Preparation method of pediatric paracetamol and amantadine hydrochloride granules

Abstract

The invention relates to the technical field of pharmaceutical preparations, discloses a preparation method of pediatric paracetamol and amantadine hydrochloride granules, and aims to improve the stability and uniformity of medicines. The method comprises the following steps: preparing an adhesive, preparing a pre-mixture, carrying out wet granulation, drying wet granules, and finally finishing the granules. Through a multi-stage premixing and optimized wet granulation process, the uniform distribution of medicine components is ensured; segmental temperature control based on dissolution rate is adopted in the drying process, so that the drying time is effectively shortened, and particle surface hardening is prevented; according to the method, the dissolution performance and bioavailability of the medicine are improved, and the production efficiency and the stability of the product quality are remarkably improved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and more specifically, to a method for preparing acetaminophen granules for children. Background Art

[0002] Paracetamol granules are a commonly used cold medicine for children, and their preparation process has an important impact on product quality. Currently, there are many patents that have improved and optimized the preparation method of paracetamol granules for children, but there are still some problems that need to be solved urgently.

[0003] A Chinese patent application with publication number CN104586892A discloses a method for preparing pediatric paracetamol and amantadine granules. The method is to prepare granular products by fully mixing and grinding the components, and then granulating, drying, and granulating. This method simplifies the preparation process, reduces manufacturing costs, and improves the purity and efficacy of the granules to a certain extent. However, the technical solution fails to fully consider the uniformity of the drug components in the mixture, especially the distribution uniformity between auxiliary materials such as artificial bezoar and the main drug, which may affect the stability of product quality.

[0004] Another Chinese patent with publication number CN109846905A also discloses a method for preparing acetaminophen granules for children. The technical solution first mixes chlorpheniramine maleate aqueous solution with artificial bezoar, and then sprays it into the main drug mixture together with caffeine ethanol solution, and obtains granules through subsequent processes. This method is relatively simple to operate, and the properties and content uniformity of the obtained granules meet the standard requirements. However, the technical solution does not dynamically monitor and adjust the key process parameters in the granulation process, particularly the change of water content and system viscosity, and it is difficult to ensure the optimal state of the granulation process, which may affect the ideal properties of the granules. In addition, the technical solution is not considered enough to the relationship between drug dissolution and drying conditions, and improper drying may cause the granule surface to harden, affecting the release and absorption of the drug.

[0005] In summary, the existing preparation methods of acetaminophen granules for children generally have problems such as uneven distribution of drug ingredients and imprecise control of the granulation process, which may ultimately affect the stability of product quality and the reliability of efficacy. Summary of the invention

[0006] In order to overcome the above-mentioned defects of the prior art, the present invention provides a method for preparing pediatric acetaminophen granules, the core of which is to ensure the uniform distribution of drug ingredients in the mixture through multi-stage premixing and optimized wet granulation process, thereby significantly improving the stability and uniformity of the granules; at the same time, the drying process adopts segmented temperature control based on dissolution, which effectively shortens the drying time and prevents the surface of the particles from hardening, thereby improving the dissolution performance of the drug; these innovations are expected to further improve the production efficiency and product quality of children's cold medicines.

[0007] To achieve the above object, the present invention provides the following technical solutions:

[0008] A method for preparing acetaminophen granules for children comprises:

[0009] Step S10, adhesive preparation: weighing preset weights of chlorpheniramine maleate, tartrazine and caffeine, dissolving the caffeine with a first solvent, then adding a second solvent, and then adding chlorpheniramine maleate and tartrazine, and stirring evenly;

[0010] Step S20, preparing a premix: premixing artificial bezoar with auxiliary materials in a first ratio to obtain artificial bezoar premix powder; mixing amantadine hydrochloride powder with artificial bezoar premix powder in a second ratio to obtain amantadine hydrochloride premix powder; placing acetaminophen, amantadine hydrochloride premix powder and auxiliary materials in a third ratio in a high-efficiency wet granulator, stirring and mixing according to a first process parameter, and de-agglomerating the whole granules to obtain a premix;

[0011] Step S30, wet granulation: the premix in the high-efficiency wet granulator is stirred and mixed according to the second process parameter; then the binder is added according to the first scheme, the binder and the premix form a mixed system, and the binder and the premix are mixed while adding until the mixed system reaches the optimal end point, thereby obtaining acetaminophen wet granules;

[0012] Step S40, drying the wet granules: placing the acetaminophen wet granules in an oven, and using a stepwise temperature-controlled drying method based on solubility to obtain acetaminophen dry granules;

[0013] Step S50, granulation: screening the acetaminophen dry granules according to the third process parameter to obtain the final prepared acetaminophen granules for children.

[0014] In some embodiments, the first solvent is heat purified at 50°C-70°C, and the second solvent is room temperature purified water;

[0015] The first process parameters are: stirring speed 120r / min, chopping speed 1500r / min, mixing time 5 minutes, and screen mesh size 40 meshes;

[0016] The second process parameters are: stirring speed 100r / min, chopping speed 1200r / min, mixing time 3 minutes;

[0017] The third process parameter is: firstly perform primary screening with an 8-mesh sieve with a vibration frequency of 20 Hz, and then perform secondary screening with a 40-mesh sieve with a vibration frequency of 50 Hz to collect 8-40 mesh acetaminophen dry particles.

[0018] In some embodiments, the first ratio is (1:10)-(1:1); the second ratio is (3:1)-(5:1); and the third ratio is 5:3:2.

[0019] In some embodiments, the first scheme is:

[0020] The binder was added into the high-efficiency wet granulator at an initial input rate of 20-50 mL / min, and the viscosity of the mixed system and the water content of the granules during the granulation process were monitored in real time;

[0021] When the water content of the particles is less than 20%, increase the rate of adding the adhesive to 50-80 mL / min; when the water content of the particles is greater than 30%, stop adding the adhesive or reduce the rate of adding the adhesive to less than 10 mL / min to reduce the water content to the target range;

[0022] When the viscosity of the mixed system is less than 800mPa·s, increase the rate of adding the adhesive to 50-80mL / min. When the viscosity of the mixed system is greater than 1200mPa·s, stop adding the adhesive or reduce the rate of adding the adhesive to below 10mL / min, and increase the stirring speed and the chopping speed at the same time until the viscosity returns to the target range.

[0023] In some embodiments, the target range of the water content is 20%-30%; the target range of the viscosity is 800-1200 mPa·s.

[0024] In some embodiments, the optimal endpoint of the mixed system means that the water content of the particles is controlled at 20%-30%, and the viscosity of the mixed system is controlled at 800-1200 mPa·s.

[0025] In some embodiments, the dissolution-based staged temperature-controlled drying method is:

[0026] In the early stage of the drying process, the drying temperature is controlled at 60-65°C;

[0027] Regularly monitor the dissolution rate of the paracetamol wet granules, and when the dissolution rate is greater than or equal to 50% and less than 80%, reduce the drying temperature to 50-55°C;

[0028] When the solubility is greater than or equal to 80%, the drying temperature is reduced to 40-45°C until the drying end point is reached;

[0029] During the drying process, turn it over every 20 minutes.

[0030] In some embodiments, the drying endpoint is that the moisture content of the particles is less than or equal to 1%, and the solubility is greater than or equal to 95%.

[0031] In some embodiments, the adhesive preparation process also includes: weighing preset weights of chlorpheniramine maleate, tartrazine and caffeine, dissolving the caffeine with a first solvent, then adding a second solvent, and then adding chlorpheniramine maleate and tartrazine, accurately controlling the volume ratio of the first solvent and the second solvent according to a dissolution rate control model, and dynamically adjusting the stirring speed and time according to a dynamic mixing optimization model until the adhesive system reaches a uniform state.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] The present invention ensures the uniform distribution of drug ingredients in the mixture through multi-stage premixing and optimized wet granulation process, and significantly improves the stability and uniformity of the particles. The dissolution-based segmented temperature control is adopted in the drying process, which not only effectively shortens the drying time, but also prevents the hardening of the particle surface and the crystallization of the drug, greatly improving the dissolution performance of the drug. In addition, the innovative dynamic control strategy keeps the granulation process in the best state, and the dual monitoring and adjustment of moisture and viscosity ensure the ideal properties of the particles. The final multi-stage screening process further optimizes the particle size distribution of the particles, making the finished particles uniform and beautiful in appearance, disintegrating rapidly, and improving the bioavailability of the drug. These technological innovations not only improve production efficiency, but also ensure the stability of product quality and the reliability of efficacy, providing important process improvements for the development of children's cold medicines. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0035] Figure 1 The present invention is a principle flow chart of a method for preparing acetaminophen granules for children;

[0036] Figure 2 The present invention is a flow chart of the principle of preparing a premix in a method for preparing acetaminophen granules for children;

[0037] Figure 3 The present invention is a principle flow chart of the first scheme of the wet granulation process of the preparation method of acetaminophen granules for children;

[0038] Figure 4 The present invention is a flow chart showing the principle of a dissolution-based segmented temperature-controlled drying method in a method for preparing acetaminophen granules for children. DETAILED DESCRIPTION

[0039] In order to facilitate the understanding of the present invention, the present invention will be described more fully below with reference to the relevant drawings. Several embodiments of the present invention are given in the drawings. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present invention more thorough and comprehensive.

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0041] See also Figure 1 , is a method for preparing acetaminophen granules for children in an embodiment of the present invention, comprising the following steps:

[0042] Step S10, adhesive preparation: weighing preset weights of chlorpheniramine maleate, tartrazine and caffeine, dissolving the caffeine with a first solvent, then adding a second solvent, and then adding chlorpheniramine maleate and tartrazine, stirring evenly, and setting aside;

[0043] In some embodiments, the first solvent is heat purified at 50°C-70°C, and the second solvent is room temperature purified water;

[0044] As a non-limiting example, the first solvent may be 50°C, 60°C, 70°C, etc.;

[0045] Chlorpheniramine maleate is a commonly used antihistamine that can effectively alleviate the symptoms of runny nose and nasal congestion caused by allergies. As a natural pigment, lemon yellow not only gives the particles a bright and attractive yellow appearance, but also has a certain antioxidant effect, which can improve the stability of the preparation. Caffeine is a central nervous system stimulant, and adding it in an appropriate amount can relieve the symptoms of fatigue, drowsiness, etc. caused by colds. This step dissolves the three drug combinations, and utilizes the polarity of water to promote the solvation and uniform dispersion of drug molecules. Adding hot water and cold water in stages is conducive to controlling the solution temperature and avoiding the decomposition of caffeine. Continuous stirring during the dissolution process accelerates the collision of solute molecules and solvent molecules, improves dissolution efficiency, ensures that the drug is fully dissolved, and provides a stable liquid phase environment for subsequent processes.

[0046] S20, premix preparation, such as Figure 2As shown in the figure: artificial bezoar and auxiliary materials are premixed in a first ratio to obtain artificial bezoar premixed powder; amantadine hydrochloride powder and artificial bezoar premixed powder are mixed in a second ratio to obtain amantadine hydrochloride premixed powder; acetaminophen, amantadine hydrochloride premixed powder and auxiliary materials are placed in a high-efficiency wet granulator in a third ratio, mixed for 1-5 minutes at a stirring speed of 100-150 r / min and a chopping speed of 1200-2000 r / min, passed through a first sieve, and granulated to obtain a premixed mixture;

[0047] The first ratio is 1:10-1:1; the auxiliary material is one or more of starch, dextrin, and sucrose; the second ratio is 3:1-5:1; the third ratio is 5:3:2; the first sieve is 10-60 mesh, preferably 40 mesh;

[0048] Preferably, the acetaminophen and amantadine hydrochloride premixed powder and the auxiliary materials are placed in a high-efficiency wet granulator according to the third ratio, and mixed for 5 minutes at a stirring speed of 120 r / min and a chopping speed of 1500 r / min;

[0049] Artificial bezoar is a precious Chinese medicine with the effects of clearing away heat and detoxifying, calming and tranquilizing the mind, but due to the small dosage, direct feeding is prone to cause local overdose. Premixing it with excipients can play a role in dilution and dispersion, reduce the agglomeration between artificial bezoar particles, and improve the uniformity of drug distribution in the preparation. The selection and dosage control of excipients are particularly critical. If the dosage of excipients is too low, the artificial bezoar will not be fully dispersed; if the dosage of excipients is too high, the drug will be diluted and the efficacy will be affected. 1-10 times of excipients is the optimal ratio range of the present invention, which achieves a good balance between drug uniformity and efficacy intensity. Amantadine hydrochloride belongs to sympathomimetic drugs, which can shrink nasal blood vessels and relieve symptoms such as nasal congestion and nasal obstruction. Mixing with artificial bezoar premixed powder can further improve the dispersibility and uniformity of each component in the powder. The ratio of the two premixed powders is controlled at the second ratio, that is, the amount ratio of amantadine hydrochloride powder to artificial bezoar premixed powder is 3:1-5:1. Multiple experiments have shown that this ratio range can make the two drugs achieve the best compatibility and the strongest synergy.

[0050] Acetaminophen is an aspirin-type antipyretic analgesic that can effectively relieve symptoms such as headaches and muscle aches caused by colds and fevers in children. It is the main ingredient of the preparation. By mixing with the premixed powders that have been mixed evenly and then adding excipients, the formation of large particles of the main drug acetaminophen and the occurrence of separation can be prevented. The optimal ratio of the third ratio of acetaminophen, amantadine hydrochloride premixed powder and excipients is 5:3:2. Under this ratio, a large number of contact surfaces can be formed between the main drug and each component, fully mixed, without drug enrichment, laying the foundation for the full release of the drug. The mixture is sieved through a 40-mesh sieve and the whole granules are de-agglomerated to further break up the lumps and improve the looseness and mixing uniformity of the powder.

[0051] Step S20 adopts the multi-stage premixing mode, and each component is mixed in stages according to proportion, which greatly improves the uniform dispersion of the drug in the mixture. First, the artificial bezoar with less consumption is premixed with auxiliary materials, which can play a dilution and dispersion effect, reduce the reunion between the artificial bezoar particles, and avoid the local drug concentration being too high. Then, amantadine hydrochloride is mixed with the artificial bezoar premixed powder in an appropriate proportion to further improve the dispersibility and uniformity of each component in the powder. Finally, the main drug acetaminophen is mixed with the above-mentioned premixed powder and auxiliary materials to prevent the formation and separation of large particles of the main drug. In the whole mixing process, the selection and dosage control of auxiliary materials are crucial, which not only ensure that the drug is evenly dispersed, but also avoid excessive dilution to affect the efficacy.

[0052] In addition, the use and parameter optimization of the high-efficiency wet granulator is also a highlight of this step. By reasonably setting the stirring and chopping speeds and controlling the mixing time, the components can be fully mixed and the lumps can be broken, significantly improving the looseness and uniformity of the powder. The stirring speed controls the movement speed and mixing degree of the premix. If the speed is too low, the premix is ​​not fully mixed; if the speed is too high, the premix is ​​easily deposited on the container wall and the mixing is uneven. 100-150r / min is the best stirring speed range, which can provide sufficient hybrid power and avoid the deposition and separation of the premix. 120r / min is the optimal speed verified by the experiment. At this speed, the premix presents an ideal motion state and the mixing uniformity is the highest. The chopping speed determines the crushing efficiency and particle size distribution of the premix. If the speed is too low, the lumps are not completely broken and the particle size distribution is uneven; if the speed is too high, too much fine powder will be produced, affecting the granulation quality. 1200-2000r / min is the best chopping speed range, which can effectively break the lumps and control the particle size distribution within a reasonable range. 1500r / min is the optimal chopping speed in the experiment, at which ideal particles with uniform particle size and no drug enrichment can be obtained. The mixture is sieved through a sieve, granulated and de-agglomerated to further improve the granulation performance.

[0053] In summary, this step maximizes the uniformity and dispersibility of each component drug in the mixture through carefully designed multi-stage premixing and optimized granulation process, while ensuring that the mixture has good granulation performance, laying a solid foundation for subsequent processes, and ultimately obtaining pediatric acetaminophen granules with stable quality and significant efficacy.

[0054] Step S30, wet granulation: the premix in the high-efficiency wet granulator is mixed for 1-5 minutes at a stirring speed of 100-150 r / min and a chopping speed of 1200-2000 r / min; then the binder is added according to the first scheme, the binder and the premix form a mixed system, and the binder and the premix are mixed while adding until the mixed system reaches the optimal end point, thereby obtaining acetaminophen wet granules.

[0055] Preferably, the premix is ​​placed in a high-efficiency wet granulator, and after the feeding is completed, the equipment is turned on and mixed for 3 minutes at a stirring speed of 100 r / min and a chopping speed of 1200 r / min;

[0056] like Figure 3 As shown, the first scheme is: adding the binder into the high-efficiency wet granulator at an initial input rate of 20-50 mL / min, and monitoring the viscosity of the mixed system and the water content of the granules during the granulation process in real time;

[0057] When the water content of the particles is less than 20%, the rate of adding the binder is increased to 50-80 mL / min; when the water content of the particles is greater than 30%, the addition of the binder is stopped or the rate of adding the binder is reduced to less than 10 mL / min to reduce the water content to the target range; the target range of the water content is 20%-30%;

[0058] When the viscosity of the mixed system is less than 800 mPa·s, the rate of adding the adhesive is increased to 50-80 mL / min; when the viscosity of the mixed system is greater than 1200 mPa·s, the rate of adding the adhesive is stopped or reduced to less than 10 mL / min, and the stirring speed and the chopping speed are increased at the same time until the viscosity returns to the target range; the target range of the viscosity is 800-1200 mPa·s;

[0059] The optimal endpoint of the mixed system refers to that the water content of the particles is controlled at 20%-30%, and the viscosity of the mixed system is controlled at 800-1200 mPa·s;

[0060] The high-efficiency wet granulator is a commonly used pharmaceutical equipment. It uses a high-speed rotating rotor to provide mechanical energy to fully mix the solid powder with the binder liquid, promote the uniform distribution of the liquid on the surface of the particles, and thus obtain ideal wet particles. The premix is ​​initially mixed in the high-efficiency wet granulator for 1-5 minutes, the stirring speed is controlled at 100-150r / min, and the chopping speed is controlled at 1200-2000r / min. The purpose of this step is to make the premix loose and uniform, creating favorable conditions for adding binders. A lower stirring speed can prevent the powder from depositing on the container wall, and a higher chopping speed helps to break up lumps and improve the uniformity of the particles. 1-5 minutes is the optimal mixing time range. If the mixing time is too short, the premix is ​​not fully dispersed; if the mixing time is too long, it is easy to cause over-crushing and affect the granulation quality. The optimal parameters of the experiment are a stirring speed of 100r / min, a chopping speed of 1200r / min, and mixing for 3 minutes. Under this condition, an ideal powder with loose uniformity and no lumps can be obtained.

[0061] Next, the first scheme is adopted to add the binder in stages, namely the solution of chlorpheniramine maleate, tartrazine and caffeine. Using it as a binder has the following advantages: chlorpheniramine maleate can reduce allergies, tartrazine has an antioxidant effect, and caffeine can refresh the mind. The three have a synergistic effect with the paracetamol compound preparation; tartrazine gives the preparation an attractive color and improves the taste; the three drugs have good water solubility, and the solution is uniform and stable, which is conducive to the dispersion and coating of drug molecules in the wet granulation process.

[0062] The addition of the binder is divided into two stages. In the initial stage, the feed rate is fed at a lower rate, and in the later stage, the feed rate is dynamically adjusted according to the moisture content of the particles and the viscosity of the system. The initial feed rate is controlled at 20-50mL / min. The low-speed feeding can prevent local over-wetting and is conducive to the uniform distribution of the binder on the surface of the powder. Two key parameters need to be monitored in real time during the granulation process: the moisture content of the particles and the viscosity of the system. The moisture content reflects the progress of granulation and the forming of the particles, and is an important factor affecting the strength and solubility of the particles. When the moisture content is <20%, the particles are in an under-wet state, the forming is incomplete, and the strength is low; when the moisture content is >30%, the particles are over-wet, it is easy to produce soft lumps, and the solubility is poor. Therefore, controlling the moisture content at 20%-30% is a major innovation of the present invention. When the moisture content is low, the feeding is accelerated, and when the moisture content exceeds the standard, the feeding is stopped or the feeding rate is greatly reduced, and the moisture content is dynamically adjusted to always fall within the target range.

[0063] The system viscosity is an important indicator to measure the bonding performance of the granulation liquid, which directly affects the judgment of the granulation endpoint. If the viscosity is too low, the bonding force between the particles is insufficient and the molding is poor; if the viscosity is too high, the system is too viscous and the mixing is uneven. 800-1200mpa·s is the optimal viscosity range determined by the present invention. The wet granules prepared within this range have good molding and uniformity. A similar dynamic adjustment strategy is adopted, and the feeding is accelerated when the viscosity is low, and the feeding is stopped and the rotation speed is increased when the viscosity is high, so that the system viscosity is always maintained at the target level.

[0064] During the granulation process, the water content and system viscosity are dually regulated to finally adjust the mixed system to the optimal endpoint, i.e., the granule water content is 20%-30% and the system viscosity is 800-1200mpa·s. At this endpoint, the binder is evenly distributed, the granules are fully formed, have appropriate strength and looseness, and subsequent drying is easy to carry out, laying the foundation for the preparation of high-quality acetaminophen granules. During production, online moisture measurement and viscosity monitoring technology are used to provide real-time feedback on granule humidity and system rheological properties. When the measured value reaches the preset optimal range, granulation is automatically stopped. This method avoids the blindness of human experience judgment, realizes the optimal control of the granulation process, and greatly improves production efficiency and product quality stability.

[0065] In summary, step S30 uses the liquid medicine of the compound preparation as a binder to simplify the process and improve the synergistic effect of the preparation; adopts a staged feeding strategy, with low-speed feeding at the beginning and dynamic adjustment in the later stage to achieve slow penetration and uniform distribution of the binder; introduces dual control means of water content and system viscosity, and keeps the granulation process in the best state through real-time monitoring and adjustment; quantification and optimization of the granulation endpoint, 20%-30% water content of the granules, and 800-1200mpa·s of system viscosity, ensure the ideal properties of the wet granules. These innovations effectively improve the preparation quality and production efficiency of acetaminophen granules, and have significant technical advantages and practical value.

[0066] Step S40, drying the wet granules: placing the acetaminophen wet granules in an oven, and using a stepwise temperature-controlled drying method based on solubility to obtain acetaminophen dry granules;

[0067] like Figure 4 As shown, the dissolution-based staged temperature controlled drying method is:

[0068] In the early stage of the drying process, the drying temperature is controlled at 60-65°C;

[0069] Regularly monitor the dissolution rate of the paracetamol wet granules, and when the dissolution rate is greater than or equal to 50% and less than 80%, reduce the drying temperature to 50-55°C;

[0070] When the solubility is greater than or equal to 80%, the drying temperature is reduced to 40-45°C until the drying end point is reached;

[0071] During the drying process, turn the machine over every 20 minutes;

[0072] The drying endpoint is that the moisture content of the particles is less than or equal to 1%, and the solubility is greater than or equal to 95%;

[0073] The degree of particle drying directly affects the dissolution performance and storage stability of the finished product. If the moisture content is too high, the particles are easy to agglomerate and the dissolution rate is unqualified; if the moisture content is too low, the particle hardness increases, and the dissolution rate decreases. Conventional constant temperature drying is difficult to take into account both drying efficiency and preparation quality. The innovation of the present invention is to establish a dynamic relationship between dissolution and drying temperature, and propose a new process of segmented temperature control drying based on dissolution. According to the law of drug dissolution, multi-stage temperature adjustment is implemented throughout the drying process: in the early stage, a higher temperature of 60-65°C is used to quickly remove most of the water. When the solubility reaches 50% and less than 80% of the solubility value, the temperature is appropriately lowered to 50-55°C, and the drying is continued at a gentle speed; when the solubility rises to 80% of the solubility value, the temperature is further lowered to 40-45°C, and the residual water is slowly removed until the drying end. This drying method fully considers the water evaporation dynamics and drug dissolution dynamics, and dynamically optimizes the drying parameters according to the changes in the properties of the particle system. Compared with single constant temperature drying, segmented temperature control effectively avoids the hardening of the particle surface and the crystallization of the drug, greatly shortens the drying time, and significantly improves the dissolution performance of the drug, making the dissolution curve of the finished product smoother and more controllable.

[0074] The change in the solubility of the particles reflects the solid-state properties and distribution state of the drug during the drying process. In the early stage of drying, due to the rapid evaporation rate of water, the fluidity of drug molecules increases, and some amorphous drugs will dissolve rapidly, resulting in a rapid increase in solubility. However, if the temperature is too high and the drying speed is too fast, the drug concentration on the surface of the particles will increase sharply, and crystallization or precipitation may occur, forming a dense shell layer, which hinders further dissolution of the drug. During the drying process, samples can be taken from the oven at regular intervals to determine the solubility of the particles. The specific operation is: a small amount of particle samples are randomly taken out of the oven at regular intervals (such as 1 hour), and an in vitro dissolution test is performed according to the dissolution determination method (such as the pharmacopoeia method), and the dissolution percentage of the particles at this time point is determined. Through the dissolution data at multiple time points, the dissolution change curve during the particle drying process can be drawn, thus establishing the relationship between the particle dissolution and the drying time.

[0075] On the other hand, the turning operation during the drying process is crucial. Turning the particles every 20 minutes can redistribute heat and moisture in the particle accumulation layer, reduce temperature and humidity gradients, and prevent local over-drying or under-drying. By controlling the final moisture content below 1.0%, the particles are prevented from agglomerating and microbial contamination, which not only ensures the microbial stability of the preparation, but also avoids the decrease in solubility caused by too low moisture. A solubility greater than or equal to 95% can ensure the rapid release of the drug in the body and improve the therapeutic effect; the solubility and water content at the drying end point make the internal structure of the particles uniform and ensure the efficacy. Therefore, this method adopts a reasonable drying strategy: a higher temperature is used in the early stage to promote rapid evaporation of water and sufficient dissolution of the drug; when the solubility reaches a certain value (such as 50%), it means that most of the drug is in a dissolved state. At this time, the drying temperature should be lowered to slow down the evaporation rate of water, so that the drug has enough time to diffuse and evenly distribute, and avoid surface enrichment and crystallization; when the solubility increases further (such as 80%), it means that the system tends to be stable and the residual moisture is low. At this time, the temperature can be further lowered and dehydration can be carried out slowly to the drying end point to ensure that the internal structure of the particles is uniform and the dissolution performance is stable.

[0076] Step S50, granulation: firstly perform primary screening with an 8-mesh sieve with a vibration frequency of 20 Hz, and then perform secondary screening with a 40-mesh sieve with a vibration frequency of 50 Hz, and collect granular products with 8-40 mesh as the final prepared pediatric acetaminophen granules.

[0077] The particle size distribution of particles is a key attribute that determines the quality of the preparation. If the particle size distribution is too wide, the particle appearance is uneven, and stratification and pulverization are likely to occur; if the particle size distribution is too narrow, the production cost is high, and it is easy to cause local overdose of the drug. Conventional single screen granulation has shortcomings in both particle size control and production efficiency. The present invention adopts a multi-stage screening process, and cleverly utilizes the multi-stage combination of vibration frequency and mesh number to remove the head and tail of the particle size distribution, respectively, and collect the main part with uniform particle size in the middle section. The combination of 20Hz vibration frequency and 8-mesh screen can efficiently remove coarse lumps; the combination of 50Hz vibration frequency and 40-mesh screen can finely separate fine particles. By reasonably matching the vibration frequency and the mesh number of the screen, multi-stage screening can significantly improve the efficiency of granulation and greatly improve the particle size uniformity of the finished particles. Compared with conventional screening, the particles prepared by multi-stage screening have the advantages of concentrated particle size distribution, no powder, and no agglomerates. The uniform and fine particles not only have beautiful appearance, but also good dissolution performance and rapid disintegration, which is conducive to the full absorption of the drug.

[0078] The pediatric acetaminophen granules prepared by the method are a compound preparation, slightly yellow in color, and are over-the-counter cold medicines. They are suitable for relieving fever, headache, limb aches, sneezing, runny nose, nasal congestion, sore throat and other symptoms caused by the common cold and influenza in children, and can also be used for the prevention and treatment of influenza in children.

[0079] Pharmacological effects of pediatric acetaminophen granules: acetaminophen can inhibit the synthesis of prostaglandins and has antipyretic and analgesic effects; amantadine can resist "sub-A" influenza virus and inhibit virus reproduction; caffeine is a central nervous system stimulant, which can enhance the antipyretic and analgesic effects of acetaminophen, and can reduce the central nervous system inhibitory effects such as drowsiness and dizziness caused by other drugs; chlorpheniramine maleate is an antiallergic drug that can relieve symptoms such as runny nose, nasal congestion, and sneezing; artificial bezoar has antipyretic and tranquilizer effects. The above drugs are combined to make a compound prescription, which can enhance the antipyretic and analgesic effects and relieve or improve various symptoms caused by colds.

[0080] Embodiment 1:

[0081] The preparation method of the pediatric paracetamol and amantadine granules of the present invention is to prepare the pediatric paracetamol and amantadine granules, and the specific steps are as follows:

[0082] Step S10, adhesive preparation: weigh preset weights of chlorpheniramine maleate, tartrazine and caffeine, dissolve the caffeine with 60° C. hot purified water, then add room temperature purified water, then add chlorpheniramine maleate and tartrazine, stir evenly, and set aside.

[0083] S20, preparation of a premix: artificial bezoar and auxiliary materials are premixed at a ratio of 1:5 to obtain artificial bezoar premix powder; amantadine hydrochloride powder and artificial bezoar premix powder are mixed at a ratio of 4:1 to obtain amantadine hydrochloride premix powder; acetaminophen, amantadine hydrochloride premix powder and auxiliary materials are placed in a high-efficiency wet granulator at a ratio of 5:3:2, mixed for 5 minutes at a stirring speed of 120 r / min and a chopping speed of 1500 r / min, passed through a 40-mesh sieve, and granulated to obtain a premix. The auxiliary materials are a combination of starch and sucrose.

[0084] Step S30, wet granulation: the premix in the high-efficiency wet granulator is mixed for 3 minutes at a stirring speed of 100r / min and a chopping speed of 1200r / min; then the binder is added by the first scheme, the binder and the premix form a mixed system, and the mixture is mixed while adding, and the moisture content of the particles and the viscosity of the mixed system are monitored in real time until the moisture content of the particles is 20%-30% and the viscosity of the mixed system is 800-1200mPa·s, and the optimal endpoint is reached to obtain acetaminophen wet granules. The initial input rate of the binder is 30mL / min, and when the moisture content of the particles is less than 20%, the input rate is accelerated to 60mL / min; when the moisture content of the particles is greater than 30%, the input rate is reduced to 5mL / min, and the moisture content is controlled at 20%-30%. When the viscosity of the mixed system is less than 800mPa·s, increase the feeding rate to 60mL / min; when the viscosity of the mixed system is greater than 1200mPa·s, reduce the feeding rate to 5mL / min, and increase the stirring speed and chopping speed at the same time to control the viscosity at 800-1200mPa·s.

[0085] Step S40, drying of wet granules: placing the amantadine wet granules in an oven, and drying them by using a staged temperature control based on the solubility. The initial drying temperature is 60°C, and the granule solubility is monitored regularly. When the solubility is greater than or equal to 50% and less than 80%, the temperature is reduced to 50°C; when the solubility is greater than or equal to 80%, the temperature is reduced to 40°C until the granule water content is less than or equal to 1% and the solubility is greater than or equal to 95%, reaching the drying end point, and obtaining the amantadine dry granules, which are turned over every 20 minutes during the drying process.

[0086] Step S50, granulation: firstly screen with an 8-mesh sieve with a vibration frequency of 20 Hz, then screen with a 40-mesh sieve with a vibration frequency of 50 Hz, and collect 8-40 mesh particles as the final product.

[0087] Comparative Example 1:

[0088] Conventional preparation process of acetaminophen granules for children:

[0089] Step 1, acetaminophen, chlorpheniramine maleate, artificial bezoar, amantadine hydrochloride, tartrazine, caffeine and auxiliary materials are mixed according to the proportions of Example 1, placed in a wet granulator, and stirred for mixing.

[0090] Step 2: Slowly add the binder to the mixing system, mixing until the particles are formed.

[0091] Step 3, placing the formed particles in an oven at a constant temperature of 60° C. and drying for 4 hours.

[0092] Step 4: The dried particles are sieved through a 40-mesh sieve and the particles are collected as the final product.

[0093] Experimental test:

[0094] The pediatric paracetamol and amantadine granules were prepared according to the processes of the embodiment and the comparative example, and the content uniformity, dissolution and water content of the granules were tested. Each index was measured 3 times in parallel, and the results were averaged. The experimental data are shown in the following table:

[0095] Table 1 Performance test results of paracetamol granules for children prepared by the process of the embodiment and the comparative example

[0096] index Example 1 Comparative Example 1 Particle appearance Uniform, yellow Uneven, mottled Dissolution (%) 98.5 85.2 Content uniformity (RSD%) 1.8 5.6 Water content (%) 0.8 2.3

[0097] Result analysis:

[0098] (1) Particle appearance:

[0099] The granules prepared in Example 1 have a uniform appearance and present an attractive yellow color, while the granules in Comparative Example 1 have a jagged appearance and a mottled color; this is because Example 1 adopts an innovative multi-stage premixing process, and the component drugs are premixed in proportion before feeding, especially the pigment tartrate, chlorpheniramine maleate, and caffeine are dissolved in the binder solution, thereby achieving uniform dispersion of the pigment; while Comparative Example 1 adopts traditional one-time mixing, and the pigment distribution is extremely uneven, resulting in different color appearance of the granules.

[0100] (2) Dissolution:

[0101] The dissolution rate of the particles in Example 1 is as high as 98.5%, while that in Comparative Example 1 is only 85.2%; the high dissolution rate of Example 1 is due to the optimized granulation and drying process; during the wet granulation process, the real-time monitoring and dynamic regulation of water content and viscosity are used to ensure that the particles are always in the best state and the drug molecules are fully dissolved and dispersed; the dissolution stage adopts dissolution stage temperature control to avoid drug crystallization and surface hardening caused by high temperature, thereby significantly improving the dissolution rate; while Comparative Example 1 adopts traditional constant temperature drying, the drug crystallization is serious, and the dissolution performance is greatly reduced.

[0102] (3) Content uniformity:

[0103] The content uniformity RSD of Example 1 is only 1.8%, which is much lower than 5.6% of Comparative Example 1, indicating that the drug content distribution of the granules prepared by the process of the embodiment is highly uniform; this is mainly attributed to the multi-stage premixing and optimized granulation process; the components are mixed in stages, especially the artificial bezoar with a small amount is premixed with the excipients, which effectively overcomes the problem of local excess of the drug; the reasonable rotation speed combination and mixing time during wet granulation further improve the mixing uniformity; while the comparative example adopts a simple one-time mixing, resulting in extremely uneven drug distribution.

[0104] (4) Water content:

[0105] The moisture content of the granules in Example 1 is controlled at 0.8%, which is much better than 2.3% in Comparative Example 1, indicating that it has better stability; this is due to the segmented temperature control based on dissolution during the drying process, which not only ensures the dissolution, but also takes into account the full removal of moisture, and finally obtains high-quality granules with extremely low moisture content; while the comparative example adopts blind constant temperature drying, resulting in a high moisture content of the granules.

[0106] In summary, the preparation method provided by the present invention optimizes and innovates multiple links such as mixing, granulation, and drying, and effectively solves the problems of uneven color, low solubility, and poor content uniformity that are common in the production of acetaminophen granules for children. Multi-stage premixing is used to ensure that the drug is highly evenly dispersed and alleviate local excess; dynamically regulated wet granulation ensures that the granules are always in the best state; segmented temperature drying based on dissolution prevents drug crystallization and significantly improves dissolution performance; multi-stage screening optimizes particle size distribution and improves appearance. Compared with traditional processes, the granules prepared by the present invention have shown great superiority in terms of appearance, dissolution performance, and content uniformity, providing a reliable guarantee for the quality of children's medication.

[0107] Embodiment 3:

[0108] In this example, the adhesive preparation process in Example 1 was further optimized.

[0109] Preparation of adhesive: Weigh preset weights of chlorpheniramine maleate, tartrazine and caffeine, dissolve the caffeine with a first solvent, then add the second solvent, and then add chlorpheniramine maleate and tartrazine, accurately control the volume ratio of the first solvent and the second solvent according to the dissolution rate control model, and dynamically adjust the stirring speed and time according to the dynamic mixing optimization model until the adhesive system reaches a uniform state.

[0110] The dissolution rate control model is:

[0111]

[0112] in:

[0113] V1: the volume of the first solvent, in mL;

[0114] V2: The volume of the second solvent, in mL. The ratio of V1 to V2 is the solution target of the dissolution rate control model and represents the optimal solvent ratio under given conditions.

[0115] C1: solubility of caffeine in the first solvent, in g / mL;

[0116] C2: solubility of caffeine in the second solvent, in g / mL;

[0117] E a: The apparent activation energy of caffeine dissolution process, in J / mol, represents the energy required for solute molecules to overcome the intermolecular forces of solvent;

[0118] R: ideal gas constant, with a value of 8.314 J / (mol·K), is a constant that is independent of temperature. Its function in the formula is to unify the units of Ea and T and ensure that the exponential term is a dimensionless number;

[0119] T: Thermodynamic temperature of the solvent, in K, can be converted from °C. When T increases, The value of will increase, Increase;

[0120] α: Correction coefficient, which reflects the effect of the properties of the solvent (such as polarity, viscosity, surface tension, etc.) on the solute dissolution behavior. α can be obtained by regression analysis of the experimental data of the same solute-solvent system. The closer α is to 1, the higher the matching degree of the properties of the selected solvent, and the more conducive it is to the dissolution of caffeine.

[0121] The solubility can be determined by the plunger tube method, ultraviolet spectrophotometry, etc., or by referring to reliable literature data. The natural logarithm of determines the ratio of the two solvents used. The larger the value of The larger the solubility, the closer the solubility of the solvent is, and the closer the usage ratio is to 1:1; E a It can be expressed by the Van't Hoff equation: The solubility-temperature curve was linearly fitted and E was obtained based on the slope. a The larger the value, the more significant the effect of temperature on solubility. The more drastic the change with T. As the temperature of hot water increases, the proportion of hot water (the first solvent) increases, which means that more hot water is used in the solution. Since the temperature of hot water is higher, caffeine is more soluble in hot water, so using more hot water can accelerate the dissolution process of caffeine; under certain conditions, increasing the proportion of hot water may help to dissolve caffeine more evenly and improve the efficiency and quality of the adhesive preparation process. The ratio of room temperature water (second solvent) decreases, which means that more room temperature water is used in the solution. Since room temperature water requires less heating, increasing the ratio of room temperature water can reduce the energy consumption and cost of the preparation process. Caffeine has a low solubility in room temperature water, so if the ratio of room temperature water increases, the dissolution process may be slower, requiring longer time or higher stirring intensity to achieve uniform dissolution.

[0122] The dissolution rate control model is used to calculate the optimal volume ratio of the first solvent to the second solvent to overcome the difference in the solubility of caffeine in the two solvents (C1 and C2) and improve the dissolution rate and uniformity. The properties of temperature, solute, and solvent are comprehensively considered, and the optimal solvent ratio conditions are quantitatively described by combining thermodynamics and kinetics. As the temperature increases, the solubility of caffeine in the first solvent (hot water) increases significantly, and the solubility ratio decreases. Therefore, the amount of the first solvent can be reduced accordingly. The correction coefficient α can correct the interaction between solvents to obtain more accurate calculation results.

[0123] The dynamic hybrid optimization model is:

[0124]

[0125] in:

[0126] N: stirring speed, in r / min;

[0127] η0: dynamic viscosity of the adhesive system at the initial moment, in mPa·s;

[0128] η: dynamic viscosity of the adhesive system at time t, in mPa·s;

[0129] (V1 / V2) t : represents the volume ratio of the first solvent to the second solvent at time t;

[0130] (V1 / V2)0: represents the volume ratio of the first solvent to the second solvent at the initial moment,

[0131] t: stirring time, in min;

[0132] β: first empirical parameter;

[0133] γ: the second empirical parameter;

[0134] δ: the third empirical parameter;

[0135] N is the solution target of the dynamic mixing optimization model. Appropriate N can achieve uniform dispersion of the solute in the shortest time without introducing too much shear energy. Dynamic viscosity reflects the flow resistance of the system under shear, and can be measured in real time using online viscometers such as coaxial cylinders and rotor-rotors; η increases with the extension of stirring time, and the square root of η0 / η is used to correct the rotation speed to offset the influence of viscosity changes. The ratio is taken as the γ power. When γ is a positive number, V1 / V2 increases and N decreases accordingly. That is, when the amount of the first solvent increases, the temperature of the adhesive increases, the fluidity of the system improves, thereby reducing the stirring resistance and reducing the required stirring speed N. When γ is a negative number, V1 / V2 increases and N increases instead, because although the temperature of the adhesive increases, the addition of high-temperature solvent changes the viscosity and density of the system, which may introduce more solid-liquid interfaces, thereby increasing the stirring resistance and increasing the required stirring speed N. The sign and size of γ do depend on the characteristics of the solvent (such as heat capacity, viscosity-temperature coefficient, etc.) and the thermal efficiency of the equipment (heat transfer coefficient, heat dissipation loss, etc.). In addition, γ is also affected by the properties of the solute (heat of solution, dissolution rate, etc.) and the solid-liquid ratio. In general, γ reflects the sensitivity of temperature changes to the rheological properties of the adhesive and the changing trend of the stirring power demand caused by it. In order to accurately determine the γ value, it is necessary to carry out a series of orthogonal experiments in the laboratory to examine the rheological curves of the adhesive under different solvent ratios and temperature conditions, and combine advanced characterization methods such as calorimeters and thermal rheometers to establish a quantitative relationship between temperature, viscosity and speed. On this basis, numerical simulation, grey correlation analysis and other methods can be used to obtain the range of γ values ​​suitable for a specific system. δ The term introduces the time factor, which describes the change of mixing degree over time. The longer t is, the smaller N is, that is, extending the stirring time can make up for the insufficient speed to a certain extent. β, γ, and δ reflect the influence weight of different factors on the stirring effect. β is related to the type and size of the stirrer; γ depends on the compatibility between solvents, the wettability of the adhesive and the container wall, and δ is related to the morphology and particle size distribution of the solute. The three parameters can be optimized by response surface method, orthogonal test and other methods to obtain the best combination of the whole process.

[0136] The dynamic mixing optimization model is used to dynamically adjust the stirring speed N according to the rheological properties of the adhesive system, shortening the mixing time while avoiding component separation caused by local overheating. As the stirring proceeds, the solute continues to dissolve and the viscosity of the system gradually increases. Properly increasing the stirring speed helps to overcome the intermolecular forces and maintain the stability of the system; after the viscosity tends to stabilize, the stirring speed can be slowed down to avoid energy waste. The exponential term can correct the impact of volume change and time accumulation effect on the mixing state, and the introduction of empirical parameters gives the formula a wider range of applicability.

[0137] The dissolution rate control model and the dynamic mixing optimization model cooperate with each other to achieve quantification and optimization control of process parameters in the solvent ratio stage and stirring and mixing stage, which can significantly improve the efficiency and quality of adhesive preparation and lay a solid foundation for the entire granulation process. The process parameters of the mathematical model need to continuously collect data with the help of online monitoring instruments, and use chemometric tools for analysis and modeling to achieve seamless connection and amplification from laboratory to industrial production, which has broad prospects for engineering application.

[0138] The dissolution rate control model achieves precise control of the dissolution state of caffeine during the preparation of the adhesive by establishing a quantitative relationship between the dissolution rate of caffeine and the solvent temperature and stirring rate. Using this model, the dissolution rate of caffeine can be accurately predicted and controlled to avoid incomplete dissolution or crystallization, and to ensure the uniformity of the adhesive components. This not only improves the preparation efficiency of the adhesive, but more importantly, lays a solid foundation for the subsequent granulation process. Only when the components of the adhesive are fully uniform can the ideal distribution of the drug ingredients be achieved in the granulation stage, ultimately ensuring the stability of the granule quality.

[0139] The dynamic mixing optimization model innovatively introduces three key factors: mixing degree, stirring power consumption, and particle size distribution, establishes a multi-objective optimization function, and realizes real-time optimization control of the mixing process. Traditional processes usually use fixed stirring time and speed, which makes it difficult to take into account both mixing uniformity and energy consumption, and cannot effectively control particle size. The optimization model can dynamically adjust the stirring speed and time according to the real-time detection of the state of the mixing system, minimize energy consumption while ensuring the mixing degree, and control the particle size to meet the expected distribution, avoiding over-crushing or agglomeration. The optimized mixing process not only shortens the granulation time and improves production efficiency, but also significantly improves the physical and chemical properties of the finished particles, making them uniform in particle size, non-agglomerate, and disintegrate well, thereby improving the dissolution and absorption performance of the drug.

[0140] More importantly, the synergistic effect of dissolution rate regulation and mixing process optimization further amplifies the superiority of the overall process. The former provides high-quality adhesives for granulation and reduces segregation and stratification between components; the latter strengthens the full mixing of components and promotes the forming and drying of particles. The organic combination of the two models ultimately enables the acetaminophen granules to achieve significant improvements in multiple quality attributes, including key indicators such as drug content uniformity, disintegration time, and dissolution curve, and the product quality is more stable and controllable. In addition, model-driven process optimization also reflects good energy-saving and emission reduction effects and cost control advantages. Dissolution rate regulation effectively avoids unnecessary energy waste, and mixing process optimization minimizes stirring power consumption. At the same time, the synergistic effect of the two models improves material conversion rate and reduces waste generation. These advantages not only save production costs, but also highlight the green and environmental value of the process.

[0141] In short, the synergistic optimization of the dissolution rate control model and the dynamic mixing optimization model ensures the uniformity of the drug ingredients from the source, strengthens the intelligent control of the mixing process, and ultimately significantly improves the key quality attributes, production efficiency and cost-effectiveness of pediatric acetaminophen granules, providing a better quality and cost-effective innovative choice for children's cold medicines. These beneficial effects fully demonstrate the important value of process innovation in improving the quality of Chinese patent medicines and promoting the modernization of traditional Chinese medicine.

[0142] The applicant declares that the above is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention shall fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing acetaminophen granules for children, It is characterized in that The method comprises: Step S10, adhesive preparation: weighing preset weights of chlorpheniramine maleate, tartrazine and caffeine, dissolving the caffeine with a first solvent, then adding a second solvent, and then adding chlorpheniramine maleate and tartrazine, and stirring evenly; Step S20, preparing a premix: premixing artificial bezoar with auxiliary materials in a first ratio to obtain artificial bezoar premix powder; mixing amantadine hydrochloride powder with artificial bezoar premix powder in a second ratio to obtain amantadine hydrochloride premix powder; placing acetaminophen, amantadine hydrochloride premix powder and auxiliary materials in a third ratio in a high-efficiency wet granulator, stirring and mixing according to a first process parameter, and de-agglomerating the whole granules to obtain a premix; Step S30, wet granulation: the premix in the high-efficiency wet granulator is stirred and mixed according to the second process parameter; then the binder is added according to the first scheme, the binder and the premix form a mixed system, and the binder and the premix are mixed while adding until the mixed system reaches the optimal end point, thereby obtaining acetaminophen wet granules; Step S40, drying the wet granules: placing the acetaminophen wet granules in an oven, and using a stepwise temperature-controlled drying method based on solubility to obtain acetaminophen dry granules; Step S50, granulation: screening the acetaminophen dry granules according to the third process parameter to obtain the final prepared acetaminophen granules for children.

2. A method for preparing acetaminophen granules for children according to claim 1, It is characterized in that The first solvent is heat purified at 50°C-70°C, and the second solvent is room temperature purified water; The first process parameters are: stirring speed 120r / min, chopping speed 1500r / min, mixing time 5 minutes, and screen mesh size 40 meshes; The second process parameters are: stirring speed 100r / min, chopping speed 1200r / min, mixing time 3 minutes; The third process parameter is: firstly perform primary screening with an 8-mesh sieve with a vibration frequency of 20 Hz, and then perform secondary screening with a 40-mesh sieve with a vibration frequency of 50 Hz to collect 8-40 mesh acetaminophen dry particles.

3. A method for preparing acetaminophen granules for children according to claim 1, It is characterized in that The first ratio is (1:10)-(1:1); the second ratio is (3:1)-(5:1); and the third ratio is 5:3:

2.

4. A method for preparing acetaminophen granules for children according to claim 1, It is characterized in that The auxiliary material is one or more of starch, dextrin and sucrose.

5. A method for preparing acetaminophen granules for children according to claim 1, It is characterized in that The first solution is: The binder was added into the high-efficiency wet granulator at an initial input rate of 20-50 mL / min, and the viscosity of the mixed system and the water content of the granules during the granulation process were monitored in real time; When the water content of the particles is less than 20%, increase the rate of adding the adhesive to 50-80 mL / min; when the water content of the particles is greater than 30%, stop adding the adhesive or reduce the rate of adding the adhesive to less than 10 mL / min to reduce the water content to the target range; When the viscosity of the mixed system is less than 800mPa·s, increase the rate of adding the adhesive to 50-80mL / min. When the viscosity of the mixed system is greater than 1200mPa·s, stop adding the adhesive or reduce the rate of adding the adhesive to below 10mL / min, and increase the stirring speed and the chopping speed at the same time until the viscosity returns to the target range.

6. A method for preparing acetaminophen granules for children according to claim 5, It is characterized in that The target range of the water content is 20%-30%; the target range of the viscosity is 800-1200 mPa·s.

7. A method for preparing acetaminophen granules for children according to claim 1, It is characterized in that The optimal end point of the mixed system means that the water content of the particles is controlled at 20%-30%, and the viscosity of the mixed system is controlled at 800-1200 mPa·s.

8. A method for preparing paracetamol and amantadine granules for children according to claim 1, It is characterized in that The dissolution-based staged temperature controlled drying method is: In the early stage of the drying process, the drying temperature is controlled at 60-65°C; Regularly monitor the dissolution rate of the paracetamol wet granules, and when the dissolution rate is greater than or equal to 50% and less than 80%, reduce the drying temperature to 50-55°C; When the solubility is greater than or equal to 80%, the drying temperature is reduced to 40-45°C until the drying end point is reached; During the drying process, turn it over every 20 minutes.

9. The method for preparing acetaminophen granules for children according to claim 7, It is characterized in that The drying end point is that the water content of the particles is less than or equal to 1%, and the solubility is greater than or equal to 95%.

10. The method for preparing acetaminophen granules for children according to claim 1, It is characterized in that The adhesive preparation process also includes: weighing preset weights of chlorpheniramine maleate, tartrazine and caffeine, dissolving the caffeine with a first solvent, then adding a second solvent, and then adding chlorpheniramine maleate and tartrazine, accurately controlling the volume ratio of the first solvent to the second solvent according to a dissolution rate control model, and dynamically adjusting the stirring speed and time according to a dynamic mixing optimization model until the adhesive system reaches a uniform state.

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