A bucumlan tablet and a method for preparing the same

Abstract

The application discloses a kind of bumetanide tablets, raw materials include bumetanide 1 according to mass ratio;Corn starch 81~85;Lactose 50~54;Agar 0.1~0.3;Povidone K304~6;Polysorbate 80, 0.1~0.2;Silicon dioxide 3~4.5;Talcum powder 2~3.3;Magnesium stearate 0.3~0.7.Its preparation method includes the following steps: pretreatment, premixing, granulation, wet granulation, drying, dry granulation, total mixing, tabletting and packaging.The application introduces the synergistic system of trace agar and polysorbate 80 in the prescription.Agar, as a natural hydrophilic colloid, can form a hydrophilic network structure during the granulation process, and synergistically act with polysorbate 80, greatly improving the wettability and dispersibility of the slurry to ultrafine bumetanide, preventing drug agglomeration, so that the drug can be more evenly distributed in the granules during the subsequent drying and tabletting process.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a bumetanide tablet and its preparation method. Background Technology

[0002] Bumetanide is a potent loop diuretic, primarily used clinically to treat renal and hepatic edema in adults and heart failure in adults. Its chemical structural formula is:

[0003] However, bumetanib is a poorly soluble drug (BCS Class II), and its oral bioavailability is limited by the dissolution rate, resulting in significant inter-individual variability. Furthermore, bumetanib active pharmaceutical ingredient (API) typically suffers from poor flowability and strong electrostatic adsorption, which can easily lead to poor mixing uniformity and unqualified content during formulation production, affecting the quality and efficacy stability of the drug.

[0004] Currently, commercially available bumetanide tablets are typically manufactured using direct compression or conventional wet granulation. Direct compression is insufficient for low-dose, difficult-to-mix drugs like bumetanide, as it fails to guarantee uniformity of content. Conventional wet granulation, on the other hand, offers limited control over bumetanide particle size and uses relatively standard excipient systems, failing to effectively address its slow dissolution rate and hygrothermal stability issues. For example, conventional formulations often use sodium carboxymethyl starch as a disintegrant, but its effect on improving the dissolution of poorly soluble drugs like bumetanide is limited. Furthermore, during granulation, the drug may migrate due to uneven wetting or drying processes, affecting tablet uniformity. Summary of the Invention

[0005] The purpose of this invention is to provide a bumetanide tablet that has the advantages of rapid dissolution, high content uniformity, and good stability.

[0006] Another objective of this invention is to provide a method for preparing the above-mentioned bumetanide tablets, which has stable process, good reproducibility, and is suitable for industrial production.

[0007] To solve the above-mentioned technical problems, the present invention provides the following technical solution: A bumetanide tablet is made from the following raw materials in parts by weight: bumetanide 1; corn starch, 81-85; lactose, 50-54; agar, 0.1-0.3; povidone K30, 4-6; polysorbate 80, 0.1-0.2; silica, 3-4.5; talc, 2-3.3; magnesium stearate, 0.3-0.7.

[0008] A method for preparing the bumetanide tablets includes the following steps: S1: Pretreatment: Weigh the prescribed amount of bumetanide and silica, pass the silica through a 30-mesh sieve, and perform air jet pulverization on the raw drug to obtain API.

[0009] Among them, the feed pressure of the raw material crushing parameters is 4.5±1.0 bar, the crushing pressure is 4.0±1.0 bar, and the feeding speed is 10 to 15 rpm, which makes it easier to control the particle size distribution of the active pharmaceutical ingredient. Controlling the particle size distribution of the active pharmaceutical ingredient is related to the dissolution and release behavior of the formulation, which in turn affects the bioequivalence of the self-made formulation and the original reference formulation.

[0010] The particle size should be controlled within the range of D50≤10μm and D90≤15μm. Once the particle size meets the requirements, the material should be pulverized according to these parameters. After pulverization, the material should be placed in a clean double-layer polyethylene bag and then placed in a stainless steel drum. After weighing, a label should be attached between the two layers of polyethylene bags and to the outside of the container, indicating the product name, batch number, specifications, weight, date, and operator. After tying the polyethylene bags, the material should be sent to the raw material storage room.

[0011] S2: Premix: Place the prescribed amounts of corn starch, lactose, agar, and povidone K30 in a wet granulator, set the stirring speed to 180-220 rpm and the cutter speed to 1600-2000 rpm, and premix for 3-7 minutes.

[0012] S3: Granulation: Slurry preparation: Weigh the prescribed amount of polysorbate 80, pretreated API, and prescribed amount of povidone K30 and disperse them in the prescribed amount of purified water to prepare a slurry for later use; In the granulation process, povidone K30, polysorbate 80 and the active pharmaceutical ingredient are prepared into a slurry at the same time, which can protect the active pharmaceutical ingredient and ensure that the active pharmaceutical ingredient is evenly dispersed in the slurry, thus ensuring the uniformity of the content of the active pharmaceutical ingredient in the formulation.

[0013] Preparation of soft material: Set the stirring speed of the mixing granulator to 180-220 rpm, the cutting speed to 1800-2200 rpm, and the atomization pressure to be determined according to the actual situation. Add the prepared slurry to the mixing granulator for 120-180 seconds to obtain the soft material. Granulation: Set the mixing speed of the granulator to 180-220 rpm or 1800-2200 rpm, and the granulation time to 2-4 min.

[0014] S4: Wet granulation: Use a 6-mesh granulation screen to wet granulate the granules after granulation.

[0015] S5: Drying: Spread the prepared wet granules evenly on drying trays (approximately 2 / 3 of the tray volume, about 1 kg / tray), and place them on the drying cart in a top-to-bottom order. After pushing the drying cart into the drying oven, control the drying temperature in the oven at 60℃±10℃, and dry until the moisture content is ≤3%. After the temperature reaches 60℃, turn the granules over every half hour and rotate the drying trays on the drying cart to make the heat distribution in the drying oven more uniform, thereby improving the drying speed and uniformity. After drying, close the steam valve and send clean air to cool the granules to room temperature.

[0016] S6: Dry granulation: Use a granulation sieve with a mesh size of 30 mesh to dry granulate the granules after drying; S7: Total Mixing: Weigh the dry granules after granulation, calculate the yield, and calculate the amount of silica, corn starch, talc, and magnesium stearate to be used; add the dry granules after granulation to the mixing granulator, add corn starch, talc, magnesium stearate, and silica (passed through a 30-mesh sieve) to the mixing granulator, set the speed of the mixing granulator to 11-13 rpm, and the mixing time to 5-10 min; S8: Tableting: Add the total mixed granules into the hopper of a fully automatic high-speed tablet press. For the 1mg specification, use a Φ8.10 circular punch. Adjust the main machine speed to 156KT / h~234KT / h, and the tablet hardness to 4~6kg to obtain the drug. Drug properties: Should be white tablets; Average tablet weight: Should be ±5.0% of the total tablet weight; Weight variation: ±7.5%, no more than 2 tablets exceeding ±7.5%, and no single tablet exceeding ±15.0%.

[0017] S9: Packaging: Aluminum-plastic packaging, full inspection, warehousing.

[0018] Compared with the prior art, the present invention has the following beneficial effects: (1) This invention creatively introduces a synergistic system of trace agar and polysorbate 80 into the formulation. As a natural hydrophilic colloid, agar can form a hydrophilic network structure during granulation. It works synergistically with polysorbate 80 (a surfactant) to greatly improve the wettability and dispersibility of the slurry for ultrafine bumetanide, preventing drug agglomeration. As a result, the drug can be more evenly distributed in the granules during subsequent drying and tableting. This not only improves the uniformity of content, but more importantly, the hydrophilic network can quickly hydrate after the tablets come into contact with water, forming a rapid channel. This, combined with the solubilizing effect of polysorbate 80, allows the ultrafine bumetanide to dissolve rapidly.

[0019] (2) This invention employs a unique process combining "API premixed airflow milling" with "partial internal addition of excipients". First, bumetanide is mixed with a small amount of silica (flow aid) and then airflow milled. Silica effectively reduces electrostatic adsorption and material adhesion to the walls during the ultrafine pulverization process, improving milling efficiency and powder flowability. Then, this pretreated API is added to the slurry, ensuring it is fully dispersed and coated by polysorbate 80 and hydrophilic colloids during the slurry stage. Simultaneously, excipients such as silica, corn starch, talc, and magnesium stearate are added externally during the final mixing, maximizing the preservation of lubricant and flow aid functions and preventing them from becoming embedded and ineffective during wet granulation. This "internal and external" excipient addition method is key to achieving excellent content uniformity, high dissolution rate, and good compressibility simultaneously.

[0020] (3) Through the synergistic innovation of the above-mentioned formulation and process, the dissolution rate of the bumetanide tablets prepared by the present invention is significantly higher than that of the commercial reference preparation within 15 minutes, the content uniformity RSD is less than 2.0%, the product shows slow growth of related substances in accelerated stability test, and the quality attributes are superior to those of products prepared by conventional methods.

[0021] (4) After the drying temperature reaches 60℃, turn the granules over every half hour and change the position of the drying trays on the drying cart. This operation can make the heat distribution in the drying oven more uniform and improve the drying speed and uniformity. Attached Figure Description

[0022] Figure 1 is a process flow diagram of the present invention; Detailed Implementation

[0023] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0024] Example 1 Preparation of bumetanide tablets (1 mg / tablet): Prescription (based on a production of 150,000 tablets): Bumetanide 150g

[0025] 12450g of corn starch

[0026] 7800g of lactose

[0027] 30g of agar

[0028] Povidone K30 (450g internal, 300g external) Total 750g

[0029] Polysorbate 80 22.5g

[0030] Silica (150g internally, 375g externally) Total 525g

[0031] Talc powder 397.5g

[0032] 75g magnesium stearate

[0033] Appropriate amount of purified water

[0034] Preparation method: API pretreatment: Weigh 150g of bumetanide and 150g of silica and mix them. Use an air jet mill with the feed pressure set at 4.5 bar, the grinding pressure at 4.0 bar, and the feed speed at 12 rpm. The API particle size after grinding is D50=8.5μm and D90=13.2μm.

[0035] Premix: Weigh 12000g corn starch, 7800g lactose, 30g agar, and 450g povidone K30 and add them to a wet granulator. Mix at 200rpm and 1800rpm for 5 minutes.

[0036] Granulation: Polysorbate 80, pretreated API, and 300g of povidone K30 were added to an appropriate amount of purified water and dispersed at high speed using a shearing method to form a slurry. Under premixed material operation (stirring 200rpm, cutter 1800rpm), the slurry was sprayed in over 150s. Then, the cutter speed was increased to 2000rpm, and granulation continued for 3 minutes.

[0037] Wet granulation: granulating the soft material through an 8-mesh sieve.

[0038] Drying: Spread the wet granules on trays and dry them in an oven at 60℃ until the moisture content is 2.1%. During this process, turn the trays over and change their positions every half hour.

[0039] Dry granulation: Dry granules are granulated by passing them through a 30-mesh sieve.

[0040] Final Mixing: Weigh the dry granules, and based on the dry granule weight, weigh out the remaining 450g corn starch, 397.5g talc, 75g magnesium stearate, and 375g silica that has passed through a 30-mesh sieve. Add all materials to a three-dimensional mixer and mix at 12 rpm for 10 minutes.

[0041] Tableting: Use a Φ8.10mm shallow concave die, adjust the tablet press parameters, and control the tablet weight to approximately 140mg and the hardness to 5.0kg.

[0042] Packaging: Aluminum-plastic blister packaging.

[0043] Example 2 Preparation of Bumetanide Tablets (1 mg / tablet)

[0044] Prescription (based on a production of 150,000 tablets):

[0045] Bumetanide 150g

[0046] 12750g of corn starch

[0047] 7500g of lactose

[0048] 45g of agar

[0049] Povidone K30 (375g internally, 300g externally) Total 675g

[0050] Polysorbate 80 30g

[0051] Silica (180g internally, 495g externally) Total 675g

[0052] 300g of talcum powder

[0053] 105g magnesium stearate

[0054] Appropriate amount of purified water

[0055] The preparation steps are the same as in Example 1, wherein the API particle size after air jet milling is D50=9.2μm and D90=14.5μm; the moisture content after drying is 2.5%; and the tablet hardness is 4.5kg.

[0056] Example 3 Preparation of Bumetanide Tablets (1 mg / tablet)

[0057] Prescription (based on a production of 150,000 tablets):

[0058] Bumetanide 150g

[0059] 12150g of corn starch

[0060] 8100g of lactose

[0061] 15g of agar

[0062] Povidone K30 (525g internal, 225g external) Total 750g

[0063] Polysorbate 80 15g

[0064] Silica (120g internally, 330g externally) Total 450g

[0065] 495g of talcum powder

[0066] 45g magnesium stearate

[0067] Appropriate amount of purified water

[0068] The preparation steps are the same as in Example 1, wherein the API particle size after air jet milling is D50=7.8μm, D90=12.8μm; the moisture content after drying is 1.9%; and the tablet hardness is 5.5kg.

[0069] Comparative Example 1 (without agar and polysorbate 80)

[0070] The formulation and process are basically the same as in Example 1, but agar and polysorbate 80 are removed, and all povidone K30 is added internally. The slurry is prepared using only API and povidone K30.

[0071] Comparative Example 2 (conventional wet granulation, without ultrafine grinding)

[0072] The formulation is the same as in Example 1, but the S1 air jet milling step is omitted, and the active pharmaceutical ingredient is directly passed through an 80-mesh sieve. No silica is added to the granulation slurry.

[0073] Comparative Example 3 (Commercially Available Reference Preparation)

[0074] Bumetanide tablets (1mg) were purchased from a listed company.

[0075] Experimental Example: Quality Comparison Study

[0076] (The testing methods and standards are the same as before)

[0077] The following tests were performed on the samples obtained in Examples 1-3 and Comparative Examples 1-3 of the present invention: Content uniformity: The content of 10 tablets was determined according to the General Chapter 0941 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0078] Dissolution test: According to the quality standard of bumetanide tablets in the 2020 edition of the Chinese Pharmacopoeia, 900 ml of pH 7.5 phosphate buffer was used as the dissolution medium. The dissolution was performed by paddle method at 50 rpm, and samples were taken at 5, 10, 15, 30 and 45 min respectively.

[0079] Accelerated stability test: The sample was placed in a constant temperature and humidity chamber at 40℃±2℃ and RH 75%±5% for 6 months. Samples were taken at the end of 0, 3 and 6 months to detect related substances (total impurities).

[0080] Test results: project Example 1 Example 2 Example 3 Comparative Example 1 Content uniformity RSD (%) 1.2 1.5 1.0 3.8 Dissolution rate in 15 minutes (%) 98.5 96.8 99.1 75.2 Stability (6 months) Total impurities increased +0.12% +0.15% 0.10% +0.45%

[0081] It should be noted that the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0082] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A bumetanide tablet, characterized in that, Raw materials, by mass ratio, include: Bumetanide 1; Corn starch, 81-85; Lactose, 50-54; Agar, 0.1–0.3; Povidone K30, 4-6; Polysorbate 80, 0.1–0.2; Silicon dioxide, 3–4.5; Talc, 2-3.3; Magnesium stearate, 0.3–0.7%.

2. A method for preparing the bumetanide tablets according to claim 1, characterized in that, Includes the following steps: S1: Pretreatment: Weigh the prescribed amount of bumetanide and silica. Pass the silica through a 30-mesh sieve. Perform air jet milling on the raw material. The particle size needs to be controlled within D50≤10μm and D90≤15μm to obtain API. S2: Premix: Premix the prescribed amounts of corn starch, lactose, agar, and povidone K30 in a wet granulator; S3: Granulation: Slurry preparation: Weigh out the prescribed amount of polysorbate 80, pretreated API, and prescribed amount of povidone K30 and disperse them in the prescribed amount of purified water to prepare a slurry for later use; Preparation of soft material: The prepared slurry is added to a mixing granulator to obtain soft material; Granulation: Set the mixing speed and cutter speed of the granulator, and start granulation; S4: Wet granulation: Wet granulation is performed on the granules after granulation using a 6-mesh granulation screen. S5: Drying: Spread the prepared wet granules evenly on the drying trays and place them on the drying cart in a top-to-bottom order. After pushing the drying cart into the drying oven, control the drying temperature of the drying oven at 60℃±10℃ and dry until the moisture content is ≤3%. After the temperature reaches 60℃, turn the granules over every half hour and change the position of the drying trays on the drying cart. After drying is completed, close the steam valve and send clean air to cool the granules to room temperature. S6: Dry granulation: Use a granulation sieve with a mesh size of 30 mesh to dry granulate the granules after drying; S7: Total Mixing: Weigh the dry granules after granulation, calculate the yield, and calculate the amount of silica, corn starch, talc, and magnesium stearate to be used; add the dry granules after granulation to the mixing granulator, add corn starch, talc, magnesium stearate, and silica (passed through a 30-mesh sieve) to the mixing granulator, and mix for 5-10 minutes. S8: Tableting: The total mixed granules are added into the hopper of a fully automatic high-speed tableting machine to produce tablets; S9: Packaging: Aluminum-plastic packaging, full inspection, warehousing.

3. The method for preparing bumetanide tablets according to claim 2, characterized in that: In step S1, the raw material crushing parameters are: feed pressure 4.5±1.0 bar, crushing pressure 4.0±1.0 bar, and feeding speed 10-15 rpm.

4. The method for preparing bumetanide tablets according to claim 2, characterized in that: In step S2, the stirring speed of the mixing granulator is set to 180-220 rpm, the cutter speed is set to 1600-2000 rpm, and the premixing time is set to 3-7 min.

5. The method for preparing bumetanide tablets according to claim 2, characterized in that: In step S3, the granulation process involves adding slurry for 120–180 seconds, setting the mixing speed of the granulator to 180–220 rpm, the cutter speed to 1800–2200 rpm, and the atomization pressure to be determined based on actual conditions.

6. The method for preparing bumetanide tablets according to claim 2, characterized in that: In step S3, the mixing speed of the granulator is set to 180-220 rpm, the cutter speed to 1800-2200 rpm, and the granulation time to 2-4 min.

7. The method for preparing bumetanide tablets according to claim 2, characterized in that: In step S7, the rotation speed of the mixing granulator is set to 11-13 rpm.

8. The method for preparing bumetanide tablets according to claim 2, characterized in that: In step S8, the 1mg tablet uses a Φ8.10 circular punch, and the speed of the fully automatic high-speed tablet press is 156KT / h~234KT / h, with a tablet hardness of 4~6kg.

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