Segmented extraction and alcohol precipitation combined preparation process of compound honeysuckle granules

Abstract

The invention relates to the field of pharmaceutics, in particular to a staged extraction and alcohol precipitation combined preparation process of compound honeysuckle granules, which comprises the following steps: slowly distilling honeysuckle and fructus forsythiae at low temperature, collecting volatile oil and first aromatic water in a staged manner based on the concentration of the volatile oil, and performing feedback regulation on distillation pressure and distillation temperature based on the liquid state characteristics of condensate in the process, determining a distillation end point according to the volatile oil concentration and collecting a first extracting solution; mixing qualified first aromatic water based on aromatic water relative density evaluation to obtain second aromatic water; dynamically and circularly extracting scutellaria baicalensis and dregs by using water and second aromatic water, feeding back and adjusting the extraction temperature and the circulating frequency on the basis of impurity state parameters, and collecting a second extracting solution; merging the extracting solutions, performing alcohol precipitation, and performing vacuum concentration to obtain extract; uniformly mixing the segmented volatile oil, the extract, a drying auxiliary agent and a flavoring agent to obtain a soft material; and granulating, drying and finishing to obtain the granules. According to the method, volatile oil recovery, solvent internal circulation, impurity look-ahead inhibition and low-heat taste correction are realized, and the yield consistency is remarkably improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a combined process of fractional extraction and alcohol precipitation for preparing compound honeysuckle granules. Background Technology

[0002] Compound honeysuckle granules are composed of three traditional Chinese medicines: honeysuckle, forsythia, and scutellaria. They possess the effects of clearing heat and detoxifying, cooling the blood and reducing swelling, and are widely used clinically for symptoms such as wind-heat colds, pharyngitis, and tonsillitis. Current preparation processes typically follow the methods described in national drug standards: honeysuckle is distilled with water to collect the distillate; the residue is decocted, filtered, and the filtrate is concentrated and then precipitated with alcohol; scutellaria and forsythia are decocted with water, filtered, concentrated, and then precipitated with alcohol; the extracts of both are combined, and then granulated with honeysuckle distillate and excipients. However, this process still has room for improvement in actual production: on the one hand, volatile oil components are easily lost during high-temperature extraction and subsequent processes, resulting in insufficient retention of the natural medicinal aroma; on the other hand, the flavoring of the preparation relies heavily on sucrose, resulting in a high sugar content, which is insufficient to meet the needs of low-sugar medication, while the bitterness masking effect in sugar-free products is not yet ideal.

[0003] Chinese invention patent publication number CN118436709A discloses a preparation process for compound honeysuckle granules. The raw materials are honeysuckle, forsythia, and scutellaria, as well as a number of excipients. 1) Honeysuckle is decocted twice under reduced pressure to obtain an extract; the extract is concentrated under reduced pressure into a thick paste, and after the paste cools down, ethanol is added, and stirring continues after the ethanol is added; the paste is allowed to stand, filtered, and the filtrate is concentrated to a final paste; 2) Scutellaria and forsythia are selected and weighed, vacuum-sealed, and steam-moistened; they are decocted twice under reduced pressure to obtain an extract; the extract is concentrated under reduced pressure into a thick paste, and after the paste cools down, ethanol is added, and stirring continues after the ethanol is added; the paste is allowed to stand, filtered, and the filtrate is concentrated to a final paste; 3) The prepared honeysuckle thick paste, scutellaria and forsythia thick paste, and excipients are mixed, and honeysuckle distillate is added. The mixture is then granulated using a wet granulation machine, sieved, and boiled dry to form drug granules. However, the following problems still exist: 1. Severe loss of volatile oil and natural medicinal aroma: Although honeysuckle distillate was collected, it was only added back as a wetting agent for granulation. The volatile oil was not separated, enriched and stabilized. A large amount of volatile active ingredients were lost in subsequent processes, resulting in a weak medicinal aroma in the product.

[0004] 2. The flavoring solutions are crude: the sugar-free formulations only use an equal amount of sucralose as a substitute, and a single high-intensity sweetener cannot effectively mask the persistent bitterness of Scutellaria baicalensis and Forsythia suspensa; the sugar-containing formulations still rely on a high proportion of sucrose, which contradicts the trend of reducing sugar in pharmaceuticals. A low-calorie, high-efficiency flavoring system has not been developed. Summary of the Invention

[0005] Therefore, this invention provides a combined process of segmented extraction and alcohol precipitation for compound honeysuckle granules, in order to overcome the problem of significant loss of volatile active ingredients and natural medicinal aroma during high-temperature extraction and concentration in the prior art.

[0006] To achieve the above objectives, this invention provides a combined process for the fractional extraction and alcohol precipitation of compound honeysuckle granules, comprising the following steps: Step S1: Honeysuckle raw material, forsythia and water are added to a multi-functional extraction tank for low-temperature slow distillation, and the distillate is collected in segments based on the concentration of volatile oil in the distillate. After stratification, volatile oil and first aromatic water of each segment are obtained. Step S2: During the low-temperature slow distillation process, the distillation pressure and / or distillation temperature are adjusted based on the droplet state characteristic parameters of the volatile oil in the condensate at the distillation outlet. When the distillation endpoint is reached, the first extract and the residue are collected. The droplet state characteristic parameters are determined by roundness, aspect ratio, droplet size and droplet frequency. The distillation endpoint is determined based on the volatile oil concentration. Step S3: Based on the relative density of the aromatic water, evaluate the qualification of the first aromatic water in each segment, and mix the qualified first aromatic waters to obtain the second aromatic water. Step S4: The raw material of Scutellaria baicalensis and the residue are put into a dynamic circulation extraction tank, water and the second aromatic water are added for dynamic circulation extraction, and the extraction temperature and circulation frequency are dynamically adjusted based on the impurity state parameters. The second extract is collected, wherein the impurity state parameters are determined by the polysaccharide concentration and the protein concentration. Step S5: The first extract and the second extract are put into an alcohol precipitation tank, ethanol is added for alcohol precipitation and the mixture is filtered to obtain a filtrate. The filtrate is then put into a concentrator for vacuum concentration to obtain an extract. Step S6: Mix the volatile oil, extract, drying aid, and flavoring agent of each segment evenly to obtain a soft material; Step S7: After granulation, drying and sizing of the soft material, compound honeysuckle granules are obtained.

[0007] Further, in step S1, based on the result that the volatile oil concentration is less than or equal to the first preset volatile oil concentration, it is determined to collect the first distillate; Alternatively, based on the result that the volatile oil concentration is greater than the first preset volatile oil concentration, it is determined to collect the second distillate.

[0008] Furthermore, the process of determining the droplet state characteristic parameters includes: The aspect ratio, the droplet size, and the droplet frequency are normalized respectively. The result of the normalization process is weighted and fused with the circularity.

[0009] Furthermore, in step S2, based on the result that the droplet state characteristic parameter is greater than or equal to the first preset droplet state characteristic parameter, it is determined to maintain the current distillation pressure and distillation temperature unchanged; Alternatively, based on the result that the droplet state characteristic parameter is greater than or equal to the second preset droplet state characteristic parameter and less than the first preset droplet state characteristic parameter, the distillation temperature is determined to be reduced. Alternatively, based on the result that the droplet state characteristic parameter is greater than or equal to the third preset droplet state characteristic parameter and less than the second preset droplet state characteristic parameter, the distillation pressure is determined to be reduced; Alternatively, based on the result that the droplet state characteristic parameter is less than the third preset droplet state characteristic parameter, it is determined to simultaneously reduce the distillation temperature and distillation pressure.

[0010] Furthermore, in step S2, based on the result that the volatile oil concentration is greater than or equal to the second preset volatile oil concentration, it is determined that the distillation endpoint has not been reached; Alternatively, the distillation endpoint can be determined based on the result that the volatile oil concentration is less than the second preset volatile oil concentration.

[0011] Furthermore, in step S3, based on the result that the relative density of the aromatic water is greater than or equal to the preset relative density of the aromatic water, the first aromatic water is determined to be qualified.

[0012] Furthermore, in step S4, the impurity state parameters are characterized by the weighted summation of polysaccharide concentration and protein concentration.

[0013] Further, in step S4, based on the result that the impurity state parameter is greater than or equal to the first preset impurity state parameter, it is determined to reduce the extraction temperature and simultaneously reduce the circulation frequency. Alternatively, based on the result that the impurity state parameter is greater than or equal to the second preset impurity state parameter and less than the first preset impurity state parameter, it is determined that only the extraction temperature should be reduced; Alternatively, based on the result that the impurity state parameter is less than the second preset impurity state parameter, it is determined that the extraction temperature and the circulation frequency should not be adjusted.

[0014] Furthermore, in step S6, the drying aid is one of dextrin, soluble starch, or lactose.

[0015] Furthermore, in step S6, the flavoring agent includes erythritol, sucralose, and menthol.

[0016] Compared with the prior art, the beneficial effects of the present invention are as follows: by integrating the process of segmented collection of volatile oil, reuse of aromatic water, droplet state feedback control, impurity feedback control, combined extraction liquid alcohol precipitation and low-temperature granulation, the entire process of efficient volatile oil harvesting, internal solvent recycling, prospective suppression of impurities and low-temperature molding of active ingredients is synergistically optimized, thereby solving the problem of large-scale loss of volatile active ingredients and natural medicinal fragrances during high-temperature extraction and concentration in the existing process.

[0017] Furthermore, by setting a first preset volatile oil concentration as a segmented collection threshold, the precise recovery of high-value component volatile oil is achieved, ensuring the purity of the effective components in the volatile oil. This not only preserves the aroma but also improves the batch-to-batch variability of volatile oil extraction and ensures the stability of the efficacy.

[0018] Furthermore, by constructing a weighted fusion parameter of droplet state characteristics, including roundness, aspect ratio, droplet size, and droplet frequency, the physical properties of volatile oils can be characterized. Based on this, the droplet state parameters are compared with preset thresholds to dynamically adjust the parameters during the extraction process, reducing the loss of effective components during preparation and thus further ensuring the stability of the drug efficacy.

[0019] Furthermore, by setting a second preset volatile oil concentration as the distillation endpoint criterion, the loss of effective components due to excessive extraction of medicinal materials is avoided, thereby further ensuring the stability of the efficacy.

[0020] Furthermore, by comparing the relative density of the aromatic water with a preset threshold, the qualification of the first aromatic water collected in each segment is determined, and the qualified first aromatic waters are merged. This ensures that the aromatic water retains the effective ingredients while increasing the concentration of the effective ingredients, thereby further ensuring the stability of the efficacy while retaining the aroma.

[0021] Furthermore, by constructing impurity state parameters during the dynamic cyclic extraction process to characterize the impurity content of the extract, and based on this, dynamically adjusting the extraction temperature and circulation frequency during the extraction process, the dissolution of impurities can be inhibited, thereby further ensuring the stability of the efficacy.

[0022] Furthermore, by determining the appropriate drying aids based on the properties of the extract, the molding rate of the soft material was improved. On this basis, by adding a flavoring combination of erythritol, sucralose, and menthol, the taste and flavor of the medicine were improved, thereby further ensuring the stability of the efficacy. Attached Figure Description

[0023] Figure 1 This is a flowchart illustrating the steps of a combined fractional extraction and alcohol precipitation process for preparing compound honeysuckle granules according to an embodiment of the present invention. Figure 2 This is a logic block diagram for collecting distillate according to an embodiment of the present invention; Figure 3 A logic block diagram for determining the adjustment of distillation pressure and / or distillation temperature in embodiments of the present invention; Figure 4 A logic block diagram for determining the distillation endpoint in an embodiment of the present invention; Figure 5 The following is a logic block diagram for determining the adjustment of extraction temperature and cycle frequency in an embodiment of the present invention. Detailed Implementation

[0024] To make the objectives and advantages of the present invention clearer, the present invention will be further described below with reference to embodiments; it should be understood that the specific embodiments described herein are merely for explaining the present invention and are not intended to limit the present invention.

[0025] Preferred embodiments of the present invention will now be described with reference to the accompanying drawings. Those skilled in the art should understand that these embodiments are merely illustrative of the technical principles of the present invention and are not intended to limit the scope of protection of the present invention.

[0026] Please see Figure 1 The diagram shows a flowchart of the steps involved in the combined fractional extraction and alcohol precipitation process for preparing compound honeysuckle granules according to an embodiment of the present invention. This embodiment of the present invention provides a combined fractional extraction and alcohol precipitation process for preparing compound honeysuckle granules, comprising: Step S1: Honeysuckle raw material, forsythia and water are added to a multi-functional extraction tank for low-temperature slow distillation, and the distillate is collected in segments based on the concentration of volatile oil in the distillate. The volatile oil and first aromatic water of each segment are obtained through stratification. Step S2: During the low-temperature slow distillation process, the distillation pressure and / or distillation temperature are adjusted based on the droplet state characteristic parameters of the volatile oil in the condensate at the distillation outlet, and the first extract and residue are collected when the distillation endpoint is reached. Step S3: Based on the relative density of the aromatic water, evaluate the qualification of each segment of the first aromatic water, and mix the qualified first aromatic waters to obtain the second aromatic water. Step S4: The raw material of Scutellaria baicalensis and the residue are put into a dynamic circulation extraction tank, water and second aromatic water are added for dynamic circulation extraction, and the extraction temperature and circulation frequency are dynamically adjusted based on the impurity state parameters to obtain the second extract. Step S5: The first extract and the second extract are put into an alcohol precipitation tank, ethanol is added for alcohol precipitation and filtered to obtain filtrate. The filtrate is put into a concentrator for vacuum concentration to obtain extract. Step S6: Mix the volatile oil, extract, drying aid, and flavoring agent of each segment evenly to obtain a soft material; Step S7: After granulation, drying and sizing of the soft material, compound honeysuckle granules are obtained.

[0027] Please see Figure 2 As shown, it is a logic block diagram of collecting distillate according to an embodiment of the present invention.

[0028] Specifically, the first distillate is collected based on the result that the volatile oil concentration is less than or equal to the first preset volatile oil concentration; Alternatively, based on the result that the concentration of volatile oil is greater than the first preset concentration of volatile oil, it is determined to collect the second distillate.

[0029] In this embodiment of the invention, a TQ-Z-1.0 multifunctional extraction vessel is used for low-temperature slow distillation, with the temperature set at 85°C, the pressure at -0.03 MPa, and the first preset volatile oil concentration set at 0.08%. The first and second distillates are respectively placed in an oil-water separator and allowed to stand and separate, yielding the corresponding upper volatile oil and lower first aromatic water, which are then stored for later use.

[0030] Understandably, during low-temperature slow distillation, the concentration of volatile oil in the distillate is not constant, but rather exhibits a dynamic pattern of first increasing and then decreasing: the initial concentration is low, gradually rising to a peak as distillation progresses, and then gradually decreasing due to the reduction in the total amount of volatile oil in the feedstock. Setting the first preset volatile oil concentration to 0.08% uses the characteristic concentration of this peak decline segment as the dividing point for segmented collection. This strategy achieves precise recovery of high-value components, avoids resource waste, and provides quality assurance for subsequent preparation processes.

[0031] Specifically, the process of determining the droplet state characteristic parameters includes: normalizing the aspect ratio, the droplet size, and the droplet frequency respectively; and weightedly combining the results of the normalization with the roundness.

[0032] In this embodiment of the invention, a camera installed at the distillation outlet acquires images in real time and performs data acquisition on the images. The camera used is a Basler acA1300-75gm (75fps, 1.3 megapixels), with a 12mm focal length, F2.8 aperture, and a telecentric lens with macro capabilities (such as the OPT-C1218-5M). The working distance is 150mm-200mm, distortion is <0.1%, and a high-brightness red LED backlight (625nm wavelength, flicker control) is used. The camera is installed on the opposite side of the condensate flow path to form a bright-field transmission imaging. An external trigger mode is used, with the camera exposure time set to 200μs, capturing ≥20 effective droplets per frame.

[0033] The circularity C, aspect ratio L, droplet size R, and droplet frequency I are calculated using the following formulas:

[0034] in, A is the projected area of ​​the droplet, in square millimeters; P is the perimeter of the droplet profile, in millimeters; This refers to the length of the major axis, in millimeters. This is the length of the minor axis, in millimeters. N represents the number of droplets detected during the detection period; i represents the i-th droplet; Let be the projected area of ​​the i-th droplet, in square millimeters; t represents the detection period, in seconds.

[0035] The droplet state characteristic parameter F is calculated using the following formula:

[0036] in, The target aspect ratio is set to 1.10; The target droplet size is set to 2 millimeters. The target droplet frequency is set to 6 drops / second; and These are weighting coefficients, 0.35, 0.35, 0.15, and 0.15, respectively.

[0037] Understandably, circularity is calculated based on the droplet's projected area and perimeter; a value closer to 1 indicates a droplet shape closer to an ideal sphere, used to characterize the balance between surface tension and gas flow shear force. The aspect ratio, the ratio of the droplet's major axis to its minor axis, quantifies the degree of droplet stretching in the flow field. Droplet size uses the Sauter mean diameter, calculated as the sum of the cubes and squares of the equivalent diameters of all droplets, used to characterize the mass transfer surface area of ​​the droplet swarm. Droplet frequency is the number of droplets passing through the detection window per unit time, directly reflecting the instantaneous distillation rate of volatile oil. Based on these characteristic parameters, multidimensional information on droplet morphology, size distribution, and motion frequency can be captured in real time. Circularity and aspect ratio together reveal the stress-deformation characteristics of droplets in gas-liquid two-phase flow, droplet size quantifies the evolution of the mass transfer interface, and droplet frequency reflects the escape dynamics of oil phase components. By integrating and analyzing these physical characteristics, the control method of the volatile oil extraction process is transformed from ex-post adjustment relying on human experience to online optimization based on real-time digital characterization of droplet states.

[0038] Please see Figure 3As shown, it is a logic block diagram for determining the adjustment of distillation pressure and / or distillation temperature in an embodiment of the present invention.

[0039] Specifically, based on the result that the droplet state characteristic parameter is greater than or equal to the first preset droplet state characteristic parameter, it is determined to maintain the current distillation pressure of -0.03MPa and the distillation temperature of 85℃ unchanged; Alternatively, based on the result that the droplet state characteristic parameter is greater than or equal to the second preset droplet state characteristic parameter and less than the first preset droplet state characteristic parameter, it is determined to reduce the distillation temperature by 2℃-5℃; Alternatively, based on the result that the droplet state characteristic parameter is greater than or equal to the third preset droplet state characteristic parameter and less than the second preset droplet state characteristic parameter, the distillation pressure is reduced by 0.003MPa-0.007MPa; Alternatively, based on the result that the droplet state characteristic parameter is less than the third preset droplet state characteristic parameter, it is determined that the distillation temperature should be reduced by 2℃-5℃ and the distillation pressure by 0.003MPa-0.007MPa.

[0040] In this embodiment of the invention, the first preset droplet state characteristic parameter is set to 0.75, the second preset droplet state characteristic parameter is set to 0.60, and the third preset droplet state characteristic parameter is set to 0.45. Since in this embodiment of the invention, within the temperature range of 80-90℃, reducing the temperature by 3℃ can lower the saturated vapor pressure by approximately 1.5 kPa and reduce the gas phase flow rate by approximately 10%, which precisely balances droplet morphology repair and distillation efficiency, avoiding over-adjustment, preferably, the distillation temperature is reduced by 3℃. Since in this embodiment of the invention, on a pressure reference of -0.03 MPa, reducing the pressure by 0.005 MPa can cause the gas phase volume to expand by approximately 7.5%, and can effectively increase the droplet frequency while meeting the minimum adjustable accuracy of the vacuum regulating valve, preferably, the distillation pressure is reduced by 0.005 MPa. Those skilled in the art can adaptively adjust the above preset thresholds and adjustment ranges according to the actual production scale, batch characteristics of medicinal materials, and equipment response accuracy.

[0041] Understandably, this step divides the real-time operating conditions of the volatile oil extraction process into four control intervals with clear physical meaning by setting four thresholds. Differentiated adjustment strategies are then configured for the dominant degradation characteristics of the droplet clusters in each interval, thereby achieving a control upgrade from passive response to precise intervention. In the first interval, the corresponding droplet state characteristic parameters are within the ideal process window; therefore, this interval is controlled to maintain the existing parameters unchanged to avoid introducing system disturbances through ineffective adjustments. In the second interval, the corresponding droplet state characteristic parameters deviate slightly from the ideal value. This is due to an imbalance between surface tension and shear force caused by excessive heating intensity; therefore, the distillation temperature is reduced to restore the droplets to a stable morphology dominated by surface tension. In the third interval, the corresponding droplet state characteristic parameters deviate moderately from the ideal value. At this time, the droplet size is too large or the droplet frequency is too low, resulting in decreased mass transfer efficiency and insufficient distillation power. This is due to excessively high back pressure or excessively low vapor-liquid two-phase flow rate. Therefore, the distillation pressure should be reduced to increase the distillation rate and accelerate the mass transfer process of volatile oil from the liquid phase to the gas phase. In the fourth interval, the corresponding droplet state characteristic parameters deviate significantly from the ideal value. The droplet group exhibits severe morphological deformation and severely impaired mass transfer, and is in a critical unstable state of violent boiling or emulsification. It is necessary to reduce both the distillation temperature and distillation pressure simultaneously. This setting can minimize the impact of parameter fluctuations on extraction efficiency while ensuring stability, significantly improving the batch consistency and resource utilization rate of compound honeysuckle granule volatile oil extraction.

[0042] Please see Figure 4 As shown, it is a logic block diagram for determining the distillation endpoint in an embodiment of the present invention.

[0043] Specifically, based on the result that the volatile oil concentration is greater than or equal to the second preset volatile oil concentration, it is determined that the distillation endpoint has not been reached; Alternatively, the distillation endpoint can be determined based on the result that the volatile oil concentration is less than the second preset volatile oil concentration.

[0044] In this embodiment of the invention, the second preset volatile oil concentration is set to 0.02%.

[0045] Understandably, this invention does not use a fixed duration as the distillation endpoint criterion, but rather makes a dynamic determination based on the real-time volatile oil concentration. Its core lies in the systematic balance between marginal benefits, material protection, detection feasibility, and process integration. During the extraction process, the volatile oil distillation rate decays exponentially. When the concentration drops below 0.02%, continued heating not only results in a severe imbalance between energy consumption and output, but also leads to excessive dissolution or degradation of heat-sensitive components in the residue, directly affecting the impurity load of subsequent Scutellaria baicalensis extraction and alcohol precipitation processes. Therefore, setting the second preset volatile oil concentration to 0.02% is a balance point achieved through comprehensive optimization across four dimensions: economic yield, residue protection, detection reliability, and solvent reuse. This reflects the design philosophy of this invention, moving from single-process optimization to full-process synergy.

[0046] Specifically, the first aromatic water is determined to be qualified based on the result that the relative density of the aromatic water is greater than or equal to the preset relative density of the aromatic water; or, the first aromatic water is determined to be unqualified based on the result that the relative density of the aromatic water is less than the preset relative density of the aromatic water.

[0047] In this embodiment of the invention, the relative density of the preset aromatic water is set to 1.005. Relative density refers to the mass ratio of soluble solids at 20°C to the mass of an equal volume of water at 20°C.

[0048] It is understood that the present invention uses the relative density of aromatic water as a characterization index, and sets it to 0.005 as the dynamic balance point for maximizing the reuse benefits and controlling the risk of impurities. Aromatic water at this density retains a sufficient amount of active components that can synergistically infiltrate medicinal materials, and does not exceed the impurity tolerance threshold of subsequent processes, thus realizing the reuse of water resources and quality control.

[0049] Specifically, the impurity state parameters are characterized by the weighted summation of polysaccharide and protein concentrations.

[0050] In this embodiment of the invention, a TQ-1000 dynamic circulation extraction tank was used to extract Scutellaria baicalensis and its residue. The initial extraction temperature was set at 95°C, and the initial circulation frequency was 10 times / hour. The polysaccharide and protein concentrations were calculated using the phenol-sulfuric acid method and the Coomassie Brilliant Blue G-250 method. The impurity state parameter M was calculated using the following formula:

[0051] in, The concentration of polysaccharides in the extract is expressed in mg / mL. The maximum permissible polysaccharide concentration, expressed in mg / mL, is set at 20 mg / mL. The concentration of protein in the extract is expressed in mg / mL. The maximum allowable protein concentration, expressed in mg / mL, is set at 5 mg / mL. and These are weighting coefficients, 0.6 and 0.4 respectively.

[0052] Understandably, this invention constructs a quantifiable, comparable, and controllable impurity evaluation index by weighted fusion of polysaccharide and protein concentrations. Polysaccharides and proteins are the two main non-target extractants in the dynamic extraction process of Scutellaria baicalensis, and their cumulative concentration directly affects the separation efficiency and extract purity of the subsequent alcohol precipitation process. The weighting coefficients are assigned based on the fact that polysaccharides contribute significantly more to the filtration resistance of alcohol precipitation than proteins; therefore, polysaccharides are given a higher weight of 0.6, and proteins a corresponding weight of 0.4. The fusion calculation result is directly input into step S4 to dynamically adjust the extraction temperature and circulation frequency, thereby achieving proactive inhibition of impurity dissolution.

[0053] Please see Figure 5 As shown, it is a logic block diagram for determining and adjusting the extraction temperature and cycle frequency in an embodiment of the present invention.

[0054] Specifically, based on the result that the impurity state parameter is greater than or equal to the first preset impurity state parameter, it is determined to reduce the extraction temperature by 8℃-12℃ and at the same time reduce the circulation frequency by 3 times / hour-5 times / hour. Alternatively, based on the result that the impurity state parameter is greater than or equal to the second preset impurity state parameter and less than the first preset impurity state parameter, it is determined that the extraction temperature should be reduced by 3℃-8℃. Alternatively, based on the result that the impurity state parameter is less than the second preset impurity state parameter, it is determined that the extraction temperature and circulation frequency should not be adjusted.

[0055] In this embodiment of the invention, a first preset impurity state parameter is set to 0.70, and a second preset impurity state parameter is set to 0.45. When the impurity state parameter is greater than or equal to the first preset impurity state parameter, within the extraction temperature range of 85-95℃, reducing the temperature by 10℃ can inhibit the dissolution of polysaccharides and proteins, while still retaining baicalin, achieving the optimal balance between inhibiting impurities and retaining target components. Reducing the circulation frequency by 4 times / hour can reduce shear force to inhibit protein dissolution, while maintaining the state of matter in the tank and avoiding local dead zones. Preferably, the extraction temperature is reduced by 10℃ and the circulation frequency is reduced by 4 times / hour. When the impurity state parameter is greater than or equal to the second preset impurity state parameter and less than the first preset impurity state parameter, the impurity dissolution rate is low, so only gentle intervention is required. Preferably, the extraction temperature reduction range is 3℃-8℃; to achieve the purpose of reducing impurities and protecting effective components, preferably, the extraction temperature is reduced by 5℃. Those skilled in the art can adaptively adjust the above preset thresholds and adjustment ranges according to the actual production scale, batch characteristics of medicinal materials, and equipment response accuracy.

[0056] Understandably, this invention divides the impurity control in the dynamic extraction process of Scutellaria baicalensis into three progressive levels: strong intervention, precise adjustment, and maintaining stability, by setting two impurity state parameter thresholds. When the impurity state parameter is ≥0.70, it indicates that polysaccharides and proteins in the extract have accumulated to a critical over-limit state. It is necessary to simultaneously reduce the extraction temperature and circulation frequency to inhibit the impurity dissolution rate and reduce the solid-liquid contact intensity, achieving rapid interception of impurities through a two-pronged approach. When the impurity state parameter is in the range of 0.45 to 0.70, although the impurity level is not exceeded, it shows an upward trend. At this time, simply reducing the extraction temperature can effectively reverse the impurity dissolution curve, while the circulation frequency, as the main driving force for baicalin mass transfer, is retained to avoid excessive intervention leading to loss of target component yield. When the impurity state parameter is <0.45, the system is in the ideal working range where impurity dissolution is controlled. The control system maintains the existing parameters unchanged and does not introduce any additional disturbances.

[0057] In this embodiment of the invention, the first and second extracts are placed into a CCG-6000 alcohol precipitation tank. The stirring device is turned on, and the rotation speed is set to 30 to 60 rpm. Simultaneously, 95% ethanol (3 times the total volume of the extract) is added at a flow rate of 50 to 200 liters per hour, so that the final volume fraction of ethanol in the precipitation system reaches 60% to 80%. After the ethanol addition is complete, stirring continues for 30 minutes, followed by standing for 24 hours for alcohol precipitation. After precipitation, the supernatant is sieved to obtain a clear filtrate. The clear filtrate is then placed into an SX1000 double-effect vacuum concentrator. The vacuum pressure does not exceed 0.12 MPa; the first-effect vacuum pressure is controlled at -0.01 MPa to -0.04 MPa, and the temperature is maintained at 70°C to 80°C; the second-effect vacuum pressure is controlled at -0.05 MPa to -0.06 MPa, and the temperature is maintained at 70°C to 80°C. During the concentration process, the ethanol distilled off is recovered by a condenser and reused in the next batch of alcohol precipitation. When the relative density of the concentrate reaches 1.10 to 1.20 (measured at 60°C), heating and vacuuming are stopped, and the material is discharged to obtain the extract.

[0058] It is understandable that this invention combines the first extract obtained in step S2 and the second extract obtained in step S4 for unified ethanol precipitation, rather than precipitating them separately and then combining them. The technical advantage lies in the following: the first extract is rich in water-soluble components from the volatile oil extraction, such as chlorogenic acid and forsythosides, while the second extract is rich in flavonoids such as baicalin. When the two are combined for ethanol precipitation, ethanol not only precipitates common impurities such as polysaccharides and proteins, but also synergistically removes cross-interfering components that are difficult to precipitate during separate ethanol precipitation, resulting in a higher purity and better batch stability of the final product extract. The preferred final volume fraction of ethanol precipitation is 60%–80% because: below 60%, protein precipitation is incomplete, and the filtrate turbidity is high; above 80%, ethanol consumption is excessive, and there is a risk of co-precipitation loss of flavonoid glycosides. Furthermore, the reduced pressure concentration temperature is controlled at 50℃–70℃ to ensure evaporation efficiency while avoiding degradation of heat-sensitive components such as chlorogenic acid and baicalin. This complete process chain ensures that compound honeysuckle granules can be industrially scaled up with high efficacy, low impurities, and low cost.

[0059] Specifically, the drying aid is one of dextrin, soluble starch or lactose, and the flavoring agent includes erythritol, sucralose and menthol.

[0060] In this embodiment of the invention, the GH-150 high-speed mixer is set to a speed of 180 rpm. Drying aids and flavoring agents are added to the high-speed mixer for mixing. After uniform mixing, the extract and volatile oil are slowly added into the machine in a thin stream while the speed is increased to 270 rpm. This results in a soft material that can be formed into a ball when grasped, crumbles easily when touched, has no white dry powder, no liquid droplets, and a uniform color. The soft material is then uniformly added to the hopper of a ZLB-300Z rotary granulator, with the granulation frequency set to 40 Hz, to produce uniformly sized wet granules. The steam pressure and compressed air pressure of the fluidized bed granulator are controlled between 0.4 MPa and 0.6 MPa, and the inlet air temperature is set to 65°C. The wet granules are then fed into the hopper of an FL-200C fluidized bed granulator for drying, yielding granules. A 10-mesh stainless steel screen is installed at the inlet of a KZL-120 granulator, and 12-mesh and 50-mesh screens are installed at the outlet. After drying, the granules are evenly fed into the hopper of the granulator. The granules that can pass through the 12-mesh sieve but not the 50-mesh sieve are collected to obtain compound honeysuckle granules.

[0061] It is understandable that the selection of drying aids and flavoring agents in this invention is not a conventional replacement of excipients, but rather a synergistic design of functional excipients to address three major formulation challenges: high viscosity of extracts, easy dispersion of volatile oils, and multiple distributions of bitterness. The flavoring agent adopts a ternary combination of erythritol, sucralose, and menthol. Erythritol achieves sequential masking of sweetness followed by bitterness through its negative heat of solution effect, sucralose fills the perceptual gap in the later stages of bitterness with its high sweetness, and menthol inhibits bitterness signals at the neurotransmission level by activating the cold receptor TRPM8.

[0062] Example: Ingredients: 750g honeysuckle, 750g forsythia, 250g scutellaria.

[0063] Process steps: S1: Honeysuckle and forsythia are placed in a multi-functional extraction tank, and 9L of purified water is added. The distillation temperature is set to 85℃ and the distillation pressure to -0.03MPa for slow distillation at low temperature. The concentration of volatile oil in the distillate is monitored online, and the first preset volatile oil concentration is set to 0.08%. When the volatile oil concentration is ≤0.08%, the distillate is collected as the first distillate; when the volatile oil concentration is >0.08%, it is collected as the second distillate. The two distillates are introduced into an oil-water separator and allowed to stand for separation, yielding an upper layer of volatile oil (segmented for storage) and a lower layer of first aromatic water (segmented for storage). The total distillation time is 95 minutes, and a total of 4.2g of volatile oil and approximately 4.8L of first aromatic water are collected.

[0064] S2: An industrial camera was installed at the distillation outlet to acquire real-time images of the condensate. At 49 minutes, the droplet roundness, aspect ratio, droplet size, and droplet frequency were detected and calculated to be 0.62, 1.20, 2.60, and 4.7, respectively. The droplet state characteristic parameter at this time was calculated to be 0.52, which is between the second preset droplet state characteristic parameter of 0.60 and the third preset droplet state characteristic parameter of 0.45. Therefore, the distillation pressure was reduced by 0.005 MPa to -0.035 MPa. At 92 minutes, the volatile oil concentration was detected to have dropped to 0.018%, which is lower than the second preset volatile oil concentration of 0.02%. Heating was stopped, and approximately 5.2 L of the first extract and residue were collected.

[0065] S3: After the first distillate separates into layers, the relative density of the first aromatic water is 1.002, which is less than the preset relative density of aromatic water, so it is unqualified and therefore discarded; after the second distillate separates into layers, the relative density of the first aromatic water is 1.009, which is qualified and retained, yielding approximately 1.3L of the second aromatic water.

[0066] S4: 250g of Scutellaria baicalensis and the residue obtained in step S2 were added to a dynamic circulation extraction tank, along with 6L of purified water and 1.3L of the second aromatic water obtained in step S3. The initial extraction temperature was 95℃, and the circulation frequency was 10 times / h. Samples were taken every 15 minutes to detect the polysaccharide and protein concentrations. At 30 minutes, the polysaccharide and protein concentrations were detected to be 14.8mg / mL and 3.6mg / mL, respectively. The calculated impurity state parameter was 0.73, which was greater than the first preset impurity state parameter of 0.70. Therefore, the temperature was lowered to 85℃, and the circulation frequency was reduced to 6 times / h. The total extraction time was 90 minutes, and approximately 6.8L of the second extract was collected.

[0067] S5: Combine the first and second extracts, with a total volume of 12.0 L. Transfer to an alcohol precipitation tank, stir at 45 rpm, and add 36 L of 95% ethanol at a flow rate of 80 L / h, resulting in a final ethanol volume fraction of 71%. Continue stirring for 30 min after the ethanol addition is complete, and let stand for 24 h. Take the supernatant and pass it through a 200-mesh sieve to obtain approximately 44 L of clear filtrate. Input the filtrate into a double-effect vacuum concentrator: first-effect vacuum -0.02 MPa, temperature 75 °C; second-effect vacuum -0.055 MPa, temperature 75 °C. Concentrate under reduced pressure to a relative density of 1.15 (measured at 60 °C), yielding an extract weighing 352 g.

[0068] S6: 598g dextrin, 50g erythritol, 2.5g sucralose, 1g menthol; volatile oil: 4.2g of the volatile oil collected in step S1; put the dextrin, erythritol, sucralose and menthol into a high-speed mixer and mix at 180rpm for 2min; then slowly add the extract and volatile oil in a thin stream while increasing the speed to 270rpm and continue mixing for 3min to obtain a soft material with uniform color, which can be formed into a ball when squeezed and crumbles when touched, with a total weight of about 1007.7g.

[0069] S7: Add the soft material to a rotary granulator (frequency 40Hz) to make wet granules; place the wet granules in a fluidized bed dryer with an inlet air temperature of 65℃ and dry until the moisture content is ≤3.0%; pass the dried granules through a granulator (10 mesh sieve at the inlet, 12 mesh and 50 mesh sieves at the outlet), collect 12-50 mesh granules, weigh 1000g, and obtain compound honeysuckle granules.

[0070] Comparative Example 1 Raw materials: Same as in the example.

[0071] Process steps: Honeysuckle processing: Add 8 times the amount of water (6L) to honeysuckle, decoct twice, 1.5h each time, combine the decoctions, filter, concentrate the filtrate under reduced pressure to a relative density of 1.15, cool, add ethanol to achieve an alcohol content of 60%, let stand for 24h, filter, recover the ethanol from the filtrate and concentrate to an extract (about 190g). Collect the honeysuckle distillate separately (about 0.5L) for later use.

[0072] Forsythia and Scutellaria: Add 8 times the amount of water (8L) to Forsythia and Scutellaria, decoct twice, 2 hours each time, combine the decoctions, filter, concentrate the filtrate to a relative density of 1.15, add ethanol to make the alcohol content reach 60%, let stand for 24 hours, filter, recover the ethanol from the filtrate and concentrate to extract (about 180g).

[0073] Combined: The two extracts were combined, with a total extract of approximately 370g.

[0074] Granulation: Add 0.5L of honeysuckle distillate, 550g of sucrose powder, 80g of dextrin, and 2g of sucralose to the extract. Perform wet granulation, dry, granulate, and add dextrin to bring the total weight to 1000g.

[0075] The differences from the previous example are: no volatile oil segmentation collection and enrichment, no droplet state feedback control, no aromatic water reuse evaluation, no impurity state parameter feedback control, flavoring agents are sucrose and sucralose, and no erythritol or menthol.

[0076] Comparative Example 2 Raw materials: Same as in the example.

[0077] S1 and S2 are exactly the same as in the previous embodiment, with segmented collection of volatile oil, droplet feedback control, and distillation endpoint determination all implemented.

[0078] S3: No relative density assessment of aromatic water is performed; all first aromatic waters in the segments are directly combined into second aromatic water (approximately 1.5L).

[0079] S4: During dynamic cyclic extraction, a second aromatic water is added, but the state parameters of impurities are not detected, and temperature and frequency feedback adjustments are not performed. The extraction temperature is kept constant at 95℃, the circulation frequency is 10 times / h, and the extraction time is 1.5h.

[0080] S5, S6, S7: Same as the example, with consistent parameters for alcohol precipitation, concentration, and granulation. The extract yield is approximately 340g, dextrin dosage is 610g, flavoring agent (erythritol 50g, sucralose 2.5g, menthol 1g) is 53.5g, volatile oil is 4g, and the total weight is brought up to 1000g.

[0081] The difference from the previous example is that it lacks a qualified assessment of the aromatic water and a feedback control for impurities.

[0082] Effect Comparison Table 1 shows a comparison of the effects of the example and comparative products.

[0083] Retention of volatile oils and active ingredients: In the example, by collecting volatile oils in segments, controlling droplet feedback, and reusing aromatic water, the volatile oil content in the particles reached 38.2 mg / 100g, which is nearly 5 times higher than that of Comparative Example 1 and 78% higher than that of Comparative Example 2; the contents of chlorogenic acid and baicalin were also significantly higher than those of the two comparative examples.

[0084] Impurity control: The impurity feedback control in the embodiment resulted in a removal rate of over 80% for both alcohol precipitation polysaccharides and proteins, which was significantly better than that of comparative examples 1 and 2, thus ensuring the high purity of the extract.

[0085] Taste and Calories: The example uses erythritol, sucralose and menthol as a three-component flavor enhancer, with the lowest bitterness score (3.1), a cooling sensation lasting 30 seconds, and only 170kcal / 100g, less than half of Comparative Example 1.

[0086] Process robustness: The batch-to-batch volatile oil content RSD of the example was 4.1%, which was much lower than that of Comparative Example 1 and Comparative Example 2, demonstrating that intelligent feedback control significantly improved process consistency.

[0087] Table 1. Comparison of effects between the examples and comparative products

[0088] In summary, this invention, by constructing a synergistically optimized preparation process encompassing extraction, separation, purification, and formulation, integrates multiple processes such as segmented volatile oil harvesting, droplet morphology feedback, aromatic water reuse evaluation, impurity prospective inhibition, combined alcohol precipitation, and ternary low-heat flavoring. This successfully solves the technical problems of severe aroma loss from volatile oils and sucrose dependence for flavoring. Simultaneously, the establishment of an aromatic water reuse evaluation mechanism provides a quantifiable quality control anchor for the internal recycling of solvents used in traditional Chinese medicine extraction, while the introduction of the ternary flavoring combination opens up a dual-optimal path for sugar reduction and improvement of traditional Chinese medicine preparations, achieving both superior taste and calorie content.

[0089] The technical solution of the present invention has been described above with reference to the preferred embodiments shown in the accompanying drawings. However, it will be readily understood by those skilled in the art that the scope of protection of the present invention is obviously not limited to these specific embodiments. Without departing from the principles of the present invention, those skilled in the art can make equivalent changes or substitutions to the relevant technical features, and the technical solutions after these changes or substitutions will all fall within the scope of protection of the present invention.

Claims

1. A combined process for fractional extraction and alcohol precipitation of compound honeysuckle granules, characterized in that, include: Step S1: Honeysuckle raw material, forsythia and water are added to a multi-functional extraction tank for low-temperature slow distillation, and the distillate is collected in segments based on the concentration of volatile oil in the distillate. After stratification, volatile oil and first aromatic water of each segment are obtained. Step S2: During the low-temperature slow distillation process, the distillation pressure and / or distillation temperature are adjusted based on the droplet state characteristic parameters of the volatile oil in the condensate at the distillation outlet. When the distillation endpoint is reached, the first extract and the residue are collected. The droplet state characteristic parameters are determined by roundness, aspect ratio, droplet size and droplet frequency. The distillation endpoint is determined based on the volatile oil concentration. Step S3: Based on the relative density of the aromatic water, evaluate the qualification of the first aromatic water in each segment, and mix the qualified first aromatic waters to obtain the second aromatic water. Step S4: The raw material of Scutellaria baicalensis and the residue are put into a dynamic circulation extraction tank, water and the second aromatic water are added for dynamic circulation extraction, and the extraction temperature and circulation frequency are dynamically adjusted based on the impurity state parameters. The second extract is collected, wherein the impurity state parameters are determined by the polysaccharide concentration and the protein concentration. Step S5: The first extract and the second extract are put into an alcohol precipitation tank, ethanol is added for alcohol precipitation and the mixture is filtered to obtain a filtrate. The filtrate is then put into a concentrator for vacuum concentration to obtain an extract. Step S6: Mix the volatile oil, extract, drying aid, and flavoring agent of each segment evenly to obtain a soft material; Step S7: After granulation, drying and sizing of the soft material, compound honeysuckle granules are obtained.

2. The combined process of fractional extraction and alcohol precipitation for preparing compound honeysuckle granules according to claim 1, characterized in that, In step S1, based on the result that the volatile oil concentration is less than or equal to the first preset volatile oil concentration, it is determined to collect the first distillate; Alternatively, based on the result that the volatile oil concentration is greater than the first preset volatile oil concentration, it is determined to collect the second distillate.

3. The combined process of fractional extraction and alcohol precipitation for preparing compound honeysuckle granules according to claim 2, characterized in that, Step S2, the process of determining the droplet state characteristic parameters includes: The aspect ratio, the droplet size, and the droplet frequency are normalized respectively. The result of the normalization process is weighted and fused with the circularity.

4. The combined process of fractional extraction and alcohol precipitation for preparing compound honeysuckle granules according to claim 3, characterized in that, In step S2, based on the result that the droplet state characteristic parameter is greater than or equal to the first preset droplet state characteristic parameter, it is determined to maintain the current distillation pressure and distillation temperature unchanged; Alternatively, based on the result that the droplet state characteristic parameter is greater than or equal to the second preset droplet state characteristic parameter and less than the first preset droplet state characteristic parameter, the distillation temperature is determined to be reduced. Alternatively, based on the result that the droplet state characteristic parameter is greater than or equal to the third preset droplet state characteristic parameter and less than the second preset droplet state characteristic parameter, the distillation pressure is determined to be reduced; Alternatively, based on the result that the droplet state characteristic parameter is less than the third preset droplet state characteristic parameter, it is determined to simultaneously reduce the distillation temperature and distillation pressure.

5. The combined process of fractional extraction and alcohol precipitation for preparing compound honeysuckle granules according to claim 4, characterized in that, In step S2, based on the result that the volatile oil concentration is less than the second preset volatile oil concentration, it is determined that the distillation endpoint has been reached.

6. The combined process of fractional extraction and alcohol precipitation for preparing compound honeysuckle granules according to claim 5, characterized in that, In step S3, based on the result that the relative density of the aromatic water is greater than or equal to the preset relative density of the aromatic water, the first aromatic water is determined to be qualified.

7. The combined process of fractional extraction and alcohol precipitation for preparing compound honeysuckle granules according to claim 6, characterized in that, In step S4, the impurity state parameters are characterized by the weighted summation of polysaccharide concentration and protein concentration.

8. The combined process of fractional extraction and alcohol precipitation for preparing compound honeysuckle granules according to claim 7, characterized in that, In step S4, based on the result that the impurity state parameter is greater than or equal to the first preset impurity state parameter, it is determined to reduce the extraction temperature and simultaneously reduce the circulation frequency. Alternatively, based on the result that the impurity state parameter is greater than or equal to the second preset impurity state parameter and less than the first preset impurity state parameter, it is determined that only the extraction temperature should be reduced; Alternatively, based on the result that the impurity state parameter is less than the second preset impurity state parameter, it is determined that the extraction temperature and the circulation frequency should not be adjusted.

9. The combined process of fractional extraction and alcohol precipitation for preparing compound honeysuckle granules according to claim 8, characterized in that, In step S6, the drying aid is one of dextrin, soluble starch, or lactose.

10. The combined process of fractional extraction and alcohol precipitation for preparing compound honeysuckle granules according to claim 9, characterized in that, In step S6, the flavoring agent includes erythritol, sucralose, and menthol.

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