A fluidized bed granulation process for acetylcysteine granules

Abstract

The present application relates to the technical field of oral solid granule preparation, and discloses a fluidized bed granulation process for acetylcysteine granules, which comprises the following steps: separately laying the sieved main drug acetylcysteine and premix material two on a hot air circulating dryer, and uniformly mixing sucrose, the dried main drug and the dried material two in a three-dimensional oscillation in a total mixing stage to obtain a solid granule composition, and then feeding the solid granule composition into a dispensing machine for hot melt sealing and packaging. In the present application, the raw materials and accessories are stepwise diluted and premixed, and the drying of the heat-sensitive components is sequentially isolated and separated, so that the thermal catalytic degradation path of the sulfhydryl molecules and the sugar carriers is blocked, the local segregation of the solid granules is avoided, the rheological properties and thermal stability of the intermediate granules under the high-speed dispensing working condition are improved, and the content uniformity and the related substance indicators of the finished product meet the specifications.

Description

Technical Field

[0001] This invention belongs to the field of oral solid granule preparation technology, and particularly relates to a fluidized bed granulation process for acetylcysteine ​​granules. Background Technology

[0002] Current oral solid granule preparation processes often employ a combination of direct mixing of solid-phase powders and hot air drying to construct pharmaceutical formulations with specific physical forms of administration. When compounding active pharmaceutical ingredients (APIs) containing thiol-sensitive groups with trace amounts of functional raw materials and excipients such as colorants, the solid-phase system often faces the challenge of uniform dispersion of materials with high dilution ratios. Due to the density and particle size differences between sensitive APIs and crystal carriers, the mechanical mixing process requires the application of continuous kinetic energy to enable interpenetration of the components. However, the active thiol groups contained in the APIs have strong reducing properties and are prone to non-enzymatic browning and Maillard degradation reactions with reducing sugar components in the formulation under warm and humid conditions, resulting in discoloration or darkening of the powder surface. This creates an irreconcilable trade-off between the mechanical energy input required to achieve uniform distribution of solid-phase materials and the thermal constraints required to maintain the chemical stability of sensitive groups. This surface degradation caused by the combination of materials not only affects the sensory quality of the final product but also causes related substance indicators to exceed the limit standards.

[0003] Linear adjustments using methods such as increasing mechanical stirring time or shear rate often lead to mechanical breakage of the crystal carrier and exacerbate frictional heat buildup between powders. Damage to the crystal structure integrity increases the surface energy of the powder, triggering chemical cross-linking and degradation between active groups. Simple attempts at mild dehumidification by lowering the drying temperature and extending the residence time are also insufficient due to moisture accumulation and local concentration gradients within the dense material layer, failing to effectively curb the reaction pathways of sensitive groups within specific humidity windows. This not only limits the limitations of static hardware operations such as mixing and dehumidification, but also presents shortcomings in existing process control methods. For example, [the following is an example from] authorization announcement number CN113750. Chinese invention patent 052B discloses an acetylcysteine ​​particle and its preparation method, which uses a moisture-proof matrix and an isolation matrix to double-coat the active pharmaceutical ingredient. However, this method relies on long-cycle water grinding and high-temperature spray drying. The material stays in the humid and hot working conditions and the warm flow field for too long, which can easily trigger the thermal catalytic degradation of active thiol molecules, resulting in excessive levels of related substances. At the same time, when the coated pills are dry-granulated with a large proportion of crystal carriers, due to the lack of multi-step spatial particle size compounding, under high-speed dispensing and high-frequency vibration conditions, the components still produce gravity stratification and particle aggregation due to polarity differences and rheological mismatch, making it difficult to guarantee the uniformity of the finished product content.

[0004] Therefore, the dual core technical problems to be solved by this invention are how to simultaneously overcome the challenges of thermocatalytic degradation and non-enzymatic browning in the preparation process of thermosensitive reduction systems, as well as the bottlenecks of gravity sedimentation and secondary segregation and stratification of multi-component raw and auxiliary materials with high dilution ratios under high-speed packaging and dispensing conditions, and how to balance the chemical steady state and physical uniform flow state of solid materials across dimensions. Summary of the Invention

[0005] This invention aims to solve the problem of achieving a uniform composite distribution and anti-segregation and anti-stratification of multiple trace solid components with high dilution ratio under dynamic high-frequency dispensing conditions while blocking the thermocatalytic degradation pathway between active thiol sensitive groups and reducing sugar components.

[0006] In this technical solution, a fluidized bed granulation process for acetylcysteine ​​particles includes the following steps:

[0007] Step S101: The active ingredient acetylcysteine, along with Material II (a trace functional excipient containing fruit juice powder, sweetener, and colorant) and sucrose, are sieved separately. Material II is then premixed with flavoring. The premixed Material II and the active ingredient are spread evenly on separate stainless steel trays and dried separately in a flowing air environment at 50°C to 70°C for 1 to 3 hours. During the drying process, the trays are turned regularly every 0.4 to 0.6 hours to eliminate the humidity gradient within the material layer until a sample is taken and tested by the loss on drying method, and the residual moisture of both Material II and the active ingredient is reduced to below 1.5%.

[0008] In step S102, the dried active pharmaceutical ingredient, the premixed material II, and the sieved sucrose are sequentially fed into a three-dimensional oscillating mixer. The mixing frequency is set to no higher than 33Hz and the mixing time is no less than 19 minutes. The alternating shear stress is generated by the spatial multi-dimensional misaligned oscillation of the three-dimensional oscillating mixer, so that the components are mixed evenly to form a solid particulate composition consisting of 70% to 85% sucrose by mass, 1% to 5% material II by mass, and the active pharmaceutical ingredient to a balance of 100%.

[0009] In step S103, the mixed solid granule composition is introduced into a dispensing machine, the horizontal and vertical sealing temperatures are adjusted to 140°C to 180°C, and the dispensing speed is controlled to 40 bags / min to 80 bags / min. The low drying weight loss powder is used to heat-melt bag moisture-proof and sealed packaging to obtain acetylcysteine ​​granules.

[0010] Preferably, in step S101, the first sieve used for sieving the active ingredient has a mesh size of 30 to 50 mesh and is made of 316L stainless steel; the second sieve used for sieving the sucrose has a mesh size of 30 to 50 mesh and is made of 304 stainless steel; the third sieve used for sieving the second material has a mesh size of 40 to 200 mesh, and after sieving the second material, it is placed in a double cone mixer and premixed with the flavoring for 15 minutes, with the rotation speed of the double cone mixer controlled at 20 rpm to 30 rpm.

[0011] Preferably, in step S101, the tray-based static drying is further subdivided into the following sub-steps: Step S1011, material two and the main drug are laid flat in separate trays, and the thickness of the material in the tray is controlled to be 10mm to 15mm; Step S1012, the tray containing the material is pushed into the drying oven, and the vertical penetration speed of the airflow is controlled to be 0.5m / s to 1.0m / s, and the hot air is circulated and dried in a constant temperature environment of 50℃ to 70℃ for 1h to 3h.

[0012] Preferably, in step S101, the sucrose is crystalline sucrose with an average particle size of 150 μm to 250 μm and a drying weight loss of no more than 0.2%.

[0013] Preferably, in step S102, the material loading coefficient of the three-dimensional oscillating mixer is 0.6 to 0.7, and the multi-dimensional misaligned oscillation includes rotational motion around the horizontal axis, oscillating motion around the vertical axis, and reciprocating motion along the axial direction. The maximum shear rate generated by the three-dimensional oscillating mixer inside the solid particle composition is 50 s⁻¹ to 80 s⁻¹.

[0014] Preferably, steps S101, S102 and S103 are all carried out in a pharmaceutical cleanroom with a cleanliness level of D, and the ambient temperature of the pharmaceutical cleanroom is controlled to be between 18°C ​​and 24°C, and the relative humidity of the environment is controlled to be no higher than 45%.

[0015] Preferably, the bulk density of the prepared acetylcysteine ​​particles is 0.55 g / cm³ to 0.65 g / cm³, and the mass percentage of particles with a particle size between 150 μm and 710 μm is not less than 92%.

[0016] Preferably, in step S103, the packaging material used for the hot melt bag moisture-proof sealed packaging is a three-layer composite film composed of polyester, aluminum foil and polyethylene, with a total thickness of 60μm to 80μm, wherein the thickness of the aluminum foil layer is 7μm to 9μm.

[0017] Preferably, the acetylcysteine ​​particles obtained have a complete solubility rate of not less than 99% in 37°C warm water within 5 minutes, and after accelerated stability testing at 20°C to 35°C and 60% relative humidity for 25 to 35 days, the increase in total impurities in the related substances of the acetylcysteine ​​particles is not higher than 0.1%.

[0018] This invention achieves a breakthrough in the conventional approach of simply superimposing unit operations by combining a pre-process of sequential isolation drying of raw materials and excipients with a post-process of three-dimensional staggered oscillating mixing. The pre-process of sequential isolation drying of raw materials and excipients is the absolute chemical and physical prerequisite for subsequent three-dimensional staggered mixing. Without prior spatial isolation drying, direct mixing of the thiol-based active pharmaceutical ingredient and the secondary ingredient containing reducing sugars and flavorings under high humidity with high free water content can easily trigger the primary pathways of non-enzymatic browning and Maillard reactions under the frictional heat and microscopic local pressure of mechanical mixing. This invention, by precisely limiting the thickness of the trays and the penetration velocity of hot air flow, forcibly reduces the drying weight loss of both the secondary ingredient and the active pharmaceutical ingredient to below 1.5% before the mixing process. Essentially, before the two components come into contact in solid phase, the solvent required for the thermocatalytic chemical reaction of active thiol molecules is removed. The medium blocks the reactivity of drug molecules; the subsequent three-dimensional misaligned oscillating mixing is a means of reconstructing the physical flow state of ultra-low drying weight loss powder. After being isolated and dried by discs, the ultra-low residual moisture powder usually undergoes specific changes in its microscopic surface energy and electrostatic polarity. If conventional two-dimensional or gravity mixing is used, due to the lack of sufficient penetrating stress, the raw materials and excipients are very likely to undergo local powder segregation or agglomeration due to electrostatic aggregation. This invention specifically limits the mixing frequency of the three-dimensional oscillating mixer to no higher than 33Hz and the mixing time to no less than 19min, and introduces a maximum shear rate of 50s⁻¹ to 80s⁻¹ into the solid particle composition. Utilizing the strong alternating shear stress and convective diffusion flow field generated by the spatial multidimensional misaligned oscillation, the active pharmaceutical ingredient and the material particles that have lost their reactive moisture medium are driven to intertwine and physically embed themselves in the gaps of the microstructure of the large proportion of crystalline sucrose carrier.

[0019] This cross-dimensional temporal control, which combines pre-dehumidification and chemical activity closure with post-low-heat, high-shear micro-intercalation, results in a final solid particle composition that possesses both anti-stratification physical rheological fluidity and extremely high resistance to Maillard thermal degradation chemical stability. Consequently, the final product exhibits stable material and content uniformity indicators across batches under subsequent fluidized bed granulation, suspension boiling, high-speed dispensing, and high-frequency vibration conditions.

[0020] Compared with existing technologies, the fluidized bed granulation process for acetylcysteine ​​particles of the present invention has the following advantages:

[0021] 1. In the fluidized bed granulation process of acetylcysteine ​​particles, the initial aggregation of trace components in the physical stacking state is eliminated by setting specific sieve mesh sizes for the active pharmaceutical ingredient and each excipient. In combination with the manual premixing of sodium saccharin and sunset yellow in trace amounts and passing them through a metal sieve twice, a primary stable dispersion system with uniform particle size distribution is constructed. The three-dimensional motion multidimensional dilution mechanism of the mixer is used to make the primary system uniformly penetrate into the fruit juice powder. The multi-step spatial compounding sequence established in this way ensures that the trace colorant is physically embedded in the micro-skeleton gaps of the large proportion of sucrose carrier. From the perspective of powder flow dynamics, it prevents spatial stratification of materials with high dilution ratios and maintains the uniformity of the content of the finished formulation under long-term storage conditions.

[0022] 2. By separately laying material 2, which contains flavoring and reducing sugar components, and acetylcysteine, the active pharmaceutical ingredient with an active thiol structure, on independent trays and drying them at 60°C for 2 hours, the sensitive groups and reducing sugars under heated and humid conditions are physically isolated from each other in a spatial dimension. This blocks the direct oxidation of thiol groups and Maillard degradation reaction pathways caused by intermolecular contact. Combined with regular turning of the materials every half hour to eliminate the humidity gradient and heat accumulation in the material trays, all intermediate components before total mixing are in a low drying weight loss state, avoiding color deterioration of solid granules under heated conditions and ensuring that the relevant substance indicators in the quality standards continue to meet the limit requirements.

[0023] 3. By sequentially adding a large proportion of sieved sucrose, dried acetylcysteine, and premixed materials into a three-dimensional oscillating mixer during the total mixing stage and setting a mixing frequency, the alternating shear stress and convective diffusion flow field generated by the multi-dimensional misaligned oscillation of the equipment space drive the particle size components of each level to interweave with each other, thereby breaking the polarity differences and density gradients between the raw and auxiliary powders. Under the premise of avoiding mechanical breakage of crystals, the material components undergo spatial disordered interpenetration, effectively suppressing the gravity sedimentation and secondary stratification of powders under rapid packaging and dispensing vibration conditions, so that the discharged particles exhibit a uniform physical form and stable melting performance. Attached Figure Description

[0024] Figure 1 This is a flowchart of the preparation steps of acetylcysteine ​​particles according to the present invention;

[0025] Figure 2 This is a diagram showing the control elements of the finished product indicators of acetylcysteine ​​granules according to the present invention. Detailed Implementation

[0026] The technical solutions of the embodiments of this application will be clearly described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0027] A fluidized bed granulation process for acetylcysteine ​​particles includes the following steps:

[0028] Step S101: The active ingredient acetylcysteine, along with Material II (a trace functional excipient containing fruit juice powder, sweetener, and colorant) and sucrose, are sieved separately. Material II is then premixed with flavoring. The premixed Material II and the active ingredient are spread evenly on separate stainless steel trays and dried separately in a flowing air environment at 50°C to 70°C for 1 to 3 hours. During the drying process, the trays are turned regularly every 0.4 to 0.6 hours to eliminate the humidity gradient within the material layer until a sample is taken and tested by the loss on drying method, and the residual moisture of both Material II and the active ingredient is reduced to below 1.5%.

[0029] In step S102, the dried active pharmaceutical ingredient, the premixed material II, and the sieved sucrose are sequentially fed into a three-dimensional oscillating mixer. The mixing frequency is set to no higher than 33Hz and the mixing time is no less than 19 minutes. The alternating shear stress is generated by the spatial multi-dimensional misaligned oscillation of the three-dimensional oscillating mixer, so that the components are mixed evenly to form a solid particulate composition consisting of 70% to 85% sucrose by mass, 1% to 5% material II by mass, and the active pharmaceutical ingredient to a balance of 100%.

[0030] In step S103, the mixed solid granule composition is introduced into a dispensing machine, the horizontal and vertical sealing temperatures are adjusted to 140°C to 180°C, and the dispensing speed is controlled to 40 bags / min to 80 bags / min. The low drying weight loss powder is used to heat-melt bag moisture-proof and sealed packaging to obtain acetylcysteine ​​granules.

[0031] Preferably, in step S101, the first sieve used for sieving the active ingredient has a mesh size of 30 to 50 mesh and is made of 316L stainless steel; the second sieve used for sieving the sucrose has a mesh size of 30 to 50 mesh and is made of 304 stainless steel; the third sieve used for sieving the second material has a mesh size of 40 to 200 mesh, and after sieving the second material, it is placed in a double cone mixer and premixed with the flavoring for 15 minutes, with the rotation speed of the double cone mixer controlled at 20 rpm to 30 rpm.

[0032] Preferably, in step S101, the tray-based static drying is further subdivided into the following sub-steps: Step S1011, material two and the main drug are laid flat in separate trays, and the thickness of the material in the tray is controlled to be 10mm to 15mm; Step S1012, the tray containing the material is pushed into the drying oven, and the vertical penetration speed of the airflow is controlled to be 0.5m / s to 1.0m / s, and the hot air is circulated and dried in a constant temperature environment of 50℃ to 70℃ for 1h to 3h.

[0033] Preferably, in step S101, the sucrose is crystalline sucrose with an average particle size of 150 μm to 250 μm and a drying weight loss of no more than 0.2%.

[0034] Preferably, in step S102, the material loading coefficient of the three-dimensional oscillating mixer is 0.6 to 0.7, and the multi-dimensional misaligned oscillation includes rotational motion around the horizontal axis, oscillating motion around the vertical axis, and reciprocating motion along the axial direction. The maximum shear rate generated by the three-dimensional oscillating mixer inside the solid particle composition is 50 s⁻¹ to 80 s⁻¹.

[0035] Preferably, steps S101, S102 and S103 are all carried out in a pharmaceutical cleanroom with a cleanliness level of D, and the ambient temperature of the pharmaceutical cleanroom is controlled to be between 18°C ​​and 24°C, and the relative humidity of the environment is controlled to be no higher than 45%.

[0036] Preferably, the bulk density of the prepared acetylcysteine ​​particles is 0.55 g / cm³ to 0.65 g / cm³, and the mass percentage of particles with a particle size between 150 μm and 710 μm is not less than 92%.

[0037] Preferably, in step S103, the packaging material used for the hot melt bag moisture-proof sealed packaging is a three-layer composite film composed of polyester, aluminum foil and polyethylene, with a total thickness of 60μm to 80μm, wherein the thickness of the aluminum foil layer is 7μm to 9μm.

[0038] Preferably, the acetylcysteine ​​particles obtained have a complete solubility rate of not less than 99% in 37°C warm water within 5 minutes, and after accelerated stability testing at 20°C to 35°C and 60% relative humidity for 25 to 35 days, the increase in total impurities in the related substances of the acetylcysteine ​​particles is not higher than 0.1%.

[0039] Example 1: In the preparation of this acetylcysteine ​​granules, the material system includes acetylcysteine ​​raw material, as well as sucrose, sodium saccharin, orange juice powder, sweet orange powder flavoring, and sunset yellow as excipients. The production process is carried out in a pharmaceutical cleanroom with a cleanliness level of D. After the raw materials and excipients are requisitioned and the material codes and batch numbers are checked, they enter the material cleanroom buffer room. The inner packaging surfaces are wiped with 75% ethanol solution for disinfection, labeled, and transferred to the clean area. The active pharmaceutical ingredient acetylcysteine ​​is independently sieved through a 40-mesh first sieve, and the crystalline sucrose is independently sieved through a 50-mesh second sieve. The sucrose used is crystalline sucrose with an average particle size of 200μm. The loss on drying of the selected raw material crystalline sucrose itself is not higher than 0.2%, and the measured loss on drying is 0.12% as measured by a loss on drying tester. The material two, which is a trace functional excipient containing orange juice powder, sodium saccharin, and sunset yellow, is sieved through a 70-mesh third sieve.

[0040] First, add 0.2% sodium saccharin and 0.05% sunset yellow (by weight percentage) of the solid particulate composition to a material bag and mix by shaking at a frequency of 45 times / min for 1 minute. Then, sieve twice through a 70-mesh third sieve to obtain intermediate premix material one. This material one is used as an intermediate premix to ensure the uniform dispersion and stable distribution of trace components. The double sieving action forcibly breaks up particle agglomeration of the colorant caused by electrostatics or polarity. This highly dispersible material one, along with sweet orange powder flavoring and orange juice powder, is then added to a double cone mixer. The double cone mixer speed is controlled at 25 rpm for premixing for 15 minutes to ensure the materials... Material 1 is prepared by uniformly penetrating and physically embedding itself into the gaps between a large proportion of porous and loose orange juice powder skeleton in a multidimensional motion flow field, resulting in premixed material 2. Material 2 is further prepared by limiting particle gravity stratification within specific ratio ranges: when the mass percentage of sodium saccharin is below 0.1%, the flavoring effect of the formulation cannot be achieved; when the mass percentage of sodium saccharin is above 0.5%, a bitter aftertaste is produced, leading to increased hygroscopicity and causing the powder to clump during storage. The mass percentages of sodium saccharin, sunset yellow, and sweet orange powder flavoring are controlled at 0.2%, sunset yellow at 0.05%, and sweet orange powder flavoring at 0.5%, with the remainder supplemented to 100% using orange juice powder. When implementing the premixing process, the material loading coefficient is set to 0.6 to 0.7, and the resulting shear rate is maintained at 50 s⁻¹ to 80 s⁻¹, providing penetrating kinetic energy for powders of different particle sizes, ensuring uniform dispersion of material II. The premixed material II and acetylcysteine ​​are separately spread in independent stainless steel trays, with a layer thickness of 12 mm. They are then left to dry in a 60℃ hot air circulation environment with a vertical airflow velocity of 0.8 m / s for 2 hours. During this period, the material is turned over every 0.5 hours to eliminate the humidity gradient within the material layer, until samples are taken and the residual moisture content of both material II and acetylcysteine ​​is reduced to a certain level as measured by the loss on drying method. For materials with a content below 1.5%, the dried material, acetylcysteine, and dried sucrose are sequentially fed into an SBH-800 three-dimensional oscillating mixer. The mixing frequency is set to 32Hz and the mixing time is 20min. After mixing, the uniformity of mixing is tested. The total mixed solid particle composition is then introduced into a particle dispensing machine. The horizontal and vertical sealing temperatures are set to 160℃, and the dispensing speed is 60 bags / min. Under this high-speed heat sealing and dispensing condition, the aforementioned powder fusion characteristics refer to the fact that after the free water content inside the material is reduced by the pre-drying with controlled temperature, the surface of the powder particles softens at high temperature and combines with the interface of the packaging material.

[0041] In actual operation, when the horizontal and vertical sealing temperatures reach 160℃, the innermost low-density polyethylene of the three-layer composite film undergoes thermal melting and flow, while the low-drying-weight loss powder crystal skeleton scattered at the sealing edge only undergoes microscopic surface plastic deformation and is embedded in the chain segment gaps of the molten plastic. This physical interlocking avoids macroscopic thermal degradation of drug molecules and utilizes the low thermal conductivity of the powder to prevent charring of the packaging material, achieving heat-melt sealing. The bulk density of the finished product is 0.60 g / cm³, and the proportion of particles in the 150μm to 710μm particle size range is 95%. According to the test, the complete solubility rate of the prepared acetylcysteine ​​granules in 37℃ warm water within 4 minutes is 99.5%. After sealing the finished product, it was placed in an environment with a temperature of 30℃ and a relative humidity of 60% for 30 days for accelerated stability testing. The total impurity increase was only 0.06%, indicating stable physicochemical properties and uniform component mixing.

[0042] Example 2: Both the experimental and control groups were operated in a constant-temperature fluidized bed granulation platform. This platform was equipped with inlet air temperature control, spray pressure regulation, and exhaust gas dust removal filter backflushing modules. The air circulation velocity was set to 1.5 m / s to simulate the gas-solid two-phase flow conditions of industrial production. In actual operation, this fluidized bed granulation process achieves drying and component stabilization by controlling the contact state of the multiphase flow. Specifically, the solid powder, which has been three-dimensionally mixed uniformly in the previous process, is fed into the granulation platform through the feed inlet. The bottom air intake system is activated to provide a high-speed upward-flowing hot airflow, causing the bed... Within the granulation layer, the active pharmaceutical ingredient acetylcysteine ​​and the carrier sucrose overcome their own gravity and remain in a suspended boiling state. Through high-frequency disordered collisions and mutual penetration of the gas-solid two-phase flow, without relying on macroscopic liquid bridge agglomeration, the micro-scale raw material particles are driven to physically intercalate in the flowing airflow, thereby constructing a uniform granulation system with excellent rheological properties online. The experiment introduced ambient background humidity noise, set the relative humidity at the air inlet to 45% ± 5%, and monitored the resistance fluctuations within the material layer. The ratio of acetylcysteine ​​to carrier sucrose was selected as the key variable, and three gradients were set. The proportions of sample group one, sample group two, and sample group three in this invention are 1:5, 1:10, and 1:15, respectively. To ensure the principle of single variable in the comparative experiment, control groups were set up with the same proportion gradient as control sample group one, control sample group two, and control sample group three. The control group adopted a conventional physical direct mixing process, that is, without pre-mixing in a stepped manner and separate drying in a tray, the raw and auxiliary materials with the same proportion were directly dry-mixed and then fed into the fluidized bed. The experimental data showed that at a flow rate of 1.5 m / s and an inlet air temperature of 65°C, under the same 1:10 proportion, the control sample group... When the second sample was running for 45 minutes, the pressure difference of the filter cartridge increased from the initial 200 Pa to 850 Pa, and the material began to stick to the wall. Control sample group 1 and control sample group 3 also showed high pressure differences of 810 Pa and 830 Pa respectively at 38 minutes and 42 minutes, accompanied by the phenomenon of sticking to the wall. The pressure difference of the filter cartridge of sample group 2 of the present invention was maintained in the range of 200 Pa to 280 Pa, and the pressure difference of the filter cartridges of sample group 1 and sample group 3 of the present invention was also stable in the range of 210 Pa to 290 Pa. This difference indicates that the primary dispersion system constructed by premixing and stratified feeding reduced the adhesion tendency of the material.

[0043] Gradient tests were conducted on the process pressure parameters. The results showed that when the spray pressure was below 0.12 MPa, the droplet morphology of the binder component was missing, the local moisture content of the material increased to 8.5%, and the finished product showed light yellow deterioration, exceeding the detection boundary of related substances. When the spray pressure was above 0.25 MPa, the droplets were too fine, causing the moisture to dry too quickly on the particle surface, and the granulation yield dropped to 65%. Within the pressure range of 0.18 MPa to 0.22 MPa, the increase in total related substances impurities in the finished product was less than 0.08%, which matched the requirements of particle surface wetting kinetics. Data analysis showed that under pressure gradient changes, the bulk density of the finished product particles in the sample group of this invention was stable between 0.58 g / cm³ and 0.62 g / cm³, with a coefficient of variation of less than 2.5%. The particle size distribution of each component particle was systematically measured. The results showed that in the control group using the conventional direct mixing process, control sample group 1 (1:5), control sample group 2 (1:10), and control sample group 3 (1:1) were significantly different. 5) The particle size distribution coefficients of the samples were 3.4, 3.2 and 3.1, respectively, while the average particle size distribution coefficient of the control group was 3.2. The particle size distribution coefficients of the samples of the present invention using the fluidized bed granulation process of the present invention were significantly reduced to 1.9, 1.8 and 1.7, respectively, and the average particle size distribution coefficient of the samples of the present invention was reduced to 1.8. In particular, under the typical ratio of 1:10, the particle size distribution coefficient of the control sample group was 3.2, while the corresponding particle size distribution coefficient of the present invention sample group was reduced to 1.8. This confirms the effect of the micro-skeleton constructed by the premixing mechanism and fluidized state on improving the uniformity of the material. The final conclusion shows that the acetylcysteine ​​particles, through multi-step spatial compounding and hot air circulation drying, achieve temporal isolation between thiol molecules and carrier components, block the thermocatalytic degradation path, and ensure the physicochemical stability and rheological properties of the particles under high-speed dispensing conditions.

[0044] Example 3: This example combines Figures 1 to 2 A fluidized bed granulation process for acetylcysteine ​​particles is described, as follows: Figure 1As shown, the raw materials and excipients for the active pharmaceutical ingredient acetylcysteine ​​were independently sieved through a first sieve. Material II, serving as a trace functional excipient, was sieved through a third sieve and then premixed with flavoring in a double-cone mixer. Subsequently, the sieved active pharmaceutical ingredient and the premixed material II were separately spread on independent stainless steel trays for spatial isolation, controlling the thickness of the spread. They were then placed in an oven and dried in a flowing air environment at 50°C to 70°C for 1 to 3 hours using hot air circulation. During the drying process, the trays were turned periodically every 0.4 to 0.6 hours to eliminate humidity gradients within the material layers. The dried materials were then subjected to a loss-of-drying determination to ensure that the residual moisture content of both the active pharmaceutical ingredient and material II, measured by the loss-of-drying method, was reduced to below 1.5%. Simultaneously, sucrose, serving as a carrier for a large proportion of crystals, was independently sieved through a second sieve and dried using hot air circulation until it reached a loss-of-drying. The content is not higher than 0.2%; the active ingredient with a drying loss of less than 1.5%, the premixed material II, and the sieved and dried sucrose are sequentially fed into a three-dimensional oscillating mixer. Alternating shear stress is generated through spatial multi-dimensional staggered oscillation. The mixing frequency is set not higher than 33Hz and the mixing time is not less than 19 minutes to form a solid granule composition consisting of 70% to 85% sucrose, 1% to 5% material II, and the active ingredient to be supplemented to 100% by mass. The total mixed solid granule composition is introduced into a dispensing machine for stable feeding. The horizontal and vertical sealing temperatures are adjusted to 140℃ to 180℃, and the dispensing speed is controlled to 40 bags / min to 80 bags / min. The low drying loss powder is used to heat-melt bag moisture-proof and sealed packaging at the sealing point. Finally, acetylcysteine ​​granules with stable physicochemical characteristics and uniform component mixing are output.

[0045] like Figure 2As shown, the finished product index control elements of this invention mainly include the control of the following six synergistic dimensions: Raw material-specific sieving process includes fine sieving of the active pharmaceutical ingredient using a stainless steel mesh, premixing of the second-phase material with the flavoring using a double-cone mill, and independent sieving of crystalline sucrose; Sequential drying and temperature control in separate trays includes controlling the thickness of the material layer, maintaining a constant temperature environment with hot air circulation, and periodically turning the material to eliminate humidity gradients; Three-dimensional multi-dimensional staggered oscillating mixing includes sequential addition of multiple raw materials and excipients, setting a stable mixing frequency, and generating alternating shear stress for mixing; High-speed dispensing and hot-melt sealing includes using a three-layer composite film moisture-proof bag and controlling the high-speed dispensing and packaging speed... And precise adjustment of horizontal and vertical sealing temperatures; control of temperature and humidity in pharmaceutical cleanrooms includes controlling the relative humidity range, controlling indoor temperature, and implementing this in a Class D pharmaceutical cleanroom environment; control of physical and chemical indicators includes ensuring complete dissolution in warm water, conducting accelerated stability tests, controlling the target particle size distribution ratio, and testing the bulk density of finished product particles; the above-mentioned specific sieving process for raw and auxiliary materials, sequential isolation drying and temperature control in trays, three-dimensional multi-dimensional staggered oscillating mixing, high-speed dispensing, hot-melt sealing, control of temperature and humidity in pharmaceutical cleanrooms, and control of physical and chemical indicators all aim to ensure the uniformity of finished product content and the stability and standardization of physicochemical indicators.

[0046] Example 4: In the production of acetylcysteine ​​granules, acetylcysteine ​​raw material and sucrose are used as the main materials. The fluidized bed granulation process is precisely controlled to improve the physical stability of the granules. The initial particle size of the raw materials is determined using a particle size analyzer. Acetylcysteine ​​is sieved through a 40-mesh first sieve, and crystalline sucrose is sieved through a 50-mesh second sieve. The sucrose is selected to have an average particle size of 200 μm. The drying loss of the selected crystalline sucrose is no higher than 0.2%, and the measured drying loss is 0.12%. Material 2, a trace functional excipient containing fruit juice powder, sweetener, and colorant, is sieved through a 70-mesh third sieve and then premixed with flavoring in a double cone mixer for 15 minutes. During the premixing stage, a three-dimensional motion mixer is used to add the components in proportion, with a mixing frequency set to 32 Hz and running continuously for 20 minutes to eliminate physical differences caused by density variations between the raw materials and excipients. In this process, the convective diffusion dry mixing completed by the three-dimensional oscillating mixer, combined with the multiphase flow control inside the fluidized bed granulator, jointly enhances the physicochemical stability of the particles. Through the alternating shear stress generated by the three-dimensional misaligned oscillation, the polarity differences and gravitational stratification between the raw and auxiliary powders are eliminated, resulting in a primary composition with high macroscopic homogeneity. This material is then transferred as a seed powder into the fluidized bed, utilizing the high specific surface area provided by the high-speed suspended fluidization state to receive the micro-wetting from the subsequent spray system. This ensures a uniform macroscopic distribution of components while reconstructing a stable crystal structure through liquid bridges, completing the convective shearing and mass-heat transfer processes. The premixed material is fed into the fluidized bed granulator, and the fluidized airflow velocity in the bed is stably controlled at 1.6 m / s by adjusting the inlet air damper. At this velocity, the material forms a stable suspension state, avoiding excessive material wear caused by excessive airflow. When the material bed temperature... When the temperature stabilizes at 48℃, the spray system is activated. Based on the principle of heat and mass transfer balance and the theory of convection drying, the dehumidification rate of the multiphase flow in suspension is controlled by the water vapor partial pressure difference on the crystal surface and the gas mass transfer efficiency. The fluidized bed inlet air temperature range is 50℃ to 70℃, and the inlet air temperature is set to 65℃. The control system operates based on the real-time bed temperature collected by the temperature sensor. The partial pressure of water vapor in the internal environment collected by the pressure sensor Calculate the real-time water evaporation rate The processing steps include: based on the bed temperature Search the saturated water vapor pressure database to determine the corresponding saturated water vapor pressure. ; Calculate saturated water vapor pressure partial pressure of water vapor in the environment The difference is calculated by multiplying the difference by the mass transfer coefficient η to determine the real-time water evaporation rate. Comparison of water evaporation rates With the endpoint threshold, when the water evaporation rate When the flow rate decreases to 0.01 g / min·cm², the control system outputs a shut-off command to the spray valve, terminating the spray and switching to the drying and cooling mode. The mass transfer coefficient η ranges from 0.024 to 0.028 kg / m²·s·kPa, characterizing the rate of change at the gas-solid interface at a specific flow rate; saturated water vapor pressure... The equilibrium vapor pressure of pure water at the corresponding temperature; the partial pressure of water vapor in the environment. The product of the hygrometer reading in the fluidized bed exhaust pipe and the total pressure is used to determine the spray pressure of the adhesive. Based on the particle surface wetting dynamics, the spray pressure is calibrated to 0.20 MPa to ensure the formation of droplets with an average diameter of 40 μm, thereby constructing a stable liquid bridging layer on the particle surface.

[0047] The process of removing moisture from the material follows the hot air penetration balance logic, and the inlet air temperature is set accordingly. The drying temperature is 65℃, and the drying time and moisture evaporation rate are dynamically adjusted by monitoring the relative humidity of the exhaust gas. With bed temperature The following engineering relationships must be satisfied: ,in, This represents the rate of water evaporation. To maintain bed temperature The saturated water vapor pressure below The partial pressure of water vapor in the fluidized bed environment, The mass transfer coefficient is determined by monitoring. The material was considered to have reached the drying endpoint when the evaporation rate decreased to 0.01 g / (min·cm²). The dried granules were processed by an automatic dispensing machine with a horizontal sealing temperature set at 160℃ and a pressure of 0.3 MPa. The bulk density of the finished granules was 0.61 g / cm³, the average particle size distribution frequency in the range of 150 μm to 710 μm was 95.2%, and the increase in total impurities was 0.06%. This indicator verified that under the set fluidized bed drying pressure and temperature control window, the acetylcysteine ​​molecular structure remained intact, and the particle physical morphology met the dispensing requirements. To ensure the accurate application of the aforementioned engineering correlation and feedback regulation logic in actual production, the binder components and control coefficients involved were standardized and limited. In this embodiment, the binder used to start the spray system was an anhydrous ethanol solution of polyvinylpyrrolidone with a mass fraction of 5%. The mass transfer coefficient in the aforementioned engineering correlation characterizes a specific bed layer. The rate of moisture migration from the particle surface to the gas phase under fluidized airflow velocity was measured in real time using a precision weighing sensor under calibration conditions of 1.6 m / s fluidized airflow velocity and 65°C inlet air temperature. The quantified value of this mass transfer coefficient was stable within the range of 0.024 to 0.028 kg / m² / s kPa. The temperature control response gain coefficient in the aforementioned feedback regulation logic relationship characterizes the compensation sensitivity of the hot air inlet temperature when the bed temperature deviates from the target value. In the offline calibration program, by inputting gradually increasing temperature deviation interference to the control system and observing the transition time of the bed temperature returning to steady state, the determined value range of this temperature control response gain coefficient was limited to 1.2 to 1.5. If the coefficient is lower than 1.2, the system's response to temperature fluctuations is too slow and cannot effectively curb local moisture accumulation; if the coefficient is higher than 1.5, the hot air inlet temperature will experience violent fluctuations, causing the bed temperature to surge instantaneously and triggering thermal degradation of the active pharmaceutical ingredient.

[0048] Example 5: In the fluidized bed granulation process of acetylcysteine ​​particles, to ensure the consistency of product properties between batches, an offline calibration process was constructed to quantify the response relationship between pressure fluctuations in the fluidized bed and the suspension state of material particles. This calibration process, in the initial state without spray injection, loads a rated batch of raw and auxiliary materials into the fluidized bed and gradually increases the airflow velocity. And record the bed pressure difference. With airflow inlet velocity Based on the corresponding data, a baseline curve characterizing fluidization quality was established. By performing linear fitting on this curve, the minimum airflow velocity required for the material to enter a stable fluidization state was determined. With bed pressure difference stability value Regarding the control parameters involved, the system sets feedback adjustment logic for the inlet air temperature and the material bed temperature based on the physical state of the material at different moisture content stages. When the monitored bed temperature... When the value deviates from the preset range, the system adjusts the temperature error accordingly. Automatically correct hot air inlet temperature This logical relationship is expressed as: ,in, The inlet air temperature is adjusted in real time. The target inlet air reference temperature set for the process. This is the temperature control response gain coefficient. This represents the real-time deviation of the bed temperature.

[0049] In the offline calibration process, the gain coefficient under the property fluctuations of different batches of active pharmaceutical ingredients was measured through a series of gradient experiments. The range of values ​​is determined to ensure that regardless of changes in the fineness distribution of the active pharmaceutical ingredient during production, it can be maintained. Under the control of bed temperature To maintain the pressure within the target range, for each production batch, an automatic detection program is initiated after feeding. The system automatically collects the initial material differential pressure response data and compares it with a preset baseline curve. If... If the deviation exceeds the preset fluctuation threshold, the operating frequency of the blower will be adjusted accordingly. Perform closed-loop correction until... Returning to the baseline fluidized bed range, based on the critical transition theory between fixed and fluidized beds in fluid mechanics, the variation of bed pressure difference with airflow velocity directly reflects the batch variability of the initial physical properties of the powder packing. The bed pressure difference ranges from 200 Pa to 280 Pa. The control system regulates the inlet fan to operate at a gradually increasing frequency. Real-time bed pressure difference ΔP is collected by pressure sensors at the bottom of the bed and at the exhaust gas end. The bed pressure difference ΔP varies with airflow velocity. When the pressure difference stops increasing linearly and tends to stabilize, the pressure difference value is confirmed as the stable bed pressure difference value ΔPs, and the corresponding airflow velocity is confirmed as the minimum fluidization velocity. The control system compares the stable bed pressure difference ΔPs with the built-in preset fluidization reference value to calculate the pressure difference deviation. When the pressure difference deviation exceeds the preset fluidization reference value by 15%, the control system outputs a current control signal of 4mA to 20mA to the frequency converter based on the pressure difference deviation value, and adjusts the operating frequency of the blower in 0.5Hz increments to correct the airflow velocity. The bed pressure difference ΔP returns to the baseline fluidization range, where the minimum fluidization velocity is... The critical velocity at which solid particles overcome gravity and enter a suspended boiling state is used; the current control signal is used to adjust the speed of the blower motor. At the end of the drying stage, the system uses a moisture content monitor to continuously track the concentration of residual solvent in the material. When the moisture content drops below the target endpoint value and no longer changes continuously, the spraying stop command is automatically triggered, and the pre-packaging cooling program is started to avoid the risk of agglomeration of the finished product at the outlet due to temperature difference. This engineering calibration and feedback mechanism eliminates the uncertainty of variables in the production process and ensures the batch stability of the granular product in terms of particle size distribution and related material indicators.

[0050] To clarify the technical inevitability of the pre-disc sequential isolation drying process and the post-three-dimensional misaligned swing mixing process at the critical process boundary of this invention, this invention systematically conducted offline quality control boundary testing and synergistic mechanism verification on the deviation state of key process parameters.

[0051] In the critical characteristic test of blocking chemical thermocatalytic degradation and non-enzymatic browning, the control group used the same raw and auxiliary material composition ratio as the present invention, containing the main drug acetylcysteine, material two and crystalline sucrose in the same mass percentage. If the drying sequence of the tray static hot air circulation in step S101 is changed, the main drug and material two premix with an initial drying weight loss of about 2.4% without isolation and dehumidification treatment, as well as the undried sucrose, are directly put into the mixer for total mixing, granulation and packaging to obtain control group granules. At the same time, the control group granules and the finished granules obtained by the process of the present invention are placed in the same comparative test environment for parallel investigation: First, parallel comparative investigation is carried out under the same accelerated test conditions: When the control group granules are placed for 3 months, due to the large amount of free water remaining in the powder, the thiol group and sugar directly undergo non-enzymatic browning under high temperature and high humidity, and obvious light yellow spots appear on the surface of the granules. By the 6th month, the whole granules turn yellow, and the total impurity content increases significantly to 1.15%, exceeding the 1.0% qualified limit. The finished product granules of this invention, after being placed in the same accelerated test for 6 months, still maintained a colorless / white fine particle appearance, with total impurities of only 0.12% and an increase in total impurities of less than 0.1%. Secondly, parallel comparative tests were conducted under the same long-term retention conditions: the control group granules began to yellow and deteriorate in appearance after 12 months, and the total impurities jumped to 0.92% by the end of 36 months; while the finished product granules of this invention, after undergoing an extremely long retention period of 36 months, showed only slight fluctuations in total impurities to 0.19% to 0.27%, with the absolute increase in total impurities consistently controlled below 0.2% throughout the entire life cycle, and the high-degradation-risk impurity II never exceeding 0.02% or being undetectable. The appearance remained stable as colorless, non-yellowing, soluble fine particles. Parallel comparative tests under identical material composition and temperature and humidity conditions confirmed the technical effectiveness of this invention in effectively blocking the thermocatalytic degradation and Maillard reaction pathways of thiol molecules through pre-sequential isolation, dehumidification, and solvent removal.

[0052] In the critical characteristic test for suppressing physical stratification and segregation dimensions of multi-component powders at high dilution ratios, to examine the independent contribution of the spatially multidimensional misaligned oscillating mixing process in step S102 to the powder's physical flowability and anti-segregation properties, under the premise of strictly implementing the pre-disc isolation drying in step S101 to ensure that the drying weight loss of each component is less than 1.5%, only the mixing process in step S102 was changed: the spatially multidimensional misaligned oscillating mixing process defined in this invention was not used; instead, a conventional fixed-shaft double-cone mixer was used with a speed controlled at 25 rpm and a mixing time set to 45 min. The dried material after mixing was then introduced into a fluidized bed granulator. Online and offline test results showed that although pre-drying eliminated high free water, unlike the severe wet wall adhesion phenomenon at 850 Pa caused by direct mixing without drying in Example 2 at 45 min, the lack of high-frequency uniform dissipation of multidimensional dislocation alternating shear stress in the double-cone mixing process resulted in increased surface energy and electrostatic repulsion of the high-dilution-ratio trace functional excipients after ultra-low drying weight loss and dehumidification. This led to the separation of fine powders under the fluidized bed 1.6 m / s airflow suspension and boiling state. Electrostatic adsorption and segregation occurred after 30 minutes of operation, causing the top filter cartridge of the fluidized bed to become clogged with fine powder. The pressure difference of the fluidized bed filter cartridge increased from the initial 200 Pa to 680 Pa, triggering bed flow deviation. Simultaneously, due to the inability to overcome the density difference and polarity gradient between powders, this conventional dry-mixed material under the high-frequency vibration conditions of the automatic packaging machine experienced severe secondary gravity sedimentation and stratification. In the later stages of packaging, the content of the effective ingredient deviated from the labeled amount by as much as -8.4%, and the intra-batch coefficient of variation (CV%) of the finished product was as high as 5.2%, posing a risk of non-compliance. This invention employs a three-dimensional misaligned oscillating mixing process with a specific mixing frequency and maximum shear rate. During the entire fluidized bed operation, the filter cartridge pressure difference is consistently maintained within the normal range of 200 Pa to 280 Pa. Furthermore, trace amounts of excipients are stably and mechanically embedded in the gaps of the sucrose crystal microstructure. The discharged particles possess anti-stratification rheological properties, and the uniformity of the finished product content in each batch meets the specifications. The labeled amount is stably controlled between 98.6% and 105.0% during long-term and 36-month sample retention, with a low coefficient of variation. This reconstructs the physical homogeneity of materials under high-frequency dynamic operating conditions.

[0053] The embodiments of this application have been described above with reference to the accompanying drawings. Unless otherwise specified, the embodiments and features in the embodiments of this application can be combined with each other. This application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit of this application and the scope of protection of this invention, and all of these forms are within the protection scope of this application.

Claims

1. A fluidized bed granulation process for acetylcysteine ​​particles, characterized in that, Includes the following steps: Step S101: The active ingredient acetylcysteine, along with Material II (a trace functional excipient containing fruit juice powder, sweetener, and colorant) and sucrose, are sieved separately. Material II is then premixed with flavoring. The premixed Material II and the active ingredient are spread evenly on separate stainless steel trays and dried separately in a flowing air environment at 50°C to 70°C for 1 to 3 hours. During the drying process, the trays are turned regularly every 0.4 to 0.6 hours to eliminate the humidity gradient within the material layer until a sample is taken and tested by the loss on drying method, and the residual moisture of both Material II and the active ingredient is reduced to below 1.5%. In step S102, the dried active pharmaceutical ingredient, the premixed material II, and the sieved sucrose are sequentially fed into a three-dimensional oscillating mixer. The mixing frequency is set to no higher than 33Hz and the mixing time is no less than 19 minutes. The alternating shear stress is generated by the spatial multi-dimensional misaligned oscillation of the three-dimensional oscillating mixer, so that the components are mixed evenly to form a solid particulate composition consisting of 70% to 85% sucrose by mass, 1% to 5% material II by mass, and the active pharmaceutical ingredient to a balance of 100%. In step S103, the mixed solid granule composition is introduced into a dispensing machine, the horizontal and vertical sealing temperatures are adjusted to 140°C to 180°C, and the dispensing speed is controlled to 40 bags / min to 80 bags / min. The low drying weight loss powder is used to heat-melt bag moisture-proof and sealed packaging to obtain acetylcysteine ​​granules.

2. The fluidized bed granulation process for acetylcysteine ​​particles according to claim 1, characterized in that, In step S101, the first sieve used for sieving the active ingredient has a mesh size of 30 to 50 and is made of 316L stainless steel; the second sieve used for sieving the sucrose has a mesh size of 30 to 50 and is made of 304 stainless steel; the third sieve used for sieving the second material has a mesh size of 40 to 200 and is placed in a double cone mixer after sieving to premix with the flavoring for 15 minutes, with the speed of the double cone mixer controlled at 20 to 30 rpm.

3. The fluidized bed granulation process for acetylcysteine ​​particles according to claim 1, characterized in that, In step S101, the separate tray static drying is further subdivided into the following sub-steps: Step S1011, material two and the main drug are laid flat in separate trays, and the thickness of the material in the tray is controlled to be 10mm to 15mm; Step S1012, the tray containing the material is pushed into the drying oven, and the vertical penetration speed of the airflow is controlled to be 0.5m / s to 1.0m / s, and the hot air is circulated and dried in a constant temperature environment of 50℃ to 70℃ for 1h to 3h.

4. The fluidized bed granulation process for acetylcysteine ​​particles according to claim 1, characterized in that, In step S101, the sucrose is crystalline sucrose with an average particle size of 150 μm to 250 μm and a drying weight loss of no more than 0.2%.

5. The fluidized bed granulation process for acetylcysteine ​​particles according to claim 1, characterized in that, In step S102, the material loading coefficient of the three-dimensional oscillating mixer is 0.6 to 0.7, and the multi-dimensional misaligned oscillation includes rotational motion around the horizontal axis, oscillating motion around the vertical axis, and reciprocating motion along the axial direction. The maximum shear rate generated by the three-dimensional oscillating mixer inside the solid particle composition is 50 s⁻¹ to 80 s⁻¹.

6. The fluidized bed granulation process for acetylcysteine ​​particles according to claim 1, characterized in that, Steps S101, S102 and S103 are all carried out in a pharmaceutical cleanroom with a cleanliness level of D. The ambient temperature of the pharmaceutical cleanroom is controlled to be between 18°C ​​and 24°C, and the relative humidity is controlled to be no higher than 45%.

7. The fluidized bed granulation process for acetylcysteine ​​particles according to claim 1, characterized in that, The prepared acetylcysteine ​​particles have a bulk density of 0.55 g / cm³ to 0.65 g / cm³, and the mass percentage of particles with a particle size between 150 μm and 710 μm is not less than 92%.

8. The fluidized bed granulation process for acetylcysteine ​​particles according to claim 1, characterized in that, In step S103, the packaging material used for the hot melt bag moisture-proof sealed packaging is a three-layer composite film composed of polyester, aluminum foil and polyethylene. The total thickness of the three-layer composite film is 60μm to 80μm, of which the thickness of the aluminum foil layer is 7μm to 9μm.

9. The fluidized bed granulation process for acetylcysteine ​​particles according to claim 1, characterized in that, The obtained acetylcysteine ​​particles have a complete solubility of not less than 99% in 37℃ warm water within 5 min, and after accelerated stability testing at 20℃ to 35℃ and relative humidity for 25 to 35 days, the increase in total impurities in the related substances of the acetylcysteine ​​particles is not higher than 0.1%.

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