An integrated preparation process for microencapsulation and synchronous granulation of volatile components of anma

Abstract

This invention belongs to the field of industrial production technology of traditional Chinese medicine compound preparations. It provides an integrated preparation process for microencapsulation and simultaneous granulation of volatile components of menthol, including the following steps: microcapsule preparation, simultaneous wet granulation, and closed-loop layered mixing and molding. Microcapsules containing borneol and menthol are prepared using the original starch and sucrose of the preparation as wall materials. The microcapsule suspension directly replaces the binder for simultaneous granulation. It is equipped with a compartmentalized negative pressure feeding system. One front-end production line can be adapted to the production of tablet and pill intermediates, eliminating the ethanol spraying and moistening processes. This invention improves the uniformity of finished product content, reduces the risk of occupational exposure to toxic dust, shortens the production cycle, and can be implemented by modifying conventional equipment. The quality of the finished product meets legal standards and has multiple advantages such as stable quality, safe production, and controllable cost.

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 preparation process for microencapsulation and simultaneous granulation of volatile components of Annao. Background Technology

[0002] For example, Chinese patent (publication number: CN1074376A) discloses Annao Pills, which fully discloses the prescription of fifteen medicinal materials for Annao Pills, as well as the complete traditional preparation process of "purifying and pulverizing medicinal materials, wet granulation and drying, dissolving borneol and menthol in ethanol and spraying it onto the granules, sealing and moistening for 2 hours, and then mixing and making pills". This is the basic production process with the most disclosed technical features and the most widespread industrial application among similar products in this field. Subsequent related technologies mainly focus on the quality testing methods and packaging structure optimization of this product. There are also a few scattered improvement schemes for single volatile oil encapsulation and ordinary sealed mixing, but there is still no complete preparation process that systematically couples microcapsule encapsulation and aroma locking, simultaneous granulation, sealed control of toxic dust, and integrated production of dual dosage forms.

[0003] This traditional process still suffers from four unavoidable technical defects in actual industrial-scale production:

[0004] Poor retention of volatile components and long production cycle: The use of ethanol solvent spraying and surface adsorption to load borneol and menthol results in continuous release of volatile components during drying, transportation and total mixing, leading to a high overall loss rate in large-scale production and large fluctuations in batch uniformity of finished product content; the process is forced to include a 2-hour soaking process, which occupies cleanroom production space and capacity, and the large amount of ethanol solvent used results in high costs for explosion-proof control in the workshop.

[0005] The process is segmented and fragmented, with high risk of cross-contamination due to open-air transfer: The preparation of adhesives, wet granulation, spraying of volatile liquids, humidification and settling, and total mixing are set up as multiple independent processes. Materials rely on open clean containers for transfer, which increases the risk of cross-contamination between different batches of materials. Each process requires separate cleaning and process verification, resulting in long production turnaround times per batch, high labor and energy costs, and insufficient uniformity of granule formation.

[0006] The control of toxic mineral drug feeding is lax, resulting in dual risks to occupational health and finished product quality: the prescription contains two types of ultrafine toxic mineral powders, cinnabar and realgar, and there is no special feeding control structure. The traditional manual open feeding mode has no dust collection device, and the concentration of heavy metals in the workshop air is likely to exceed the occupational health limit, resulting in a high risk of occupational exposure for operators; manual feeding makes it difficult to achieve uniform dispersion of mineral drugs, and the content of arsenic and mercury in the finished product is likely to be close to the legal limit, resulting in insufficient quality and safety margin.

[0007] Covering only a single pill dosage form, its industrial adaptability is insufficient: only the preparation process of Annao Pill is disclosed. In actual production, Annao Tablets and Annao Pills require two independent granulation and mixing production lines, which doubles the workload of factory space, equipment procurement and maintenance, and process verification. Two independent operating procedures increase the probability of human error, making production and quality control management more complex and the overall production cost of enterprises higher.

[0008] Therefore, an integrated preparation process for the microencapsulation and simultaneous granulation of the volatile components of menthol is needed to solve the above problems. Summary of the Invention

[0009] The purpose of this invention is to provide an integrated preparation process for the microencapsulation and simultaneous granulation of volatile components of menthol to solve the problems mentioned in the background art.

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

[0011] A microencapsulation and simultaneous granulation integrated preparation process for the volatile components of menthol includes the following steps:

[0012] S1. Microcapsule preparation: Starch and sucrose, granulation excipients, are mixed and heated to gelatinize and form a water-soluble wall material. After cooling, a mixture of borneol and menthol ethanol is added and homogenized and emulsified at low temperature to obtain a microcapsule suspension with a particle size of 5-20 μm.

[0013] S2, Simultaneous wet granulation: The mixed powder of Annao obtained by legal pretreatment is put into the wet equipment for dry mixing for 0.8 to 1.2 min, and the microcapsule suspension obtained by S1 is introduced to replace the starch binder for wet mixing for 45 to 60 s. Wet granules are prepared by passing through a 14 to 18 mesh sieve and boiling dry at 70 to 80℃ for 50 to 60 min.

[0014] S3. Closed-loop layered mixing: Herbs, precious medicinal materials, cinnabar and realgar are fed into three closed-loop silos, equipped with negative pressure dust collection pipelines, and layered equal-volume closed-loop mixing for 0.8 to 1.2 hours. The mixed materials are discharged in two closed loops.

[0015] S4. Molding and processing: One batch of materials is compressed to prepare film-coated tablets, and the other batch of materials is combined with refined honey to prepare small honey pills;

[0016] All medicinal materials are selected, cleaned, dried, and sterilized using legally mandated process parameters. The entire material pipeline is used for closed-loop transportation, eliminating the separate ethanol spraying and soaking / resting processes.

[0017] This solution sequentially sets up four coupled processes: microcapsule preparation, simultaneous wet granulation, closed-loop layered mixing, and dual-dosage form molding. It uses only the original excipients of the formulation to construct the microscopic aroma-locking coating layer. The entire process uses closed pipelines to transport materials. One front-end preparation system can output tablets and honey pill intermediates respectively, which can alleviate various defects of traditional processes from multiple dimensions.

[0018] Further technical solutions: S1 uses only the original starch and sucrose of the formulation as microcapsule wall materials, without adding exogenous polymeric excipients. The microcapsule suspension does not need to be dried independently and is directly and sealed to the wet mixing equipment.

[0019] This step relies on the pre-formulated molding excipients to construct the encapsulation carrier, eliminating the need for additional polymer materials with questionable compliance, thus reducing the workload related to drug registration and application; it also eliminates the separate spray drying section for microcapsules, which can appropriately shorten the overall production turnaround time, and the closed pipeline transportation can also reduce the probability of premature loss of volatile components.

[0020] Further technical solution: The microcapsule wall structure remains intact in the S2 boiling drying zone, and the dried whole granules and bagged fine powder are sent together to the S3 mixing process without the need for static soaking.

[0021] This step fully follows the temperature and time control range of the standard granulation method. The coating film can withstand the hot air environment and will not cause large-area rupture. Simultaneously recovering the fine powder from the dried bag and participating in the total mixing helps to improve the composition uniformity of the entire batch of materials. By eliminating the forced wetting step, the time occupied in the clean room can also be reduced.

[0022] Further technical solutions: Pretreatment parameters for the mixed brain medicine: 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 through a 150-200 mesh sieve, and all powders are sterilized by moist heat at 105℃ for 45-55 minutes, with a layer thickness of ≤1.5cm.

[0023] The pretreatment, sterilization, and pulverization of medicinal materials all follow the legally prescribed range parameters. The basic quality control standards for raw materials have not been significantly changed, the quality baseline of intermediates remains stable, and most of the company's original process validation data can be used. The validation workload caused by process changes is relatively small.

[0024] Further technical solutions: The S3 is equipped with three sets of independent sealed feeding bins, corresponding to common herbs, precious medicinal materials, and toxic minerals such as cinnabar and realgar, respectively. Each feeding bin is matched with an independent negative pressure dust collection branch pipe to continuously collect ultrafine mineral dust.

[0025] Ordinary medicinal materials, precious medicinal materials, and toxic minerals can be physically isolated at the source of feeding. With the addition of independent negative pressure pipelines, ultrafine mineral dust can be adsorbed in real time, making it easier to maintain the concentration of heavy metals in the workshop air within the occupational standard range, which meets the control requirements of GMP for the production of toxic medicinal materials.

[0026] Further technical solutions: S3 layered feeding follows the legally required equal increment order, and the mixed materials are diverted through dual closed pipelines. The two pipelines can be opened and switched independently for conveying.

[0027] The layered automated feeding strictly follows the equal-quantity incremental mixing logic, which can reduce the risk of local mineral enrichment caused by manual operation; the dual-path closed discharge pipeline does not require adjustment of the front-end granulation and mixing equipment, and can supply two molding sections separately by simply switching the pipeline, thus improving the versatility of the production line.

[0028] Further technical solutions: S4 tablet forming range: single tablet weight 4.850~5.150g, film-coated tablet weight warning range 0.4800~0.5180g, correction range 0.4775~0.5225g; honey pill forming range: refined honey 116~118℃, warm honey 80~100℃, medicinal honey ratio 0.7~0.9, resting time 20~30min, total weight of 11 pills 3g.

[0029] Both dosage forms are manufactured using legally defined weight, temperature, and ratio control ranges. No adjustments are needed to the front-end preparation process; only the discharge pipeline needs to be switched to produce tablet and honey pill intermediates respectively. The quality control standards for the molding section do not need to be redefined and can be adapted to the company's existing quality inspection system.

[0030] Further technical solutions: Finished product testing limit range: Total content of borneol and isoborneol per tablet of Annao tablets ≥ 4.4 mg, menthol ≥ 1.9 mg; Borneol per 1g of Annao pills ≥ 8.0 mg, menthol ≥ 3.0 mg, and the arsenic spot color of arsenic trioxide is not deeper than the standard arsenic spot.

[0031] The gas chromatography and arsenic salt testing items and judgment limits for finished products are completely consistent with the statutory quality standards. Existing testing equipment and operating procedures of enterprises do not need to be modified. The test data can be directly used for the release judgment of finished products, and the transformation cost of the quality inspection process is relatively low.

[0032] Further technical solutions: The entire process is implemented by modifying conventional wet granulation machines and two-dimensional closed mixers, without the need for customized non-standard special production equipment.

[0033] Conventional Chinese medicine granulation and mixing equipment on the market can be easily adapted to this step-by-step process by simply modifying the pipelines and feeding hoppers. There is no need to invest a large amount of money to customize non-standard special equipment. Small and medium-sized pharmaceutical companies can complete the production line technical transformation at low cost and the production cycle is relatively short.

[0034] Further technical solutions: The crushing and granulation waste generated during the production process will be uniformly recycled and reused in accordance with the company's existing waste management standards.

[0035] The process of reusing the tailings generated in the crushing and granulation stages follows the company's mature management system, without the need for new tailings disposal procedures. This can improve the overall utilization rate of materials and slightly reduce the loss of raw materials in production.

[0036] Compared with the prior art, the beneficial effects of the present invention are:

[0037] This invention improves the retention of volatile components and shortens the overall production cycle: by encapsulating borneol and menthol in situ with starch-sucrose microcapsules, the volatile components are embedded inside the particles to isolate them from hot air and air, effectively reducing volatilization loss during the production process and improving the uniformity of the finished product content; the separate spraying and forced wetting process of ethanol is eliminated, reducing the amount of ethanol used, shortening the production time of a single batch, and reducing the pressure of explosion-proof control in the workshop.

[0038] This invention enables continuous and closed-loop operation of the process, reducing the risk of cross-contamination: the microcapsule suspension directly replaces the traditional granulation binder, and granulation and aroma locking are completed simultaneously, reducing multiple open transfer links; it also reduces the frequency of equipment cleaning, reduces the overall energy consumption and labor costs of single-batch production, optimizes the internal forming quality of granules, and reduces defective products such as tablet cracking and pill powder shedding.

[0039] This invention achieves closed-loop management of toxic dust, improving production compliance and finished product safety: three types of materials are fed into closed compartments with independent negative pressure dust collection pipes, capturing ultrafine mineral dust from the source of feeding, effectively reducing the concentration of heavy metals in the workshop air, meeting GMP requirements for the production and control of toxic medicinal materials, and reducing the risk of occupational exposure for operators; layered and equal feeding ensures uniform dispersion of mineral medicines, reducing fluctuations in arsenic and mercury content in the finished product, and increasing the quality and safety margin;

[0040] This invention provides a single front-end production line that can accommodate two dosage forms, improving industrial adaptability and reducing overall investment: the front-end microcapsule preparation, granulation, and mixing processes are completely shared, and the tablet and pill forming sections are supplied separately only by switching the discharge pipeline, reducing redundant investment in plant and equipment; unified operating procedures and quality control standards reduce production management and process validation costs, and improve batch-to-batch quality consistency between different dosage forms.

[0041] 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

[0042] Figure 1 This is a schematic diagram of the overall process of the present invention. Detailed Implementation

[0043] 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.

[0044] Example 1

[0045] like Figure 1As shown, this embodiment of the invention provides an integrated preparation process for the microencapsulation and simultaneous granulation of volatile components of Annauer, which fully executes the four core processes of microencapsulation preparation, simultaneous wet granulation, closed-layer mixing, and molding. It covers all equipment structure, process parameters, quality control standards, equipment selection, and waste material management requirements. All process parameters are tested in multiple parallel sets, and the corresponding production effects are fully detected.

[0046] S1 Microcapsule Preparation: Using only the existing starch and sucrose from the formulation as wall materials, without adding any exogenous polymeric excipients, three microcapsule suspensions with different particle sizes were prepared by adjusting the homogenization speed: The low particle size group, with reduced homogenization speed, produced a microcapsule suspension with an average particle size of 5 μm, exhibiting fine particles, good dispersibility, and a relatively thin wall film thickness; the conventional particle size group, using conventional homogenization speed, produced a microcapsule suspension with an average particle size of 12 μm, exhibiting uniform particle size distribution and a moderate wall film thickness; the high particle size group, with increased homogenization speed, produced a microcapsule suspension with an average particle size of 20 μm, exhibiting larger particles and a thicker wall film. All three suspensions were directly transported to a wet mixing granulator via a closed pipeline without independent drying processes, ensuring no open exposure throughout the process. Subsequent finished product testing showed that the RSD of volatile oil content within the batch was 3.1% for the 5 μm group, 2.5% for the 12 μm group, and 2.8% for the 20 μm group. All three groups met the production uniformity requirements, with the conventional particle size group showing relatively better overall performance.

[0047] S2 Medicinal Herb Pretreatment: Scutellaria baicalensis, Coptis chinensis, Gardenia jasminoides, and Curcuma longa were selected, cleaned by spraying at room temperature, and then dried in three groups: Low-temperature drying group: 60℃ for 20 hours, with a 4cm layer thickness, preserving the color of the herbs and meeting moisture content standards; Medium-temperature drying group: 70℃ for 18 hours, with a 3cm layer thickness, achieving a balance between drying efficiency and herb quality; High-temperature drying group: 80℃ for 16 hours, with a 2cm layer thickness, achieving rapid drying without scorching or deterioration. Pearls were roasted over medium heat and then pulverized with calcined hematite in three groups, passing through 150-mesh, 180-mesh, and 200-mesh sieves. All powdered herbs were then subjected to 105℃ moist heat sterilization in three groups: 45min, 50min, and 55min, with a layer thickness ≤1.5cm in each group. Testing showed that the microbial limits of all three groups of herbs met the standards, with the medium-temperature drying + 50min sterilization group showing the best balance between sterilization effect and retention of active ingredients.

[0048] S2 Simultaneous Wet Granulation: Three groups of pre-treated drug powders were fed into a wet mixing granulator, with corresponding dry mixing times of 0.8 min, 1.0 min, and 1.2 min. Microcapsule suspensions of the corresponding particle size were introduced to replace the traditional starch binder, with corresponding wet mixing times of 45 s, 52 s, and 60 s. The soft material was processed into wet granules through 14-mesh, 16-mesh, and 18-mesh swirl sieves. Fluidized bed drying was performed in three groups: 70℃ for 60 min, 75℃ for 55 min, and 80℃ for 50 min. During the drying process, the microcapsule wall structure remained intact without large-area damage. Fine powder collected in the drying bag was combined with whole granules and sent to the final mixing process; no soaking or settling step was included in the entire process. Tests showed that the overall retention rate of volatile oil in the 70℃ group was 96.2%, in the 75℃ group it was 94.8%, and in the 80℃ group it was 92.1%. All three groups were far higher than the level of traditional processes. The lower the temperature, the higher the retention rate. The 80℃ working condition can still meet the quality requirements. The uniformity of the content of the whole batch of materials after the fine powder was combined was improved by about 12% compared with the whole granulation alone.

[0049] S3 Closed-Loop Layered Mixing: Three independent closed feeding hoppers are set up to feed ordinary herbal powder, precious and rare medicinal materials, and toxic mineral powders such as cinnabar and realgar, respectively. Each feeding hopper is equipped with an independent negative pressure dust collection branch pipe to continuously collect the ultrafine mineral dust generated during feeding. Layered feeding strictly follows the legally required equal-quantity incremental order, with three mixing times: 0.8h, 1.0h, and 1.2h. After mixing, the materials are diverted through dual closed pipelines, with tablet conveying branch pipes and honey pill conveying branch pipes that can be independently opened and switched. Tests show that the RSD of mineral drug content is 4.2% in the 0.8h group, 2.8% in the 1.0h group, and 2.5% in the 1.2h group, all three groups meeting the uniformity standard; with the negative pressure branch pipes fully open, the concentration of arsenic and mercury dust in the workshop air decreases by approximately 85%, stably meeting the occupational health limits.

[0050] S4 Forming Process: ① Tablet Branch: Uncoated tablets were divided into three groups with controlled single-tablet weights: 4.850g, 5.000g, and 5.150g; film-coated tablet weights strictly adhered to the warning range of 0.4800~0.5180g and the correction range of 0.4775~0.5225g. Finished product testing showed that the total content of borneol and isoborneol per tablet in all three groups of samples was at least 4.51mg, and the minimum content of menthol was 2.01mg, all meeting the legal limits; the arsenic trioxide spots were all significantly lighter in color than the standard arsenic spots. ② Honey pill preparation: Honey refining was conducted at three different temperatures: 116℃, 117℃, and 118℃; warming honey was conducted at three different temperatures: 80℃, 90℃, and 100℃; the medicinal honey ratio was set at three different ratios: 0.7, 0.8, and 0.9; and the soaking time was set at three different times: 20 min, 25 min, and 30 min. This yielded small honey pills weighing 3g each (11 pills per group). Finished product testing showed that the lowest concentration of borneol per 1g was 8.12mg, and the lowest concentration of menthol per 1g was 3.05mg, both meeting the legal limits. The highest moisture content was 13.5%, and the longest dissolution time was 49min, both meeting the standard requirements.

[0051] The entire set of production equipment is modified from existing conventional wet granulation machines and two-dimensional closed mixers by adding closed pipelines, feeding silos, and negative pressure branch pipes, without the need for customized non-standard special equipment; the crushed tailings and granulated fine powder tailings generated during the production process are all uniformly recycled and reused in accordance with the company's existing tailings management specifications, and complete production records are kept.

[0052] In this embodiment, all process parameters under different operating conditions were fully implemented, and all groups of gradient samples met the legal quality standards. The material uniformity and volatile oil retention of the batches with conventional parameters were relatively better, which fully verified that the process parameter range has the feasibility of stable industrial production.

[0053] Example 2

[0054] The difference between this embodiment and Embodiment 1 is that all other processes, equipment, and process parameters are selected from commonly used values ​​in conventional production. Only the microcapsule emulsion particle size is controlled to 5μm. No exogenous polymer wall materials are introduced throughout the process. The microcapsule suspension is not dried separately but is transported to the wet granulation equipment through a closed pipeline. The pretreatment of Annao medicinal materials uniformly adopts the following methods: drying at 70℃ for 18 hours, sterilization for 50 minutes, and pulverization through an 180-mesh sieve; dry mixing for 1 minute, wet mixing for 52 seconds, granulation through a 16-mesh sieve, drying at 75℃ for 55 minutes, and the dried fine powder and whole granules are sent together to the total mixing section without any wetting. Three sets of closed feeding silos are equipped with negative pressure branch pipes and operate continuously, mixing in equal amounts in layers for 1 hour. The discharge pipeline is switched to the tablet branch. The weight of the uncoated tablets is controlled at 5.000g, and the film coating is subject to the full set of weight control ranges.

[0055] In this embodiment, the gas chromatography analysis of the finished product showed that each tablet contained a total of 4.51 mg of borneol and isoborneol, and 2.02 mg of menthol, with a batch-to-batch relative standard deviation of approximately 4.1. No significant mineral dust was observed floating during the material feeding process in the workshop. The fine powder ratio was slightly lower than that of traditional processes, and the arsenic trioxide arsenic spot color was much lighter than the standard arsenic spot. The entire set of equipment consisted of modified conventional formulation equipment, and the production waste was normally recycled and reused. The low-particle-size microcapsules exhibited better dispersibility. Although the film thickness was slightly thinner and the volatile oil retention rate was slightly lower than that of the conventional particle size group, it could still stably produce Annatinoa film-coated tablets that met legal standards, verifying that this particle size parameter has practical production adaptability.

[0056] Example 3

[0057] The difference between this embodiment and Embodiment 1 is that the microcapsule particle size is selected as 12μm, and all other pretreatment, total mixing, and molding parameters are all based on conventional production values. Only the boiling drying temperature is adjusted to 80℃ and the drying time is fixed at 50min, while the other granulation and sieving conditions remain unchanged. The medicinal materials are dried at 70℃ for 18 hours, sterilized for 50 minutes, dry mixed for 1 minute, wet mixed for 52 seconds, granulated through a 16-mesh sieve, and the dried fine powder and granules are combined in a cloth bag and sent to the total mixing process without any soaking or standing. The independent sealed feeding hopper and negative pressure dust extraction branch pipe are kept open throughout the process, and the mixture is mixed in equal amounts in layers for 1 hour. The material is then switched to the honey pill diversion pipeline. The honey is refined at 117℃, warmed at 90℃, and the ratio of medicinal materials to honey is 0.8. After resting for 25 minutes, small honey pills weighing 3g each are obtained with 11 pills.

[0058] In this embodiment, each 1g of the finished product contains 8.21mg of borneol, 3.12mg of menthol, and 13.1% moisture, with a dispersibility time of 48min. After high-temperature drying, the microcapsule walls showed no large-scale damage, with only a very small number of microcapsules exhibiting slight deformation. The loss of volatile components was within a controllable range, arsenic salt testing met standards, the entire set of conventionally modified equipment operated stably, and the tailings were recycled according to specifications. This verifies that the coating structure can remain intact under this drying temperature condition, meeting the subsequent molding requirements without the need for soaking, demonstrating the effect of fine powder consolidation on improving material uniformity.

[0059] Example 4

[0060] The difference between this embodiment and Embodiment 1 is that the microcapsule, granulation, mixing, and molding processes all use conventional production values. The only adjustment is to use pretreatment drying conditions of 60℃ for 20 hours, a spreading thickness of 4 cm, and to pulverize pearl and calcined hematite through a 150-mesh sieve. All drug powders are sterilized at 105℃ for 45 minutes with a spreading thickness of 1.5 cm. All other process parameters remain unchanged. 12μm microcapsules are prepared without exogenous excipients; the suspension is directly fed to the granulator. Dry mixing takes 1 minute, wet mixing 52 seconds, and is sieved through a 16-mesh sieve. Drying at 75℃ for 55 minutes is performed, and all fine powders are incorporated into the total mixing. The closed-compartment, negative pressure pipeline, and 1-hour stratified mixing system operate normally, and the material is discharged to the tablet molding section. The uncoated tablets weigh 5.000g, and the film coating adheres to weight control standards.

[0061] In this embodiment, each finished tablet contains 4.72 mg of borneol + isoborneol and 2.10 mg of menthol, with an inter-batch RSD of approximately 3.2, and passes the arsenic trioxide test. The medicinal material properties and extract indicators all meet legal requirements. Low-temperature, long-term drying can retain more heat-sensitive components of the medicinal material without affecting the subsequent microcapsule granulation effect. The entire equipment and waste material management method remain unchanged. This verifies that the pretreatment parameter range is feasible for production, and the boundary parameters can stably produce qualified intermediates.

[0062] Example 5

[0063] The difference between this embodiment and Embodiment 1 is that: microcapsulation, granulation, pretreatment, and molding all use conventional production values; only the independent negative pressure dust extraction pipes are removed. Cinnabar and realgar are still manually added in a dedicated sealed feeding hopper, without a dust recovery device. The other aspects, such as layered feeding, mixing time, and dual-channel discharge structure, remain unchanged. 12μm microcapsules are used, with no external excipients. Drying is performed at 75℃ for 55 minutes, with all fine powders participating in the overall mixing; layered equal-volume mixing is performed for 1 hour, and the material is discharged to the tablet forming section; 5.000g of unprocessed tablets are produced, and the volatile oil content of the finished product is qualified. The entire set of equipment and waste material management methods remain unchanged.

[0064] In this embodiment, fine orange-yellow mineral dust was observed floating in the workshop feeding area, and the heavy metal detection value in the workshop air was close to the occupational control limit. The residual amount of arsenic trioxide in the finished product was significantly reduced compared to Example 1. Although qualified finished products could still be produced, the production compliance and occupational protection level were significantly reduced. By comparing with Example 1, the technical value of the independent feeding silo with the negative pressure dust collection branch pipe can be intuitively verified. The lack of a negative pressure structure will bring obvious production safety and finished product quality hazards, demonstrating the actual role of the negative pressure branch pipe in controlling toxic dust.

[0065] Example 6

[0066] The difference between this embodiment and Embodiment 1 is that: all processes of microcapsulation, granulation, and molding are carried out under conventional production conditions; the closed-loop layered mixing time is adjusted to 0.8 hours; the negative pressure dust extraction branch pipe is normally opened; the three types of medicinal materials are still separately sealed and fed in equal amounts in layers; and the dual-outlet pipeline is switched to the tablet branch. The microcapsules are 12μm in size and dried at 75℃ for 55 minutes; all fine powders are included in the total mixing; the unprocessed tablets weigh 5.000g; the entire set of conventionally modified equipment operates normally; and the waste materials are uniformly recycled and reused.

[0067] In this embodiment, the difference in mineral content at different sampling points of the finished product increased slightly, and the intra-batch uniformity was weaker than that of the 1h and 1.2h mixing groups, but it was still within the fluctuation range allowed by legal standards. The layered equal-volume feeding structure can effectively reduce the impact of the decrease in uniformity caused by the shortened mixing time. It can be verified that the mixing time parameter can complete the preparation of qualified intermediates, and the layered equal-volume feeding structure plays a key role in the uniform dispersion of minerals, demonstrating the flexibility of the dual-channel switchable discharge structure.

[0068] Example 7

[0069] The difference between this embodiment and Embodiment 1 is that the entire process of microcapsulation, granulation, and total mixing adopts conventional production conditions. Only the honey pill delivery branch is turned on and the tablet distribution pipeline is turned off. The entire front-end microcapsulation, granulation, and closed total mixing equipment does not require any parameter adjustments. Only the discharge valve is switched to produce the intermediate of Annao small honey pills. 12μm microcapsules are prepared and dried at 75℃ for 55min. All fine powder is added to the total mixture. The closed negative pressure and 1h layered mixing are carried out normally. The honey is refined at 117℃, warmed at 90℃, and the ratio of medicine to honey is 0.8. After resting for 25min, small honey pills of 3g each with 11 pills are obtained. The subsequent wax sealing and transfer printing processes are carried out according to the legal procedures.

[0070] In this embodiment, each 1g of the finished product contains 8.76mg of borneol, 3.31mg of menthol, 13.2% moisture, and a dissolution time of 42 minutes, meeting all standards. No adjustments to any front-end equipment are required; only pipeline switching is needed to achieve continuous large-scale production of a single dosage form, while equipment modifications and waste material recycling rules remain unchanged. This verifies the practical advantages of the independently switchable dual-path discharge structure, demonstrating that a single front-end process can be flexibly adapted to continuous production of a single dosage form, showcasing the industrialization advantages of a universal dual-dosage design.

[0071] Example 8

[0072] The difference between this embodiment and Embodiment 1 is that the parameters for the pretreatment of medicinal materials and the forming process are all selected from conventional production values. The integrated coupling of the whole process is completely eliminated, and the traditional segmented production process is adopted: starch binder is prepared separately, borneol and menthol are dissolved in ethanol after the granules are dried and sprayed manually with an open nozzle. After spraying, the mixture is forced to be sealed and moistened for 2 hours. The sealed feeding silo for cinnabar and realgar is eliminated, and the mixture is manually fed into the mixing equipment with an open nozzle. There is no negative pressure dust recovery pipeline and no automatic feeding mechanism for layered equal quantities.

[0073] In this embodiment, the total content of borneol and isoborneol in each finished tablet is only 4.02 mg, lower than the legal minimum limit. Menthol content of 1.51 mg also fails to meet the standard. The batch-to-batch relative standard deviation is approximately 9.6, and the complete flow time of a single batch of intermediates reaches 32 hours. A large amount of ultrafine mineral dust is visible floating in the workshop, and approximately 12% of batches fail the volatile oil test. Although the equipment is conventional granulation equipment, the traditional segmented mode cannot achieve integrated closed production. The blank control visually highlights the multiple improvement effects brought about by the entire progressive coupling technology, indirectly demonstrating the creativity and practical value of all the technical features of this process, and verifying the actual role of the triple progressive process in solving common pain points in the industry.

[0074] 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. A process for the integrated preparation of volatile components of menthol through microencapsulation and simultaneous granulation, characterized in that, Includes the following steps: S1. Microcapsule preparation: Starch and sucrose, granulation excipients, are mixed and heated to gelatinize and form a water-soluble wall material. After cooling, a mixture of borneol and menthol ethanol is added and homogenized and emulsified at low temperature to obtain a microcapsule suspension with a particle size of 5-20 μm. S2, Simultaneous wet granulation: The mixed powder of Annao obtained by legal pretreatment is put into the wet equipment for dry mixing for 0.8 to 1.2 min, and the microcapsule suspension obtained by S1 is introduced to replace the starch binder for wet mixing for 45 to 60 s. Wet granules are prepared by passing through a 14 to 18 mesh sieve and boiling dry at 70 to 80℃ for 50 to 60 min. S3. Closed-loop layered mixing: Herbs, precious medicinal materials, cinnabar and realgar are fed into three closed-loop silos, equipped with negative pressure dust collection pipelines, and layered equal-volume closed-loop mixing for 0.8 to 1.2 hours. The mixed materials are discharged in two closed loops. S4. Molding and processing: One batch of materials is compressed to prepare film-coated tablets, and the other batch of materials is combined with refined honey to prepare small honey pills; All medicinal materials are selected, cleaned, dried, and sterilized using legally mandated process parameters. The entire material pipeline is used for closed-loop transportation, eliminating the separate ethanol spraying and soaking / resting processes.

2. The integrated preparation process for microencapsulation and simultaneous granulation of volatile components of menthol according to claim 1, characterized in that, S1 uses only the original starch and sucrose from the formulation as the microcapsule wall material, without adding any exogenous polymeric excipients. The microcapsule suspension does not need to be dried independently and is directly and sealed to the wet mixing equipment.

3. The integrated preparation process for microencapsulation and simultaneous granulation of volatile components of menthol according to claim 1, characterized in that, The microcapsule wall structure remains intact within the S2 boiling drying zone. The dried whole granules and fine powder from the cloth bag are then fed into the S3 mixing process without the need for a static soaking process.

4. The integrated preparation process for microencapsulation and simultaneous granulation of volatile components of menthol according to claim 1, characterized in that, Pretreatment parameters for the mixed brain medicine: 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 through a 150-200 mesh sieve, and all powders are sterilized by moist heat at 105℃ for 45-55 minutes, with a layer thickness of ≤1.5cm.

5. The integrated preparation process for microencapsulation and simultaneous granulation of volatile components of menthol according to claim 1, characterized in that, The S3 is equipped with three independent sealed feeding chambers, corresponding to common herbs, precious medicinal materials, and toxic minerals such as cinnabar and realgar. Each feeding chamber is matched with an independent negative pressure dust collection branch pipe to continuously collect ultrafine mineral dust.

6. The integrated preparation process for microencapsulation and simultaneous granulation of volatile components of menthol according to claim 1, characterized in that, The S3 layered feeding follows the legally mandated equal-quantity incremental order. The mixed materials are diverted through dual closed pipelines, and the two pipelines can be opened and switched independently for conveying.

7. The integrated preparation process for microencapsulation and simultaneous granulation of volatile components of menthol according to claim 1, characterized in that, S4 tablet forming range: single tablet weight 4.850~5.150g, film-coated tablet weight warning range 0.4800~0.5180g, correction range 0.4775~0.5225g; honey pill forming range: refined honey 116~118℃, warm honey 80~100℃, medicine-to-honey ratio 0.7~0.9, resting time 20~30min, total weight of 11 pills 3g.

8. The integrated preparation process for microencapsulation and simultaneous granulation of volatile components of menthol according to claim 1, characterized in that, Finished product testing limit range: For Annao tablets, the total content of borneol and isoborneol per tablet is ≥4.4mg, and menthol is ≥1.9mg; for Annao pills, the content of borneol per 1g is ≥8.0mg, menthol is ≥3.0mg, and the arsenic spot color of arsenic trioxide is not deeper than that of standard arsenic spot.

9. The integrated preparation process for microencapsulation and simultaneous granulation of volatile components of menthol according to claim 1, characterized in that, The entire process relies on the modification and implementation of conventional wet granulation machines and two-dimensional closed mixers, without the need for customized non-standard special production equipment.

10. The integrated preparation process for microencapsulation and simultaneous granulation of volatile components of menthol according to claim 1, characterized in that, The crushed and granulated waste generated during the production process shall be recycled and reused in accordance with the company’s existing waste management standards.

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