Ibuprofen granules and preparation method thereof

Abstract

The invention discloses an ibuprofen granule and a preparation method thereof, and the preparation method comprises the following steps: mixing ibuprofen, a filling agent, a disintegrating agent and an adhesive to obtain premixed medicine powder; dissolving a sweetening agent in water to serve as a wetting agent; spraying a wetting agent into the premixed medicine powder to prepare a soft material; the soft material is subjected to granulation; after the granulation is completed, carrying out rolling operation to obtain rolled particles; the rounded particles are dried; the dried particles are subjected to particle finishing; and mixing the whole granules with an aromatic agent to obtain the ibuprofen granules. According to the invention, the process is optimized, so that the ibuprofen granules obtained by the invention have good dissolution, stability and absorption.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical preparations, and particularly relates to an ibuprofen granule and its preparation method. Background Art

[0002] Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID). As an effective cyclooxygenase inhibitor, it has antipyretic, analgesic, and anti-inflammatory effects.

[0004] Currently, ibuprofen preparations mainly administered orally on the market include various forms such as sustained-release capsules, tablets, granules, suspensions, and soft capsules. As a BCS class II drug, ibuprofen is characterized by low solubility but high biofilm permeability, which determines its special requirements in formulation development.

[0005] Although ibuprofen has significant efficacy, when administered orally, there is a problem of low bioavailability. Due to its low solubility, the bioavailability of ibuprofen is limited. Ibuprofen is easily affected by high temperature and high humidity, resulting in a decrease in the stability of the preparation. In some cases, ibuprofen may cause adverse reactions.

[0006] To solve these problems, currently commonly used technical means include: adding solubilizers or cosolvents to increase the solubility of ibuprofen. Preparing solid dispersions to enhance the dissolution rate of the drug. Using cyclodextrin for inclusion to improve the stability and absorption efficiency of the drug.

[0007] Therefore, in the development and production of ibuprofen preparations, optimizing the formulation design and process parameters is crucial. Through a carefully designed combination of technical features, not only can the inherent challenges in the physicochemical properties of ibuprofen granules be solved, but also its bioavailability and stability can be significantly improved, providing a more reliable and safer medication option. The optimized ibuprofen granules can not only dissolve quickly and be absorbed by the body, providing rapid and lasting efficacy, but also maintain good physical and chemical stability for a long time, reducing quality changes caused by particle aggregation or environmental factors, thereby improving the patient's medication experience.

[0008] Patent CN115581673B discloses an ibuprofen granule and its preparation method, which is prepared by preferentially premixing ibuprofen with a filler having stable properties to form a stable structure, and then premixing with a filler and a disintegrant having relatively poor stability, and using the centrifugal granulation method at specific parameters to improve the uniformity and stability of the ibuprofen granule content.

[0009] Patent CN113318081A discloses an ibuprofen granule and its preparation method, which optimizes the prescription composition to improve the binding degree between the active ingredient, excipients, and binder, thereby improving the uniformity and dissolution performance of the drug.

[0010] The above methods all improve the quality of ibuprofen granules, but the types of excipients used are numerous, which will increase the related substances of ibuprofen and the instability of in vivo effects. Moreover, the preparation process is relatively complex and not suitable for large-scale industrial production. Summary of the Invention

[0011] The present application provides a preparation method of ibuprofen granules for solving the technical problems existing in the prior art, which includes the following steps: mixing ibuprofen, a filler, a disintegrant and a binder to obtain a premixed powder; dissolving a sweetener in water as a wetting agent; spraying the wetting agent into the premixed powder to prepare a soft material; granulating the soft material; performing a rounding operation after granulation to obtain rounded granules; drying the rounded granules; sizing the dried granules; and mixing the sized granules with an aromatic agent to obtain ibuprofen granules.

[0012] Further, the temperature of the granules obtained after drying is 40°C < granule temperature < 60°C.

[0013] Further, the moisture content of the granules obtained after drying is 0.3% < moisture content < 1.0%.

[0014] Further, the particle size of the ibuprofen is 10μm ≤ D90 ≤ 60μm, D50 ≤ 30μm.

[0015] Further, the filler passes through a 40-mesh sieve.

[0016] Further, the preparation method further includes the following step: spraying the wetting agent solution into the premixed powder to prepare a soft material under the conditions that the stirring speed of the wet granulator is 150 - 200 rpm, the shearing speed is 1500 - 2000 rpm, and the spraying pressure is 0.5 - 1.0 MPa.

[0017] Further, the preparation method further includes the following step: granulating the soft material using an 18-mesh nylon sieve.

[0018] Further, the preparation method further includes the following step: sizing the dried granules using a three-way vibrating sieve.

[0019] Further, by weight, the mass composition of the ibuprofen granules includes:

[0020] 180 - 220 parts of ibuprofen, 700 - 750 parts of filler, 25 - 35 parts of disintegrant, 25 - 35 parts of binder, 2 - 7 parts of sweetener, 5 - 15 parts of aromatic agent. The filler is lactose, the disintegrant is croscarmellose sodium, the binder is hydroxypropyl cellulose, the sweetener is sucralose, and the aromatic agent is acid orange powder essence.

[0021] On the other hand, the present invention provides ibuprofen granules prepared by the above method, and the total impurities of the ibuprofen granules are less than 0.06%.

[0022] Compared with the prior art, the preparation method of the ibuprofen granules of the present invention has the following advantages:

[0023] (1) Optimized dissolution characteristics: The release curve of the ibuprofen granules of the present invention in the dissolution test is closer to that of the reference drug, ensuring the smoothness and consistency of in vivo absorption. This improvement helps to maintain a stable blood drug concentration, thereby improving the therapeutic effect and reducing the occurrence of toxic and side effects.

[0024] (2) Excellent product quality: The ibuprofen granules obtained by the present invention have uniform content, consistent appearance, good fluidity and accurate filling volume.

[0025] (3) Improved product yield: By significantly optimizing the preparation process, the present invention has successfully achieved a higher product yield, improving production efficiency and economic benefits.

[0026] (4) Good stability: The ibuprofen granules prepared by the present invention show excellent stability in terms of related substances, ensuring the quality of the drug and the safety of long-term storage.

[0027] (5) Enhanced bioequivalence: The ibuprofen granules of the present invention show excellent performance in in vivo absorption and have better bioequivalence with the reference drug, ensuring the consistency and reliability of clinical efficacy.

[0028] (6) Simplified production process: The innovative preparation method not only simplifies the production process flow, but also may reduce the consumption of raw materials and production costs, improving the economic efficiency and sustainability of production. Specific embodiments

[0029] The technical solutions in the embodiments of the present application will be clearly described below. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art belong to the scope of protection of the present application.

[0030] The terms "first", "second", etc. in the description and claims of this application are used to distinguish similar objects, rather than to describe a specific order or sequence. It should be understood that the data used in this way can be interchanged under appropriate circumstances, so that the embodiments of this application can be implemented in an order other than those described herein, and the objects distinguished by "first", "second", etc. are generally of the same category, and do not limit the number of objects. For example, the first object can be one or more. In addition, "and / or" in the description and claims means at least one of the connected objects, and the character " / ", generally represents an "or" relationship between the associated objects before and after.

[0031] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, etc. used in the following examples can all be obtained from commercial channels unless otherwise specified.

[0032] The inventor found that by strictly controlling the key processes in the preparation method of ibuprofen granules, not only the dissolution characteristics highly similar to those of the reference preparation were achieved, but also the content of related substances was significantly reduced. In addition, this method can maintain a high product yield and ensure that the absorption amount of ibuprofen granules in the body reaches an ideal level. The whole process includes the following main steps:

[0033] (1) Crush the ibuprofen raw material drug, and control the particle size range to be 10μm ≤ D90 ≤ 60μm; at the same time, D50 ≤ 30μm; the filler passes through a 40-mesh sieve.

[0034] (2) Add ibuprofen, filler, disintegrant and binder to a wet granulator, set the stirring speed of the wet granulator to 180 rpm, the shearing (granulating) speed to 1000 rpm, and mix for 15 minutes to obtain a premixed powder; the present invention does not limit the mixing equipment and parameters, as long as the raw and auxiliary materials can be mixed evenly.

[0035] (3) Add the sweetening agent to water as a wetting agent, stir for more than 2 minutes until completely dissolved to obtain a wetting agent solution; the amount of water can be 30% - 70% of the total amount of other raw and auxiliary materials. The wetting agent water in the present invention will be removed during drying and only plays a wetting role.

[0036] (4) Under the conditions that the stirring speed of the wet granulator is 150 - 200 rpm, the shearing speed is 1500 - 2000 rpm, and the spraying pressure is 0.5 - 1.0 MPa, spray the wetting agent solution into the premixed powder to make soft materials.

[0037] (5) Granulate the soft material obtained in step (4) using a rocking granulator equipped with an 18-mesh nylon sieve. After granulation is completed, transfer it to a spherical shot blasting machine in operation (set the air blowing frequency at 30 Hz to 50 Hz and the rotary table speed at 10 Hz to 30 Hz), and roll for 3 to 6 minutes to obtain rolled granules.

[0038] (6) After the rolling operation is completed, transfer all the rolled granules to a fluidized bed granulator, set the inlet air temperature at 55 ± 5 °C, the material temperature at 50 ± 5 °C, and the fan frequency at 25 Hz to 40 Hz, and start heating for drying; control the particle temperature to be greater than 40 °C and less than 60 °C, excluding 40 °C and 60 °C, 40 °C < particle temperature < 60 °C, preferably 45 °C to 55 °C, including 45 °C and 55 °C, further preferably 48 °C to 52 °C, including 48 °C and 52 °C, such as 48 °C, 49 °C, 50 °C, 51 °C or 52 °C, but not limited to the listed values, and other unlisted values within this numerical range are equally applicable; the particle moisture < 1.0%, preferably 0.3% < moisture < 1.0%, greater than 0.3% and less than 1.0%, excluding 0.3% and 1.0%, further preferably 0.5 to 0.9%, including 0.5% and 0.9%, such as 0.5%, 0.6%, 0.7%, 0.8% or 0.9%, but not limited to the listed values, and other unlisted values within this numerical range are equally applicable. The moisture content in the granules of the present invention can be measured by a rapid moisture analyzer at 105 °C / 5 min.

[0039] Although the drying time and temperature are important, in the preparation process of ibuprofen granules, controlling the particle temperature during granulation is crucial for the formation of granules and the stability of the final product. Higher temperatures can accelerate solvent evaporation and shorten the drying time, but may also cause degradation of heat-sensitive components. Too low a temperature may result in poor particle hardness and poor water solubility, thus affecting the drug release rate and efficacy. An appropriate temperature range helps maintain the stability of the active ingredient and the integrity of the particle structure.

[0040] Controlling the particle moisture content is equally important for ensuring product quality. An appropriate moisture content helps maintain the physical stability, chemical stability, and microbial stability of the granules, and also ensures the smooth progress of the processing process.

[0041] (7) Screen the dried granules using a three-layer vibrating screen (equipped with a 16-mesh stainless steel sieve on the upper layer and a 60-mesh stainless steel sieve on the lower layer), and screen out the granules between 16 and 60 meshes.

[0042] (8) Total mixing: Mix the granules obtained in step (7) with the flavoring agent, set the mixer speed at 12 rpm, and mix for 15 minutes to obtain ibuprofen granules. Then package them according to the predetermined specifications. The present invention does not limit the mixing equipment and parameters, as long as the raw and auxiliary materials can be mixed evenly.

[0043] The mass composition of the ibuprofen granules, by weight, includes:

[0044] 180 - 220 parts of ibuprofen, 700 - 750 parts of filler, 25 - 35 parts of disintegrant, 25 - 35 parts of binder, 2 - 7 parts of sweetener, 5 - 15 parts of fragrance. Preferably, the amount of water used is 300 - 350 parts. Further preferably, it is 200 parts of ibuprofen, 725 parts of filler, 30 parts of disintegrant, 30 parts of binder, 5 parts of sweetener, 10 parts of fragrance, and the water is purified water with an amount of 320 parts.

[0045] The inventors found that although the principle is not yet clear, in the preparation process of the whole system, the change of actual experimental conditions has a very great impact on the effect of the invention.

[0046] During the granulation process, the preparation of the wetting agent, especially the timing of adding the binder, sweetener, and fragrance, will directly affect the quality of the ibuprofen product. In addition, the particle size of ibuprofen, the particle temperature, the moisture content, and whether there is a rounding process will all affect the dissolution, content uniformity, related substances, yield, and absorption of the ibuprofen granules.

[0047] The specific examples and comparative examples of the present invention are listed as follows, but the present invention is not limited to the following examples.

[0048] Example 1

[0049] Table 1 Prescription Composition

[0050] Ingredients 0.2g Specification mg Function Ibuprofen 200.00 Active ingredient Lactose 725.00 Filler Croscarmellose sodium 30.00 Disintegrant Hydroxypropyl cellulose 30.00 Binder Sucralose 5.00 Sweetener Tangerine powder essence 10.00 Fragrance Purified water 320.00 Wetting agent

[0051] The preparation process is as follows: (6000 bags)

[0052] (1) Pretreatment of raw and auxiliary materials: Crush the ibuprofen raw material, and control the particle size range to be 10μm ≤ D90 ≤ 60μm; D50 ≤ 30μm; Sieve lactose through a 40 - mesh sieve.

[0053] (2) Premixing: Add 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (after crushing) in the prescription amount to the wet granulator in sequence. Set the stirring speed of the wet granulator to 180 rpm, the shearing (granulation) speed to 1000 rpm, and mix for 15 minutes.

[0054] (3) Preparation of soft material: Weigh 1.92 kg of purified water, add 30 g of sucralose, stir for more than 2 minutes until completely dissolved, and use it as the wetting agent solution for standby. Set the stirring speed of the wet granulator to 180 rpm, the shearing (granulation) speed to 1800 rpm, the spraying pressure to 0.7 MPa, and spray the wetting agent solution into the premixed powder while starting the machine to prepare the soft material.

[0055] (4) Oscillating granulation and rolling: Take the soft material and granulate it with an oscillating granulator equipped with an 18-mesh nylon sieve. After granulation, transfer it to a spherical shot blasting machine in operation (set the air blowing frequency at 30 Hz - 50 Hz and the turntable rotation speed at 10 Hz - 30 Hz), and roll for 3 - 6 minutes to obtain rolled granules.

[0056] (5) Drying: After the rolling operation is completed, transfer all the rolled granules to a fluidized bed granulator. Set the inlet air temperature at 55 ± 5 °C, the material temperature at 50 ± 5 °C, and the fan frequency at 25 Hz - 40 Hz, and start heating for drying; control the particle temperature at 50 °C and the particle moisture content at 0.9%.

[0057] (6) Screening: Screen the dried granules with a three - layer vibrating screen (equipped with a 16 - mesh stainless steel sieve on the upper layer and a 60 - mesh stainless steel sieve on the lower layer), and screen out the granules between 16 - 60 meshes.

[0058] (7) Total mixing: Mix the granules obtained in step (6) with 60 g of acid orange powder essence. Set the rotation speed of the mixer at 12 rpm and mix for 15 minutes to obtain ibuprofen granules.

[0059] Example 2

[0060] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0061] (1) Pretreatment of raw and auxiliary materials: Crush the ibuprofen raw material, and control the particle size range as 10 μm ≤ D90 ≤ 60 μm; D50 ≤ 30 μm; sieve lactose through a 40 - mesh sieve.

[0062] (2) Premixing: Add 4.35 kg of lactose, 0.18 kg of cross - linked carboxymethylcellulose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (after crushing) in the prescription amount to a wet granulator in sequence. Set the stirring rotation speed of the wet granulator at 180 rpm, the shearing (granulation) rotation speed at 1000 rpm, and mix for 15 minutes.

[0063] (3) Preparation of soft material: Weigh 1.92 kg of purified water, add 30 g of sucralose, stir for more than 2 minutes until completely dissolved to obtain a wetting agent solution for standby. Set the stirring rotation speed of the wet granulator at 180 rpm, the shearing (granulation) rotation speed at 1800 rpm, and the spraying pressure at 0.7 MPa. While starting the machine, spray the wetting agent solution into the premixed powder to prepare the soft material.

[0064] (4) Oscillating granulation and rolling: Take the soft material and granulate it with an oscillating granulator equipped with an 18 - mesh nylon sieve. After granulation, transfer it to a spherical shot blasting machine in operation (set the air blowing frequency at 30 Hz - 50 Hz and the turntable rotation speed at 10 Hz - 30 Hz), and roll for 3 - 6 minutes to obtain rolled granules.

[0065] (5) Drying: After the round granulation operation is completed, all the round granules are transferred to a fluidized bed granulator. Set the inlet air temperature at 55 ± 5 °C, the material temperature at 50 ± 5 °C, and the fan frequency at 25 Hz - 40 Hz. Start heating for drying; control the granule temperature at 48 °C and the granule moisture at 0.9%.

[0066] (6) Screening: The dried granules are screened using a three - layer gyratory shaker (equipped with a stainless - steel screen with 16 meshes on the upper layer and 60 meshes on the lower layer), and the granules between 16 - 60 meshes are sieved out.

[0067] (7) Blending: The granules obtained in step (6) are mixed with 60 g of acid orange powder essence. Set the rotation speed of the blender at 12 rpm and mix for 15 minutes to obtain ibuprofen granules.

[0068] Example 3

[0069] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0070] (1) Pretreatment of raw and auxiliary materials: The ibuprofen raw material drug is pulverized, and the particle size range is controlled as 10 μm ≤ D90 ≤ 60 μm; D50 ≤ 30 μm; lactose is sieved through a 40 - mesh sieve.

[0071] (2) Premixing: 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (after pulverization) in the prescription amount are sequentially added to a wet granulator. Set the stirring speed of the wet granulator at 180 rpm, the shearing (granulation) speed at 1000 rpm, and mix for 15 minutes.

[0072] (3) Preparation of soft material: Weigh 1.92 kg of purified water, add 30 g of sucralose, stir for more than 2 minutes until completely dissolved to obtain a wetting agent solution for standby. Set the stirring speed of the wet granulator at 180 rpm, the shearing (granulation) speed at 1800 rpm, and the spraying pressure at 0.7 MPa. While starting the machine, spray the wetting agent solution into the premixed powder to prepare the soft material.

[0073] (4) Granulation by oscillating granulator and round granulation: Take the soft material and granulate it using an oscillating granulator equipped with an 18 - mesh nylon screen. After granulation is completed, transfer it to a spherical shot blasting machine in operation (set the air - blowing frequency at 30 Hz - 50 Hz and the turntable rotation speed at 10 Hz - 30 Hz), and perform round granulation for 3 - 6 minutes to obtain round granules.

[0074] (5) Drying: After the round granulation operation is completed, all the round granules are transferred to a fluidized bed granulator. Set the inlet air temperature at 55 ± 5 °C, the material temperature at 50 ± 5 °C, and the fan frequency at 25 Hz - 40 Hz. Start heating for drying; control the granule temperature at 52 °C and the granule moisture at 0.9%.

[0075] (6) Granulation: The dried granules are screened using a three - layer vibrating sieve (equipped with a 16 - mesh stainless - steel sieve on the upper layer and a 60 - mesh stainless - steel sieve on the lower layer), and the granules between 16 and 60 meshes are sieved out.

[0076] (7) Total mixing: The granules obtained in step (6) are mixed with 60 g of tangerine powder essence. Set the rotation speed of the mixer to 12 rpm and mix for 15 minutes to obtain ibuprofen granules.

[0077] Example 4

[0078] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0079] (1) Pretreatment of raw and auxiliary materials: The ibuprofen raw material drug is pulverized, and the particle size range is controlled as 10μm ≤ D90 ≤ 60μm; D50 ≤ 30μm; lactose is sieved through a 40 - mesh sieve.

[0080] (2) Premixing: 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (after pulverization) in the prescription amount are sequentially added to a wet granulator. Set the stirring speed of the wet granulator to 180 rpm, the shearing (granulating) speed to 1000 rpm, and mix for 15 minutes.

[0081] (3) Preparation of soft material: Weigh 1.92 kg of purified water, add 30 g of sucralose, stir for more than 2 minutes until completely dissolved to obtain a wetting agent solution for standby. Set the stirring speed of the wet granulator to 180 rpm, the shearing (granulating) speed to 1800 rpm, and the spraying pressure to 0.7 MPa. While starting the machine, spray the wetting agent solution into the premixed powder to prepare the soft material.

[0082] (4) Swing granulation and rounding: The soft material is granulated using a swing granulator equipped with an 18 - mesh nylon sieve. After granulation is completed, it is transferred to a spherical shot - blasting machine in operation (set the air - blowing frequency to 30 Hz - 50 Hz and the turntable rotation speed to 10 Hz - 30 Hz), and rounded for 3 - 6 minutes to obtain rounded granules.

[0083] (5) Drying: After the rounding operation is completed, all the rounded granules are transferred to a fluidized - bed granulator. Set the inlet air temperature to 55 ± 5°C, the material temperature to 50 ± 5°C, and the fan frequency to 25 Hz - 40 Hz, and start heating for drying; control the particle temperature to 50°C and the particle moisture content to 0.5%.

[0084] (6) Granulation: The dried granules are screened using a three - layer vibrating sieve (equipped with a 16 - mesh stainless - steel sieve on the upper layer and a 60 - mesh stainless - steel sieve on the lower layer), and the granules between 16 and 60 meshes are sieved out.

[0085] (7) Total mixing: The granules obtained in step (6) are mixed with 60 g of tangerine powder essence. Set the rotation speed of the mixer to 12 rpm and mix for 15 minutes to obtain ibuprofen granules.

[0086] Example 5

[0087] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0088] (1) Pretreatment of raw and auxiliary materials: The ibuprofen raw material drug is pulverized, and the particle size range is controlled to be 10μm ≤ D90 ≤ 60μm; D50 ≤ 30μm; lactose is sieved through a 40-mesh sieve.

[0089] (2) Premixing: 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (after pulverization) in the prescription amount are sequentially added to a wet granulator. Set the stirring speed of the wet granulator to 180 rpm, the shearing (granulating) speed to 1000 rpm, and mix for 15 minutes.

[0090] (3) Preparation of soft material: Weigh 1.92 kg of purified water, add 30 g of sucralose, stir for more than 2 minutes until completely dissolved, and use it as a wetting agent solution for standby. Set the stirring speed of the wet granulator to 180 rpm, the shearing (granulating) speed to 1800 rpm, and the spraying pressure to 0.7 MPa. While starting the machine, spray the wetting agent solution into the premixed powder to prepare the soft material.

[0091] (4) Swing granulation and spheronization: Take the soft material and granulate it with a swing granulator equipped with an 18-mesh nylon sieve. After granulation is completed, transfer it to a spherical shot blasting machine in operation (set the air blowing frequency to 30 Hz - 50 Hz, the rotary table speed to 10 Hz - 30 Hz), and spheronize for 3 - 6 minutes to obtain spheronized granules.

[0092] (5) Drying: After the spheronization operation is completed, transfer all the spheronized granules to a fluidized bed granulator. Set the inlet air temperature to 55 ± 5°C, the material temperature to 50 ± 5°C, and the fan frequency to 25 Hz - 40 Hz, and start heating for drying; control the particle temperature to 50°C and the particle moisture to 0.8%.

[0093] (6) Screening: Screen the dried granules with a three - layer vibrating screen (equipped with a 16 - mesh stainless steel sieve on the upper layer and a 60 - mesh stainless steel sieve on the lower layer), and screen out the granules between 16 - 60 meshes.

[0094] (7) Total mixing: Mix the granules obtained in step (6) with 60 g of tangerine powder essence. Set the mixing machine speed to 12 rpm and mix for 15 minutes to obtain ibuprofen granules.

[0095] Comparative Example 1

[0096] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0097] (1) Pretreatment of raw and auxiliary materials: The ibuprofen raw material drug is not pulverized, and the detected particle sizes are D90 = 109.867 μm; D50 = 45.044 μm; lactose is passed through a 40-mesh sieve.

[0098] (2) Premixing: 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (not pulverized) in the prescription amount are successively added to a wet granulator. Set the stirring speed of the wet granulator to 180 rpm, the shearing (granulating) speed to 1000 rpm, and mix for 15 minutes.

[0099] (3) Preparation of soft material: Weigh 1.92 kg of purified water, add 30 g of sucralose, stir for more than 2 minutes until completely dissolved, and use it as a wetting agent solution for standby. Set the stirring speed of the wet granulator to 180 rpm, the shearing (granulating) speed to 1800 rpm, and the spraying pressure to 0.7 MPa. While starting the machine, spray the wetting agent solution into the premixed powder to prepare the soft material.

[0100] (4) Swing granulation and spheronization: Take the soft material and granulate it with a swing granulator equipped with an 18-mesh nylon sieve. After granulation is completed, transfer it to a spherical shot blasting machine in operation (set the air blowing frequency to 30 Hz - 50 Hz, the turntable speed to 10 Hz - 30 Hz), and spheronize for 3 - 6 minutes to obtain spheronized granules.

[0101] (5) Drying: After the spheronization operation is completed, transfer all the spheronized granules to a fluidized bed granulator. Set the inlet air temperature to 55 ± 5 °C, the material temperature to 50 ± 5 °C, and the fan frequency to 25 Hz - 40 Hz, and start heating for drying; control the particle temperature to 50 °C and the particle moisture to 0.9%.

[0102] (6) Screening: Screen the dried granules with a three - layer vibrating screen (equipped with a 16 - mesh stainless steel sieve on the upper layer and a 60 - mesh stainless steel sieve on the lower layer), and screen out the granules between 16 - 60 meshes.

[0103] (7) Total mixing: Mix the granules obtained in step (6) with 60 g of tangerine powder essence. Set the mixing machine speed to 12 rpm and mix for 15 minutes to obtain ibuprofen granules.

[0104] Comparative Example 2

[0105] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0106] (1) Pretreatment of raw and auxiliary materials: Pulverize the ibuprofen raw material drug, and control the particle size range to be 10 μm ≤ D90 ≤ 60 μm; D50 ≤ 30 μm; lactose is passed through a 40 - mesh sieve.

[0107] (2) Premixing: Add 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (after pulverization) in the prescription amount to the wet granulator in sequence. Set the stirring speed of the wet granulator at 180 rpm, the shearing (granulating) speed at 1000 rpm, and mix for 15 minutes.

[0108] (3) Preparing soft material: Weigh 1.92 kg of purified water, add 30 g of sucralose, stir for more than 2 minutes until completely dissolved, and use it as the wetting agent solution for standby. Set the stirring speed of the wet granulator at 180 rpm, the shearing (granulating) speed at 1800 rpm, and the spraying pressure at 0.7 MPa. While starting the machine, spray the wetting agent solution into the premixed powder to prepare the soft material.

[0109] (4) Swing granulation: Take the soft material and granulate it with a swing granulator equipped with an 18-mesh nylon sieve. After granulation, granulated particles are obtained.

[0110] (5) Drying: After the swing granulation is completed, transfer all the particles to a fluidized bed granulator. Set the inlet air temperature at 55 ± 5 °C, the material temperature at 50 ± 5 °C, and the fan frequency at 25 Hz - 40 Hz, and start heating for drying; control the particle temperature at 50 °C and the particle moisture at 0.9%.

[0111] (6) Screening: Screen the dried particles with a three-layer vibrating screen (equipped with a 16-mesh stainless steel sieve on the upper layer and a 60-mesh stainless steel sieve on the lower layer), and screen out the particles between 16 and 60 meshes.

[0112] (7) Final mixing: Mix the particles obtained in step (6) with 60 g of tangerine powder essence. Set the mixing speed of the mixer at 12 rpm and mix for 15 minutes to obtain ibuprofen granules.

[0113] Comparative Example 3

[0114] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0115] (1) Pretreatment of raw and auxiliary materials: Pulverize the ibuprofen raw material, and control the particle size range to be 10 μm ≤ D90 ≤ 60 μm; D50 ≤ 30 μm; sieve lactose through a 40-mesh sieve.

[0116] (2) Premixing: Add 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (after pulverization) in the prescription amount to the wet granulator in sequence. Set the stirring speed of the wet granulator at 180 rpm, the shearing (granulating) speed at 1000 rpm, and mix for 15 minutes.

[0117] (3) Preparation of soft material: Weigh 1.92 kg of purified water, add 30 g of sucralose and 60 g of acid orange powder flavor, stir for more than 2 minutes until completely dissolved to obtain a wetting agent solution for standby. Set the stirring speed of the wet granulator at 180 rpm, the shearing (granulating) speed at 1800 rpm, and the spraying pressure at 0.7 MPa. While starting the machine, spray the wetting agent solution onto the premixed powder to prepare the soft material.

[0118] (4) Swing granulation and spheronization: Take the soft material and granulate it with a swing granulator equipped with an 18-mesh nylon sieve. After granulation, transfer it to a spherical shot blasting machine in operation (set the air blowing frequency at 30 Hz - 50 Hz and the turntable speed at 10 Hz - 30 Hz), and spheronize for 3 - 6 minutes to obtain spheronized granules.

[0119] (5) Drying: After the spheronization operation is completed, transfer all the spheronized granules to a fluidized bed granulator. Set the inlet air temperature at 55 ± 5 °C, the material temperature at 50 ± 5 °C, and the fan frequency at 25 Hz - 40 Hz, and start heating for drying; control the particle temperature at 50 °C and the particle moisture at 0.9%.

[0120] (6) Screening: Screen the dried granules with a three - layer vibrating screen (equipped with a 16 - mesh stainless steel sieve on the upper layer and a 60 - mesh stainless steel sieve on the lower layer), and screen out the granules between 16 - 60 meshes.

[0121] (7) Total mixing: Mix the granules obtained in step (6), set the mixing speed of the mixer at 12 rpm, and mix for 15 minutes to obtain ibuprofen granules.

[0122] Comparative Example 4

[0123] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0124] (1) Pretreatment of raw and auxiliary materials: Crush the ibuprofen raw material, control the particle size range as 10 μm ≤ D90 ≤ 60 μm; D50 ≤ 30 μm; sieve the lactose through a 40 - mesh sieve.

[0125] (2) Premixing: Add 4.35 kg of lactose, 0.18 kg of cross - linked carboxymethylcellulose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (after crushing) in the prescribed amounts to the wet granulator in sequence. Set the stirring speed of the wet granulator at 180 rpm, the shearing (granulating) speed at 1000 rpm, and mix for 15 minutes.

[0126] (3) Preparation of soft material: Weigh 0.96 kg of purified water, add 30 g of sucralose, stir for more than 2 minutes until completely dissolved to obtain a wetting agent solution for standby. Add the wetting agent solution to the premixed powder and wet - mix for about 5 minutes to prepare the soft material. The soft material should be able to form a ball when pinched by hand and break up when lightly pressed, with uniform wetness and color.

[0127] (4) Oscillating granulation and rounding: Take the soft material and granulate it with an oscillating granulator equipped with an 18-mesh nylon sieve. After granulation, transfer it to a spherical shot blasting machine in operation (set the air blowing frequency at 30 Hz - 50 Hz, and the turntable rotation speed at 10 Hz - 30 Hz), and round for 3 - 6 minutes to obtain rounded granules.

[0128] (5) Drying: After the rounding operation is completed, transfer all the rounded granules to a fluidized bed granulator. Set the inlet air temperature at 55 ± 5 °C, the material temperature at 50 ± 5 °C, and the fan frequency at 25 Hz - 40 Hz, and start heating for drying; control the granule temperature at 50 °C and the granule moisture at 0.9%.

[0129] (6) Screening: Screen the dried granules with a three - layer vibrating screen (equipped with a 16 - mesh stainless steel sieve on the upper layer and a 60 - mesh stainless steel sieve on the lower layer), and screen out the granules between 16 - 60 meshes.

[0130] (7) Total mixing: Mix the granules obtained in step (6) with 60 g of tangerine powder flavor. Set the rotation speed of the mixer at 12 rpm and mix for 15 minutes to obtain ibuprofen granules.

[0131] Comparative Example 5

[0132] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0133] (1) Pretreatment of raw and auxiliary materials: Crush the ibuprofen raw material, and control the particle size range as 10 μm ≤ D90 ≤ 60 μm; D50 ≤ 30 μm; sieve lactose through a 40 - mesh sieve.

[0134] (2) Premixing: Add 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (after crushing) in the prescription amount to a wet granulator in sequence. Set the stirring speed of the wet granulator at 180 rpm, the shearing (granulation) speed at 1000 rpm, and mix for 15 minutes.

[0135] (3) Preparation of soft material: Weigh 1.92 kg of purified water, add 30 g of sucralose, stir for more than 2 minutes until completely dissolved to obtain a wetting agent solution for standby. Set the stirring speed of the wet granulator at 180 rpm, the shearing (granulation) speed at 1800 rpm, and the spraying pressure at 0.7 MPa. While starting the machine, spray the wetting agent solution into the premixed powder to prepare the soft material.

[0136] (4) Oscillating granulation and rounding: Take the soft material and granulate it with an oscillating granulator equipped with an 18 - mesh nylon sieve. After granulation, transfer it to a spherical shot blasting machine in operation (set the air blowing frequency at 30 Hz - 50 Hz, and the turntable rotation speed at 10 Hz - 30 Hz), and round for 3 - 6 minutes to obtain rounded granules.

[0137] (5) Drying: After the rounding operation is completed, all the rounded granules are transferred to a fluidized bed granulator. Set the inlet air temperature to 60 ± 5°C, the material temperature to 60 ± 5°C, and the fan frequency to 25 Hz - 40 Hz, and start heating for drying; control the granule temperature at 60°C and the granule moisture content at 0.9%.

[0138] (6) Sieving: The dried granules are sieved using a three - layer vibrating sieve (equipped with a 16 - mesh stainless - steel sieve on the upper layer and a 60 - mesh stainless - steel sieve on the lower layer), and the granules between 16 and 60 meshes are sieved out.

[0139] (7) Blending: The granules obtained in step (6) are mixed with 60 g of acid tangerine powder essence. Set the rotation speed of the mixer to 12 rpm and mix for 15 minutes to obtain ibuprofen granules.

[0140] Comparative Example 6

[0141] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0142] (1) Pretreatment of raw and auxiliary materials: The ibuprofen raw material drug is pulverized, and the particle size range is controlled as 10 μm ≤ D90 ≤ 60 μm; D50 ≤ 30 μm; lactose is sieved through a 40 - mesh sieve.

[0143] (2) Premixing: 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (after pulverization) in the prescription amount are sequentially added to a wet granulator. Set the stirring speed of the wet granulator to 180 rpm, the shearing (granulating) speed to 1000 rpm, and mix for 15 minutes.

[0144] (3) Preparation of soft material: Weigh 1.92 kg of purified water, add 30 g of sucralose, stir for more than 2 minutes until completely dissolved to obtain a wetting agent solution for standby. Set the stirring speed of the wet granulator to 180 rpm, the shearing (granulating) speed to 1800 rpm, and the spraying pressure to 0.7 MPa. While starting the machine, spray the wetting agent solution into the premixed powder to prepare soft material.

[0145] (4) Granulation by oscillating granulator and rounding: Take the soft material and granulate it using an oscillating granulator equipped with an 18 - mesh nylon sieve. After granulation is completed, transfer it to a spherical shot blasting machine in operation (set the air - blowing frequency to 30 Hz - 50 Hz and the turntable rotation speed to 10 Hz - 30 Hz), and round for 3 - 6 minutes to obtain rounded granules.

[0146] (5) Drying: After the rounding operation is completed, all the rounded granules are transferred to a fluidized bed granulator. Set the inlet air temperature to 40 ± 5°C, the material temperature to 40 ± 5°C, and the fan frequency to 25 Hz - 40 Hz, and start heating for drying; control the granule temperature at 40°C and the granule moisture content at 0.9%.

[0147] (6) Granulation: The dried granules are screened using a three - layer vibrating sieve (equipped with a 16 - mesh stainless - steel sieve on the upper layer and a 60 - mesh stainless - steel sieve on the lower layer), and the granules between 16 and 60 meshes are sieved out.

[0148] (7) Total mixing: The granules obtained in step (6) are mixed with 60 g of tangerine powder flavor. Set the rotation speed of the mixer to 12 rpm and mix for 15 minutes to obtain ibuprofen granules.

[0149] Comparative Example 7

[0150] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0151] (1) Pretreatment of raw and auxiliary materials: The ibuprofen raw material drug is crushed, and the particle size range is controlled as 10 μm ≤ D90 ≤ 60 μm; D50 ≤ 30 μm; lactose is sieved through a 40 - mesh sieve.

[0152] (2) Premixing: 4.35 kg of lactose, 0.18 kg of cross - linked carboxymethylcellulose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (after crushing) in the prescription amount are successively added to a wet granulator. Set the stirring speed of the wet granulator to 180 rpm, the shearing (granulation) speed to 1000 rpm, and mix for 15 minutes.

[0153] (3) Preparation of soft material: Weigh 1.92 kg of purified water, add 30 g of sucralose, stir for more than 2 minutes until completely dissolved to obtain a wetting agent solution for standby. Set the stirring speed of the wet granulator to 180 rpm, the shearing (granulation) speed to 1800 rpm, and the spraying pressure to 0.7 MPa. While starting the machine, spray the wetting agent solution into the premixed powder to prepare the soft material.

[0154] (4) Swing granulation and spheronization: The soft material is granulated using a swing granulator equipped with an 18 - mesh nylon sieve. After granulation is completed, it is transferred to a spherical shot - blasting machine in operation (set the air - blowing frequency to 30 Hz - 50 Hz and the turntable rotation speed to 10 Hz - 30 Hz), and spheronized for 3 - 6 minutes to obtain spheronized granules.

[0155] (5) Drying: After the spheronization operation is completed, all the spheronized granules are transferred to a fluidized - bed granulator. Set the inlet air temperature to 55 ± 5 °C, the material temperature to 50 ± 5 °C, and the fan frequency to 25 Hz - 40 Hz, and start heating for drying; control the particle temperature at 50 °C and the particle moisture content at 1.5%.

[0156] (6) Granulation: The dried granules are screened using a three - layer vibrating sieve (equipped with a 16 - mesh stainless - steel sieve on the upper layer and a 60 - mesh stainless - steel sieve on the lower layer), and the granules between 16 and 60 meshes are sieved out.

[0157] (7) Total mixing: The granules obtained in step (6) are mixed with 60 g of tangerine powder flavor. Set the rotation speed of the mixer to 12 rpm and mix for 15 minutes to obtain ibuprofen granules.

[0158] Comparative Example 8

[0159] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0160] (1) Pretreatment of raw and auxiliary materials: Ibuprofen raw material medicine is crushed, and the particle size range is controlled to be 10μm ≤ D90 ≤ 60μm; D50 ≤ 30μm; lactose is sieved through a 40-mesh sieve.

[0161] (2) Premixing: 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (after crushing) in the prescription amount are sequentially added to a wet granulator. Set the stirring speed of the wet granulator to 180 rpm, the shearing (granulating) speed to 1000 rpm, and mix for 15 minutes.

[0162] (3) Preparation of soft material: Weigh 1.92 kg of purified water, add 30 g of sucralose, stir for more than 2 minutes until completely dissolved, and use it as a wetting agent solution for standby. Set the stirring speed of the wet granulator to 180 rpm, the shearing (granulating) speed to 1800 rpm, and the spraying pressure to 0.7 MPa. While starting the machine, spray the wetting agent solution into the premixed powder to prepare the soft material.

[0163] (4) Swing granulation and spheronization: Take the soft material and granulate it with a swing granulator equipped with an 18-mesh nylon sieve. After granulation is completed, transfer it to a spherical shot blasting machine in operation (set the air blowing frequency to 30 Hz - 50 Hz, the turntable speed to 10 Hz - 30 Hz), and spheronize for 3 - 6 minutes to obtain spheronized granules.

[0164] (5) Drying: After the spheronization operation is completed, transfer all the spheronized granules to a fluidized bed granulator. Set the inlet air temperature to 55 ± 5°C, the material temperature to 50 ± 5°C, and the fan frequency to 25 Hz - 40 Hz, and start heating for drying; control the particle temperature to 50°C and the particle moisture to 0.3%.

[0165] (6) Screening: Screen the dried granules with a three - layer vibrating screen (equipped with a 16 - mesh stainless steel sieve on the upper layer and a 60 - mesh stainless steel sieve on the lower layer), and screen out the granules between 16 - 60 meshes.

[0166] (7) Total mixing: Mix the granules obtained in step (6) with 60 g of tangerine powder essence, set the mixing machine speed to 12 rpm, and mix for 15 minutes to obtain ibuprofen granules.

[0167] Comparative Example 9

[0168] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0169] (1) Pretreatment of raw and auxiliary materials: The ibuprofen raw material drug is crushed, and the particle size range is controlled as 10μm ≤ D90 ≤ 60μm; D50 ≤ 30μm; lactose is sieved through a 40-mesh sieve.

[0170] (2) Premixing: 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (after crushing) in the prescription amount are sequentially added to a wet granulator. Set the stirring speed of the wet granulator to 180 rpm, the shearing (granulating) speed to 1000 rpm, and mix for 15 minutes.

[0171] (3) Preparation of soft material: Weigh 1.92 kg of purified water, add 30 g of sucralose, stir for more than 2 minutes until completely dissolved, and use it as a wetting agent solution for standby. Set the stirring speed of the wet granulator to 180 rpm, the shearing (granulating) speed to 1800 rpm, and the spraying pressure to 0.7 MPa. While starting the machine, spray the wetting agent solution into the premixed powder to prepare the soft material.

[0172] (4) Swing granulation and spheronization: Take the soft material and granulate it with a swing granulator equipped with a 10-mesh nylon sieve. After granulation is completed, transfer it to a running spherical shot blasting machine (set the air blowing frequency to 30 Hz - 50 Hz, the turntable speed to 10 Hz - 30 Hz), and spheronize for 3 - 6 minutes to obtain spheronized granules.

[0173] (5) Drying: After the spheronization operation is completed, transfer all the spheronized granules to a fluidized bed granulator. Set the inlet air temperature to 55 ± 5°C, the material temperature to 50 ± 5°C, and the fan frequency to 25 Hz - 40 Hz, and start heating for drying; control the particle temperature to 50°C and the particle moisture to 0.9%.

[0174] (6) Screening: Screen the dried granules with a three - layer vibrating screen (equipped with a 16 - mesh stainless steel sieve on the upper layer and a 60 - mesh stainless steel sieve on the lower layer), and screen out the granules between 16 - 60 meshes.

[0175] (7) Total mixing: Mix the granules obtained in step (6) with 60 g of tangerine powder essence. Set the mixing machine speed to 12 rpm and mix for 15 minutes to obtain ibuprofen granules.

[0176] Control Example 10

[0177] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0178] (1) Pretreatment of raw and auxiliary materials: The ibuprofen raw material drug is crushed, and the particle size range is controlled as 10μm ≤ D90 ≤ 60μm; D50 ≤ 30μm; lactose is sieved through a 40 - mesh sieve.

[0179] (2) Premixing: Add 4.35 kg of lactose, 0.18 kg of cross-linked carboxymethyl cellulose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (after crushing) in the prescribed amount into a wet granulator in sequence. Set the stirring speed of the wet granulator to 180 rpm and the shear (granulation) speed to 1000 rpm, and mix for 15 minutes.

[0180] (3) Preparation of soft material: Weigh 1.92 kg of purified water, add 30 g of sucralose, stir for more than 2 minutes until completely dissolved, as the wetting agent solution, set aside. Set the stirring speed of the wet granulator to 180 rpm, the shear (granulation) speed to 1800 rpm, and the spray pressure to 0.7 MPa. Start the machine and spray the wetting agent solution into the premixed powder to prepare the soft material.

[0181] (4) Oscillating granulation and spheronization: The soft material is granulated by an oscillating granulator equipped with an 18-mesh nylon screen. After granulation, it is transferred to a ball shot blasting machine in operation (with a blast frequency of 30 Hz to 50 Hz and a turntable speed of 10 Hz to 30 Hz) and spheronized for 3 to 6 minutes to obtain spherical particles.

[0182] (5) Drying: After the spheronization operation is completed, all spheronized particles are transferred to a boiling granulator. The inlet air temperature is set at 40±5°C, the material temperature is set at 40±5°C, and the fan frequency is set at 25Hz to 40Hz. The heating is started for drying. The particle temperature is controlled at 40°C and the particle moisture is controlled at 1.5%.

[0183] (6) Granulation: The dried granules are sieved using a three-dimensional rotary vibrating sieve (with a stainless steel sieve of 16 mesh on the upper layer and 60 mesh on the lower layer) to select granules between 16 and 60 mesh.

[0184] (7) Total mixing: The granules obtained in step (6) were mixed with 60 g of sour orange powder flavor, the mixer speed was set to 12 rpm, and the mixture was mixed for 15 minutes to obtain ibuprofen granules.

[0185] Effect verification

[0186] For the above Examples 1 to 5, Comparative Examples 1 to 10 and the reference preparation (Kaken Pharmaceutical Co., Ltd., trade name: GRANULE 20%; specification: 20% 1g, batch number: L14970) were used to measure the dissolution rate, yield, related substances and in vivo absorption of ibuprofen granules.

[0187] Determine the dissolution rate. The specific determination method is as follows:

[0188] Select sodium citrate - disodium hydrogen phosphate buffer (pH 5.5) (Solution A: Dissolve 5.25 g of citric acid in water to make 1000 ml; Solution B: Dissolve 17.91 g of disodium hydrogen phosphate in water to make 1000 ml. Adjust the pH value of Solution B to 5.5 with Solution A) 900 ml as the dissolution medium of this product, the rotation speed is: 50 revolutions per minute, the sampling time and limit are: the dissolution at 15 minutes is not less than 85% of the labeled amount.

[0189] Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler; use sodium acetate buffer solution (Take 6.13 g of sodium acetate, dissolve it in 750 ml of water, and adjust the pH value to 2.5 with glacial acetic acid) - acetonitrile (40:60) as the mobile phase; the detection wavelength is 263 nm; the injection volume is 20 μl.

[0190] Test solution: Take an appropriate amount of the dissolution solution, filter it, and take the subsequent filtrate.

[0191] Reference solution: Take an appropriate amount of ibuprofen reference substance, weigh it accurately, dissolve it in an appropriate amount of methanol, and quantitatively dilute it with the dissolution medium to prepare a solution containing about 0.11 mg of ibuprofen per 1 ml (0.1 g specification) or 0.22 mg of ibuprofen per 1 ml (0.2 g specification).

[0192] System suitability requirements: The number of theoretical plates calculated by the ibuprofen peak is not less than 2500.

[0193] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Calculate the dissolution amount per bag by the external standard method based on the peak area.

[0194] Table 2 Dissolution results

[0195] Batch 15-minute dissolution rate (%) Batch 15-minute dissolution rate (%) Reference preparation 88 Comparative example 1 73.5 Example 1 97.8 Comparative example 2 95.6 Example 2 95.3 Comparative example 3 96.2 Example 3 96.7 Comparative example 4 97.4 Example 4 97.5 Comparative example 5 87.6 Example 5 95.4 Comparative example 6 95.7 / / Comparative example 7 96.5 / / Comparative example 8 80.2 / / Comparative example 9 97.2 / / Comparative example 10 88.4

[0196] As can be seen from Table 2, the dissolution of the reference preparation in the pH 5.5 medium at 15 minutes is 88%, belonging to rapid dissolution. The ibuprofen granules obtained in Examples 1 - 5 all have a dissolution of more than 85% at 15 minutes, and the dissolution is similar to that of the reference preparation.

[0197] Under the same other conditions, in Comparative Example 1, ibuprofen raw materials with larger particle sizes were used for granulation, and the dissolution of the obtained ibuprofen granules at 15 minutes was 73.5%, which was significantly less than that of the reference preparation, and the dissolution behavior was not similar.

[0198] Under the same other conditions, in Comparative Example 8, the moisture content of the granules was too low during the granulation process, and the dissolution of the obtained ibuprofen granules at 15 minutes was 80.2%, which was significantly less than that of the reference preparation, and the dissolution behavior was not similar.

[0199] Determine the content and content uniformity. The specific determination method is as follows:

[0200] According to the provisions in General Rules 0941, "Test for Content Uniformity", in Part IV of Chinese Pharmacopoeia (2020 Edition), the content uniformity of this product is determined by the method under the content determination of this product.

[0201] (1) Determination method: Determined by high performance liquid chromatography (General Rules 0512 in Part IV of Chinese Pharmacopoeia 2020 Edition).

[0202] (2) Test solution: Take 1 bag of this product and place it in a 200 ml (0.2 g specification) volumetric flask. Add an appropriate amount of methanol, shake to dissolve and dilute to the mark, shake well, filter. Accurately measure 10 ml of the subsequent filtrate and place it in a 20 ml volumetric flask, dilute to the mark with methanol, and shake well.

[0203] (3) Reference solution: Take an appropriate amount of ibuprofen reference substance, accurately weigh, dissolve with methanol and quantitatively dilute to prepare a solution containing about 0.5 mg per 1 ml.

[0204] (4) Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler (YMC-Triart C18 4.6 mm × 150 mm, 5 μm or a chromatographic column with equivalent efficiency); use sodium acetate buffer solution (take 6.13 g of sodium acetate, add 750 ml of water to dissolve, adjust the pH value to 2.5 with glacial acetic acid)-acetonitrile (40:60) as the mobile phase; the flow rate is 1.0 ml per minute; the detection wavelength is 263 nm; the injection volume is 20 μl.

[0205] (5) System suitability requirements: The number of theoretical plates calculated based on the ibuprofen peak is not less than 2500.

[0206] (6) Determination method: Accurately measure the test solution and the reference solution, and inject them into the liquid chromatograph respectively, record the chromatogram. Calculate by the external standard method based on the peak area.

[0207] (7) Calculation formula:

[0208] Content (%) = W S × Reference substance content × A T × D T / A S × D S × Labeled amount × 100%

[0209] In the formula:

[0210] W S Is the weighed amount of ibuprofen reference substance, g;

[0211] A T Is the peak area of the ibuprofen peak in the chromatogram of the test solution;

[0212] A S Is the peak area of the ibuprofen peak in the chromatogram of the reference solution;

[0213] D S Dilution factor of reference substance solution

[0214] (8) Limit: If A + 2.2S ≤ 15, the content uniformity of the test sample complies with the regulations;

[0215] If A + S > 15, it does not comply with the regulations;

[0216] If A + 2.2S > 15 and A + S < 15, 20 additional test samples should be taken for retesting.

[0217] Table 3 Content and content uniformity of ibuprofen granules

[0218]

[0219]

[0220] Note: Content limit is 90% - 110%

[0221] Examples 1 - 5 are ibuprofen granules prepared according to the formulation and preparation process of the present invention, and the corresponding content uniformity and content are within the scope specified in the pharmacopoeia.

[0222] In Comparative Example 1, the particle size of ibuprofen was not controlled, and compared with Example 1, the content uniformity decreased and the particle homogeneity was slightly poor.

[0223] Under the condition that other conditions are the same, in Comparative Example 2, the rolling process was not used compared with Example 1, and the content uniformity of its product decreased significantly, doubling compared with Example 1.

[0224] Similarly, on the premise that other conditions are the same, in Comparative Examples 3 and 4, different methods for preparing the wetting agent were adopted. In Comparative Example 3, water, sucralose, and tangy powder essence were used as the wetting agent at the same time, and the content uniformity of the obtained product decreased compared with Example 1, and the particle homogeneity was slightly poor. While in Comparative Example 4, the ibuprofen granules prepared by direct wet mixing had a content uniformity significantly exceeding the limit value.

[0225] In Comparative Examples 5 and 6, different particle temperature control strategies were adopted respectively. For the product obtained in Comparative Example 5 (higher particle temperature), compared with Example 1, the content uniformity decreased and the particle homogeneity was slightly poor. For the product obtained in Comparative Example 6 (lower particle temperature), the particle content uniformity decreased significantly, tripling compared with Example 1.

[0226] When the particle moisture content deviated from the optimal control range (Comparative Examples 7 and 8), the content uniformity of the obtained product decreased compared with Example 1, and the particle homogeneity was slightly poor.

[0227] The product produced by using different sieves in Comparative Example 9 had a lower content uniformity and slightly poorer particle homogeneity compared with Example 1.

[0228] Finally, in Comparative Example 10, both the particle temperature and moisture were controlled, but the obtained product had a lower content uniformity compared to Example 1, and the particle homogeneity was slightly worse.

[0229] The above comparative experimental results show that the technical process according to the present invention can effectively ensure that ibuprofen granules have good homogeneity.

[0230] Determine the yield of ibuprofen granules

[0231] It is used to measure the efficiency of converting raw materials into the target drug product, and the calculation formula is as follows:

[0232] Yield (%) = (amount of target product actually obtained / amount of target product theoretically should be obtained) × 100%

[0233] Table 4 Yield of ibuprofen granules

[0234] Batch Yield (%) Batch Yield (%) Example 1 93.44 Comparative example 1 92.01 Example 2 93.22 Comparative example 2 72.43 Example 3 93.44 Comparative example 3 87.52 Example 4 93.89 Comparative example 4 12.34 Example 5 93.86 Comparative example 5 93.14 / / Comparative example 6 82.26 / / Comparative example 7 86.45 / / Comparative example 8 89.34 / / Comparative example 9 56.24 / / Comparative example 10 81.86

[0235] According to the data in Table 4, the preparation method of ibuprofen granules adopted in the present invention shows good yields, all of which can reach more than 93%. In contrast, under the same conditions, the preparation methods in the comparative examples show inconsistent yields.

[0236] The spheronization process is crucial for improving the yield of the final product. For example, if the spheronization step is not carried out after granulation (as shown in Comparative Example 2), the yield can only reach 72.43%, which is an unsatisfactory low yield level for large-scale production.

[0237] The composition of the wetting agent and its addition method also significantly affect the preparation efficiency of ibuprofen granules. When the sweetener and flavoring agent are used together as the wetting agent (as shown in Comparative Example 3), although it can be seen from Table 2 that the dissolution rate of the ibuprofen granules obtained under this treatment exceeds 85% within 15 minutes, the total yield is only 87.52%. Although this is at a relatively high level, it is still significantly lower than the yield of 93.44% achieved in Example 1. In addition, when the ibuprofen granules are prepared by the direct wet mixing method (as shown in Comparative Example 4), although its dissolution rate also exceeds 85%, the yield is only 12.34%, greatly reducing the production efficiency.

[0238] It can be seen from Comparative Examples 5 to 8 that the temperature and moisture content of the dried granules during the granulation process will also have a certain impact on the yield of the final product. Although the yields under these conditions generally still remain at a relatively good level, they are all lower than the yield of 93.44% achieved in Example 1. In addition, when the temperature and moisture content of the granules are not within the ideal range (such as in Comparative Example 10), although the dissolution rate of the obtained ibuprofen granules meets the requirements, the yield is significantly lower than that of Example 1.

[0239] In addition, selecting a suitable sieve is also crucial for the granulation process. For example, when using a 10-mesh sieve for granulation (as shown in Comparative Example 9), the yield is only 56.24%, which is extremely unfavorable for actual production. In summary, optimizing the above-mentioned various factors can effectively improve the preparation efficiency and product yield of ibuprofen granules.

[0240] Determine the related substances. The specific determination method is as follows:

[0241] Related substances are determined by high performance liquid chromatography (General Chapter 0512, Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0242] Test solution: Take an appropriate amount of the fine powder under the content determination item (equivalent to about 0.2 g of ibuprofen), place it in a 100-ml volumetric flask, add 30 ml of acetonitrile, ultrasonically dissolve ibuprofen for 15 minutes, cool to room temperature, dilute to the mark with the mobile phase, shake well, filter, and take the subsequent filtrate.

[0243] Reference solution: Accurately measure an appropriate amount of the test solution, and dilute it with the mobile phase to prepare a solution containing 2 μg of ibuprofen per 1 ml.

[0244] Sensitivity solution: Accurately measure 5 ml of the reference solution, place it in a 10-ml volumetric flask, dilute to the mark with the mobile phase, and shake well.

[0245] Excipient reference solution: Take an appropriate amount of blank excipients (equivalent to about 0.2 g of ibuprofen), place it in a 100-ml volumetric flask, add 30 ml of acetonitrile, ultrasonically dissolve it for 15 minutes, cool to room temperature, dilute to the mark with the mobile phase, shake well, filter, and take the subsequent filtrate.

[0246] System suitability solution: Take appropriate amounts of ibuprofen and reference substances of impurities A, B, C, E, J, M, N, and Q, dissolve them with an appropriate amount of acetonitrile and dilute with the mobile phase to prepare a mixed solution containing about 2 mg of ibuprofen, 4 μg each of impurities A, B, C, E, J, M, N, and Q per 1 ml.

[0247] Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler (YMC-Pack ODS-A, 4.6 mm × 150 mm,

[0248] 5 μm or a chromatographic column of equivalent efficiency); use water (adjusted to pH 2.5 with phosphoric acid)-acetonitrile (66:34) as the mobile phase;

[0249] The flow rate is 2.0 ml per minute; the detection wavelength is 214 nm; the injection volume is 20 μl.

[0250] System suitability requirements: In the chromatogram of the system suitability solution, the elution order is the peak of impurity J, the peak of impurity N,

[0251] The resolution between the peaks of impurity M, impurity C, impurity Q, impurity A, ibuprofen, impurity B and impurity E shall meet the requirements. In the chromatogram of the sensitivity solution, the signal-to-noise ratio of the main component chromatographic peak height shall be greater than 10.

[0252] Assay Accurately measure the test solution and the reference solution, and inject them into the liquid chromatograph respectively. Record the chromatogram until twice the retention time of the ibuprofen peak.

[0253] Limit If there are impurity peaks in the chromatogram of the test solution, except for the solvent peak and the excipient peak, impurity A, impurity B, impurity J, impurity N, and impurity Q shall not be greater than twice the area of the main peak of the reference solution (0.20%). Impurity C, impurity E, and impurity M calculated according to the corrected peak area (multiplied by the correction factors 1.8, 0.6, and 1.2 respectively) shall not be greater than twice the area of the main peak of the reference solution (0.20%). The area of other individual impurity peaks shall not be greater than twice the area of the main peak of the reference solution (0.20%). The sum of the corrected peak areas of each impurity shall not be greater than 10 times the area of the main peak of the reference solution (1.0%). Peaks in the chromatogram of the test solution smaller than the main peak area of the sensitivity solution shall be ignored (0.05%).

[0254] Table 5 Impurity Information

[0255]

[0256]

[0257] Table 6 Results of Related Substances Detection

[0258]

[0259]

[0260]

[0261]

[0262]

[0263] We investigated the impurity situation in ibuprofen granules according to the requirements for the limits of related substances in the current quality standard of ibuprofen granules, and in accordance with the Technical Guidelines for the Study of Impurities in Chemical Drugs and the identification limits and quality control limits for organic impurities in ICH Q3A and ICH Q3B.

[0264] The preparations obtained in Examples 1 to 5 and the reference preparation were placed under the same conditions, and there were no significant differences in various detection indexes. Even in terms of the types and contents of impurities, they were better than the reference preparation, indicating that the preparations obtained in the examples and the reference preparation had good stability under these conditions. In addition, from the change of the total impurity content of the reference preparation, it can be known that the impurity content on the 0th day was 0.09%, and after being placed at high temperature for 30 days, the impurity content was 0.16%. However, the change of the total impurity content under high humidity and light was not obvious. Thus, it can be seen that ibuprofen granules are more sensitive to temperature. And the total impurity content of the preparations obtained in Examples 1 to 5 did not change significantly under high temperature, indicating their good stability under high temperature.

[0265] According to the data in Table 6, when the ibuprofen granules of Comparative Examples 1 to 10 and the examples and the reference preparation were placed under the same conditions, the fluctuations of various impurity contents were significant. Specifically:

[0266] In Comparative Example 1, the particle size of ibuprofen was not controlled, resulting in the content of impurity A reaching 0.19% after the product was placed at high temperature for 30 days, approaching the limit value of 0.20%. In addition, under high humidity and light conditions, the contents of impurity A and total impurities both increased significantly, indicating that the ibuprofen granules in Comparative Example 1 had poor stability.

[0267] Under the condition that other conditions were the same, compared with Example 1, the rolling process was not used in Comparative Example 2, and the contents of impurity A and total impurities in its product under high temperature, high humidity and light conditions increased significantly, higher than the relevant impurity contents of Example 1.

[0268] Similarly, on the premise that other conditions were the same, different wetting agent preparation methods were adopted in Comparative Examples 3 and 4, and the initial impurity contents of the obtained products were relatively high, especially impurity A and total impurities, and these impurities further increased under high temperature, high humidity and light conditions. Among them, after the products of Comparative Examples 3 and 4 were placed at high temperature for 30 days, the content of impurity A exceeded the limit value of 0.20%.

[0269] Although different particle temperature control strategies were adopted in Comparative Examples 5 and 6 respectively, the impurity growth rate of their products in the accelerated test was significantly faster than that of Example 1 and very close to the limit value. It is proved that precise particle temperature control is of decisive significance for maintaining impurity stability.

[0270] When the particle moisture content deviated from the optimal control range (Comparative Examples 7 and 8), the degradation rate of impurity A under high temperature conditions increased significantly, and the content exceeded the limit value after 30 days. Strict moisture control is one of the core elements to ensure product stability.

[0271] Although the products produced by using different sieves in Comparative Example 9 had relatively low impurity contents, due to the large number of impurity types, this increased the stability risk of the products.

[0272] Comparative example 10 with synchronous implementation of particle temperature and moisture control has a relatively high initial impurity content, and the final impurity content still exceeds the quality standard, indicating that the optimization of a single parameter is difficult to completely compensate for other process defects.

[0273] The above comparative experiment results show that only by integrating multiple technical means such as particle size control, rounding process, optimizing the wetting system, and precise temperature and humidity control can the effective control of impurity content and the significant improvement of preparation stability be achieved.

[0274] In summary, during the preparation process of ibuprofen granules, multiple technical means such as controlling the composition and addition method of the wetting agent, the temperature of the dried granules, the moisture content of the granules, and the addition of the rounding process are involved. These factors act synergistically and cooperate with each other, resulting in the ibuprofen granules finally obtained achieving good effects in terms of dissolution rate, content, yield, and the stability of related substances.

[0275] Determine the in vivo absorption

[0276] In vivo absorption determination method: Refer to the Guidelines for Bioavailability and Bioequivalence Studies of Pharmaceutical Preparations in Humans (General Guidelines for the Fourth Volume of the Chinese Pharmacopoeia 2020, Guideline 9011). If the 90% confidence intervals of the ratios of Cmax, AUC(0→t), and AUC(0→∞) of the logarithmically transformed values of the investigational preparation and the reference preparation fall between 80% and 125%, it is considered that the investigational preparation and the reference preparation are bioequivalent.

[0277] Table 7 Drug absorption situation

[0278]

[0279] As can be seen from Table 7, the 90% confidence intervals of the ratios of Cmax, AUC(0→t), and AUC(0→∞) of the logarithmically transformed values of the ibuprofen granules of Example 1 as the investigational preparation and the reference preparation fall between 80% and 125%, which is equivalent to the reference preparation.

[0280] From this, it can be known that the ibuprofen granules prepared by the present invention not only exhibit good in vitro performance, such as excellent dissolution rate, high yield, and low related substance content, but also show good in vivo absorption characteristics. Combining these advantages indicates that the drug is both safe and effective.

[0281] Table 8 Comparison of conditions between examples and comparative examples

[0282]

[0283] The embodiments of the present application have been described above. However, the present application is not limited to the above specific embodiments. The above specific embodiments are merely illustrative rather than restrictive. Under the inspiration of the present application, those of ordinary skill in the art can also make many forms without departing from the purpose of the present application and the scope protected by the claims, and all of them belong to the protection scope of the present application.

Claims

1. A method for preparing ibuprofen granules, characterized in that: The method comprises the following steps: mixing ibuprofen, a filler, a disintegrant and a binder to obtain a premixed medicine powder; dissolving a sweetener in water as a wetting agent; spraying the wetting agent into the premixed medicine powder to prepare a soft material; and granulating the soft material; After the granulation is completed, a spheronization operation is performed to obtain spheronized particles; the spheronized particles are dried; the dried particles are sized; and the sized particles are mixed with a fragrance to obtain ibuprofen particles.

2. The method for preparing ibuprofen granules according to claim 1, wherein The temperature of the particles obtained after the drying is 40°C < particle temperature < 60°C.

3. The method for preparing ibuprofen granules according to claim 1, wherein The moisture content of the particles obtained after drying is 0.3%<moisture content<1.0%.

4. The method for preparing ibuprofen granules according to any one of claims 1 to 3, characterized in that: The particle size of the ibuprofen is 10 μm≤D90≤60 μm, and D50≤30 μm.

5. The method for preparing ibuprofen granules according to claim 4, characterized in that, The filler is passed through a 40-mesh sieve.

6. The method for preparing ibuprofen granules according to any one of claims 1 to 5, characterized in that: The method further comprises the following steps: spraying the wetting agent solution into the premixed powder to prepare a soft material under the conditions that the stirring speed of the wet granulator is 150-200 rpm, the shearing speed is 1500-2000 rpm, and the spraying pressure is 0.5-1.0 MPa.

7. The method for preparing ibuprofen granules according to claim 6, characterized in that: The method further comprises the following step: granulating the soft material using an 18-mesh nylon sieve.

8. The method for preparing ibuprofen granules according to claim 7, characterized in that: The method also includes the following step: using a three-dimensional rotary vibrating screen to size the dried particles.

9. The method for preparing ibuprofen granules according to any one of claims 1 to 8, characterized in that: In parts by weight, the mass composition of the ibuprofen granules comprises: 180-220 parts of ibuprofen, 700-750 parts of filler, 25-35 parts of disintegrant, 25-35 parts of binder, 2-7 parts of sweetener, 5-15 parts of flavoring agent. The filler is lactose, the disintegrant is cross-linked sodium hydroxymethylcellulose, the binder is hydroxypropyl cellulose, the sweetener is sucralose, and the fragrance is sour orange powder flavor.

10. The ibuprofen granules prepared by the method according to any one of claims 1 to 9, wherein the total impurities in the ibuprofen granules are less than 0.06%.

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