhesion, moisture absorption, and difficult to accurately weigh, thus limiting their application. Summary of the Invention

[0003] 1. Problems to be solved

[0004] To address the poor fluidity and limited weighing accuracy of existing high-viscosity chemical reagents, this application provides an automated weighing chemical reagent, preparation method, and application. The entire method significantly improves fluidity (Carr's index is reduced by ≥20%, and the angle of repose is ≤40°), completely resolving the problem of sticking and clumping, meeting the needs of high-throughput parallel reaction systems, and is suitable for automated synthesis platforms in fields such as medicine and materials chemistry.

[0005] 2. Technical solution

[0006] To solve the above problems, the present invention adopts the following technical solutions.

[0007] A method for preparing an automatically weighed chemical reagent comprises mixing a chemical reagent with an inert carrier to obtain a mixture; subjecting the mixture to mechanical impact, thereby crushing the chemical reagent in the mixture into powder using the mechanical impact force; and coating the powder on the surface of the inert carrier to obtain a composite powder, namely, the automatically weighed chemical reagent.

[0008] The inert carrier is a spherical carrier that will not break when mechanically impacted and will not affect the subsequent reaction of the chemical reagent, and the particle size unit of the inert carrier is micrometer.

[0009] The technical scheme is adopted, firstly, the morphology of the chemical reagent is modified, so that the powder is finally formed and wrapped on the surface of the inert carrier, so that the three flow indexes of CI, HR and θr all reach the free-flowing level, and the chemical reagent caking and electrostatic adsorption are reduced; secondly, the selected inert carrier is spherical and the particle size is micron level, the surface of the spherical particle is regular and has few defects, the physical adsorption of the chemical reagent is prevented; the spherical structure is easy to roll in the mechanical impact process, and the agglomeration phenomenon is reduced; meanwhile, the stress is uniformly distributed in the mechanical impact, and the spherical structure is not easy to break and will not leak in the subsequent process; the micron-level particle size distribution is narrow, the mass fluctuation during weighing is reduced, and the weighing accuracy and efficiency are improved; then, the mechanical impact method is used to form the composite powder, the mechanical impact method is simple to operate, and the required equipment is simple and low in cost; finally, the chemical reagent and the inert carrier are mixed before mechanical impact, which can break the agglomeration of the chemical reagent, so that it is more uniformly crushed and wrapped around the inert carrier in the subsequent mechanical impact, and the mechanical impact efficiency is improved.

[0010] In summary, the preparation method of the present application can effectively improve the flowability of solid / semi-solid / high-viscosity liquid chemical reagents which are easy to adhere, easy to absorb moisture and difficult to accurately weigh, so that the quantification accuracy is high, and sub-milligram level weighing can be realized to meet the accuracy requirements of HTE for trace reagents; at the same time, the whole preparation method does not require any organic solvent or binder, realizes green production, and has a wide application prospect.

[0011] Further, the method specifically comprises the following steps:

[0012] S1: mixing the chemical reagent and the inert carrier according to a preset mass ratio to obtain a mixture;

[0013] S2: mechanically impacting the mixture, the rotation speed during mechanical impact is 2000-30000 rpm, the temperature is 20-40℃, and the time length is 0.5-5 min to obtain a composite powder;

[0014] S3: screening the composite powder to obtain a standardized composite powder with uniform size.

[0015] The technical scheme is adopted, firstly, the morphology of the chemical reagent is modified, so that the powder is finally formed and wrapped on the surface of the inert carrier, so that the three flow indexes of CI, HR and θr all reach the free-flowing level, and the chemical reagent caking and electrostatic adsorption are reduced; secondly, the selected inert carrier is spherical and the particle size is micron level, the surface of the spherical particle is regular and has few defects, the physical adsorption of the chemical reagent is prevented; the spherical structure is easy to roll in the mechanical impact process, and the agglomeration phenomenon is reduced; meanwhile, the stress is uniformly distributed in the mechanical impact, and the spherical structure is not easy to break and will not leak in the subsequent process; the micron-level particle size distribution is narrow, the mass fluctuation during weighing is reduced, and the weighing accuracy and efficiency are improved; then, the mechanical impact method is used to form the composite powder, the mechanical impact method is simple to operate, and the required equipment is simple and low in cost; finally, the chemical reagent and the inert carrier are mixed before mechanical impact, which can break the agglomeration of the chemical reagent, so that it is more uniformly crushed and wrapped around the inert carrier in the subsequent mechanical impact, and the mechanical impact efficiency is improved.

[0016] The prepared composite powder is sieved to further ensure the uniformity and consistency of the composite powder in the same batch, which is convenient for subsequent processing.

[0017] Furthermore, in step S1, the mass ratio of the chemical reagent to the inert carrier is (0.01-99.9):1; and the particle size of the inert carrier is 30-100 μm.

[0018] The above technical solution is adopted to adapt to the needs of different application scenarios by adjusting the mass ratio of chemical reagents to inert carriers over a wide range, balancing the properties of chemical reagents, process parameters and performance costs. By adjusting the mass ratio, the protection of inert carriers, mixing efficiency and mechanical impact effect can be optimized, ultimately achieving high-precision and high-stability weighing of chemical reagents.

[0019] At the same time, the particle size of the inert carrier is limited. When the particle size of the inert carrier is <30μm, the specific surface area increases dramatically, resulting in the dominance of van der Waals forces, and the particles are easy to agglomerate (angle of repose > 45°), which hinders the stable feeding of the subsequent vibrating funnel / screw feeder; when the particle size is >100μm, the gravity of the inert carrier itself is enhanced, resulting in significant inertial deviation in micro-distribution, resulting in weighing fluctuations >±5%; at the same time, if the particle size is not restricted, the non-uniform particle size destroys the consistency of powder stacking (Carr index >35%), and the error of volume measurement method (such as metering spoon) is expanded to more than 10%, accompanied by a decrease in filling uniformity.

[0020] Furthermore, in step S1, the preset mass ratio between the chemical reagent and the inert carrier is adjusted and determined according to the weighing requirements of the standardized composite powder, as follows:

[0021] When the weighing requirement of the standardized composite powder is milligram-level weighing (>5 mg), the mass proportion of the chemical reagent is 3-10 wt%; the mass proportion of the inert carrier is 90-97 wt%;

[0022] When the weighing requirement of the standardized composite powder is sub-milligram weighing (<2 mg), the weight proportion of the chemical reagent is 1-20 wt%; the weight proportion of the inert carrier is 80-99 wt%;

[0023] Alternatively, the preset mass ratio between the chemical reagent and the inert carrier may be adjusted based on the use requirements of the standardized composite powder, as follows:

[0024] When the use requirement of the standardized composite powder is to control the density of the standardized composite powder, the weight proportion of the chemical reagent is less than 50%, and the weight proportion of the inert carrier is 70-90wt%;

[0025] When the use requirements of the standardized composite powder are to control fluidity and prevent agglomeration, the weight proportion of the chemical reagent is greater than 90%, and the weight proportion of the inert carrier is 0.1-0.5 wt%.

[0026] Furthermore, the inert carrier includes at least one of hollow glass microspheres, solid glass microspheres or spherical silica; and the chemical reagent includes one of a solid chemical reagent, a semi-solid chemical reagent or a viscous liquid chemical reagent.

[0027] Furthermore, when the chemical reagent is potassium iodide, the inert carrier is spherical silica; when the chemical reagent is triphenylphosphine, the inert carrier is hollow glass microspheres or solid glass microspheres.

[0028] Furthermore, the inert carrier is a solid glass microsphere with a surface roughness of Ra≤5nm and a sphericity>99%; and when subjected to mechanical impact, A×f≤150 and 10≤f≤50, where A is the amplitude of the mechanical impact, in μm; f is the frequency of the mechanical impact, in Hz.

[0029] By adopting the above technical solution, zero interference of the inert carrier is achieved by further limiting the inert carrier: the surface characteristics are smooth to prevent physical adsorption of chemical reagents; mechanical properties: high hardness, not easy to break, sphericity, to ensure that no traces are left during the subsequent automated transportation process; and a suitable thermal expansion ratio, which will not cause thermal expansion and cracking; by further limiting the parameters of mechanical impact to match the elastic modulus of solid glass microbeads, "damage-free dispersion" is achieved, so that the contaminated chemical reagents will not be damaged, ensuring the integrity of the carrier and zero chemical reagent adsorption.

[0030] Furthermore, before mixing the chemical reagent with the inert carrier, the inert carrier is dried to a moisture content of 0.2 wt % or less. This drying process protects the chemical reagent, preventing it from agglomerating or hydrolyzing due to the high moisture content of the inert carrier, which could damage its physical form and chemical activity. It also prevents subsequent mechanical impacts, as well as stability, weighing accuracy, and process reliability in subsequent applications.

[0031] An automated weighing chemical reagent, the automated weighing chemical reagent is prepared using any of the above-described methods for preparing an automated weighing chemical reagent. The automated weighing chemical reagent in this application can achieve an error of <±5% in the range of 0.1 to 5 mg, meeting the HTE accuracy requirements for trace reagents. At the same time, the fluidity and anti-caking properties are greatly improved, with an angle of repose ≤40° and a bulk density ≥0.4 g / cm 3 .

[0032] The application of the automated weighed chemical reagent as described above is used in the weighing field in milligram or sub-milligram units. In the present application, the general milligram or sub-milligram unit weighing provides an efficient and environmentally friendly solution for the accurate transfer of micro solid / viscous liquid reagents used in the fields of medicine, pesticides and material chemistry. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 The reaction process of the present application is schematically shown. DETAILED DESCRIPTION

[0034] The present application will be further described below in combination with specific examples and drawings.

[0035] As shown in Figure 1 A preparation method of an automated weighed chemical reagent is provided, which comprises mixing a chemical reagent with an inert carrier to obtain a mixture; mechanically impacting the mixture to crush the chemical reagent in the mixture into a powder by mechanical impact force, and wrapping the powder on the surface of the inert carrier to obtain a composite powder, i.e., the automated weighed chemical reagent.

[0036] The inert carrier is a spherical carrier that does not break during mechanical impact and does not affect the subsequent reaction of the chemical reagent, and the particle size unit of the inert carrier is microns.

[0037] Specifically, in the detailed scheme of the present embodiment, the present applicant briefly introduces the prior art: at present, in the fields of medicine, pesticides and material chemistry, with the development of high-throughput technology, it is difficult to achieve high-precision dispensing (±2% @ 0.3 mg level) of microgram to hundred-milligram chemical reagents of a kind of chemical reagent such as solid / semi-solid / high-viscosity liquid which is easy to stick, easy to absorb moisture and difficult to accurately weigh, to meet the needs of high-throughput parallel reaction system. Although there are solutions to the difficulties faced by the above-mentioned chemical reagents in the prior art, but all have to be either the equipment used is mostly expensive, and not suitable for synchronous multi-batch weighing; or rely on manual operation, low efficiency and poor accuracy.

[0038] Therefore, the inventors of the present application have continuously overcome the difficulties, especially for a kind of chemical reagent such as solid / semi-solid / high-viscosity liquid which is easy to stick, easy to absorb moisture and difficult to accurately weigh, especially when facing high-viscosity solid, by designing high-frequency micro-amplitude vibration (200-500 Hz) of the impact head of mechanical impact, the 10 cP high-viscosity solid is realized to be instantaneous fluidization, the conveying efficiency is improved by 5 times, and the pipeline blockage is avoided; at the same time, according to the real-time weighing accuracy, the load is dynamically adjusted, the impact feedback system (temperature, rotating speed, etc.) is adjusted, the 5 / 50 mg ± 0.1 mg weighing accuracy is ensured, and the demand of high-throughput screening of drugs is met; the core innovation points of the technical scheme of the present embodiment are as follows:

[0039] First, an inert carrier is introduced during chemical pulverization to modify the chemical reagent's morphology, ultimately forming a powder coated on the surface of the inert carrier. This achieves free-flowing levels for the three fluidity indicators, CI, HR, and θr, and reduces chemical reagent agglomeration and electrostatic adsorption. Due to its inert chemical properties, the inert carrier does not affect subsequent reactions of the chemical reagent. Furthermore, the inert carrier is spherical, with a regular surface and few defects, preventing physical adsorption of the chemical reagent. It is easy to roll during mechanical impact, reducing agglomeration. Furthermore, the spherical structure has high physical hardness, uniform stress distribution during mechanical impact, and is not easily broken, preventing leakage during subsequent processes. The inert carrier acts to modify the surface of the chemical reagent that has been crushed into powder, preventing the chemical reagent from sticking and agglomerating. The inventors have discovered that if the chemical reagent is directly pulverized, the pulverized chemical reagent particles typically exhibit an irregular surface morphology with sharp edges and cracks, making it difficult to form smooth spherical particles. This irregular shape enhances the van der Waals forces between the particles, resulting in easy agglomeration and poor fluidity.

[0040] Second, when pulverizing the mixture of chemical reagents and inert carriers, mechanical impact is used. Mechanical impact is easy to operate, requires simple equipment, and is low-cost. More importantly, mechanical impact can effectively pulverize any form of material and has a wide range of applications. The inventors also considered using the ChemBeads technology proposed by the AbbVie team to mix chemical reagents with inert carriers through resonant acoustic mixing. However, this technology has significant limitations: limited loading capacity and poor performance at high solids content; it is not suitable for high-viscosity, high-density solids; the particle size is uncontrollable; the equipment is expensive and the cost is high, especially for high-viscosity chemical reagents, its effect is average.

[0041] Third, the particle size of the inert carrier is limited to the micron level. The narrow particle size distribution of the micron-level inert carrier can reduce the subsequent mass fluctuation during weighing, improve the weighing accuracy and weighing efficiency. At the same time, the inventors found that if the particle size of the inert carrier is too large, it will be unfavorable for the encapsulation of chemical reagents and it will be difficult to achieve the subsequent micro-weighing requirements of chemical reagents.

[0042] Fourth, before mechanical impact, the inert carrier and the chemical reagent are mixed first. This operation can break up the agglomeration of the chemical reagent, so that it can be more evenly crushed and wrapped around the inert carrier during the subsequent mechanical impact, thereby improving the efficiency of the mechanical impact. At the same time, the inventors found that if the two are directly placed in the equipment for mechanical impact, the crushing effect of the chemical reagent is uneven and the chemical reagent cannot be fully wrapped on the surface of the inert carrier, and it is time-consuming and inefficient.

[0043] Therefore, in summary, the preparation method of the automatically weighed chemical reagent of the embodiment can realize significant improvement of the flowability of solid / semi-solid / high-viscosity liquid chemical reagents which are prone to adhesion, moisture absorption and difficult to accurately weigh, and completely solves the problem of adhesion and caking of such chemical reagents; by converting such chemical reagents into composite powders with good flowability and controllable density, high-precision dispensing (±2% @ 0.3 mg level) of microgram to hundred milligram reagents is realized, meeting the needs of high-throughput parallel reaction systems, especially suitable for automated synthesis platforms in the fields of medicine, material chemistry and the like; at the same time, the entire preparation method does not require any organic solvent or binder throughout the process, realizing green production, and achieving a balance between cost and performance.

[0044] In one specific embodiment, the steps specifically include:

[0045] S1: mixing the chemical reagent and the inert carrier according to a preset mass ratio to obtain a mixture;

[0046] S2: mechanically impacting the mixture, the rotation speed being 2000-30000 rpm, the temperature being 20-40°C, and the time being 0.5-5 min, to obtain a composite powder;

[0047] S3: sieving the composite powder to obtain a standardized composite powder with uniform size.

[0048] In the embodiment, specific process steps are given, and it is worth noting that the mass ratio of the chemical reagent to the inert carrier in step S1 can be determined according to actual use scenarios and use requirements; step S2 limits the specific parameters during mechanical impact, which is a very important factor for the subsequent formation of the composite powder. Too low temperature or too long stirring time can cause the viscosity of part of the chemical reagent (such as viscous liquid) to increase, resulting in uneven coating of the inert carrier surface, which promotes agglomeration; too high temperature, stirring rate and time can cause the thermoplastic chemical reagent to adhere or the carrier structure to collapse or be damaged; therefore, through appropriate rotation speed, efficient crushing and uniform coating are realized, and the inert carrier structure is protected; appropriate temperature avoids adhesion or agglomeration of the chemical reagent; appropriate time balances efficiency and effect, and ensures batch consistency and cost optimization; of course, as a further preferred solution, the rotation speed during mechanical impact is 3000-10000 rpm, the temperature is 20-40°C, and the time is 1-3 min; step S3 is to further ensure the consistency and uniformity of the composite powder for subsequent use; the sieve size is matched with the use requirements.

[0049] In one specific embodiment, the mass ratio of the chemical reagent to the inert carrier in step S1 is (0.01-99.9):1; and the particle size of the inert carrier is 30-100 μm (i.e. um).

[0050] The mass ratio span of the chemical reagent and the inert carrier in this embodiment ranges widely, so as to adapt to the requirements in different scenarios; the limitation on the particle size of the inert carrier is to balance the subsequent accurate weighing and the flowability of the chemical reagent.

[0051] Specifically, in order to further verify the influence of the particle size of the inert carrier, the inventors of the present application specially made the following test in this embodiment: the chemical reagent PPh was mixed with the inert carrier hollow glass microspheres, and then was put into a high-speed mechanical impact mixer to be mechanically impacted, with a rotation speed of 9000 rpm and a temperature of 35℃, and was processed for 1 min to obtain a composite powder. The inert carrier-hollow glass microspheres were set as follows: the first group: the particle size of the hollow glass microspheres was not specified and was taken at will; the second group: the particle size of the hollow glass microspheres was 20 um; the third group: the particle size of the hollow glass microspheres was 250 um; the fourth group: the particle size of the hollow glass microspheres was 40 um; and the fifth group: the particle size of the hollow glass microspheres was 60 um. The five groups of tests only differed in the particle size of the inert carrier, and the rest were kept the same. The results are shown in Table 1 below:

[0052] Table 1 Influence of the particle size of the inert carrier

[0053]

[0054] As can be seen from Table 1, when the particle size of the hollow glass microspheres is < 30 um, not only the flowability and stability of the particles are poor, but also the weighing accuracy is poor because the feeding equipment such as the vibrating funnel / screw feeder is easily blocked; when the particle size of the hollow glass microspheres is > 100 um, the flowability of the particles can be significantly improved and the stacking consistency is enhanced, but the weighing effect is poor because the gravity of the carrier itself is enhanced, the relative deviation is > 5%, and when the ball load exceeds a certain limit, the piston fast aperture of the weighing system is directly blocked, directly leading to weighing failure. Therefore, in order to balance the flowability and the weighing deviation, the particle size is limited to 30-100 um.

[0055] In one specific embodiment, in the step S1, the preset mass ratio between the chemical reagent and the inert carrier is adjusted and determined according to the weighing requirements of the standardized composite powder, which is specifically as follows:

[0056] When the weighing requirement of the standardized composite powder is milligram-level weighing, the mass proportion of the chemical reagent is 3-10 wt%, and the mass proportion of the inert carrier is 90-97 wt%;

[0057] When the weighing requirement of the standardized composite powder is sub-milligram-level weighing, the mass proportion of the chemical reagent is 1-20 wt%, and the mass proportion of the inert carrier is 80-99 wt%;

[0058] It is particularly worth noting that within a certain range, the smaller the chemical reagent particle loading, the higher the weighing accuracy. However, when the loading is small enough, such as less than 3%, new technical challenges will be introduced, such as the formation of island structures rather than continuous films, which deteriorates the uniformity of particle coating. At the same time, because the film is uneven and the thinness is close to the detection limit of the equipment, the functional reliability, detection accuracy and inspection consistency are all poor. When the chemical reagent particle loading increases beyond the specified value (>20%), the excessively thick loading layer (such as polymer or metal oxide) does not match the thermal expansion coefficient of the glass matrix-type inert carrier, generating stress when the temperature changes, causing the coating to crack and the structure to be destroyed. At the same time, because the coating obscures the surface properties of the glass matrix-type inert carrier, the measurement accuracy is reduced. In order to verify this effect, the inventors of this application conducted the following experiment: the chemical reagent PPh was mixed with the inert carrier hollow glass microspheres, and after mixing, they were placed in a high-speed mechanical impact mixer for mechanical impact, with a speed of 9000 rpm, a temperature of 35°C, and a treatment of 1 minute to obtain a composite powder. The chemical reagent PPh was set as follows: Group 1: The mass proportion of the chemical reagent PPh was 1wt%; Group 2: The mass proportion of the chemical reagent PPh was 5wt%; Group 3: The mass proportion of the chemical reagent PPh was 15wt%; Group 4: The mass proportion of the chemical reagent PPh was 35wt%. The four groups of experiments only differed in the mass proportion of the chemical reagent, and the rest remained the same. The test results are shown in Table 2 below:

[0059] Table 2 Effect of changes in loading amount (percentage of chemical reagent mass)

[0060]

[0061]

[0062] As shown in Table 2, too small or too large a proportion of the chemical reagent mass will lead to a large weighing deviation and a decrease in coating uniformity.

[0063] Alternatively, the preset mass ratio between the chemical reagent and the inert carrier may be adjusted based on the use requirements of the standardized composite powder, as follows:

[0064] When the use requirement of the standardized composite powder is to control the density of the standardized composite powder, the weight proportion of the chemical reagent is less than 50%, and the weight proportion of the inert carrier is 70-90wt%;

[0065] When the use requirements of the standardized composite powder are to control fluidity and prevent agglomeration, the weight proportion of the chemical reagent is greater than 90%, and the weight proportion of the inert carrier is 0.1-0.5 wt%.

[0066] In one embodiment, the inert carrier comprises at least one of hollow glass microspheres, solid glass microspheres or spherical silica; the chemical reagent comprises one of a solid chemical reagent, a semi-solid chemical reagent or a viscous liquid chemical reagent, in particular a chemical reagent such as potassium iodide, triphenylphosphine, a copper salt or a halogenated aromatic compound.

[0067] In one embodiment, when the chemical agent is potassium iodide, the inert carrier is spherical silica; when the chemical agent is triphenylphosphine, the inert carrier is hollow glass microspheres or solid glass microspheres.

[0068] It is particularly worth noting that in this embodiment, a specific chemical reagent is used with a specific inert carrier. The inventors of this application found in their research that different inert carriers can produce different effects on a specific chemical reagent, and the same inert carrier also has different effects on different chemical reagents. Therefore, on this basis, the inventors used a variety of different chemical reagents and a variety of different inert carriers to conduct experiments, and obtained the following results as shown in Table 3:

[0069] Table 3 Effect

[0070]

[0071]

[0072]

[0073] As shown in Table 3, the same type of inert carrier at the same content has different flow and adhesion effects when facing different chemical reagents; the same chemical reagent has different flow and adhesion effects when facing different types of inert carriers at different contents. Therefore, when facing different chemical reagents, the selection and specific content of the inert carrier require further creative work.

[0074] In one embodiment, the inert carrier is a solid glass microsphere with a surface roughness Ra ≤ 5 nm and a sphericity > 99%; and when subjected to mechanical impact, A×f ≤ 150 and 10 ≤ f ≤ 50, where A is the amplitude of the mechanical impact, in μm; f is the frequency of the mechanical impact, in Hz.

[0075] Specifically, in this embodiment, the inert carrier is further limited to ensure zero interference with the inert carrier; and the parameters during mechanical impact are further limited based on the characteristics of the inert carrier to match the elastic modulus of the solid glass microbeads to achieve "damage-free dispersion", so as not to destroy the contaminated chemical reagents, thereby ensuring the integrity of the carrier and zero chemical reagent adsorption.

[0076] In one embodiment, before mixing the chemical reagent with the inert carrier, the inert carrier is dried to a moisture content of 0.2 wt % or less. This prevents the high moisture content of the inert carrier from causing agglomeration or hydrolysis of the chemical reagent, thereby destroying its physical form and chemical activity. This also prevents the chemical reagent from being affected by subsequent mechanical impact, stability, weighing accuracy, and process reliability in subsequent applications.

[0077] An automatically weighed chemical reagent, wherein the automatically weighed chemical reagent is prepared by a preparation method of an automatically weighed chemical reagent as described in any one of the above embodiments. It is worth noting that the introduction of an inert carrier into the automatically weighed chemical reagent will not cause any obstacles in the subsequent reaction and recovery process. Its recycling and regeneration can be completed through three steps of screening, pickling and calcination, and is fully compatible with our existing high-throughput automated recycling production line: the screening step can utilize a vibrating screen; the pickling process uses magnetic stirring to enhance mass transfer, the equipment can process 24 samples in parallel at a time, and can be easily expanded to a 48 or 96-well plate scale to achieve efficient batch cleaning. XPS analysis confirmed that after 50 cycles of use, the surface composition of the reagent remained unchanged, truly achieving a zero-pollution closed-loop cycle.

[0078] An application of the above-mentioned automatic weighing chemical reagent is used in the field of weighing in milligram or sub-milligram units.

[0079] It is particularly worth explaining why this application emphasizes the use in the field of weighing in milligrams or sub-milligrams; because achieving weighing in milligrams and sub-milligrams is very valuable in certain fields, such as the pharmaceutical industry: the pharmaceutical industry is a key application field of high-throughput technology. One is to solve the problem of R&D efficiency. Usually, the pharmaceutical R&D cycle is very long. This application realizes technology arraying through batch weighing, and automatically drives dozens or hundreds of reactions in the cloud at one time, which is valuable; another is the difference between high-throughput technology and ordinary technology. Miniaturization, milliliter, and micromole levels are just suitable for the pharmaceutical industry because reagents in the pharmaceutical industry are very expensive, and reaction screening is usually done on a small scale, so the weighing is targeted.

[0080] In order to further understand the technical solution of the present application, the following examples are given as examples; at the same time, the inert carrier used in the examples includes hollow glass microspheres (3M TM K46, d85μm, ρ=0.46gcm -3 ; or 3M TM H20), solid glass beads (Potters 3000, d45μm), spherical SiO (d30μm), nano-SiO (d1-100nm), moisture content <0.2wt%; evaluation methods: automatic angle of repose meter, automatic bulk density tester, powder rheometer (FT4), visual inspection for agglomeration, etc.; high-speed mechanical impact mixer: high-speed metal stirring paddle or blade (diameter 50-100mm) at 2000-30000rpm, rotor blade material SUS316L, stainless steel inner cylinder with cooling jacket.

[0081] Example 1

[0082] 8.0 g of H20 microspheres were preheated in a 45°C vacuum oven for 1 hour (to remove surface moisture), then 1.0 g of PPh powder (11.11 wt%) was added and mixed. The mixture was then transferred to a high-speed mechanical impact mixer at a speed of 9000 rpm and a temperature of 35°C for 1 minute, and sieved. The particle size d = 70 μm was measured. Flowability indexes: CI = 18%, HR = 1.22, θr = 55°. 30 portions of the mixed particles (target total mass 150 mg) were weighed and the triphenylphosphine content was determined (using the organic solvent dissolution weighing method). The average error in the triphenylphosphine content was 4.1%.

[0083] Example 2

[0084] 8.0 g of K46 microspheres were preheated in a 45°C vacuum oven for 1 hour (to remove surface moisture), added with 2.0 g of PPh powder (20 wt%), and mixed. The mixture was then transferred to a high-speed mechanical impact mixer at 9000 rpm and a controlled temperature of 35°C for 1 minute. The particle size, d = 88 μm, was measured. Flowability parameters were: CI = 15%, HR = 1.21, θr = 29°. Thirty portions of the mixed particles (target total mass 150 mg) were weighed and the triphenylphosphine content was determined (using the organic solvent dissolution and weighing method). The average error in triphenylphosphine content was 2.9%.

[0085] Example 3

[0086] Basically the same as Example 1, H60 (ρ = 0.60gcm -3 ) hollow microspheres 8.0g + KI 1.0g (11.11wt%). The average error of KI is ±5.0%. The original density of KI particles is about 1.9gcm -3 , modified density 0.65gcm -3 For the same reagent (KI), K46 (ρ = 0.46 gcm -3 ) and H20(ρ=0.20gcm -3 ) hollow spheres to prepare 20 wt% carrier powder, the density after modification was 0.55 gcm -3 and 0.24gcm-3 .

[0087] Example 4

[0088] 8.0 g of K46 microspheres were preheated in a vacuum oven at 45°C for 1 h (to remove surface moisture), 1.0 g of p-methoxybenzoic acid powder (11.11 wt%) was added and mixed, and then transferred to a high-speed mechanical impact mixer, set to a rotation speed of 13000 rpm, and controlled to a temperature of 35°C, and treated for 1 min. Sampling showed that the particle size d = 78 μm. The flowability index: CI = 20%, HR = 1.28, θr = 32°. 30 parts of the mixed particles (target total mass 150 mg) were weighed, and the triphenylphosphine content was measured (using an organic solvent dissolution weighing method), and the average error of the triphenylphosphine content was 6.4%.

[0089] Example 5

[0090] 8.0 g of K46 microspheres were preheated in a vacuum oven at 45°C for 1 h (to remove surface moisture), 1.0 g of PPh powder (11.11 wt%) was added and mixed, and then transferred to a high-speed mechanical impact mixer, set to a rotation speed of 1000 rpm, and controlled to a temperature of 35°C, and treated for 8 min. Sampling showed that the particle size d = 68 μm. The flowability index: CI = 17%, HR = 1.23, θr = 33°. 30 parts of the mixed particles (target total mass 150 mg) were weighed, and the triphenylphosphine content was measured (using an organic solvent dissolution weighing method), and the average error of the triphenylphosphine content was 5.5%.

[0091] Example 6

[0092] 8.0 g of K46 microspheres were preheated in a vacuum oven at 45°C for 1 h (to remove surface moisture), 1.0 g of PPh powder (11.11 wt%) was added and mixed, and then transferred to a high-speed mechanical impact mixer, set to a rotation speed of 9000 rpm, and treated for 1 min. Sampling showed that the particle size d = 108 μm. The flowability index: CI = 18%, HR = 1.29, θr = 37°. 30 parts of the mixed particles (target total mass 150 mg) were weighed, and the triphenylphosphine content was measured (using an organic solvent dissolution weighing method), and the average error of the triphenylphosphine content was 5.6%.

[0093] Example 7

[0094] Compared with Example 1, the coated composite powder was not sieved, and sampling showed that the particle size d = 88 μm. The flowability index: CI = 19%, HR = 1.31, θr = 36°. 30 parts of the mixed particles (target total mass 150 mg) were weighed, and the triphenylphosphine content was measured (using an organic solvent dissolution weighing method), and the average error of the triphenylphosphine content was 6.9%.

[0095] At the same time, the following test was conducted on the accuracy of weighing: the product was filled into a 96-well slide dispenser, and a single slide dispensed 3 mg of particles into 96 4 μmol reaction wells. The test is shown in Table 4:

[0096] Table 4 Weighing accuracy

[0097]

[0098]

[0099] As shown in Table 4, the chemical reagents obtained by the automated weighing method of the present application have high weighing accuracy and small error, providing a universal, green and easily scalable solution for HTE, automated synthesis and trace ingredients.

[0100] The examples described in the present invention are merely descriptions of the preferred embodiments of the present invention and are not intended to limit the concept and scope of the present invention. Without departing from the design concept of the present invention, various modifications and improvements made to the technical solutions of the present invention by engineers and technicians in this field should fall within the scope of protection of the present invention.

Claims

1. A method for preparing a chemical reagent by automated weighing, characterized in that: A chemical reagent is mixed with an inert carrier to obtain a mixture; the mixture is subjected to mechanical impact, and the chemical reagent in the mixture is crushed into powder by the mechanical impact force, and the powder is coated on the surface of the inert carrier to obtain a composite powder, that is, an automatically weighed chemical reagent; The inert carrier is a spherical carrier that will not break when mechanically impacted and will not affect the subsequent reaction of the chemical reagent, and the particle size unit of the inert carrier is micrometer.

2. The method for preparing a chemical reagent by automated weighing according to claim 1, wherein: The specific steps include: S1: mixing a chemical reagent and an inert carrier according to a preset mass ratio to obtain a mixture; S2: mechanically impacting the mixture at a rotation speed of 2000 to 30000 rpm, a temperature of 20 to 40°C, and a duration of 0.5 to 5 minutes to obtain a composite powder; S3: The composite powder is sieved to obtain standardized composite powder of uniform size.

3. The method for preparing a chemical reagent by automated weighing according to claim 2, wherein: In step S1, the mass ratio of the chemical reagent to the inert carrier is (0.01-99.9):1; and the particle size of the inert carrier is 30-100 μm.

4. The method for preparing a chemical reagent by automated weighing according to claim 3, wherein: In step S1, the preset mass ratio between the chemical reagent and the inert carrier is adjusted and determined according to the weighing requirements of the standardized composite powder, as follows: When the weighing requirement of the standardized composite powder is milligram-level weighing, the mass proportion of the chemical reagent is 3-10wt%; the mass proportion of the inert carrier is 90-97wt%; When the weighing requirement of the standardized composite powder is sub-milligram weighing, the weight proportion of the chemical reagent is 1 to 20 wt%; the weight proportion of the inert carrier is 80 to 99%; Alternatively, the preset mass ratio between the chemical reagent and the inert carrier may be adjusted based on the use requirements of the standardized composite powder, as follows: When the use requirement of the standardized composite powder is to control the density of the standardized composite powder, the weight proportion of the chemical reagent is less than 50%, and the weight proportion of the inert carrier is 70-90wt%; When the use requirements of the standardized composite powder are to control fluidity and prevent agglomeration, the weight proportion of the chemical reagent is greater than 90%, and the weight proportion of the inert carrier is 0.1-0.5 wt%.

5. The method for preparing a chemical reagent by automated weighing according to claim 1 or 2, characterized in that: The inert carrier includes at least one of hollow glass microspheres, solid glass microspheres or spherical silica; the chemical reagent includes one of solid chemical reagent, semi-solid chemical reagent or viscous liquid chemical reagent.

6. The method for preparing a chemical reagent by automated weighing according to claim 6, wherein: When the chemical reagent is potassium iodide, the inert carrier is spherical silica; when the chemical reagent is triphenylphosphine, the inert carrier is hollow glass microspheres or solid glass microspheres.

7. The method for preparing a chemical reagent by automated weighing according to claim 6, characterized in that: The inert carrier is a solid glass microsphere with a surface roughness of Ra≤5nm and a sphericity>99%; and when subjected to mechanical impact, A×f≤150 and 10≤f≤50, where A is the amplitude of the mechanical impact, in μm; and f is the frequency of the mechanical impact, in Hz.

8. The method for preparing a chemical reagent by automated weighing according to claim 1, wherein: Before mixing the chemical reagent with the inert carrier, the inert carrier is dried so that the moisture content of the inert carrier is less than or equal to 0.2 wt %.

9. A chemical reagent for automatic weighing, characterized in that: The automatically weighed chemical reagent is prepared by the method for preparing an automatically weighed chemical reagent according to any one of claims 1 to 8.

10. An application of the automated weighing chemical reagent according to claim 9, characterized in that: It is used in the field of weighing in milligram or sub-milligram units.

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