Production process of benzbromarone tablets

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and relates to a production process of benzbromarone tablets. The method comprises the following specific operation steps: sieving a benzbromarone raw material, sieving auxiliary materials, and weighing; the preparation method comprises the following steps: adding benzbromarone and 50% of auxiliary materials into a wet granulation mixer, premixing, atomizing, spraying ultrapure water, preliminarily granulating wet granules by a crushing granulator, transferring the wet granules to a fluidized bed for drying, and finishing drying after the moisture is reduced to 5-10%; mixing the semi-dry granules with the remaining auxiliary materials, carrying out secondary granulation by using a crushing and granulating machine, and sieving; adding talcum powder and magnesium stearate into the granules according to the conversion of the yield, transferring into a three-dimensional mixer, and mixing to form total mixed granules; calculating the tablet weight according to the content of the total mixed particles, and pressing the total mixed particles into slices; and carrying out secondary drying on the formed tablets through a fluidized bed until the water content is less than 2.5%, packaging and carrying out heat sealing. According to the process, a wet process and a dry process are combined, so that the process complementarity is enhanced, the uniformity and the dissolution rate of the tablet are improved, the dosage of auxiliary materials is small, and the economic benefit is good.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a production process of benzbromarone tablets. Background Art

[0002] Benzbromarone has a strong deuricosuric effect and can also effectively inhibit the production of uric acid. It has a dual effect of lowering the concentration of blood uric acid, relieving pain and swelling, and eliminating gout stones. It can be used to treat primary hyperuricemia, gouty arthritis intermittent period and gouty nodules. It is soluble in ether, slightly soluble in ethanol, and almost insoluble in water.

[0003] Chinese invention patent application CN 102429881A provides a method for preparing benzbromarone tablets, which requires the addition of a large amount of additives as adhesives. There are many types of adhesives, and the compatibility between the excipients and the main drug, as well as impurities in the excipients, pose hidden dangers to the safety of drug production.

[0004] Chinese invention patent application CN 104473863A provides a benzbromarone composition freeze-dried tablet and its preparation method. In combination with the physicochemical properties of benzbromarone, a large amount of starch aqueous solution is used as an auxiliary material. The corn starch is heated to gelatinize it, which provides the adhesive function. However, the system has poor fluidity, making it difficult to disperse the raw materials evenly. If the corn starch is not highly gelatinized, the resulting freeze-dried tablets are poorly brittle and difficult to meet pharmaceutical requirements. The addition of a large amount of water to the system results in a long drying time.

[0005] Chinese invention patent CN 115068437A provides a method for preparing benzbromarone capsules, which uses a secondary dry granulation process to form capsules. However, this process does not require friability testing of the formed capsules. However, the capsules increase production costs, and the dissolution of the capsules is determined by the melting of the capsule mold in the human body. The capsules are absorbed slowly by the human body, and the therapeutic effect is slow to take effect. In addition, the use of capsule molds also increases production costs. Summary of the Invention

[0006] The technical problem to be solved by the present invention is: in response to the above-mentioned defects, the present invention provides a production process for benzbromarone tablets, which combines wet and dry processes to enhance process complementarity, improve tablet uniformity and dissolution, use less excipients, and has good economic benefits.

[0007] The present invention solves the technical problem by adopting the following technical solution: a production process of benzbromarone tablets, comprising the following steps:

[0008] Step 1, pretreatment of raw materials, sieving the benzbromarone raw material, sieving the auxiliary materials, and weighing them; the auxiliary materials are corn starch, lactose, and hydroxypropyl cellulose;

[0009] Step 2, wet forming, adding benzbromarone and 50% of the excipients into a wet granulation mixer, premixing, spraying ultrapure water into the wet granules to a moisture content of 15%-25%, passing the wet granules through a pulverizer for preliminary granulation, and transferring the wet granules to a fluidized bed dryer to reduce the moisture content to 5%-10% before finishing the drying;

[0010] Step 3, dry consolidation, mixing the semi-dry granules and the remaining excipients in a three-dimensional mixer, the granules coated with the dry powder are granulated again by a crushing and granulating machine, and sieved; talc and magnesium stearate are added to the granules according to the yield, and the granules are transferred to a three-dimensional mixer for mixing to form a total mixed granule;

[0011] Step 4, tableting and packaging: The tablet weight is calculated based on the content of the total mixed particles, and the total mixed particles are pressed into thin sheets using a dry roller press. A pre-pressing and main pressing dual-stage mode is adopted to control the tablet weight difference to ±5% and the hardness to 40±10N; the formed tablets are dried in a fluidized bed for a second time until the moisture content is less than 2.5%, and then packaged and heat-sealed.

[0012] The production process of benzbromarone tablets claimed for protection in this application adopts a granulation process combining wet molding and dry consolidation, wherein only 50% of the excipients are added in the wet stage, and the remaining excipients are added during the dry consolidation, which not only ensures that the wet granules have moderate viscosity, but also avoids excessive excipients interfering with the dispersion of benzbromarone, thereby improving the uniformity of the content; the moisture content of the wet granules is controlled, and they are dried once and twice, which can not only retain the viscosity during dry consolidation, but also reduce production energy consumption, and effectively avoid the risk of benzbromarone crystallization, thereby maintaining the stability of the raw materials; only necessary excipients such as corn starch, lactose, and hydroxypropyl cellulose are used to reduce interference from impurities, wherein corn starch is adapted to the process to enhance adhesion and disintegration, promote drug release, and ensure the dissolution rate of benzbromarone tablets.

[0013] In addition, this process uses a dry secondary granulation method and adds talc powder and magnesium stearate in the final stage to avoid premature mixing that affects granule fluidity, thereby taking into account both granule uniformity and tableting operability. The tableting operation adopts dual control of pre-compression and main compression to reduce the risk of flakes and ensure appropriate mechanical strength. The finished tablets undergo secondary low-temperature dehydration to completely eliminate the potential degradation risk caused by residual moisture and extend the shelf life.

[0014] Furthermore, in the benzbromarone tablets, the mass fractions of benzbromarone and excipients in each tablet are as follows: benzbromarone 50 mg, corn starch 40-60 mg, lactose 20-40 mg, hydroxypropyl cellulose 10-20 mg, talc 1-2 mg, and magnesium stearate 1-2 mg. By controlling the content of each benzbromarone tablet, on the one hand, the efficacy is ensured, and on the other hand, combined with the process, the introduction of fewer excipients and other auxiliary agents can be reduced, reducing the difficulty of benzbromarone tablet auxiliary agents in the human body. Corn starch acts as a filler and disintegrant to ensure the disintegration rate of the benzbromarone tablets, and lactose acts as a filler to effectively improve the fluidity of the powder during mixing and granulation. A small amount of hydroxypropyl cellulose is used as a binder under the action of ultrapure water.

[0015] Furthermore, in the raw material pretreatment of step 1, benzbromarone is screened with a 60-80 mesh sieve, and the auxiliary materials are screened with a 20-60 mesh sieve. By limiting the precise screening of benzbromarone and the auxiliary materials, the fineness of the raw materials is ensured to be uniform, dead corners in mixing are reduced, local content deviation is avoided, and uniform mixing is achieved.

[0016] Furthermore, in step 2, the wet granulation mixer has a stirring speed of 10-100 rpm and a cutting speed of 100-1000 rpm. During the atomization and injection of ultrapure water, the peristaltic pump has a speed of 200-600 rpm, and the water addition time is 10-120 seconds. The wet granulation is passed through a granulator with a speed of 100-300 rpm and a screen aperture of 0.5-1.5 mm. The wet granulation process utilizes a combination of low-speed stirring and high-speed cutting, coupled with atomization and water spraying, to form uniform, loose granules, thereby improving subsequent dissolution efficiency.

[0017] Furthermore, during the dry consolidation in step 3, the speed of the pulverizer is 100-300 rpm, and the sieve aperture is 2.0-2.5 mm; the speed when the semi-dry granules are mixed with the remaining excipients is 10-100 rpm, and the speed in the three-dimensional mixer after adding talc and magnesium stearate is 10-20 rpm.

[0018] Furthermore, in the tablet packaging in step 4, the pre-compression pressure is 3-5 kN and the main compression pressure is 12-20 kN.

[0019] Furthermore, the fluidized bed drying temperature during wet forming in step 2 is 40-70°C, and during tablet packaging in step 4, the fluidized bed secondary drying temperature is 40-45°C. The primary drying process can quickly remove moisture and operate at a low temperature, effectively and significantly reducing the risk of benzbromarone crystallization and maintaining the chemical stability of the raw material. The secondary drying process strictly controls the low temperature to remove moisture and prevent excessive moisture loss, which may reduce the brittleness of the tablets.

[0020] Furthermore, in the tablet packaging step 4, the heat sealing temperature is 170-200° C. The heat sealing at 170-200° C. avoids heat damage to the packaging material while ensuring sealing.

[0021] The beneficial effects of the present invention are:

[0022] 1. The production process of benzbromarone tablets claimed in the present application adopts a granulation process combining wet forming and dry consolidation, wherein only 50% of the excipients are added in the wet stage, and the remaining excipients are added during the dry consolidation, which not only ensures that the wet granules have moderate viscosity, but also avoids excessive excipients interfering with the dispersion of benzbromarone, thereby improving the uniformity of the content; the moisture content of the wet granules is controlled, and they are dried once and twice, which can not only retain the viscosity during dry consolidation, but also reduce production energy consumption, and effectively avoid the risk of benzbromarone crystallization, thereby maintaining the stability of the raw materials; only necessary excipients such as corn starch, lactose, and hydroxypropyl cellulose are used to reduce interference from impurities, wherein corn starch is adapted to the process to enhance the bonding and disintegration effects, promote drug release, and ensure the dissolution rate of benzbromarone tablets.

[0023] 2. This process uses a dry secondary granulation method and adds talc and magnesium stearate at the final stage to avoid premature mixing that affects granule flowability, thereby balancing granule uniformity and tableting operability. The tableting operation uses dual control of pre-compression and main compression to reduce the risk of flakes and ensure appropriate mechanical strength. The finished tablets undergo a secondary low-temperature dehydration to completely eliminate the potential degradation risk caused by residual moisture and extend shelf life.

[0024] 3. This process addresses the issues of uneven dissolution and poor storage stability encountered in traditional processes through four core measures: staged water control, low-temperature operation to prevent crystallization, gradient pressure tableting, and step-by-step addition of excipients. While ensuring the stability of benzbromarone, it also takes into account dissolution efficiency and production controllability, providing a reliable path for highly bioequivalent tablets. DETAILED DESCRIPTION

[0025] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below with reference to examples. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0026] Example 1

[0027] In the benzbromarone tablets of this embodiment, the mass fractions of benzbromarone and excipients in each tablet are as follows: benzbromarone 50 mg, corn starch 60 mg, lactose 20 mg, hydroxypropyl cellulose 20 mg, talc 1 mg, and magnesium stearate 2 mg.

[0028] A production process for benzbromarone tablets comprises the following steps:

[0029] Step 1, pretreatment of raw materials, sieving the benzbromarone raw material through an 80-mesh sieve, sieving the auxiliary materials through a 50-mesh sieve, and weighing them; the auxiliary materials are corn starch, lactose, and hydroxypropyl cellulose;

[0030] Step 2, wet forming, adding benzbromarone and 50% of the excipients to a wet granulation mixer, premixing, stirring at a speed of 15 rpm and a cutting speed of 100 rpm in the wet granulation mixer; spraying ultrapure water by atomization, with the peristaltic pump speed at 200 rpm during the spraying of ultrapure water, and the water addition time for 100 seconds; the wet granules have a moisture content of 25%, and the wet granules are initially granulated by a pulverizer at a speed of 100 rpm and a screen aperture of 1.5 mm; the wet granules are transferred to a fluidized bed dryer at a fluidized bed drying temperature of 65° C. and the drying is completed after the moisture content is reduced to 10%;

[0031] Step 3, dry consolidation, the semi-dry granules and the remaining excipients are mixed uniformly in a three-dimensional mixer at a speed of 10 rpm; the granules coated with the dry powder are passed through a crushing and granulating machine for secondary granulation, and sieved, the speed of the crushing and granulating machine is 100 rpm, and the mesh size is 2.5 mm; talc and magnesium stearate are added to the granules according to the yield, and the granules are transferred to a three-dimensional mixer for mixing at a speed of 10 rpm to form a total mixed granule;

[0032] Step 4, tableting and packaging: the tablet weight is calculated based on the content of the total mixed particles, and the total mixed particles are pressed into thin sheets using a dry roller press. A pre-pressing and main pressing dual-section mode is adopted, with a pre-pressing pressure of 3 kN and a main pressing pressure of 12 kN. The tablet weight difference is controlled to ±5%, and the hardness is controlled to 40 ± 10 N. The formed tablets are subjected to secondary fluidized bed drying at a drying temperature of 45° C. and a moisture content of less than 2.5%. They are then packaged and heat-sealed at a heat sealing temperature of 180° C.

[0033] Example 2

[0034] In the benzbromarone tablets of this embodiment, the mass fractions of benzbromarone and excipients in each tablet are as follows: benzbromarone 50 mg, corn starch 50 mg, lactose 35 mg, hydroxypropyl cellulose 15 mg, talc 2 mg, and magnesium stearate 2 mg.

[0035] A production process for benzbromarone tablets comprises the following steps:

[0036] Step 1, pretreatment of raw materials, sieving the benzbromarone raw material through a 60-mesh sieve, sieving the auxiliary materials through a 24-mesh sieve, and weighing them; the auxiliary materials are corn starch, lactose, and hydroxypropyl cellulose;

[0037] Step 2, wet forming, adding benzbromarone and 50% of the excipients to a wet granulation mixer, premixing, stirring at 80 rpm and cutting at 800 rpm in the wet granulation mixer; spraying ultrapure water by atomization, with the peristaltic pump speed at 600 rpm during the spraying of ultrapure water, and the water addition time for 60 seconds; the wet granules have a moisture content of 18%, and are initially granulated by a pulverizer at a speed of 300 rpm and a screen aperture of 1.0 mm; the wet granules are transferred to a fluidized bed dryer at a fluidized bed drying temperature of 50° C., and drying is completed after the moisture content is reduced to 8%;

[0038] Step 3, dry consolidation, the semi-dry granules and the remaining excipients are mixed uniformly in a three-dimensional mixer at a speed of 100 rpm; the granules coated with the dry powder are passed through a crushing and granulating machine for secondary granulation, and sieved, the speed of the crushing and granulating machine is 300 rpm, and the mesh size is 2.0 mm; talc and magnesium stearate are added to the granules according to the yield, and the granules are transferred to a three-dimensional mixer for mixing at a speed of 18 rpm to form a total mixed granule;

[0039] Step 4, tableting and packaging: the tablet weight is calculated based on the content of the total mixed particles, and the total mixed particles are pressed into thin sheets using a dry roller press. A pre-pressing and main pressing dual-section mode is adopted, with a pre-pressing pressure of 4 kN and a main pressing pressure of 15 kN. The tablet weight difference is controlled to ±5%, and the hardness is controlled to 40 ± 10 N. The formed tablets are subjected to secondary fluidized bed drying at a drying temperature of 45°C and a moisture content of less than 2.5%. They are then packaged and heat-sealed at a heat sealing temperature of 200°C.

[0040] Example 3

[0041] In the benzbromarone tablets of this embodiment, the mass fractions of benzbromarone and excipients in each tablet are as follows: benzbromarone 50 mg, corn starch 40 mg, lactose 40 mg, hydroxypropyl cellulose 10 mg, talc 1.5 mg, and magnesium stearate 1.5 mg.

[0042] A production process for benzbromarone tablets comprises the following steps:

[0043] Step 1, pretreatment of raw materials, sieving the benzbromarone raw material through a 60-mesh sieve, sieving the auxiliary materials through a 40-mesh sieve, and weighing them; the auxiliary materials are corn starch, lactose, and hydroxypropyl cellulose;

[0044] Step 2, wet forming, adding benzbromarone and 50% of the excipients to a wet granulation mixer, premixing, stirring at 50 rpm and cutting at 500 rpm in the wet granulation mixer; spraying ultrapure water by atomization, with the peristaltic pump speed at 400 rpm during the spraying of ultrapure water, and adding water for 30 seconds; the wet granules have a moisture content of 15%, and are initially granulated by a pulverizer at a speed of 100 rpm and a screen aperture of 0.5 mm; the wet granules are transferred to a fluidized bed dryer at a fluidized bed drying temperature of 40° C., and drying is completed after the moisture content is reduced to 5%;

[0045] Step 3, dry consolidation, the semi-dry granules and the remaining excipients are evenly mixed in a three-dimensional mixer at a speed of 20 rpm; the granules coated with the dry powder are granulated twice in a pulverizer at a speed of 100 rpm and a sieve aperture of 2.0 mm; talc and magnesium stearate are added to the granules according to the yield, and the granules are transferred to a three-dimensional mixer for mixing at a speed of 12 rpm to form a total mixed granule;

[0046] Step 4, tableting and packaging: the tablet weight is calculated based on the content of the total mixed particles, and the total mixed particles are pressed into thin sheets using a dry roller press. A pre-pressing and main pressing dual-section mode is adopted, with a pre-pressing pressure of 4 kN and a main pressing pressure of 12 kN. The tablet weight difference is controlled to ±5%, and the hardness is controlled to 40 ± 10 N. The formed tablets are subjected to secondary fluidized bed drying at a drying temperature of 40° C. and a moisture content of less than 2.5%. The tablets are then packaged and heat-sealed at a heat sealing temperature of 200° C.

[0047] The benzbromarone tablets prepared in the above example were compared with commercially available randomly selected benzbromarone tablets, and the friability and dissolution were tested according to the method provided in the 2015 edition of the Chinese Pharmacopoeia:

[0048]

[0049] According to the quality standards for benzbromarone tablets in the 2015 edition of the "Chinese Pharmacopoeia", the benzbromarone tablets prepared using this process meet the requirements; according to the dissolution rates measured at different times, the dissolution rate of the benzbromarone tablets reached more than 85% at 30 minutes and more than 45% at 15 minutes. The time it takes for the benzbromarone tablets to reach peak blood concentration is short and the bioavailability is high.

[0050] With the above-mentioned ideal embodiment of the present invention as inspiration, and through the above description, relevant personnel can make various changes and modifications without departing from the scope of the technical concept of this invention patent. The technical scope of this invention patent is not limited to the content of the specification, but must be determined according to the scope of the claims.

Claims

1. A production process for benzbromarone tablets, characterized in that: The following steps are included: Step 1, pretreatment of raw materials, sieving the benzbromarone raw material, sieving the auxiliary materials, and weighing them; the auxiliary materials are corn starch, lactose, and hydroxypropyl cellulose; Step 2, wet forming, adding benzbromarone and 50% of the excipients into a wet granulation mixer, premixing, spraying ultrapure water into the wet granules to a moisture content of 15%-25%, passing the wet granules through a pulverizer for preliminary granulation, and transferring the wet granules to a fluidized bed dryer to reduce the moisture content to 5%-10% before finishing the drying; Step 3, dry consolidation, mixing the semi-dry granules and the remaining excipients in a three-dimensional mixer, the granules coated with the dry powder are granulated again by a crushing and granulating machine, and sieved; talc and magnesium stearate are added to the granules according to the yield, and the granules are transferred to a three-dimensional mixer for mixing to form a total mixed granule; Step 4, tableting and packaging: The tablet weight is calculated based on the content of the total mixed particles, and the total mixed particles are pressed into thin sheets using a dry roller press. A pre-pressing and main pressing dual-stage mode is adopted to control the tablet weight difference to ±5% and the hardness to 40±10N; the formed tablets are dried in a fluidized bed for a second time until the moisture content is less than 2.5%, and then packaged and heat-sealed.

2. The production process of a benzbromarone tablet according to claim 1, characterized in that: In the benzbromarone tablets, the mass fractions of benzbromarone and excipients in each tablet are as follows: benzbromarone 50 mg, corn starch 40-60 mg, lactose 20-40 mg, hydroxypropyl cellulose 10-20 mg, talc 1-2 mg, and magnesium stearate 1-2 mg.

3. The production process of a benzbromarone tablet according to claim 1, wherein: In the raw material pretreatment of step 1, benzbromarone is screened using a 60-80 mesh sieve, and the auxiliary materials are screened using a 20-60 mesh sieve.

4. The production process of a benzbromarone tablet according to claim 1, wherein: In the wet forming in step 2, the stirring speed in the wet granulation mixer is 10-100 rpm, and the cutting speed is 100-1000 rpm. When the ultrapure water is sprayed into the atomized form, the peristaltic pump speed is 200-600 rpm, and the water addition time is 10-120 seconds. The speed of the wet granule grinding and granulation machine is 100-300 rpm, and the screen aperture is 0.5-1.5 mm.

5. The production process of a benzbromarone tablet according to claim 1, characterized in that: During dry consolidation in step 3, the rotation speed of the pulverizer is 100-300 rpm, and the sieve aperture is 2.0-2.5 mm; the rotation speed when the semi-dry granules are mixed with the remaining excipients is 10-100 rpm, and the rotation speed in the three-dimensional mixer after adding talc and magnesium stearate is 10-20 rpm.

6. The production process of a benzbromarone tablet according to claim 1, characterized in that: In the tablet packaging step 4, the pre-compression pressure is 3-5 kN and the main compression pressure is 12-20 kN.

7. The production process of a benzbromarone tablet according to claim 1, characterized in that: The fluidized bed drying temperature during the wet forming process in step 2 is 40-70° C., and the fluidized bed secondary drying temperature during the tableting and packaging process in step 4 is 40-45° C.

8. The production process of a benzbromarone tablet according to claim 1, characterized in that: In the tablet packaging step 4, the heat sealing temperature is 170-200°C.

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