Ibuprofen granules and a process for their preparation

Abstract

The application discloses ibuprofen granules and a preparation method thereof, and comprises the following steps: mixing ibuprofen, a filling agent, a disintegrating agent and a binder to obtain a premixed medicine powder; dissolving a sweetening agent in water as a wetting agent; spraying the wetting agent into the premixed medicine powder to prepare a soft material; granulating the soft material; performing a rounding operation after the granulation is completed to obtain rounded granules; drying the rounded granules; performing whole-granulation on the dried granules; and mixing the whole-granulated granules with a fragrant agent to obtain the ibuprofen granules. Through optimization of the process, the ibuprofen granules obtained by the application have good dissolution, stability and absorption.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and particularly relates to a ibuprofen granule and a preparation method thereof. BACKGROUND

[0002] Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) that acts as an effective cyclooxygenase inhibitor, and has the effects of antipyretic, analgesic and anti-inflammatory.

[0003] At present, the ibuprofen preparations on the market mainly include sustained-release capsules, tablets, granules, suspensions and soft capsules, etc. As a BCS II drug, ibuprofen has the characteristics of low solubility but high biological membrane permeability, which determines its special requirements in the development of preparations.

[0004] Although ibuprofen has significant efficacy, it has the problem of low bioavailability when administered orally. 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 can cause adverse reactions.

[0005] In order to solve these problems, the current commonly used technical means include: adding a solubilizer or a cosolvent to improve the solubility of ibuprofen. Preparing a solid dispersion to enhance the dissolution rate of the drug. Using cyclodextrin for inclusion to improve the stability and absorption efficiency of the drug.

[0006] Therefore, in the development and production of ibuprofen preparations, it is crucial to optimize the formulation design and process parameters. Through the combination of carefully designed technical features, not only the inherent challenges of ibuprofen granules in physical and chemical properties can be solved, but also the bioavailability and stability can be significantly improved, providing a more reliable and safer medication option. The optimized ibuprofen granules not only can be quickly dissolved and absorbed by the body, providing rapid and lasting efficacy, but also can maintain good physical and chemical stability for a long time, reducing the quality changes caused by particle aggregation or environmental factors, thereby improving the patient's medication experience.

[0007] Patent CN115581673B discloses an ibuprofen granule and a preparation method thereof, which is prepared by preferentially premixing ibuprofen with a filler with stable properties to form a stable structure, and then premixing with a filler with relatively poor stability and a disintegrant, and using a centrifugal granulation method under specific parameters to improve the uniformity and stability of the ibuprofen granule content.

[0008] Patent CN113318081A discloses an ibuprofen granule and a preparation method thereof, which optimizes the prescription composition to improve the bonding degree between the raw materials and the excipients and the binder, thereby improving the uniformity and dissolution performance of the drug.

[0009] The above methods can improve the quality of ibuprofen granules, but the types of excipients used are more, which can increase the related substances of ibuprofen and the instability of in-vivo effect, and the preparation process is more complex, which is not suitable for mass industrial production. SUMMARY

[0010] The present application provides a preparation method of ibuprofen granules, which comprises the following steps: mixing ibuprofen, a filler, a disintegrant and a binder to obtain a premixed drug powder; dissolving a sweetening agent in water as a wetting agent; spraying the wetting agent into the premixed drug powder to prepare a soft material; granulating the soft material; performing a rounding operation after the granulation is completed to obtain rounded granules; drying the rounded granules; sizing the dried granules; and mixing the sized granules with a fragrance to obtain ibuprofen granules.

[0011] Further, the temperature of the granules obtained after drying is 40℃<granule temperature<60℃.

[0012] Further, the moisture of the granules obtained after drying is 0.3%<moisture<1.0%.

[0013] Further, the particle size of the ibuprofen is 10μm≤D90≤60μm, and D50≤30μm.

[0014] Further, the filler passes through a 40-mesh sieve.

[0015] Further, the preparation method further comprises the following step: under the conditions that the stirring speed of the wet granulator is 150-200rpm, the shearing speed is 1500-2000rpm, and the liquid spraying pressure is 0.5-1.0MPa, spraying the wetting agent solution into the premixed drug powder to prepare a soft material.

[0016] Further, the preparation method further comprises the following step: using an 18-mesh nylon sieve to granulate the soft material.

[0017] Further, the preparation method further comprises the following step: using a ternary rotary vibrating screen to size the dried granules.

[0018] Further, the mass composition of the ibuprofen granules comprises, by weight:

[0019] 180-220 parts of ibuprofen, 700-750 parts of a filler, 25-35 parts of a disintegrant, 25-35 parts of a binder, 2-7 parts of a sweetening agent, and 5-15 parts of a fragrance, wherein the filler is lactose, the disintegrant is croscarmellose sodium, the binder is hydroxypropyl cellulose, the sweetening agent is sucralose, and the fragrance is lime powder essence.

[0020] In another aspect, the present application provides ibuprofen granules prepared by the above method, wherein the total impurities of the ibuprofen granules are less than 0.06%.

[0021] Compared with the prior art, the preparation method of the ibuprofen granules of the present application has the following advantages:

[0022] (1) Optimized dissolution characteristics: The release profile of the ibuprofen granules of the present application in dissolution tests is closer to the original drug, ensuring the stability and consistency of in vivo absorption. This improvement helps to maintain stable blood drug concentration, thereby improving therapeutic effect and reducing the occurrence of toxic side effects.

[0023] (2) Excellent product quality: The ibuprofen granules obtained by the present application have uniform content, consistent appearance, good flowability and accurate loading.

[0024] (3) Improved product yield: By significantly optimizing the preparation process, the present application successfully achieves higher product yield, improving production efficiency and economic benefits.

[0025] (4) Good stability: The ibuprofen granules prepared by the present application show excellent stability in related substances, ensuring the quality of the drug and the safety of long-term storage.

[0026] (5) Enhanced bioequivalence: The ibuprofen granules of the present application perform well in in vivo absorption and have better bioequivalence with the original drug, ensuring the consistency and reliability of clinical efficacy.

[0027] (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. DETAILED DESCRIPTION

[0028] The technical solutions in the embodiments of the present application will be described below. Obviously, the described embodiments are part of the embodiments of the present application, not all 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.

[0029] The terms "first", "second", etc. in the specification and claims of the present application are used to distinguish similar objects, and are not used to describe a particular order or sequence. It should be understood that the data thus used can be interchanged under appropriate circumstances so that the embodiments of the present application can be implemented in an order other than that described herein, and the objects distinguished by "first", "second", etc. are generally a class and do not limit the number of objects, for example, the first object can be one or more. In addition, "and / or" in the specification and claims indicates at least one of the connected objects, and the character " / ", generally indicates that the objects before and after are in an "or" relationship.

[0030] The experimental methods used in the following examples are conventional methods unless otherwise specified; the reagents, materials, etc. used in the following examples can be obtained from commercial channels unless otherwise specified.

[0031] The inventors found that by strictly controlling the key processes in the preparation method of ibuprofen granules, not only the dissolution characteristics similar to 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 of ibuprofen granules in vivo reaches the desired level. The entire process includes the following main steps:

[0032] (1) The ibuprofen raw material is crushed to control the particle size range to be 10 μm≤D90≤60 μm; at the same time, D50≤30 μm; and the filler is passed through a 40-mesh sieve.

[0033] (2) The ibuprofen, filler, disintegrant and binder are added to a wet granulator, the stirring speed of the wet granulator is set to 180 rpm, the shearing (granulating) speed is set to 1000 rpm, and the mixture is mixed for 15 minutes to obtain a premixed drug powder; the mixing equipment and parameters are not limited in the present application, as long as the raw and auxiliary materials can be uniformly mixed.

[0034] (3) The sweetener is added to water as a wetting agent, stirred for more than 2 minutes until completely dissolved, and used as a wetting agent solution; the amount of water can be 30% to 70% of the total amount of other raw and auxiliary materials, and the wetting agent water in the present application will be removed in drying, only to play a wetting role.

[0035] (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 liquid spraying pressure is 0.5-1.0 MPa, the wetting agent solution is sprayed into the premixed drug powder to prepare a soft material.

[0036] (5) The soft material obtained in step (4) is granulated using a swing granulator equipped with an 18-mesh nylon screen. After granulation is complete, the granules are transferred to a spherical shot blasting machine in operation (set the air blowing frequency to 30-50 Hz and the rotating disc speed to 10-30 Hz) and rounded for 3-6 minutes to obtain rounded granules.

[0037] (6) After the rounding operation is completed, all the rounded granules are transferred to a fluidized bed granulator. The inlet air temperature is set to 55±5°C, the material temperature is set to 50±5°C, and the fan frequency is set to 25-40 Hz. The heating is started to dry the granules. The granule temperature is controlled to be greater than 40°C and less than 60°C, not including 40°C and 60°C, 40°C < granule temperature < 60°C, preferably 45-55°C, including 45°C and 55°C, further preferably 48-52°C, including 48°C and 52°C, for example 48°C, 49°C, 50°C, 51°C or 52°C, but not limited to the listed values, other values not listed in this range are also applicable. The moisture content of the granules is less than 1.0%, preferably 0.3% < moisture content < 1.0%, greater than 0.3% and less than 1.0%, not including 0.3% and 1.0%, further preferably 0.5-0.9%, 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, other values not listed in this range are also applicable. The moisture content of the granules of the present application can be determined by a rapid moisture meter at 105°C / 5 min.

[0038] Although the time and temperature of drying are important, in the preparation of ibuprofen granules, controlling the granule temperature during granulation is crucial for the formation of the granules and the stability of the final product. Higher temperatures can accelerate solvent evaporation and shorten drying time, but may also cause degradation of heat-sensitive ingredients. Too low a temperature can result in poor granule hardness and poor water solubility, affecting the release rate of the drug and the therapeutic effect. An appropriate temperature range helps to maintain the stability of the active ingredients and the integrity of the granule structure.

[0039] Controlling the moisture content of the granules is also important for ensuring product quality. An appropriate moisture content helps to maintain the physical, chemical and microbial stability of the granules, and also ensures the smooth progress of the processing.

[0040] (7) The dried granules are sieved using a ternary rotary vibrating screen (equipped with a 16-mesh stainless steel screen on the upper layer and a 60-mesh stainless steel screen on the lower layer) to obtain granules with a size of 16-60 mesh.

[0041] (8) Total mixing: The granules obtained in step (7) are mixed with a fragrance. The mixing machine is set to a rotating speed of 12 rpm and mixed for 15 minutes to obtain ibuprofen granules. Then, the ibuprofen granules can be packaged according to the predetermined specifications. The present application does not limit the mixing equipment and parameters, as long as the raw and auxiliary materials can be uniformly mixed.

[0042] The mass composition of the ibuprofen granules comprises, by weight:

[0043] The amount of ibuprofen is 180-220 parts, the amount of filler is 700-750 parts, the amount of disintegrant is 25-35 parts, the amount of binder is 25-35 parts, the amount of sweetening agent is 2-7 parts, the amount of flavoring agent is 5-15 parts, and the amount of water is preferably 300-350 parts, and further preferably the amount of ibuprofen is 200 parts, the amount of filler is 725 parts, the amount of disintegrant is 30 parts, the amount of binder is 30 parts, the amount of sweetening agent is 5 parts, the amount of flavoring agent is 10 parts, the amount of water is 320 parts, and the water is purified water.

[0044] The inventor found that, although the principle is not clear, the change of actual experimental conditions has a very great influence on the effect of the invention in the whole preparation process of the system.

[0045] The configuration of the wetting agent in the granulation process, especially the timing of the addition of the binder, the sweetening agent and the flavoring agent, will directly affect the quality of the ibuprofen product. In addition, the ibuprofen particle size, the granule temperature, the moisture and whether there is a rounding process will affect the dissolution, the content uniformity, the related substances, the yield and the absorption of the ibuprofen granules.

[0046] The embodiments and comparative examples of the present application are specifically listed as follows, but the present application is not limited to the following examples.

[0047] Example 1

[0048] Table 1 Prescription composition

[0049] Ingredients 0.2 g strength mg Action Ibuprofen 200.00 Active ingredient Lactose 725.00 Filling agent Sodium croscarmellose 30.00 Disintegrant Hydroxypropyl cellulose 30.00 Binder Sucralose 5.00 Sweetening agent Powdered lime essence 10.00 Flavoring agent Purified water 320.00 Wetting agent

[0050] The preparation process is as follows: (6000 bags)

[0051] (1) Pretreatment of raw materials: the ibuprofen raw material is crushed, and the particle size range is controlled to be 10 μm≤D90≤60 μm; D50≤30 μm; the lactose is passed through a 40-mesh sieve.

[0052] (2) Premixing: the prescription amount of 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose and 1.2 kg of ibuprofen (crushed) are sequentially added into a wet granulator, the stirring speed of the wet granulator is set to 180 rpm, the shearing (granulation) speed is set to 1000 rpm, and the mixture is mixed for 15 minutes.

[0053] (3) Soft material preparation: 1.92 kg of purified water is weighed, 30 g of sucralose is added, stirred for more than 2 minutes until completely dissolved, as a wetting agent solution, and standby. The stirring speed of the wet granulator is set to 180 rpm, the shearing (granulation) speed is set to 1800 rpm, the liquid spraying pressure is set to 0.7 MPa, the machine is started at the same time, and the wetting agent solution is sprayed into the premixed drug powder to prepare soft material.

[0054] (4) Soft material preparation: 1.92 kg of purified water was weighed, 30 g of sucralose was added, and stirred for more than 2 minutes until completely dissolved as a wetting agent solution, ready for use. The wet granulator was set to a stirring speed of 180 rpm, a shearing (granulating) speed of 1800 rpm, and a liquid spraying pressure of 0.7 MPa. The machine was started, and the wetting agent solution was sprayed into the premixed drug powder to prepare soft material.

[0055] (5) Drying: After the completion of the rounding operation, all the rounded particles were transferred to the fluidized bed granulator, set to an inlet air temperature of 55±5°C, a material temperature of 50±5°C, and a fan frequency of 25Hz-40Hz, and started to heat and dry. The particle temperature was controlled at 50°C, and the particle moisture was 0.9%.

[0056] (6) Granulation: The dried particles were sieved with a ternary rotary vibrating screen (stainless steel screen with 16 mesh on the upper layer and 60 mesh on the lower layer) to screen particles between 16-60 mesh.

[0057] (7) Total mixing: The particles obtained in step (6) were mixed with 60 g of lime powder essence, the mixing machine was set to a speed of 12 rpm, and mixed for 15 minutes to obtain ibuprofen granules.

[0058] Example 2

[0059] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0060] (1) Pretreatment of raw materials: Ibuprofen raw material was crushed, and the particle size range was controlled to be 10μm≤D90≤60μm; D50≤30μm; lactose was passed through a 40 mesh sieve.

[0061] (2) Premixing: The prescription amount of 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (crushed) were sequentially added to the wet granulator, which was set to a stirring speed of 180 rpm and a shearing (granulating) speed of 1000 rpm, and mixed for 15 minutes.

[0062] (3) Soft material preparation: 1.92 kg of purified water was weighed, 30 g of sucralose was added, and stirred for more than 2 minutes until completely dissolved as a wetting agent solution, ready for use. The wet granulator was set to a stirring speed of 180 rpm, a shearing (granulating) speed of 1800 rpm, and a liquid spraying pressure of 0.7 MPa. The machine was started, and the wetting agent solution was sprayed into the premixed drug powder to prepare soft material.

[0063] (4) Soft material preparation: 1.92 kg of purified water was weighed, 30 g of sucralose was added, and stirred for more than 2 minutes until completely dissolved as a wetting agent solution, ready for use. The wet granulator was set to a stirring speed of 180 rpm, a shearing (granulating) speed of 1800 rpm, and a liquid spraying pressure of 0.7 MPa. The machine was started, and the wetting agent solution was sprayed into the premixed drug powder to prepare soft material.

[0064] (5) Drying: After the end of the rounding operation, all the rounded particles are transferred to the fluidized bed granulator, the inlet air temperature is set to 55±5°C, the material temperature is set to 50±5°C, and the fan frequency is set to 25Hz-40Hz. Start heating to dry. The particle temperature is controlled at 48°C, and the particle moisture is 0.9%.

[0065] (6) Granulation: The dried particles are screened with a ternary rotary vibrating screen (with a 16-mesh upper layer and a 60-mesh lower layer of stainless steel screen) to screen particles between 16-60 mesh.

[0066] (7) Total mixing: The particles obtained in step (6) are mixed with 60g of lime powder essence, the mixing machine speed is set to 12rpm, and the mixture is mixed for 15 minutes to obtain ibuprofen granules.

[0067] Example 3

[0068] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0069] (1) Pretreatment of raw materials: Ibuprofen raw material is crushed, and the particle size range is controlled to be 10μm≤D90≤60μm; D50≤30μm; lactose is passed through a 40-mesh screen.

[0070] (2) Premixing: The prescription amount of 4.35kg of lactose, 0.18kg of croscarmellose sodium, 0.18kg of hydroxypropyl cellulose, and 1.2kg of ibuprofen (crushed) are sequentially added to the wet granulator, the stirring speed of the wet granulator is set to 180rpm, the shearing (granulation) speed is set to 1000rpm, and the mixture is mixed for 15 minutes.

[0071] (3) Soft material preparation: 1.92kg of purified water is weighed, 30g of sucralose is added, and stirred for more than 2 minutes until completely dissolved as a wetting agent solution. Set the stirring speed of the wet granulator to 180rpm, the shearing (granulation) speed to 1800rpm, and the liquid spraying pressure to 0.7MPa. Start the machine while spraying the wetting agent solution into the premixed drug powder to prepare the soft material.

[0072] (4) Oscillating granulation and rounding: The soft material is granulated using an oscillating granulator equipped with an 18-mesh nylon screen, and after granulation is complete, it is transferred to a running spherical shot blasting machine (set the air blowing frequency to 30Hz-50Hz and the turntable speed to 10Hz-30Hz) for 3-6 minutes of rounding to obtain rounded particles.

[0073] (5) Drying: After the end of the rounding operation, all the rounded particles are transferred to the fluidized bed granulator, the inlet air temperature is set to 55±5°C, the material temperature is set to 50±5°C, and the fan frequency is set to 25Hz-40Hz. Start heating to dry. The particle temperature is controlled at 48°C, and the particle moisture is 0.9%.

[0074] (6) Screening: The dried granules were screened by a ternary rotary vibrating screen (with a 16-mesh upper layer and a 60-mesh lower layer of stainless steel screen) to obtain the granules with a size of 16-60 mesh.

[0075] (7) Total mixing: The granules obtained in step (6) were mixed with 60 g of lime powder essence, the rotating speed of the mixer was set to 12 rpm, and the mixture was mixed for 15 minutes to obtain ibuprofen granules.

[0076] Example 4

[0077] The prescription composition was the same as in Example 1, and the preparation process was as follows: (6000 bags)

[0078] (1) Pretreatment of raw materials and accessories: The ibuprofen raw material was crushed, and the particle size was controlled to be in the range of 10 μm≤D90≤60 μm; D50≤30 μm; and the lactose was passed through a 40-mesh screen.

[0079] (2) Premixing: The prescription amount of 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (crushed) were sequentially added into a wet granulator, the stirring speed of the wet granulator was set to 180 rpm, the shearing (granulating) speed was set to 1000 rpm, and the mixture was mixed for 15 minutes.

[0080] (3) Soft material preparation: 1.92 kg of purified water was weighed, 30 g of sucralose was added, and the mixture was stirred for more than 2 minutes until the sucralose was completely dissolved to obtain a wetting agent solution, which was prepared for use. The stirring speed of the wet granulator was set to 180 rpm, the shearing (granulating) speed was set to 1800 rpm, the liquid spraying pressure was set to 0.7 MPa, the machine was started, and the wetting agent solution was sprayed into the premixed drug powder to prepare the soft material.

[0081] (4) Swing granulation and rounding: The soft material was granulated by using a swing granulator equipped with an 18-mesh nylon screen, and then was transferred to a spherical shot blasting machine in operation (with the air blowing frequency set to 30-50 Hz and the rotating disc speed set to 10-30 Hz) for rounding for 3-6 minutes to obtain rounded granules.

[0082] (5) Drying: After the rounding operation was completed, all the rounded granules were transferred to a boiling granulator, the inlet air temperature was set to 55±5℃, the material temperature was set to 50±5℃, and the fan frequency was set to 25-40 Hz, and the heating was started for drying; the granule temperature was controlled to be 50℃, and the moisture content of the granules was 0.5%.

[0083] (6) Screening: The dried granules were screened by a ternary rotary vibrating screen (with a 16-mesh upper layer and a 60-mesh lower layer of stainless steel screen) to obtain the granules with a size of 16-60 mesh.

[0084] (7) Total mixing: The granules obtained in step (6) were mixed with 60 g of lime powder essence, the rotating speed of the mixer was set to 12 rpm, and the mixture was mixed for 15 minutes to obtain ibuprofen granules.

[0085] Example 5

[0086] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0087] (1) Pretreatment of raw materials: the ibuprofen raw material is crushed, and the particle size range is controlled to be 10 μm≤D90≤60 μm; D50≤30 μm; the lactose is passed through a 40-mesh sieve.

[0088] (2) Premixing: the prescription amount of 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (crushed) are sequentially added into a wet granulator, the stirring speed of the wet granulator is set to 180 rpm, the shearing (granulating) speed is set to 1000 rpm, and the mixture is mixed for 15 minutes.

[0089] (3) Soft material preparation: 1.92 kg of purified water is weighed, 30 g of sucralose is added, and stirred for more than 2 minutes until completely dissolved to serve as a wetting agent solution, which is ready for use. The stirring speed of the wet granulator is set to 180 rpm, the shearing (granulating) speed is set to 1800 rpm, the liquid spraying pressure is set to 0.7 MPa, the machine is started at the same time, and the wetting agent solution is sprayed into the premixed medicine powder to prepare soft material.

[0090] (4) Swing granulation and spherification: the soft material is taken to a swing granulator equipped with an 18-mesh nylon screen to perform granulation, and after the granulation is completed, it is transferred to a spherical shot blasting machine in operation (the air blowing frequency is set to 30 Hz-50 Hz, and the rotating disc speed is set to 10 Hz-30 Hz) for spherification for 3-6 minutes to obtain spherified granules.

[0091] (5) Drying: after the spherification operation is completed, all the spheroidized granules are transferred to a boiling granulator, the inlet air temperature is set to 55±5℃, the material temperature is set to 50±5℃, the fan frequency is set to 25 Hz-40 Hz, and the heating is started for drying; the granule temperature is controlled to be 50℃, and the granule moisture is 0.8%.

[0092] (6) Granulation: the dried granules are screened by a ternary rotary screen (equipped with an upper layer of 16-mesh and a lower layer of 60-mesh stainless steel screen) to screen the granules between 16-60 mesh.

[0093] (7) Total mixing: the granules obtained in step (6) are mixed with 60 g of lime powder essence, the mixing machine speed is set to 12 rpm, and the mixture is mixed for 15 minutes to obtain ibuprofen granules.

[0094] Comparative Example 1

[0095] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0096] (1) Raw material pretreatment: Ibuprofen raw material was not crushed, and the particle size D90 was 109.867 μm; D50 was 45.044 μm; lactose was passed through a 40 mesh sieve.

[0097] (2) Premixing: The prescription amount of 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose, 1.2 kg of ibuprofen (not crushed) was sequentially added into a wet granulator, and the wet granulator was set at a stirring speed of 180 rpm, a shearing (granulating) speed of 1000 rpm, and mixed for 15 minutes.

[0098] (3) Soft material preparation: 1.92 kg of purified water was weighed, 30 g of sucralose was added, and stirred for more than 2 minutes until completely dissolved as a wetting agent solution, and was prepared for use. The wet granulator was set at a stirring speed of 180 rpm, a shearing (granulating) speed of 1800 rpm, and a liquid spraying pressure of 0.7 MPa, and the machine was started at the same time as the wetting agent solution was sprayed into the premixed drug powder to prepare the soft material.

[0099] (4) Swing granulation and spherification: the soft material was taken to a swing granulator equipped with an 18 mesh nylon screen for granulation, and after the granulation was completed, it was transferred to a running spherical shot blasting machine (set at an air blowing frequency of 30 Hz to 50 Hz and a turntable speed of 10 Hz to 30 Hz) for spherification for 3 to 6 minutes to obtain spheroidized particles.

[0100] (5) Drying: after the spheroidization operation was completed, all the spheroidized particles were transferred to a boiling granulator, and the inlet air temperature was set at 55±5℃, the material temperature was set at 50±5℃, and the fan frequency was set at 25 Hz to 40 Hz, and the heating was started for drying; the particle temperature was controlled at 50℃, and the particle moisture was 0.9%.

[0101] (6) Particle sizing: the dried particles were sieved by a ternary rotary vibrating screen (equipped with an upper layer of 16 mesh and a lower layer of 60 mesh stainless steel screen) to screen the particles between 16 to 60 mesh.

[0102] (7) Total mixing: the particles obtained in step (6) were mixed with 60 g of lime powder essence, and the mixer was set at a speed of 12 rpm and mixed for 15 minutes to obtain ibuprofen granules.

[0103] Comparative Example 2

[0104] The prescription composition was the same as in Example 1, and the preparation process was as follows: (6000 bags)

[0105] (1) Raw material pretreatment: Ibuprofen raw material was not crushed, and the particle size D90 was 109.867 μm; D50 was 45.044 μm; lactose was passed through a 40 mesh sieve.

[0106] (2) Premix: 4.35 kg of lactose, 0.18 kg of sodium croscarmellose, 0.18 kg of hydroxypropyl cellulose, 1.2 kg of ibuprofen (after being crushed) of the prescription amount were sequentially added into a wet granulator, the stirring speed of the wet granulator was set to 180 rpm, the shearing (granulating) speed was set to 1000 rpm, and the mixture was mixed for 15 minutes.

[0107] (3) Soft material preparation: 1.92 kg of purified water was weighed, 30 g of sucralose was added, and stirred for more than 2 minutes until completely dissolved to serve as a wetting agent solution. The stirring speed of the wet granulator was set to 180 rpm, the shearing (granulating) speed was set to 1800 rpm, the liquid spraying pressure was set to 0.7 MPa, the machine was started, and the wetting agent solution was sprayed into the premixed drug powder to prepare the soft material.

[0108] (4) Swing granulation: the soft material was taken to a swing granulator equipped with an 18-mesh nylon screen for granulation, and the granulated particles were obtained after the granulation was completed.

[0109] (5) Drying: after the swing granulation was completed, all the particles were transferred to a boiling granulator, the inlet air temperature was set to 55 ± 5°C, the material temperature was set to 50 ± 5°C, the fan frequency was set to 25 Hz to 40 Hz, the heating was started for drying; the particle temperature was controlled to be 50°C, and the particle moisture was 0.9%.

[0110] (6) Particle sizing: the dried particles were sieved by a ternary rotary vibrating screen (equipped with an upper layer of 16-mesh and a lower layer of 60-mesh stainless steel screen), and the particles between 16-mesh and 60-mesh were sieved.

[0111] (7) Total mixing: the particles obtained in step (6) were mixed with 60 g of lime powder essence, the mixing machine was set to a speed of 12 rpm, and the mixture was mixed for 15 minutes to obtain ibuprofen granules.

[0112] Comparative Example 3

[0113] The prescription composition was as in Example 1, and the preparation process was as follows: (6000 bags)

[0114] (1) Pretreatment of raw and auxiliary materials: the ibuprofen raw material was crushed, and the particle size range was controlled to be 10 μm ≤ D90 ≤ 60 μm; D50 ≤ 30 μm; the lactose was passed through a 40-mesh screen.

[0115] (2) Premix: 4.35 kg of lactose, 0.18 kg of sodium croscarmellose, 0.18 kg of hydroxypropyl cellulose, 1.2 kg of ibuprofen (after being crushed) of the prescription amount were sequentially added into a wet granulator, the stirring speed of the wet granulator was set to 180 rpm, the shearing (granulating) speed was set to 1000 rpm, and the mixture was mixed for 15 minutes.

[0116] (3) Soft material preparation: 1.92 kg of purified water was weighed and 30 g of sucralose and 60 g of lime powder flavor were added and stirred for more than 2 minutes until completely dissolved to serve as a wetting agent solution, which was prepared for use. The stirring speed of the wet granulator was set to 180 rpm, the shearing (granulating) speed was set to 1800 rpm, and the liquid spraying pressure was set to 0.7 MPa. The machine was started at the same time as the pre-mixed drug powder was sprayed with the wetting agent solution to prepare the soft material.

[0117] (4) Swing granulation and spherification: the soft material was taken to a swing granulator with an 18-mesh nylon screen to perform granulation. After the granulation was completed, the granules were transferred to a spherical shot blasting machine in operation (with the air blowing frequency set to 30-50 Hz and the rotating disc speed set to 10-30 Hz) for 3-6 minutes of spherification to obtain spherically shaped granules.

[0118] (5) Drying: after the spherification operation was completed, all the spherically shaped granules were transferred to a boiling granulator. The inlet air temperature was set to 55±5°C, the material temperature was set to 50±5°C, and the fan frequency was set to 25-40 Hz. The heating was started to perform drying. The granule temperature was controlled to be 50°C, and the granule moisture was 0.9%.

[0119] (6) Particle sizing: the dried granules were sieved using a ternary rotary vibrating screen (with a 16-mesh upper layer and a 60-mesh lower layer of stainless steel screen) to screen the granules between 16-60 mesh.

[0120] (7) Total mixing: the granules obtained in step (6) were mixed. The mixing machine was set to a speed of 12 rpm, and the mixing was performed for 15 minutes to obtain ibuprofen granules.

[0121] Comparative Example 4

[0122] The prescription composition was the same as in Example 1, and the preparation process was as follows: (6000 bags)

[0123] (1) Pretreatment of raw and auxiliary materials: the ibuprofen raw material was crushed to control the particle size range to be 10 μm≤D90≤60 μm; D50≤30 μm; and the lactose was passed through a 40-mesh screen.

[0124] (2) Premixing: the prescription amount of 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (crushed) were sequentially added to a wet granulator. The stirring speed of the wet granulator was set to 180 rpm, the shearing (granulating) speed was set to 1000 rpm, and the mixing was performed for 15 minutes.

[0125] (3) Soft material preparation: 0.96 kg of purified water was weighed and 30 g of sucralose was added and stirred for more than 2 minutes until completely dissolved to serve as a wetting agent solution, which was prepared for use. The wetting agent solution was added to the pre-mixed drug powder, and wet mixing was performed for about 5 minutes to prepare the soft material. The soft material was required to be able to form a ball when kneaded by hand, to be scattered by light pressure, to be evenly moistened, and to have uniform color and consistency.

[0126] (4) Soft material granulation and rounding: the soft material was granulated by a swing granulator with a 18-mesh nylon screen, and then transferred to a spherical shot blasting machine (set the air blowing frequency of 30-50 Hz and the rotating disc speed of 10-30 Hz) to round for 3-6 minutes to obtain rounded granules.

[0127] (5) Drying: after the rounding operation was completed, all the rounded granules were transferred to a fluidized bed granulator, set the inlet air temperature of 55±5°C, the material temperature of 50±5°C, and the fan frequency of 25-40 Hz, and then started to heat and dry; the granule temperature was controlled at 50°C and the granule moisture was 0.9%.

[0128] (6) Granule sizing: the dried granules were sieved by a ternary rotary vibrating screen (loaded with a 16-mesh stainless steel screen on the upper layer and a 60-mesh stainless steel screen on the lower layer) to obtain the granules with a size of 16-60 mesh.

[0129] (7) Total mixing: the granules obtained in step (6) were mixed with 60 g of lime powder essence, the mixing machine was set at a rotating speed of 12 rpm, and the mixture was mixed for 15 minutes to obtain ibuprofen granules.

[0130] Comparative Example 5

[0131] The prescription composition was the same as that in Example 1, and the preparation process was as follows: (6000 bags)

[0132] (1) Pretreatment of raw materials and excipients: the ibuprofen raw material was crushed, and the particle size range was controlled to be 10 μm≤D90≤60 μm; D50≤30 μm; the lactose was passed through a 40-mesh screen.

[0133] (2) Premixing: the prescription amount of 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (crushed) were sequentially added to a wet granulator, the wet granulator was set at a stirring speed of 180 rpm and a shearing (granulating) speed of 1000 rpm, and the mixture was mixed for 15 minutes.

[0134] (3) Soft material preparation: 1.92 kg of purified water was weighed, 30 g of sucralose was added, and stirred for more than 2 minutes until completely dissolved to obtain a wetting agent solution, which was prepared for use. The wet granulator was set at a stirring speed of 180 rpm, a shearing (granulating) speed of 1800 rpm, and a liquid spraying pressure of 0.7 MPa, and the machine was started at the same time to spray the wetting agent solution into the premixed drug powder to prepare the soft material.

[0135] (4) Soft material granulation and rounding: the soft material was granulated by a swing granulator with a 18-mesh nylon screen, and then transferred to a spherical shot blasting machine (set the air blowing frequency of 30-50 Hz and the rotating disc speed of 10-30 Hz) to round for 3-6 minutes to obtain rounded granules.

[0136] (5) Drying: After the end of the rounding operation, all the rounded particles are transferred to the fluidized bed granulator, the inlet air temperature is set to 60±5°C, the material temperature is set to 60±5°C, and the fan frequency is set to 25Hz-40Hz. Start heating to dry. The particle temperature is controlled at 60°C, and the particle moisture is 0.9%.

[0137] (6) Granulation: The dried particles are screened with a ternary rotary vibrating screen (with a 16-mesh upper layer and a 60-mesh lower layer of stainless steel screen) to screen particles between 16-60 mesh.

[0138] (7) Total mixing: The particles obtained in step (6) are mixed with 60g of lime powder essence, the mixing machine speed is set to 12rpm, and the mixture is mixed for 15 minutes to obtain ibuprofen granules.

[0139] Comparative Example 6

[0140] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0141] (1) Pretreatment of raw materials: Ibuprofen raw material is crushed, and the particle size range is controlled to be 10μm≤D90≤60μm; D50≤30μm; lactose is passed through a 40-mesh screen.

[0142] (2) Premixing: The prescription amount of 4.35kg of lactose, 0.18kg of croscarmellose sodium, 0.18kg of hydroxypropyl cellulose, and 1.2kg of ibuprofen (crushed) are sequentially added to the wet granulator, the stirring speed of the wet granulator is set to 180rpm, the shearing (granulation) speed is set to 1000rpm, and the mixture is mixed for 15 minutes.

[0143] (3) Soft material preparation: 1.92kg of purified water is weighed, 30g of sucralose is added, and stirred for more than 2 minutes until completely dissolved as a wetting agent solution, ready for use. The stirring speed of the wet granulator is set to 180rpm, the shearing (granulation) speed is set to 1800rpm, the liquid spraying pressure is set to 0.7MPa, and the machine is started at the same time. Spray the wetting agent solution into the premixed drug powder to prepare the soft material.

[0144] (4) Oscillating granulation and rounding: The soft material is granulated with an oscillating granulator equipped with an 18-mesh nylon screen, and after granulation, it is transferred to a running spherical shot blasting machine (set the air blowing frequency to 30Hz-50Hz, and the turntable speed to 10Hz-30Hz) for 3-6 minutes of rounding to obtain rounded particles.

[0145] (5) Drying: After the end of the rounding operation, all the rounded particles are transferred to the fluidized bed granulator, the inlet air temperature is set to 60±5°C, the material temperature is set to 60±5°C, and the fan frequency is set to 25Hz-40Hz. Start heating to dry. The particle temperature is controlled at 60°C, and the particle moisture is 0.9%.

[0146] (6) Screening: The dried granules were screened by a ternary rotary vibrating screen (with a 16-mesh upper layer and a 60-mesh lower layer of stainless steel screen) to obtain the granules with a size of 16-60 mesh.

[0147] (7) Total mixing: The granules obtained in step (6) were mixed with 60 g of lime powder essence, the rotating speed of the mixer was set to 12 rpm, and the mixture was mixed for 15 minutes to obtain ibuprofen granules.

[0148] Comparative Example 7

[0149] The prescription composition was the same as in Example 1, and the preparation process was as follows: (6000 bags)

[0150] (1) Pretreatment of raw materials and accessories: The ibuprofen raw material was crushed to control the particle size range to be 10 μm≤D90≤60 μm; D50≤30 μm; and the lactose was passed through a 40-mesh screen.

[0151] (2) Premixing: The prescription amount of 4.35 kg of lactose, 0.18 kg of croscarmellose sodium, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (crushed) were sequentially added to a wet granulator, the stirring speed of the wet granulator was set to 180 rpm, the shearing (granulating) speed was set to 1000 rpm, and the mixture was mixed for 15 minutes.

[0152] (3) Soft material preparation: 1.92 kg of purified water was weighed, 30 g of sucralose was added, and the mixture was stirred for more than 2 minutes until the sucralose was completely dissolved to obtain a wetting agent solution, which was prepared for use. The stirring speed of the wet granulator was set to 180 rpm, the shearing (granulating) speed was set to 1800 rpm, the liquid spraying pressure was set to 0.7 MPa, the machine was started, and the wetting agent solution was sprayed into the premixed drug powder to prepare the soft material.

[0153] (4) Swing granulation and rounding: The soft material was granulated by a swing granulator equipped with an 18-mesh nylon screen, and then was transferred to a spherical shot blasting machine in operation (with the air blowing frequency set to 30-50 Hz and the rotating disc speed set to 10-30 Hz) for rounding for 3-6 minutes to obtain rounded granules.

[0154] (5) Drying: After the rounding operation was completed, all the rounded granules were transferred to a boiling granulator, the inlet air temperature was set to 55±5℃, the material temperature was set to 50±5℃, and the fan frequency was set to 25-40 Hz, and the heating was started for drying; the granule temperature was controlled to be 50℃, and the moisture content of the granules was 1.5%.

[0155] (6) Screening: The dried granules were screened by a ternary rotary vibrating screen (with a 16-mesh upper layer and a 60-mesh lower layer of stainless steel screen) to obtain the granules with a size of 16-60 mesh.

[0156] (7) Total mixing: The granules obtained in step (6) were mixed with 60 g of lime powder essence, the rotating speed of the mixer was set to 12 rpm, and the mixture was mixed for 15 minutes to obtain ibuprofen granules.

[0157] Comparative Example 8

[0158] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0159] (1) Pretreatment of raw materials: the ibuprofen raw material is crushed to control the particle size range to be 10 μm≤D90≤60 μm; D50≤30 μm; and the lactose is passed through a 40-mesh sieve.

[0160] (2) Premixing: the prescription amount of 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) are sequentially added into a wet granulator, the stirring speed of the wet granulator is set to 180 rpm, the shearing (granulating) speed is set to 1000 rpm, and the mixture is mixed for 15 minutes.

[0161] (3) Soft material preparation: 1.92 kg of purified water is weighed, 30 g of sucralose is added, and the mixture is stirred for more than 2 minutes until the sucralose is completely dissolved to obtain a wetting agent solution, which is prepared for use. The stirring speed of the wet granulator is set to 180 rpm, the shearing (granulating) speed is set to 1800 rpm, the liquid spraying pressure is set to 0.7 MPa, the machine is started, and the wetting agent solution is sprayed into the premixed medicine powder to prepare soft material.

[0162] (4) Swing granulation and spherification: the soft material is taken to a swing granulator equipped with an 18-mesh nylon screen to perform granulation, and after the granulation is completed, the spherification is performed in a spherical shot blasting machine (set to an air blowing frequency of 30 Hz to 50 Hz and a rotating disc speed of 10 Hz to 30 Hz) to obtain spherified particles.

[0163] (5) Drying: after the spherification operation is completed, all the spherified particles are transferred to a boiling granulator, the inlet air temperature is set to 55±5℃, the material temperature is set to 50±5℃, the fan frequency is set to 25 Hz to 40 Hz, the heating is started, and the drying is performed; the particle temperature is controlled to be 50℃, and the particle moisture is 0.3%.

[0164] (6) Particle sizing: the dried particles are sieved by a ternary rotary vibrating screen (equipped with an upper layer of 16-mesh and a lower layer of 60-mesh stainless steel screen) to obtain particles with a size of 16 to 60 mesh.

[0165] (7) Total mixing: the particles obtained in step (6) are mixed with 60 g of lime powder essence, the mixing machine is set to a speed of 12 rpm, and the mixture is mixed for 15 minutes to obtain ibuprofen granules.

[0166] Comparative Example 9

[0167] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0168] (1) Raw material pretreatment: Ibuprofen bulk drug is crushed to control the particle size range of 10 μm≤D90≤60 μm; D50≤30 μm; lactose is passed through a 40 mesh sieve.

[0169] (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 (crushed) in the prescription amount are sequentially added into a wet granulator, the stirring speed of the wet granulator is set to 180 rpm, the shearing (granulation) speed is set to 1000 rpm, and mixing is performed for 15 minutes.

[0170] (3) Soft material preparation: 1.92 kg of purified water is weighed, 30 g of sucralose is added, and stirring is performed for more than 2 minutes until complete dissolution to obtain a wetting agent solution, which is prepared for use. The stirring speed of the wet granulator is set to 180 rpm, the shearing (granulation) speed is set to 1800 rpm, the liquid spraying pressure is set to 0.7 MPa, the machine is started, and the wetting agent solution is sprayed into the premixed drug powder to prepare a soft material.

[0171] (4) Swing granulation and spherification: the soft material is taken to a swing granulator equipped with a 10 mesh nylon screen to perform granulation, and after the granulation is completed, the granules are transferred to a spherical shot blasting machine in operation (the air blowing frequency is set to 30 Hz-50 Hz, and the rotating disc speed is set to 10 Hz-30 Hz) to spherify for 3-6 minutes to obtain spherified granules.

[0172] (5) Drying: after the spherification operation is completed, all the spherified granules are transferred to a boiling granulator, the inlet air temperature is set to 55±5℃, the material temperature is set to 50±5℃, and the fan frequency is set to 25 Hz-40 Hz, and the heating is started to perform drying; the granule temperature is controlled to be 50℃, and the granule moisture is 0.9%.

[0173] (6) Granule sizing: the dried granules are sieved by a ternary rotary vibrating screen (equipped with an upper layer of 16 mesh and a lower layer of 60 mesh stainless steel screen) to screen the granules between 16-60 mesh.

[0174] (7) Total mixing: the granules obtained in step (6) are mixed with 60 g of lime powder essence, the mixing machine speed is set to 12 rpm, and mixing is performed for 15 minutes to obtain ibuprofen granules.

[0175] Comparative Example 10

[0176] The prescription composition is as in Example 1, and the preparation process is as follows: (6000 bags)

[0177] (1) Raw material pretreatment: Ibuprofen bulk drug is crushed to control the particle size range of 10 μm≤D90≤60 μm; D50≤30 μm; lactose is passed through a 40 mesh sieve.

[0178] (2) Premixing: The prescribed amounts of 4.35 kg of lactose, 0.18 kg of sodium croscarmellose, 0.18 kg of hydroxypropyl cellulose, and 1.2 kg of ibuprofen (pulverized) were sequentially added to a wet granulator, and the wet granulator was set to a stirring speed of 180 rpm and a shearing (granulating) speed of 1000 rpm, and mixed for 15 minutes.

[0179] (3) Soft material preparation: 1.92 kg of purified water was weighed, 30 g of sucralose was added thereto, and stirred for more than 2 minutes until completely dissolved, to prepare a wetting agent solution. The wet granulator was set to a stirring speed of 180 rpm, a shearing (granulating) speed of 1800 rpm, and a liquid spraying pressure of 0.7 MPa, and the wetting agent solution was sprayed to the premixed drug powder while the machine was started, to prepare a soft material.

[0180] (4) Oscillating granulation and spheronization: The soft material was transferred to an oscillating granulator equipped with an 18-mesh nylon screen, and granulated. After the granulation was completed, the granulated material was transferred to a spherical marvering machine (set to an air blowing frequency of 30 to 50 Hz and a turntable speed of 10 to 30 Hz), and spheronized for 3 to 6 minutes, to obtain spheronized granules.

[0181] (5) Drying: After the spheronization was completed, the spheronized granules were transferred to a fluid bed granulator, and set to an inlet air temperature of 40 ± 5°C, a material temperature of 40 ± 5°C, and a fan frequency of 25 to 40 Hz, and the heating was started to dry the granules. The granule temperature was controlled to 40°C, and the moisture content of the granules was controlled to 1.5%.

[0182] (6) Size reduction: The dried granules were sieved using a three-dimensional rotary sieve (equipped with an upper 16-mesh and a lower 60-mesh stainless steel screen), and the granules having a size of 16 to 60 mesh were collected.

[0183] (7) Total mixing: The granules obtained in step (6) were mixed with 60 g of lime powder flavor, and the mixing machine was set to a speed of 12 rpm, and mixed for 15 minutes, to obtain ibuprofen granules.

[0184] Verification of effect

[0185] The dissolution rate, yield, related substances, and in vivo absorption of the ibuprofen granules of Examples 1 to 5, Comparative Examples 1 to 10, and a reference preparation (Kaken Pharmaceutical Co., Ltd., trade name: "GRANULE 20%", specification: 20% 1 g, batch number: L14970) were measured.

[0186] Determination of dissolution, the specific determination method as follows:

[0187] ​Select citric acid-disodium hydrogen phosphate buffer (pH 5.5) (mixture A: take citric acid 5.25 g, add water to dissolve into 1000 ml; mixture B: take disodium hydrogen phosphate 17.91 g, add water to dissolve into 1000 ml. Adjust the pH of mixture B to 5.5 with mixture A) 900 ml as the dissolution medium of the product, the rotation speed is 50 revolutions per minute, the sampling time and limit are: the dissolution is not less than 85% of the labeled amount at 15 minutes.

[0188] Chromatographic conditions: octadecylsilane-bonded silica gel as the filler; sodium acetate buffer (take sodium acetate 6.13 g, add water 750 ml to dissolve, adjust the pH 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.

[0189] The test solution is taken from the dissolution solution, filtered, and the filtrate is taken.

[0190] The control solution is taken from the ibuprofen control substance, accurately weighed, dissolved in methanol, and diluted 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 (0.2 g specification).

[0191] The system suitability requirement is that the theoretical plate number calculated based on the ibuprofen peak is not less than 2500.

[0192] The determination method is to accurately take the test solution and the control solution, inject them into the liquid chromatograph, and record the chromatogram. The dissolution amount per bag is calculated by peak area according to the external standard method.

[0193] Table 2 Dissolution results

[0194] Batch Dissolution at 15 minutes (%) Batch Dissolution at 15 minutes (%) 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

[0195] As can be seen from Table 2, the dissolution of the reference preparation in pH 5.5 medium is 88% at 15 minutes, which belongs to fast dissolution. The ibuprofen granules obtained in Examples 1-5 have a dissolution of more than 85% at 15 minutes, which is similar to the dissolution of the reference preparation.

[0196] Under the same other conditions, Comparative Example 1 uses ibuprofen raw material with a larger particle size for granulation, and the ibuprofen granules obtained have a dissolution of 73.5% at 15 minutes, which is significantly less than the reference preparation, and the dissolution behavior is not similar.

[0197] Under the same other conditions, Comparative Example 8 has too low moisture in the granulation process, and the ibuprofen granules obtained have a dissolution of 80.2% at 15 minutes, which is significantly less than the reference preparation, and the dissolution behavior is not similar.

[0198] Determination of content and content uniformity, the specific determination method as follows:

[0199] According to the "Content Uniformity Test Method" in the fourth part of the Chinese Pharmacopoeia 2020 edition 0941, the content of the product is determined by the method in the content determination item,

[0200] (1) Determination method: high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition fourth part 0512)

[0201] (2) Test solution: take 1 bag of the product, add methanol to 200ml (0.2g specification) flask, shake to dissolve and dilute to the mark, shake well, filter, accurately take 10ml of the filtrate, dilute to the mark with methanol, shake well,

[0202] (3) Control solution: take the appropriate amount of ibuprofen control, accurately weigh, dissolve and dilute to make a solution containing about 0.5mg per 1ml.

[0203] (4) Chromatographic conditions: octadecylsilane bonded silica gel as filler (YMC-Triart C18 4.6mm x 150mm, 5μm or equivalent performance chromatographic column); with sodium acetate buffer solution (take sodium acetate 6.13g, add water 750ml to dissolve, adjust pH value to 2.5 with glacial acetic acid)-acetonitrile (40∶60) as mobile phase; flow rate is 1.0ml per minute; detection wavelength is 263nm; injection volume is 20μl.

[0204] (5) System suitability requirements: the theoretical plate number calculated by ibuprofen peak should not be less than 2500.

[0205] (6) Determination method: accurately take the test solution and the control solution, respectively, inject into the liquid chromatograph, record the chromatogram. Calculate by peak area according to external standard method.

[0206] (7) Calculation formula:

[0207] Content (%) = W S × control content × A T × D T / A S × D S × labeled amount × 100%

[0208] In the formula:

[0209] W S is the sample weight of ibuprofen control, g;

[0210] A T is the peak area of ibuprofen peak in the chromatogram of test solution;

[0211] A S is the peak area of ibuprofen peak in the chromatogram of control solution;

[0212] D S Dilution fold for control solution

[0213] (8) Limit: if A+2.2S≤15, the content uniformity of the test sample is in conformity with the requirements;

[0214] If A+S>15, it is not in conformity with the requirements;

[0215] If A+2.2S>15 and A+S<15, 20 more test samples should be taken.

[0216] Table 3 Content and content uniformity of ibuprofen granules

[0217]

[0218]

[0219] Note: content limit 90%~110%

[0220] Examples 1~5 are ibuprofen granules prepared according to the composition and preparation process of the present application, and the corresponding content uniformity and content are within the range specified in the pharmacopoeia.

[0221] Comparative Example 1 does not control the particle size of ibuprofen, and the content uniformity is lower than that of Example 1, and the granule uniformity is slightly worse.

[0222] Under the condition that other conditions are the same, Comparative Example 2 does not use the rounding process compared with Example 1, and the content uniformity of the product is significantly reduced, which is 1 times higher than that of Example 1.

[0223] Similarly, under the premise that other conditions are the same, Comparative Examples 3 and 4 use different wetting agent preparation methods. Comparative Example 3 uses water, sucralose and lime powder essence as wetting agents at the same time, and the content uniformity of the product obtained is lower than that of Example 1, and the granule uniformity is slightly worse. Comparative Example 4 uses a direct wet mixing method to prepare ibuprofen granules, and the content uniformity is significantly higher than the limit value.

[0224] Comparative Examples 5 and 6 use different granule temperature control strategies. Comparative Example 5 (higher granule temperature) obtains a product with lower content uniformity than Example 1, and the granule uniformity is slightly worse. Comparative Example 6 (lower granule temperature) obtains a product with significantly lower content uniformity, which is 3 times higher than that of Example 1.

[0225] When the moisture content of the granules deviates from the optimal control range (Comparative Examples 7 and 8), the content uniformity of the product obtained is lower than that of Example 1, and the granule uniformity is slightly worse.

[0226] Comparative Example 9 uses different screens to produce products with lower content uniformity than Example 1, and the granule uniformity is slightly worse.

[0227] Finally, Comparative Example 10 controls both the temperature and moisture of the granules, but the product obtained has a lower content uniformity and slightly poorer granule uniformity than the product of Example 1.

[0228] The above comparative results show that the process according to the present application can effectively ensure that the ibuprofen granules have good uniformity.

[0229] Determination of ibuprofen granule yield

[0230] The efficiency of the conversion of the raw materials into the target pharmaceutical product is measured by the following formula:

[0231] Yield (%) = (actual amount of target product obtained / theoretical amount of target product that should be obtained) x 100%

[0232] Table 4: Yield of ibuprofen granules

[0233] 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

[0234] According to the data in Table 4, the ibuprofen granule preparation method according to the present application shows a good yield, all of which can reach more than 93%. In contrast, the preparation methods in the comparative examples show inconsistent yields under the same conditions.

[0235] The rounding process is crucial for improving the yield of the final product. For example, if the rounding step is not performed after granulation (as shown in Comparative Example 2), the yield can only reach 72.43%, which is an unacceptably low yield level for mass production.

[0236] The composition of the wetting agent and the way it is added also significantly affect the efficiency of ibuprofen granule preparation. When the sweetener and the flavoring agent are used together as a wetting agent (as shown in Comparative Example 3), although the dissolution of the ibuprofen granules obtained under this treatment is more than 85% within 15 minutes, as can be seen from Table 2, the total yield is only 87.52%, which is at a relatively high level, but still significantly lower than the 93.44% yield achieved in Example 1. In addition, using the direct wet mixing method to prepare ibuprofen granules (as shown in Comparative Example 4), although the dissolution is also more than 85%, the yield is only 12.34%, greatly reducing the production efficiency.

[0237] As can be seen from Comparative Examples 5 to 8, the temperature and moisture content of the dried granules during the granulation process also have some effect on the yield of the final product, although the yields under these conditions are generally still at a relatively good level, but are lower than the 93.44% yield achieved in Example 1. In addition, when the temperature and moisture content of the granules are both not within the ideal range (as in Comparative Example 10), although the dissolution of the ibuprofen granules obtained meets the requirements, the yield is significantly lower than that of Example 1.

[0238] Furthermore, selecting a suitable sieve is crucial for the granulation process. For example, using a 10-mesh sieve (as shown in Comparative Example 9) results in a yield of only 56.24%, which is extremely detrimental to actual production. In conclusion, optimizing the above factors can effectively improve the preparation efficiency and product yield of ibuprofen granules.

[0239] Determination of related substances, the specific determination method as follows:

[0240] The relevant substances were determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0241] Take an appropriate amount of the fine powder from the assay section (approximately equivalent to 0.2 g of ibuprofen), place it in a 100 ml volumetric flask, add 30 ml of acetonitrile, sonicate for 15 minutes to dissolve the ibuprofen, cool, dilute to the mark with the mobile phase, shake well, filter, and collect the filtrate.

[0242] 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.

[0243] Accurately measure 5 ml of the control solution into a 10 ml volumetric flask, dilute to the mark with the mobile phase, and shake well.

[0244] Take an appropriate amount of blank excipient (approximately equivalent to 0.2g of ibuprofen) and place it in a 100ml volumetric flask. Add 30ml of acetonitrile, sonicate for 15 minutes to dissolve, cool, dilute to the mark with the mobile phase, shake well, filter, and collect the filtrate.

[0245] For system suitability solution, take appropriate amounts of ibuprofen and reference standards A, B, C, E, J, M, N, and Q, add an appropriate amount of acetonitrile to dissolve them, and dilute with the mobile phase to prepare a mixed solution containing approximately 2 mg of ibuprofen and 4 μg each of impurities A, B, C, E, J, M, N, and Q per ml.

[0246] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (YMC-Pack ODS-A, 4.6 mm × 150 mm).

[0247] A 5 μm or equivalent chromatographic column was used; the mobile phase was water (pH adjusted to 2.5 with phosphoric acid)-acetonitrile (66:34);

[0248] The flow rate was 2.0 ml per minute; the detection wavelength was 214 nm; and the injection volume was 20 μl.

[0249] System suitability requirements: In the chromatogram of the solution, the elution order is as follows: impurity J peak, impurity N peak, ...

[0250] The separation degree of impurity M peak, impurity C peak, impurity Q peak, impurity A peak, ibuprofen, impurity B peak and impurity E peak should meet the requirements. In the chromatogram of the sensitivity solution, the signal-to-noise ratio of the peak height of the main component chromatographic peak should be greater than 10.

[0251] The test solution and the control solution were precisely measured and injected into the liquid chromatograph, and the chromatogram was recorded to 2 times the retention time of the ibuprofen peak.

[0252] In the chromatogram of the test solution, if there are impurity peaks, in addition to the solvent peak and the excipient peak, impurity A, impurity B, impurity J, impurity N and impurity Q should not be greater than 2 times (0.20%) of the main peak area of the control solution, impurity C, impurity E and impurity M should not be greater than 2 times (0.20%) of the main peak area of the control solution according to the corrected peak area (multiplied by the correction factor 1.8, 0.6 and 1.2 respectively), and other single impurity peak area should not be greater than 2 times (0.20%) of the main peak area of the control solution, the sum of the corrected peak areas of each impurity should not be greater than 10 times (1.0%) of the main peak area of the control solution, and the peak less than the main peak area of the sensitivity solution in the chromatogram of the test solution is ignored (0.05%).

[0253] Table 5 Impurity information

[0254]

[0255]

[0256] Table 6 Related substance test results

[0257]

[0258]

[0259]

[0260]

[0261]

[0262] We investigated the impurities involved in ibuprofen granules according to the current quality standard for ibuprofen granules, the requirements for identification limit and quality control limit of organic impurities in the "Guiding Principles for the Research of Chemical Drug Impurities" and ICH Q3A, ICH Q3B.

[0263] The formulations obtained in Examples 1-5 were placed under the same conditions as the reference formulation, and there were no significant differences in the various test indicators, and even the types and amounts of impurities were better than those of the reference formulation, indicating that the formulations obtained in the examples and the reference formulation were both stable under these conditions. In addition, from the change in the total impurity content of the reference formulation, the impurity content was 0.09% on day 0, and after 30 days under high temperature, the impurity content was 0.16%, while the total impurity content did not change significantly under high humidity and light, indicating that the ibuprofen granules were sensitive to temperature. The total impurity content of the formulations obtained in Examples 1-5 also did not change significantly under high temperature, indicating that they were stable under high temperature.

[0264] According to the data in Table 6, the ibuprofen granules of Comparative Examples 1-10 and the formulations of Examples and the reference formulation were placed under the same conditions, and the impurity content fluctuated significantly. Specifically:

[0265] Comparative Example 1 did not control the particle size of ibuprofen, resulting in a product with an impurity A content of 0.19% after 30 days under high temperature conditions, close to the limit value of 0.20%. In addition, under high humidity and light conditions, the impurity A and total impurity contents increased significantly, indicating that the ibuprofen granules of Comparative Example 1 had poor stability.

[0266] Under the same conditions, Comparative Example 2 did not use a rounding process compared to Example 1, and the impurity A and total impurity contents of its product increased significantly under high temperature, high humidity, and light conditions, higher than the relevant impurity contents of Example 1.

[0267] Similarly, under the same conditions, Comparative Examples 3 and 4 used different wetting agent preparation methods, and the initial impurity content of the products was high, especially for impurity A and total impurities, and these impurities further increased under high temperature, high humidity, and light conditions. Among them, the impurity A content of the products of Comparative Examples 3 and 4 exceeded the limit value of 0.20% after 30 days under high temperature.

[0268] Although Comparative Examples 5 and 6 used different granule temperature control strategies, the impurity growth rate of their products in the accelerated test was significantly faster than that of Example 1, very close to the limit value. This proves that accurate granule temperature control is crucial for maintaining impurity stability.

[0269] When the moisture content of the granules deviates from the optimal control range (Comparative Examples 7 and 8), the degradation rate of impurity A under high temperature conditions is significantly accelerated, and the content exceeds the limit value after 30 days, and strict moisture control is one of the core elements to ensure product stability.

[0270] Although Comparative Example 9 used a different screen to produce a product with lower impurity content, the presence of many types of impurities increased the risk of product stability.

[0271] The comparative example 10 with higher initial impurity content and still exceeding the quality standard in the final impurity content, indicates that the optimization of a single parameter is difficult to completely compensate for other process defects.

[0272] The above comparative experiment results show that only the integration of multiple technical means such as particle size control, rounding process, optimization of wetting system, precise temperature and humidity control, can realize effective control of impurity content and significant improvement of preparation stability.

[0273] In summary, in the preparation process of ibuprofen granules, the composition and addition method of wetting agent, the temperature of dried granules, the addition of granulation process or not, and other technical means, these factors synergistically act and cooperate with each other, so that the final ibuprofen granules achieve good results in dissolution, content, yield and stability of related substances.

[0274] Determination of in vivo absorption

[0275] In vivo absorption determination method: refer to the Guiding Principles for Human Bioavailability and Bioequivalence Test of Pharmaceutical Preparations (Guiding Principles of Chinese Pharmacopoeia 2020 Edition Part IV 9011). The 90% confidence interval of the ratio of the logarithmic transformation value of Cmax, the ratio of AUC(0→t) and the ratio of AUC(0→∞) of the research and development preparation and the reference preparation falls between 80% and 125%, that is, the research and development preparation and the reference preparation are bioequivalent.

[0276] Table 7 Drug absorption

[0277]

[0278] As can be seen from Table 7, the Cmax ratio of the logarithmic transformation value of ibuprofen granules of Example 1 as the test preparation and the reference preparation, the 90% confidence interval of the ratio of AUC(0→t) and the ratio of AUC(0→∞) falls between 80% and 125%, and is equivalent to the reference preparation.

[0279] Therefore, the ibuprofen granules prepared by the present application not only exhibit good in vitro performance, such as excellent dissolution, high yield and low related substance content, but also show good in vivo absorption characteristics. Combining these advantages, it is shown that the drug is safe and effective.

[0280] Table 8 Comparative conditions of examples and comparative examples

[0281]

[0282] The above describes the embodiments of the present application, but the present application is not limited to the above-described specific embodiments, and the above-described specific embodiments are only illustrative but not restrictive, and those skilled in the art can make many forms under the inspiration of the present application without departing from the purpose of the present application and the scope protected by the claims, which all belong to the protection of the present application.

Claims

1. A process for the preparation of 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; granulating the soft material; After the granulation is completed, a rounding operation is performed to obtain rounded particles; the rounded particles are dried; the dried particles are sized; and the sized particles are mixed with a flavoring agent to obtain ibuprofen particles. The temperature of the particles obtained after drying is 40℃<particle temperature<60℃. The moisture content of the particles obtained after drying is 0.3%<moisture<1.0%. The particle size of the ibuprofen is 10μm≤D90≤60μm and D50≤30μm. The method for preparing the ibuprofen particles further comprises the following step: using an 18-mesh nylon sieve to granulate the soft material. The filler is lactose, the disintegrant is croscarmellose sodium, the binder is hydroxypropyl cellulose, the sweetener is sucralose, and the flavoring agent is lime powder essence.

2. The process for the preparation of ibuprofen granules as claimed in claim 1 wherein, The filler passes through a 40-mesh sieve.

3. The process for the preparation of ibuprofen granules as claimed in claim 2 wherein, The method further comprises the following step: under the conditions that the stirring speed of the wet granulator is 150-200rpm, the shearing speed is 1500-2000rpm, and the liquid spraying pressure is 0.5-1.0MPa, the wetting agent solution is sprayed into the premixed medicine powder to prepare a soft material.

4. The process for the preparation of ibuprofen granules as claimed in claim 3 wherein, The method further comprises the following step: using a ternary rotary screen to size the dried particles.

5. A process for the preparation of ibuprofen granules according to any one of claims 1 to 4, characterised in that: The mass composition of the ibuprofen particles comprises, by weight: ibuprofen 180-220 parts, a filler 700-750 parts, a disintegrant 25-35 parts, a binder 25-35 parts, a sweetener 2-7 parts, and a flavoring agent 5-15 parts; The filler is lactose, the disintegrant is croscarmellose sodium, the binder is hydroxypropyl cellulose, the sweetener is sucralose, and the flavoring agent is lime powder essence.

6. The ibuprofen particles prepared by the method of any one of claims 1-5, wherein the total impurities of the ibuprofen particles are less than 0.06%.

Images