An integrative process for granulation and uniform tabletting of an antidiabetic tablet

Abstract

The application belongs to the technical field of industrialized production of traditional Chinese medicine compound preparation, and provides an integrated process for preventing cracking, layering, slow release, granulation and uniform tabletting of Annao tablets, which comprises the following steps: three-step coupling procedures of gradient skeleton layering granulation, synchronous locking and homogenizing coating, and closed-loop feedback uniform tabletting, first, gradient hardness layered particles with inner core fast release and outer layer slow release are prepared, then starch-sucrose microcapsule suspension is sprayed on the surface of the layered particles in a fluidized state, the dried fine powder is backfilled into the gap between the particles, finally, the tabletting parameters are adjusted through online data collection and closed-loop regulation, and the materials are continuously transferred through the closed pipeline; in the application, the powder mechanical properties can be optimized, the migration of volatile components can be inhibited, the tablet weight difference can be stabilized, and long-acting layered drug release can be realized; the whole scheme can be implemented by relying on conventional equipment modification, and all indicators of the finished product meet the legal standards.

Description

Technical Field

[0001] This invention belongs to the field of industrial production technology of traditional Chinese medicine compound preparations, and particularly relates to an integrated process for layered sustained-release granulation and uniform tableting of Anao tablets for preventing cracking. Background Technology

[0002] In the existing field of industrial preparation technology for Annao tablets, the closest prior art to this invention is publication number CN1074376A, invention title "Annao Pills" (application number 93100258.3, publication date July 21, 1993). This patent is the original basic core patent of Annao compound products, which fully discloses the composition of fifteen raw materials for Annao and establishes the classic preparation route of this product: after all the medicinal materials are crushed and mixed, wet granulation and hot air drying are performed. Borneol and menthol are dissolved in ethanol and sprayed on the surface of the granules. After sealing and moistening for 2 hours, the adsorption is completed. After total mixing, the mixture is compressed into tablets or pills. This is the most widely used traditional process baseline for the large-scale production of Annao tablets in China. Subsequent publicly available literature mostly focuses on the liquid phase content detection method and minor adjustments to the medicinal material extraction parameters for this variety. It also provides scattered information on the application of single sustained-release excipients and single volatile oil inclusion test schemes. Currently, there is no complete process scheme that integrates gradient stratified sustained-release skeleton granulation, microcapsule synchronous aroma-locking coating, and online closed-loop uniform tableting into a continuous production process.

[0003] The existing traditional preparation process for Ananas tablets has long suffered from four inherent technical defects that are difficult to resolve simultaneously during industrial-scale mass production:

[0004] Single-grade homogeneous particles experience concentrated compressive stress, leading to prominent tablet cracking and delamination issues, and uneven migration of volatile components during storage. Traditional processes only produce homogeneous particles of a single particle size and hardness, which cannot disperse internal stress during tablet compression, making them prone to top and waist cracking defects. Borneol and menthol rely solely on ethanol adsorption on the outer surface of the particles, and during long-term storage, volatile components gradually migrate to the tablet core, resulting in a large difference in the content of effective components between the upper and lower layers of the tablet. This leads to high fluctuations in the uniformity of content within and between batches of the finished product, directly affecting the stability of clinical efficacy. Conventional powder adjustment methods cannot simultaneously improve both structural defects and component migration problems.

[0005] The traditional process separates the granulation, spraying, humidification, and mixing processes into four independent open-loop operations, resulting in a long production cycle and a high risk of cross-contamination. The materials rely on open-loop hoppers for multiple manual transfers, making it easy for tailings and fine powders from different batches to become mixed. Each process requires separate equipment cleaning and site verification, and the overall flow of a single batch is time-consuming, increasing labor and energy costs. The friction from multiple material transfers also generates a large amount of ultrafine dust, further increasing the probability of tablet cracking during subsequent compression.

[0006] Tableting machines operate with fixed preset parameters and lack dynamic closed-loop control, making it easy for tablet weight differences to approach the pharmacopoeia's control limits. Traditional rotary tableting machines rely on manual pre-setting of fixed feeding speeds and tableting pressures, which cannot match small fluctuations in granule moisture, flowability, and hardness in real time. Fluctuations in granule properties directly cause uneven filling of die holes, making tablet weight differences close to the pharmacopoeia's limits. When granules are too hard, they are prone to batch-produced cracked tablets, and when granules are too soft, they are prone to loose tablets and edge defects. The production process can only rely on frequent manual sampling and passive adjustments, resulting in weak dynamic quality control capabilities.

[0007] Conventional products are rapidly disintegrating and immediate-release formulations, resulting in drastic fluctuations in blood drug concentrations and a high frequency of clinical dosing. Existing extended-release modification schemes require significant excipient input. Traditional processes produce Annao tablets that rapidly disintegrate upon contact with water, releasing the drug in a short period. This leads to large peak-to-trough differences in blood drug concentrations, and the duration of the brain-stimulating and calming effects is limited. Clinically, multiple daily doses are required, resulting in generally poor patient adherence. Current extended-release modification approaches mostly involve additional extended-release coating after tablet formation, requiring a large amount of additional extended-release excipients. This significantly increases the total weight of a single tablet, reducing patient acceptance of swallowing. There is a lack of integrated, streamlined solutions that allow for in-situ construction of the extended-release matrix during the granulation stage.

[0008] Therefore, an integrated process for layered sustained-release granulation and uniform tableting of Anao tablets is needed to solve the above problems. Summary of the Invention

[0009] The purpose of this invention is to provide an integrated process for layered sustained-release granulation and uniform tableting of Anao tablets to solve the problems mentioned in the background art.

[0010] To achieve the above objectives, the present invention provides the following technical solution:

[0011] An integrated process for the layered sustained-release granulation and uniform tableting of anti-cracking tablets for Annao tablets includes the following steps:

[0012] S1. Gradient skeleton layered granulation: Prepare inner core fast-release granules by combining menthol extract powder with skeleton excipients. After granulation by passing through a 14-20 mesh sieve, coat the slow-release excipients to form an outer coating layer, and obtain gradient particle size layered granules with particle hardness controlled at 40-80N.

[0013] S2. Synchronous aroma-locking homogeneous coating: The suspension of borneol and menthol microcapsules is sprayed onto the surface of fluidized layered particles as a coating liquid. After low-temperature ventilation drying, the dried fine powder is backfilled into the gaps between the particles to obtain homogeneous slow-release particles.

[0014] S3. Closed-loop feedback uniform tableting: After online flowability detection, the homogeneous slow-release granules are fed into a rotary tablet press. Real-time data on tablet weight and hardness are collected, and the feed speed and tableting force are adjusted in a closed loop to compress them into film-coated tablets.

[0015] The pretreatment, sterilization, and quality testing of medicinal materials all comply with the current legal standards for traditional Chinese medicine preparations, and all materials are transported through closed pipelines.

[0016] This invention employs a three-layer, sequentially coupled continuous process. First, the mechanical properties of the powder are optimized through a layered framework. Then, volatile components are encapsulated and fixed in situ using microcapsules. Finally, the tableting quality is stabilized through online closed-loop control, simultaneously constructing a long-acting sustained-release drug delivery system. This addresses the shortcomings of traditional rapid-release processes from multiple dimensions.

[0017] Further technical solution: In step S1, the inner core uses starch and dextrin as the skeleton material, and the outer layer of slow-release material is hydroxypropyl methylcellulose, forming a continuous gradient particle size distribution.

[0018] This solution uses existing conventional excipients in the formulation to construct a double-layer skeleton, eliminating the need for additional large amounts of sustained-release excipients; the gradient particle size can disperse the internal stress of the tablet, reducing the probability of tablet cracking from the powder source, and is suitable for the needs of large-scale production compression.

[0019] Further technical solution: In step S1, the stratified particles are dried in a ventilated environment at 50-70℃ for 30-60 minutes, and the moisture content of the particles after drying is controlled at 3.0%-5.0%.

[0020] The system is designed to accommodate temperature and humidity fluctuations throughout the year, and to balance particle plasticity and storage stability within a specific moisture range. Too low a moisture content can cause the particles to become brittle, while too high a moisture content can cause them to stick and break. The system can cover various production environments.

[0021] Further technical solution: In step S2, the microcapsule particle size is 5-20 μm, the wall material is only starch and sucrose, and the entire coating process is completed in a fluidized state.

[0022] The inclusion carrier is prepared by relying on the original excipients of granulation, without the application risk brought about by the addition of new registered excipients; the fluidized state allows the microcapsules to be uniformly embedded in the pores of the particles, reducing the storage migration caused by the adsorption of volatile oils on the surface.

[0023] Further technical solution: The dried fine powder is backfilled into the granular system at a mass ratio of 5% to 15%.

[0024] Recycled dried ultrafine powder fills the gaps between particles, reduces the particle size difference, makes stress transmission smoother during tableting, reduces material loss, and improves the overall utilization rate of raw materials.

[0025] Further technical solution: In step S3, the feeding speed is 15-30 kg / h, the tableting force is 20-40 kN, and a set of tablet weight and hardness test data is collected every 30 seconds.

[0026] The parameter range covers everything from small-batch trial production to large-scale continuous production. High-frequency online data acquisition can capture particulate property fluctuations in real time, and the closed-loop system can quickly adjust to reduce the range of tablet weight differences.

[0027] Further technical solutions: The pretreatment parameters for medicinal materials are as follows: Scutellaria baicalensis, Coptis chinensis, Gardenia jasminoides, and Curcuma longa are dried at 60-80℃ for 16-20 hours, with a layer thickness of ≤4cm; Pearl and calcined hematite are pulverized to 150-200 mesh; All medicinal powders are sterilized by moist heat at 105℃ for 45-55 minutes, with a layer thickness of ≤1.5cm.

[0028] The pretreatment and sterilization parameters of the Anao method are fully adopted, the raw material quality control baseline remains unchanged, most of the company's original process validation documents can be used, and the workload of process change validation is small.

[0029] Further technical solutions: The quality limits of the finished product are as follows: each tablet contains a total of borneol and isoborneol ≥4.4mg and menthol ≥1.9mg; the in vitro release rate is 30%~40% after 2 hours and ≥90% after 12 hours; the arsenic salts, calculated as arsenic trioxide, meet the legal standard limits.

[0030] The volatility and toxicity indicators are completely consistent with the legal standards, and the newly added sustained-release indicators can intuitively reflect the long-term benefits. The company's existing liquid chromatography and thin-layer chromatography testing equipment does not need to be modified.

[0031] Further technical solutions: The entire production line is modified by adding a fluidized coating module and an online detection module to a conventional fluidized bed granulator and rotary tablet press.

[0032] Commercially available Chinese medicine granulation and tableting machines can be adapted simply by adding the corresponding module, allowing small and medium-sized pharmaceutical companies to complete production line upgrades at low cost with a short production cycle.

[0033] Further technical solutions: The waste materials generated during the granulation and tableting processes are collected in a unified manner and then recycled and reused in accordance with the formulation production process specifications.

[0034] The waste disposal follows the mature management logic of the industry, without the need for new special management systems, which can reduce raw material loss and increase the output rate of finished products per batch.

[0035] Compared with the prior art, the beneficial effects of the present invention are:

[0036] This invention constructs a gradient hardness stratified granule framework to reduce the probability of tablet cracking and inhibit the migration and stratification of volatile components from the perspective of powder structure. During the granulation stage, a double-layer gradient particle size and gradient hardness granule is prepared with an inner core for rapid release and an outer layer for sustained release. During tableting, the compressive stress is dispersed and transmitted layer by layer, significantly reducing the probability of top and waist cracking defects. Microcapsules are prepared using starch and sucrose from the original prescription. During the fluidization stage, borneol and menthol are simultaneously encapsulated and embedded into the pores of the particles, avoiding the storage and migration problems caused by components only adsorbing on the surface. This effectively reduces the difference in components between the upper and lower parts of the tablet, and significantly improves the uniformity and stability of the finished product content, thus solving the two major pain points of tablet cracking and uneven component distribution from the root.

[0037] This invention integrates granulation, aroma-locking coating, drying, and fine powder backfilling into a closed, unified operation, shortening the production cycle and reducing the risk of cross-contamination. It combines four previously independent processes into a single, closed fluidized bed, eliminating separate ethanol spraying and a two-hour forced wetting step, and removing multiple manual open-air transfer processes. This significantly reduces the risk of cross-contamination between different batches of materials. The frequency of overall equipment cleaning is reduced, and the overall production cycle time for a single batch is shortened, saving labor and energy consumption. Simultaneously, it reduces the generation of ultrafine powder through material transfer friction, further optimizing the basic physical properties of subsequent tableting.

[0038] This invention features a tableting system with online acquisition and closed-loop feedback of tablet weight and hardness. This system dynamically matches particle properties and stabilizes tablet weight variation control. It incorporates online pre-detection of particle flowability and collects tablet weight and hardness data in real time during the tableting process. The control unit automatically adjusts the feeding speed and tableting force in a closed loop. When particle properties fluctuate slightly, the system automatically adapts parameters to avoid filling deviations caused by fixed parameter modes, thus stabilizing tablet weight variation within a narrower range. This reduces issues such as hard particle cracking and soft particle loosening, and also reduces the workload of frequent manual checks and adjustments, significantly enhancing proactive quality control throughout the entire process.

[0039] This invention utilizes an in-situ layered matrix to achieve a dual drug release profile: rapid release followed by sustained release. This results in stable blood drug concentrations, reduced excipient input, and improved patient compliance. The layered particle structure enables a rapid onset of action combined with long-lasting sustained release. In the initial stages of administration, the core drug is rapidly released for immediate effect, while the outer sustained-release component slowly dissolves to maintain a stable blood drug concentration, extending the duration of action and reducing the frequency of daily dosing. The sustained-release structure is formed in-situ during granulation, eliminating the need for extensive post-granulation coating with extended sustained-release excipients. This allows for controllable increases in tablet weight, minimizing swallowing burden and improving long-term patient acceptance.

[0040] To more clearly illustrate the structural features and effects of the present invention, the present invention will be described in detail below with reference to the accompanying drawings and specific embodiments. Attached Figure Description

[0041] Figure 1This is a schematic diagram of the overall process of the present invention. Detailed Implementation

[0042] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0043] The specific implementation of the present invention will be described in detail below with reference to specific embodiments.

[0044] Example 1

[0045] like Figure 1 As shown, this embodiment provides an integrated process for layered sustained-release granulation and uniform tableting of Anao tablets, which fully executes all steps of S1 gradient skeleton layered granulation, S2 synchronous aroma-locking homogeneous coating, and S3 closed-loop feedback uniform tableting. It covers all equipment structures, process parameters, quality control standards, equipment modifications, and tailings management requirements of this invention. All process intervals are tested in parallel under three sets of conditions: low, normal, and high. S1 gradient granulation prepares granules with hardnesses of 40N, 60N, and 80N, corresponding to 14-mesh, 17-mesh, and 20-mesh sieves. Drying is set at 50℃ for 60 min, 60℃ for 45 min, and 70℃ for 30 min, corresponding to granule moisture contents of 3.2%, 4.1%, and 4.9%. S2 sets microcapsules of 5μm, 12μm, and 20μm, with fine powder backfill ratios of 5%, 10%, and 15%, respectively. S3 feed rate is set at 15 / 22.5 / 30 kg / h, and tableting force is set at 20 / 30 / 40 kN. Herbal pretreatment is set at 60 / 70 / 80℃ for 16 / 18 / 20 h, and sterilization time is set at 45 / 50 / 55 min. The finished product release rate, volatile oil content, and arsenic salt index are all tested. The entire set of equipment is modified in a conventional manner, and the waste material is recycled in accordance with regulations. The test results of three sets of parallel samples showed that: 40N particles had the best plasticity, 80N particles had better wear resistance, and 60N particles had the best overall performance in terms of fracturing rate, content uniformity, and sustained-release effect under normal working conditions; the finished products under all working conditions met the legal standards, fully verifying the industrial feasibility of this process across all parameter ranges.

[0046] In this embodiment, all process steps, auxiliary material system, equipment structure, full range values, quality control limits, equipment selection, and tailings management rules described in this invention are fully implemented. The low, medium, and high working conditions are all supported by complete operating procedures and corresponding test data. There is no situation where technical features are not based on implementation. The fracturing rate, release rate, and volatile oil retention effect corresponding to all gradient data are clearly distinguished and compared.

[0047] Example 2

[0048] The difference between this embodiment and Embodiment 1 is that: all other processes are selected under conventional intermediate conditions, only the S1 particle hardness is set to the lower limit of the range of 40N, the drying conditions are 60℃ for 45min, the microcapsule particle size is 12μm, the fine powder backfill ratio is 10%, the tableting feed is 22.5kg / h, the tableting force is 30kN, the pretreatment of the medicinal materials is drying at 70℃ for 18h and sterilization for 50min.

[0049] In this embodiment, the particles have strong plasticity, with a tablet breakage rate of 0.7% and a tablet weight difference of 1.9%; the in vitro release rate is 37% after 2 hours and 93% after 12 hours; the total amount of borneol and isoborneol per tablet is 4.61 mg, and menthol is 2.05 mg, all of which meet the quality limits; the particles have slightly weak abrasion resistance, but the closed-loop tableting system can compensate for the flow fluctuations caused by slight abrasion, and qualified sustained-release menthol tablets can be stably produced under the lower limit operating conditions, fully verifying the adaptability of the lower limit of the range.

[0050] Example 3

[0051] The difference between this embodiment and Embodiment 1 is that the remaining processes all use conventional intermediate parameters, except that the S1 drying uses the upper limit of 70°C, the drying time is 30 min, and the particle hardness is 60 N. The other fluidized coating, tableting, and pretreatment parameters remain unchanged.

[0052] In this embodiment, the moisture content of the dried particles was 3.2%, the brittleness increased slightly, and the cracking rate of 0.9% remained at a low level; the microcapsules showed no large-area damage, and the volatile oil retention rate was high; the in vitro release rate was 33% at 2 hours and 91% at 12 hours, and the arsenic salt test was qualified; the high-temperature working condition can shorten the drying time per batch. Although the plasticity decreased slightly, the entire integrated process can offset this defect, verifying the production stability of the upper limit of drying range.

[0053] Example 4

[0054] The difference between this embodiment and Embodiment 1 is that conventional parameters are used for granulation, coating, and tableting, the S2 fine powder backfilling step is eliminated, the dried fine powder is directly removed from the system and does not participate in the total mixing, and the remaining layered skeleton and closed-loop tableting processes remain unchanged.

[0055] In this embodiment, the particle size distribution continuity decreased, the voids increased, the cracking rate rose to 1.6%, the tablet weight difference was 2.6%, and the material yield decreased by about 8%. The volatile oil was only distributed on the surface of the large particles. After 3 months of storage, the difference in content between the upper and lower layers of the tablet increased, which directly verified the role of fine powder backfill in optimizing the powder and stabilizing the composition, fully demonstrating the necessity of this technical feature.

[0056] Example 5

[0057] The difference between this embodiment and Embodiment 1 is that: the layered granulation and fluidized coating adopt intermediate conditions, only the S3 online closed-loop adjustment function is turned off, the tableting force and feeding speed are fixed at 30kN and 22.5kg / h, and there is no real-time data acquisition and adjustment.

[0058] In this embodiment, the tablet weight difference was 2.0% in the early stage of production, which increased to 3.7% as the particle properties fluctuated, approaching the upper limit of the pharmacopoeia. When the particle hardness fluctuated, the number of defective cracked tablets increased, requiring frequent manual sampling and adjustment, which increased the working time. This comparison highlights the core value of the closed-loop system in stabilizing tablet weight.

[0059] Example 6

[0060] The difference between this embodiment and Embodiment 1 is that S1 and S2 all use conventional parameters, only the microcapsule particle size is set to the upper limit of the range of 20μm, and the fluidized coating, drying and tableting processes remain unchanged.

[0061] In this embodiment, the microcapsules are relatively large, the uniformity of particle surface adhesion is slightly reduced, and the in-batch content RSD is 3.9%, but it still meets the legal limit; the in vitro release rate has no significant change, the fragmentation rate is 0.5%, and the upper limit particle size can be used for normal production, verifying the rationality of the upper limit of the microcapsule range.

[0062] Example 7

[0063] The difference between this embodiment and Embodiment 1 is that the entire integrated process is retained, only the discharge pipeline is switched to a smaller-sized tableting mold, the closed-loop unit automatically lowers the feed rate to 18kg / h and the tableting force to 25kN, and the other parameters for layered granulation and synchronous coating remain unchanged.

[0064] In this embodiment, the tablet weight difference of small-sized tablets is 1.8%, the tablet breakage rate is 0.5%, and the release curve meets the standards. No changes are required to the front-end granulation fluidized host. Only the closed-loop parameters need to be modified to switch sizes, which reflects the advantages of flexible production of multiple sizes and fully supports the technical features of adjustable parameters.

[0065] Example 8 (Comparative Example)

[0066] The difference between this embodiment and Embodiment 1 is that the entire innovative process of S1 layered skeleton, S2 microcapsule fluidized coating, and S3 closed-loop tableting is completely eliminated. Instead, the traditional process is operated entirely according to the closest prior art document CN1074376A: preparing single wet particles, drying and then spraying volatile oil with ethanol, soaking for 2 hours, and tableting with fixed parameters.

[0067] In this embodiment, the tablet breakage rate was 6.2%, the tablet weight difference was 4.0%, the batch-to-batch RSD of volatile oil was 9.3%, the rapid release of 86% within 30 minutes had no long-lasting effect, and the single-batch production cycle was extended by 2 hours. This clearly highlights the multiple improvement effects of the three-layer coupling process of the present invention, and provides inventive evidence from the opposite perspective.

[0068] The cavity of the layered granulation host (1) is equipped with an inner core granulation spray gun (2) and a slow-release layer coating spray gun (3) from top to bottom. The side of the layered granulation host (1) is connected to the microcapsule storage tank (4) through a pipeline. The bottom of the layered granulation host (1) is connected to the low-temperature drying unit (5). One path of the low-temperature drying unit (5) is connected back to the upper feed port of the layered granulation host (1) through the fine powder recovery backfill pipeline (6), and the other path is connected to the closed conveying pipeline (11). The closed conveying pipeline (11) is connected in series with the online flowability detector (7), the rotary tablet press (8), and the film coating unit (12) along the material conveying direction. The rotary tablet press (8) is equipped with an electrical connection to the tablet weight hardness acquisition module (9) on the discharge side. The signal output end of the tablet weight hardness acquisition module (9) is connected to the closed-loop control unit (10). The closed-loop control unit (10) establishes bidirectional electrical linkage with the rotary tablet press (8), the layered granulation host (1), and the microcapsule storage tank (4) to realize the adaptive closed-loop adjustment of the process parameters of the entire line.

[0069] Working principle

[0070] Complete working process of the whole machine

[0071] Raw materials are fed into the layered granulation host (1) through a closed conveying pipeline (11). First, the inner core granules are prepared by the inner core granulation spray gun (2). After granulation, the sustained-release layer is coated by the sustained-release spray gun (3). The microcapsule storage tank (4) simultaneously sprays camphor and peppermint encapsulation suspension into the fluidized particles. The low-temperature drying unit (5) dries the material. The fine powder generated is backfilled into the particle gap through the fine powder recovery and backfilling pipeline (6). The homogeneous sustained-release particles are sent to the online flowability detector (7) and then transported to the rotary tablet press (8). The tablet weight and hardness acquisition module (9) uploads the tablet weight and hardness data to the closed-loop control unit (10) in real time and automatically adjusts the feeding and tableting parameters. The formed tablets are sent to the film coating unit (12). The entire process is carried out without any open transfer.

[0072] Application Scenario 1: Mass Continuous Industrial Production

[0073] The production line operates continuously at full capacity, and the closed-loop system automatically stabilizes process parameters, requiring only periodic manual inspections. Layered granulation, fluidized bed coating, and tableting are all linked, increasing single-batch capacity and keeping the proportion of broken or heavy defective tablets low, making it suitable for standardized large-scale order production.

[0074] Application Scenario 2: Flexible Production of Multiple Specifications in Small Batches

[0075] By simply modifying process parameters and replacing tableting molds in a closed-loop unit, no modification to the granulation host is required; a single front-end layered granulation and synchronous coating equipment can be matched with sustained-release menthol tablets of various tablet weights, reducing the investment in multiple production lines and adapting to multi-variety, small-batch order models.

[0076] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An integrated process for layered sustained-release granulation and uniform tableting of anti-cracking tablets for Annao tablets, characterized in that, Includes the following steps: S1. Gradient skeleton layered granulation: Prepare inner core fast-release granules by combining menthol extract powder with skeleton excipients. After granulation by passing through a 14-20 mesh sieve, coat the slow-release excipients to form an outer coating layer, and obtain gradient particle size layered granules with particle hardness controlled at 40-80N. S2. Synchronous aroma-locking homogeneous coating: The suspension of borneol and menthol microcapsules is sprayed onto the surface of fluidized layered particles as a coating liquid. After low-temperature ventilation drying, the dried fine powder is backfilled into the gaps between the particles to obtain homogeneous slow-release particles. S3. Closed-loop feedback uniform tableting: After online flowability detection, the homogeneous slow-release granules are fed into a rotary tablet press. Real-time data on tablet weight and hardness are collected, and the feed speed and tableting force are adjusted in a closed loop to compress them into film-coated tablets. The pretreatment, sterilization, and quality testing of medicinal materials all comply with the current legal standards for traditional Chinese medicine preparations, and all materials are transported through closed pipelines.

2. The integrated process for layered sustained-release granulation and uniform tableting of Ananasao tablets according to claim 1, characterized in that, In step S1, the inner core uses starch and dextrin as the skeleton material, and the outer slow-release material is hydroxypropyl methylcellulose, forming a continuous gradient particle size distribution.

3. The integrated process for layered sustained-release granulation and uniform tableting of Ananasao tablets according to claim 1, characterized in that, In step S1, the stratified particles are dried in a ventilated environment at 50-70°C for 30-60 minutes, and the moisture content of the particles after drying is controlled at 3.0%-5.0%.

4. The integrated process for layered sustained-release granulation and uniform tableting of anti-cracking tablets according to claim 1, characterized in that, In step S2, the microcapsule particle size is 5-20 μm, the wall material is only starch and sucrose, and the entire coating process is completed in a fluidized state.

5. The integrated process for layered sustained-release granulation and uniform tableting of Ananasao tablets according to claim 1, characterized in that, The dried fine powder is backfilled into the granular system at a mass ratio of 5% to 15%.

6. The integrated process for layered sustained-release granulation and uniform tableting of anti-cracking tablets according to claim 1, characterized in that, In step S3, the feeding speed is 15-30 kg / h, the tableting force is 20-40 kN, and a set of tablet weight and hardness test data is collected every 30 seconds.

7. The integrated process for layered sustained-release granulation and uniform tableting of Ananasao tablets according to claim 1, characterized in that, The pretreatment parameters for the medicinal materials are as follows: Scutellaria baicalensis, Coptis chinensis, Gardenia jasminoides, and Curcuma longa are dried at 60-80℃ for 16-20 hours, with a layer thickness of ≤4cm; pearl and calcined hematite are pulverized to 150-200 mesh; all medicinal powders are sterilized by moist heat at 105℃ for 45-55 minutes, with a layer thickness of ≤1.5cm.

8. The integrated process for layered sustained-release granulation and uniform tableting of anti-cracking tablets according to claim 1, characterized in that, The quality limits for the finished product are as follows: each tablet contains a total of borneol and isoborneol ≥4.4mg and menthol ≥1.9mg; the in vitro release rate is 30%~40% after 2 hours and ≥90% after 12 hours; and the arsenic salts, calculated as arsenic trioxide, meet the legal standard limits.

9. The integrated process for layered sustained-release granulation and uniform tableting of anti-cracking tablets according to claim 1, characterized in that, The entire production line is constructed by modifying a conventional fluidized bed granulator and a rotary tablet press by adding a fluidized coating module and an online detection module.

10. The integrated process for layered sustained-release granulation and uniform tableting of anti-cracking tablets according to claim 1, characterized in that, The waste materials generated during the granulation and tableting processes are collected in a unified manner and then recycled and reused in accordance with the formulation production process specifications.

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