Method for preparing large baical skullcap root fish effervescent tablets through non-aqueous granulation and tabletting

Abstract

The invention discloses a method for preparing large baical skullcap root fish effervescent tablets through non-aqueous granulation and tabletting. The method comprises the following steps: 1, raw material pretreatment: mixing a rhubarb extract, a baical skullcap root extract, heartleaf houttuynia herb volatile oil, a disintegrating agent and auxiliary materials in proportion; 2, non-aqueous bonding granulation: using 5% PVP-absolute ethyl alcohol atomized spray as an adhesive, and bonding the adhesive with the mixed powder in a fluidized bed granulator to form particles; 3, tabletting and packaging: feeding the granules obtained in the step 2 into a rotary tabletting machine for tabletting; and 4, aluminum-plastic packaging: carrying out aluminum-plastic packaging on the tablets obtained in the step 3, and controlling the environment humidity to be less than or equal to 30%. The invention has the following advantages: 1, active ingredients of traditional Chinese medicines are protected, and the retention rate of key ingredients such as baicalin is greater than or equal to 95%; 2, the process chain is simplified; 3, the cost is reduced and the benefit is increased in economic benefit; the moisture content in the whole process is smaller than or equal to 0.5%.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a method for preparing large-flowered skullcap fish effervescent tablets by non-aqueous granulation and tabletting. Background Art

[0002] The wet granulation process uses water or organic solvents as binders, and drugs and excipients need to be fully wetted during granulation. However, Chinese herbal medicine active ingredients (such as flavonoids and glycosides in rhubarb and skullcap) are sensitive to water and prone to the following reactions:

[0003] I. Poor component stability: Hydrolysis and degradation of active ingredients

[0004] 1. Hydrolysis reaction: Water molecules combine with the glycosidic bond of flavonoid compounds, resulting in the cleavage of aglycone and sugar chain (such as baicalin → baicalein + glucose), and the loss rate of pharmacodynamic components can reach 15%-30% (literature data).

[0005] 2. Oxidation and isomerization: Dissolved oxygen in the solvent and process temperature fluctuations (such as 40-60°C in the drying stage) may cause oxidation of phenolic hydroxyl groups or changes in stereoconfiguration, further reducing bioavailability.

[0006] 3. Case support: In this study, skullcap extract granules prepared by wet method and non-aqueous method were compared. HPLC detection showed that the baicalin content decreased from 90% to 72% after wet granulation, while the retention rate of the non-aqueous method was >95%.

[0007] II. Hygroscopicity problem: Risk of moisture out of control in the process chain

[0008] 1. It is difficult to completely remove moisture in the drying link of wet granulation, and it is easy to absorb moisture during subsequent storage. The specific manifestations are as follows: Moisture absorption of the porous structure of granules: The granules formed by wet granulation have micropores (pore diameter 1-10μm) inside, and the specific surface area increases. When exposed to environmental humidity >40%, the moisture adsorption amount can reach 5%-8% (weight ratio), resulting in: (1) Caking and delayed dissolution: After moisture absorption, a water film is formed on the surface of the granules, and the disintegration time of the effervescent tablets is extended from 60 seconds to more than 3 minutes (national standard requirement ≤5 minutes); (2) Decreased chemical stability: Residual moisture accelerates the pre-reaction of effervescent agents (such as sodium bicarbonate and citric acid), generating CO2 and escaping, reducing the disintegration efficacy of the tablets.

[0009] 2. Storage and transportation restrictions: The product needs to strictly control humidity (such as RH≤30%), increasing packaging costs (such as aluminum-plastic composite film + desiccant), and restricting market expansion in hot and humid regions.

[0010] 3. Low production efficiency: Energy consumption and time loss in multiple links.

[0011] The wet granulation process includes multiple steps such as mixing, granulation, drying, and sieving. Its inefficiency is reflected in:

[0012] (1) Long drying time: Fluidized bed drying takes 1 - 2 hours (temperature 50 - 60 °C), and the energy consumption accounts for more than 40% of the total process cost.

[0013] (2) High screening and rework rates: After drying, the hardness of wet granules is uneven, and multiple screenings are required (such as 20 - 40 mesh sieves). Approximately 10% - 15% of the granules need to be re - granulated due to non - compliant particle sizes.

[0014] (3) Long equipment occupation cycle: Taking an 8 - hour production batch as an example, the effective production time of wet granulation only accounts for 50%, and the rest is used for equipment cleaning and switching.

[0015] Data comparison:

[0016]

[0017] The above problems do not exist in isolation but form a vicious cycle of "process - ingredient - stability":

[0018] (1) Residual moisture → moisture absorption and caking → delayed disintegration → decreased patient compliance;

[0019] (2) Long - term drying → degradation of heat - sensitive ingredients → reduced drug efficacy → doubts about clinical efficacy;

[0020] (3) High energy consumption and low qualification rate → rising production costs → weakening of market competitiveness.

[0021] Therefore, developing non - aqueous granulation and tableting to avoid the intervention of moisture, simplify the process chain, and improve the stability of ingredients has become an inevitable direction to break through the existing technical bottlenecks. Summary of the Invention

[0022] The object of the present invention is to provide a method for preparing a large - skullcap - fish - bladder effervescent tablet by non - aqueous granulation and tableting. By completely avoiding the use of water as a binder, the above problems are fundamentally solved, while improving production efficiency and product performance, and being applicable to large - scale industrial production. The specific steps are as follows:

[0023] I. Raw material pretreatment: Accurately weigh rhubarb extract, skullcap extract, volatile oil of houttuynia cordata, disintegrant, 13.4% mannitol, and 5% PEG - 6000.

[0024] II. Non - aqueous binder granulation: Use 5% PVP - absolute ethanol atomized spray as a binder to bond the mixed powder into granules in a fluidized bed granulator.

[0025] III. Tableting and packaging: Feed the granules obtained in step II into a rotary tablet press for tableting.

[0026] IV. Aluminum-plastic packaging: The tablets obtained in Step 3 are subjected to aluminum-plastic packaging, and the environmental humidity is controlled to be ≤ 30%.

[0027] Furthermore, in Step 1, the content of active ingredients in the rhubarb extract is ≥ 80%, the content of active ingredients in the skullcap extract is ≥ 85%, and the content of active ingredients in the volatile oil of houttuynia cordata is ≥ 80%.

[0028] Furthermore, the mass ratio of the rhubarb extract, skullcap extract, and volatile oil of houttuynia cordata in Step 1 is 540:325:135.

[0029] Furthermore, the disintegrant in Step 1 contains sodium bicarbonate and citric acid, and the mass ratio is 1.3:1.

[0030] Furthermore, the particle size of the mixed powder is 80 - 100 mesh, and the particle density is 0.4 - 0.6 g / cm 3 ; the moisture content of the particles is ≤ 0.5%, the angle of repose is ≤ 30°, and the bulk density is 0.5 - 0.7 g / cm 3 .

[0031] Furthermore, in Step 2, the dosage of the binder is 5% - 15% of the total mass of the mixed powder.

[0032] Furthermore, for the atomizing spray in Step 2, the spray pressure is 0.3 MPa, and the atomizing particle size is 20 - 50 μm.

[0033] Furthermore, for the granulation in Step 2, the inlet air temperature is maintained at 35°C for 10 minutes.

[0034] Furthermore, for the tablet pressing in Step 3, the pressure of the rotary tablet press is 8 - 10 kN, and the weight of the obtained tablet is 0.5 g.

[0035] To sum up, the present invention has the following beneficial effects: 1. Protection of traditional Chinese medicine active ingredients: Through a completely anhydrous process, the retention rate of key components such as baicalin is increased from ≤ 85% in the traditional process to ≥ 95%;

[0036] 2. Simplification of the process chain: The traditional wet granulation process requires 6 - 8 steps (i.e., mixing, granulation, drying, sizing, etc.), while the present invention compresses the core processes to 3 steps, namely mixing, granulation, and tablet pressing;

[0037] 3. Cost reduction and efficiency improvement in economic benefits: The production cost is significantly reduced. The energy consumption per batch in the traditional process is 9.2 kW·h / kg, while the present invention only requires 3.5 kW·h / kg, with an energy saving rate of 70%; The utilization rate of raw materials is improved: The qualified rate of particles is increased from 85% - 90% to ≥ 98%, saving raw material costs; The equipment maintenance cost is reduced: The anhydrous process avoids equipment corrosion.

[0038] 4. The moisture content throughout the process is ≤0.5%. Brief Description of the Drawings

[0039] Figure 1 This is a flow chart of the present invention. Detailed Description of the Invention

[0040] The present invention will be further described in detail below in conjunction with the Figure 1 drawings and embodiments:

[0041] Example 1

[0042] I. Raw material pretreatment: Mix rhubarb extract (active ingredient content ≥80%), scutellaria baicalensis extract (active ingredient content ≥80%), houttuynia cordata volatile oil (active ingredient content ≥80%), disintegrant (sodium bicarbonate to citric acid mass ratio 1:1.3) and excipients (mannitol, lubricant) in proportion. The particle size of the mixed powder is 80 - 100 mesh, and the particle density is 0.4 - 0.6 g / cm 3 ; the moisture content of the particles is ≤0.5%, the angle of repose is ≤30°, and the bulk density is 0.5 - 0.7 g / cm 3 , and the following is the formula table for 20 g of effervescent tablets:

[0043]

[0044]

[0045] II. Non-aqueous granulation with adhesion: Use 5% PVP-anhydrous ethanol atomized spray as the binder (spray pressure 0.3 MPa, atomization particle size 20 - 50 μm), and bond the mixed powder into granules in a fluidized bed (inlet air temperature 35 °C, time 10 minutes).

[0046] III. Tabletting and packaging: Directly tablet the granules (pressure 8 - 10 kN, tablet weight 0.5 g), and package them with aluminum-plastic, controlling the environmental humidity ≤30%

[0047] IV. Aluminum-plastic packaging: Package the tablets obtained in step 3 with aluminum-plastic, controlling the environmental humidity ≤30%.

[0048] Detection:

[0049] 1. Determine the retention rate of active ingredients by high performance liquid chromatography (HPLC)

[0050] Instrument preparation: Use a high performance liquid chromatograph equipped with a suitable detector such as an ultraviolet detector. Select a C18 reverse phase chromatographic column, and the mobile phase can be eluted with acetonitrile - 0.1% acetic acid water according to the following gradient.

[0051]

[0052]

[0053] Preparation of reference substance and test solution: Accurately weigh reference substances of active ingredients such as emodin and baicalin with known purity, and prepare a reference substance solution with a certain concentration using methanol as the solvent. For the test sample, after pulverizing medicinal material samples such as rhubarb, scutellaria baicalensis, and houttuynia cordata, ultrasonic extraction is used to extract the active ingredients therein. The extract is filtered, concentrated, and made up to a constant volume with an appropriate solvent to prepare the test solution.

[0054] Chromatographic conditions and content determination: Inject the reference substance solution and the test solution into a liquid chromatograph respectively. C18 chromatographic column (4.6mm×250mm, 5μm), column temperature 30°C, flow rate 1.0ml / min, detection wavelengths 254nm (for emodin), 278nm (for baicalin), and 326nm (for houttuynia cordata). Separation and detection are carried out. Absorption peaks of emodin are obtained near 254nm, absorption peaks of baicalin are near 278nm, and absorption peaks of houttuynia cordata are near 205nm (hyperin and quercitrin in houttuynia cordata), 326nm (rutin in houttuynia cordata), and 254nm (quercetin in houttuynia cordata). The contents of each active ingredient in the test sample are calculated by the external standard method or the internal standard method, and then its retention rate is calculated. The retention rates of the active ingredients in rhubarb, scutellaria baicalensis, and houttuynia cordata are ≥95%, while those of the traditional method are ≤85%.

[0055] 2. The disintegration time of the effervescent tablet ≤60 seconds (national standard requirement ≤5 minutes)

[0056] 3. The energy consumption in the granulation process is reduced by nearly 40%, the raw material cost is saved by 10%, and the waste treatment cost is reduced

[0057] Energy consumption analysis of the traditional process: The traditional wet granulation process includes steps such as mixing, granulation, drying, and sieving. The energy consumption of each link is as follows (producing 1kg of granules): Mixing: 1.5kW·h; Wet granulation: 2.8kW·h; Fluidized bed drying: 4.2kW·h (temperature 50 - 60°C, duration 2 hours); Sieving: 0.7kW·h; Total energy consumption: 1.5 + 2.8 + 4.2 + 0.7 = 9.2kW·h / kg

[0058] Energy consumption analysis of the process of the present invention: The non-aqueous granulation process completes granulation and drying through a fluidized bed integration, and the energy consumption is significantly reduced: Mixing: 1.5kW·h (the same as the traditional process); Fluidized bed granulation: 1.3kW·h (spray granulation + drying synchronously, duration 10 minutes); Tabletting: 0.7kW·h; Total energy consumption: 1.5 + 1.3 + 0.7 = 3.5kW·h / kg;

[0059] Calculation of energy saving rate: Energy saving rate = (traditional energy consumption - energy consumption of the present invention) / traditional energy consumption × 100% = (9.2 - 3.5) / 9.2 × 100% ≈ 62%

[0060] Relationship between qualified rate and raw material demand: To produce 100 kg of qualified pellets: Traditional process (qualified rate 85%-90%, taking the average value of 87.5%): Required feeding amount = 100 / 0.875 ≈ 114.29 kg; The process of the present invention (qualified rate ≥ 98%, taking 98%): Required feeding amount = 100 / 0.98 ≈ 102.04 kg; Raw material savings: Savings amount = 114.29 kg - 102.04 kg = 12.25 kg;

[0061] Proportion of raw material cost savings = 12.25 / 114.29 × 100% ≈ 10.7%;

[0062] Expansion of economic benefits

[0063] Reduce waste treatment cost: The waste rate of the traditional process is 12.5%, and that of the present invention is only 2%, and the waste treatment cost is reduced by 80%; Reduce rework cost: The traditional process requires additional energy consumption (0.5 kW·h / kg) and labor cost due to screening unqualified pellets, and the present invention does not require rework.

[0064] 4. Accelerated stability test

[0065] Take the tablets prepared in the examples and conduct a 6-month test under the conditions of 40°C ± 2°C and RH 75% ± 5%. Sample and detect the inspection indicators at the end of the 0th, 1st, 2nd, 3rd, and 6th months during the test. The moisture absorption weight gain of the product ≤ 1.5% (≥ 5% by the traditional method).

[0066] This specific embodiment is only an explanation of the present invention and is not a limitation thereof. Those skilled in the art can make modifications without creative contributions to this embodiment according to needs after reading this specification, but as long as it is within the scope of the claims of the present invention, it is protected by the patent law.

Claims

1. A method for preparing large skullcap and fish swim bladder effervescent tablets by non-aqueous granulation and tabletting, characterized in that, It includes the following steps: I. Raw material pretreatment: Obtain a mixed powder by mixing rhubarb extract, skullcap root extract, volatile oil of houttuynia cordata, disintegrant, 13.4% mannitol, and 5% PEG-6000 in proportion; II. Non-aqueous binder granulation: Use 5% PVP-anhydrous ethanol atomized spray as the binder to bond with the mixed powder into granules in a fluidized bed granulator; III. Tabletting and packaging: Feed the granules obtained in step II into a rotary tablet press for tabletting; IV. Aluminum-plastic packaging: Perform aluminum-plastic packaging on the tablets obtained in step III, and control the environmental humidity ≤ 30%; 2. The method for preparing the large skullcap and fish swim bladder effervescent tablets by non-aqueous granulation and tabletting according to claim 1, wherein In step I, the effective ingredient content of the rhubarb extract ≥ 80%, the effective ingredient content of the skullcap root extract ≥ 85%, and the effective ingredient content of the volatile oil of houttuynia cordata ≥ 80%; 3. A method for preparing the Dahuangqin Yupao Effervescent Tablets by non-aqueous granulation and tabletting according to claim 1, characterized in that, In step I, the mass ratio of the rhubarb extract, skullcap root extract, and volatile oil of houttuynia cordata is 540:325:135; 4. A method for preparing a large-flowered skullcap fish effervescent tablet by non-aqueous granulation and tabletting according to claim 1, characterized in that, The disintegrant in step I contains sodium bicarbonate and citric acid, and the mass ratio is 1.3:1; 5. The method for preparing the large skullcap and fish swim bladder effervescent tablets by non-aqueous granulation and tabletting according to claim 1, wherein, The particle size of the mixed powder is 80 - 100 mesh, and the particle density is 0.4 - 0.6 g / cm 3 ; the moisture content of the particles ≤ 0.5%, the angle of repose ≤ 30°, and the bulk density is 0.5 - 0.7 g / cm 3 .

6. The method for preparing the large-flowered skullcap and fish swim bladder effervescent tablets by non-aqueous granulation and tabletting according to claim 1, characterized in that, In step II, the dosage of the binder is 5%-15% of the total mass of the mixed powder; 7. A method for preparing a large-flowered skullcap and fish swim bladder effervescent tablet by non-aqueous granulation and tabletting according to claim 1, characterized in that, For the atomized spray in step II, the spray pressure is 0.3 MPa, and the atomization particle size is 20-50 μm; 8. A method for preparing the large skullcap and fish swim bladder effervescent tablets by non-aqueous granulation and tabletting according to claim 1, characterized in that For the granulation in step II, maintain the inlet air temperature at 35°C for 10 minutes; 9. A method for preparing the large skullcap and fish swim bladder effervescent tablets by non-aqueous granulation and tabletting according to claim 1, characterized in that, For the tabletting in step III, the pressure of the rotary tablet press is 8-10 kN, and the tablet weight of the obtained tablets is 0.5 g.

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