Acetaminophen ibuprofen tablet and preparation method thereof
By controlling the particle size difference and optimizing the granulation process, the problem of content uniformity in acetaminophen ibuprofen tablets was solved, achieving stable tablet production that is suitable for large-scale production.
Patent Information
- Application Number
- CN202512035190.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-31
- Publication Date
- 2026-02-17
AI Technical Summary
The existing technology for acetaminophen ibuprofen tablets has poor content uniformity, which leads to production difficulties and unstable quality, especially in large-scale production where it is difficult to control.
By controlling the particle size difference between acetaminophen and ibuprofen within the range of 20μm to 50μm, and combining the dry mixing, granulation, drying, sizing, and blending steps in the granulation process, material uniformity is ensured. This includes extending the amount of binder solution and granulation time, collecting materials on the fluidized bed and filter bags, and batch testing and multi-stage mixing of lubricant to ensure the uniformity of the final tablets.
This method significantly improves the content uniformity of acetaminophen-ibuprofen tablets, reduces the difficulty of tableting, ensures quality stability, and is suitable for large-scale production.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to an acetaminophen ibuprofen tablet and its preparation method. Background Technology
[0002] Acetaminophen and ibuprofen are both commonly used antipyretic analgesics, but their mechanisms of action, indications, and contraindications differ. Acetaminophen is suitable for mild to moderate pain (such as headaches and toothaches) and fever reduction, but it has no anti-inflammatory effect and carries a higher risk of liver damage (requiring controlled dosage). Ibuprofen has analgesic, antipyretic, and anti-inflammatory effects (such as arthritis and dysmenorrhea), but it is more irritating to the gastrointestinal tract.
[0003] Acetaminophen-ibuprofen tablets were approved for marketing in the United States in 2020, with the approved indication being: temporary relief of mild pain caused by the following reasons, such as headache, toothache, back pain, dysmenorrhea, muscle aches, and mild pain from arthritis. Because this tablet is a formulation prepared with two active ingredients, tablet uniformity has always been a challenge in drug development. Chinese patent application number 2021114324311 addresses this formulation issue through acetaminophen-ibuprofen co-crystallization technology. However, this method requires organic solvents, which is almost impossible to implement in a formulation workshop or requires additional production equipment and explosion-proof equipment, causing many difficulties in tablet production. Therefore, researching and developing a new preparation method for this tablet is of great significance for the product's market launch in China. Summary of the Invention
[0004] Based on the above reasons, the applicant, through multiple creative studies, discovered that for acetaminophen and ibuprofen particle size (D... 90 After control, the uniformity is exceptionally good. The purpose of this invention is to solve the problem of poor uniformity or large content differences between acetaminophen and ibuprofen, and thus provide a method for preparing acetaminophen-ibuprofen tablets. The preparation method is simple, controllable, and has no complex process steps, making it suitable for large-scale continuous production.
[0005] To achieve the above-mentioned technical objectives, the present invention is implemented through the following technical solutions.
[0006] An acetaminophen-ibuprofen tablet, the tablet being prepared from acetaminophen, ibuprofen and pharmaceutical excipients, wherein the difference between the D90 particle size of acetaminophen and the D90 particle size of ibuprofen is greater than 20 μm and less than or equal to 50 μm.
[0007] The aforementioned acetaminophen-ibuprofen tablets contain acetaminophen with a D90 particle size difference of greater than 20 μm and less than or equal to 30 μm compared to the D90 particle size of ibuprofen.
[0008] The aforementioned acetaminophen ibuprofen tablets contain pharmaceutical excipients including fillers, binders, disintegrants, flow aids, and lubricants.
[0009] The acetaminophen-ibuprofen tablets contain 250 parts by weight of acetaminophen, 125 parts by weight of ibuprofen, 60-70 parts by weight of filler, 5-15 parts by weight of binder, 15-25 parts by weight of internal disintegrant, 10-20 parts by weight of external disintegrant, 8-12 parts by weight of flow aid, and 4-6 parts by weight of lubricant.
[0010] The aforementioned acetaminophen ibuprofen tablets, wherein the amount of purified water added to the binder is greater than 0.15g / tablet and less than or equal to 0.20g / tablet, and the granulation time for adding the binder shall not be less than 2min.
[0011] The acetaminophen ibuprofen tablets are characterized in that the preparation method of the tablets includes the following process steps: pretreatment, granulation (dry mixing, granulation), drying, sizing, mixing, and tableting.
[0012] In the preparation method of the aforementioned acetaminophen ibuprofen tablets, the mixing uniformity is measured after dry mixing in the granulation process, and granulation is carried out only after confirming that the mixing is uniform.
[0013] The acetaminophen ibuprofen tablets are characterized in that the granulation process controls the granulation parameters to fully wet the material during granulation, thereby reducing the amount of fine powder.
[0014] The aforementioned acetaminophen ibuprofen tablets are characterized in that, after drying, the material on the inner wall of the fluidized bed and the filter bag needs to be collected into the dried granules.
[0015] The acetaminophen ibuprofen tablets described above are characterized in that the mixing time during the mixing process shall not be less than 10 minutes. Detailed Implementation
[0016] To make the technical means, creative features, objectives, and effects of this invention easier to understand, the invention is further illustrated below with reference to specific embodiments. However, the following embodiments are merely preferred embodiments of this invention and not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments described herein without creative effort are all within the protection scope of this invention.
[0017] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, and the materials and reagents used in the following examples are commercially available unless otherwise specified.
[0018] The research process of this application is as follows:
[0019] 1. Acetaminophen-ibuprofen tablets are a compound preparation. Acetaminophen is a BCS class III and ibuprofen is a BCS class II. Due to the difference in water solubility between acetaminophen and ibuprofen, acetaminophen granulates better and is easier to granulate, while ibuprofen granulates poorly and is not easy to granulate. This leads to stratification of the two components, with higher acetaminophen content in the granules and higher ibuprofen content in the powder. During drying, the powder is more easily blown onto the aluminum bag and the inner wall of the fluidized bed, resulting in poor content uniformity and a large difference in the content of acetaminophen and ibuprofen. Acetaminophen-ibuprofen tablets weigh more than 200mg and are a compound preparation; the tablet weight difference should be less than 5%. When the content difference is large, the tablet weight range is small, which places strict requirements on the tableting equipment and may even make it impossible to compress a preparation that meets the content requirements.
[0020] 2. This invention provides a preparation method that requires acetaminophen and ibuprofen to have similar particle sizes before pretreatment, with a particle size difference of no more than 50 μm. During pretreatment, acetaminophen and ibuprofen are mixed and sieved. After dry mixing in the granulation process, the mixing uniformity is measured. The purpose is to ensure that acetaminophen and ibuprofen are mixed uniformly before granulation. Acetaminophen can increase the granulation properties of ibuprofen and improve the mixing uniformity.
[0021] 3. This invention provides a preparation method that requires that the amount of purified water, including the binder solution, added during granulation should not be less than 0.15 g / tablet, and the granulation time including the addition of the binder should not be less than 2 min. Increasing the amount of water and extending the granulation time can fully wet the material during granulation, reduce the amount of fine powder, and ensure that acetaminophen and ibuprofen are fully bonded together, thereby improving the uniformity of content and reducing the content difference.
[0022] 4. This invention provides a preparation method that requires collecting the material on the inner wall of the fluidized bed and the filter bag after drying into the dried particles. The material on the fluidized bed and the filter bag has a higher ibuprofen content. Collecting it can reduce ibuprofen loss and narrow the content gap between acetaminophen and ibuprofen.
[0023] 5. This invention provides a preparation method that requires that if the same batch is granulated in multiple sub-batches, the uniformity of the content after granulation in different sub-batches must be tested to ensure that the material uniformity is good before mixing with the added materials; the mixing time of the mixing process shall not be less than 10 minutes. In order to reduce the influence of long mixing time on the dissolution of the lubricant, the lubricant and the added excipients should be mixed separately. First, the granulated particles are mixed with the excipients other than the lubricant for 15 minutes, and then the lubricant is added and mixed for 5 minutes. This method ensures the uniformity of material mixing and does not affect the dissolution rate.
[0024] 6. To achieve the above, the preparation process of the present invention is as follows:
[0025] Step 1 Pretreatment: Add the prescribed amounts of acetaminophen, ibuprofen, pregelatinized starch, and croscarmellose sodium (added internally) to a mobile granulator for mixing and sieving;
[0026] Step 2: Preparation of adhesive solution: Add the prescribed amount of hydroxypropyl methylcellulose to purified water (0.17g / tablet) and stir to dissolve;
[0027] Step 3: Granulation: Pretreated acetaminophen, ibuprofen, pregelatinized starch, and croscarmellose sodium (added internally) are added to a wet granulation mixer for mixing. After mixing, the uniformity of the mixture is measured. If it passes the test, the prepared binder solution is added to the wet granulation mixer for granulation. The binder addition and granulation time is 2 minutes and 30 seconds.
[0028] Step 4: Drying: Use a multi-functional fluidized bed granulator to dry the granules. After drying, collect the material on the inner wall of the fluidized bed and the filter bag into the dried granules.
[0029] Step 5 Granulation: The dried acetaminophen ibuprofen tablets are granulated, and different sub-batch granules are placed into containers to test the content uniformity of different sub-batch granules.
[0030] Step 6 Mixing: Add the granulated particles to the mixer hopper and mix with the prescribed amount of cross-linked sodium carboxymethyl cellulose (added) and colloidal silica for 15 min; then add behenicol glyceride to the mixer hopper for total mixing for 5 min, and measure the uniformity of intermediate particle content after total mixing.
[0031] Step 7: Tableting: Calculate the tablet weight range of acetaminophen and ibuprofen based on the intermediate content, and then compress the tablets after taking the intersection.
[0032] To provide a clearer understanding of the technical content of this invention, the following embodiments are provided for detailed description. Unless otherwise specified, percentages, parts, ratios, concentrations, etc., are all based on weight.
[0033] Example 1
[0034] Acetaminophen was purchased from Hebei Jiheng (Group) Pharmaceutical Co., Ltd.; ibuprofen was purchased from Hubei Hengdi Pharmaceutical Co., Ltd.; pregelatinized starch was purchased from Carbohydrate; hydroxypropyl methylcellulose was purchased from Nutrition & Biosciences USA 1, LLC; croscarmellose sodium was purchased from International N&H USA, Inc.; colloidal silica was purchased from Evonik Operations GmbH; and behenate glyceride was purchased from GATTEFOSSE SAS. The formulation composition is shown in the table below.
[0035] Table 1 Prescription Composition
[0036]
[0037] Note: The particle size D of acetaminophen is... 90 The particle size of ibuprofen is 98.96 μm. 90 It is 74.89 μm.
[0038] Brief description of the preparation process and test results of intermediates in each step:
[0039] (1) Weighing of raw materials and auxiliary materials: Weigh hydroxypropyl methylcellulose (divided into 2 equal parts), pregelatinized starch (divided into 2 equal parts), croscarmellose sodium (added internally, divided into 2 equal parts), croscarmellose sodium (added externally), colloidal silica, behenicol glyceride, ibuprofen (divided into 2 equal parts), and acetaminophen (divided into 2 equal parts).
[0040] (2) Pretreatment: Add one prescription amount of acetaminophen, ibuprofen, pregelatinized starch and croscarmellose sodium (internal addition) to a mobile granulator for mixing and sieving; external excipients croscarmellose sodium, colloidal silica and behenicol glyceryl ester are passed through a 60-mesh stainless steel sieve.
[0041] (3) Preparation of adhesive solution: Add one part of hydroxypropyl methylcellulose to purified water (0.17g / tablet) and stir to dissolve.
[0042] (4) Granulation: Pretreated acetaminophen, ibuprofen, pregelatinized starch, and croscarmellose sodium (added internally) are added to a wet granulator for mixing. After mixing, the uniformity of mixing is measured, and the test results are shown in the table below. After passing the test, the prepared binder solution is added to the wet granulator for granulation. The binder is added for 90 seconds, and the granulation time is 60 seconds.
[0043] Table 2 Results of the test on the uniformity of mixing after dry mixing in the granulation process
[0044]
[0045] (5) Drying: The granules are dried using a multi-functional fluidized bed granulator. After drying, the material on the inner wall of the fluidized bed and the filter bag is collected in the dried granules.
[0046] (6) Granulation: The dried acetaminophen ibuprofen tablets were granulated, and different batches of granules were placed into containers. The content uniformity of different batches was tested, and the test results are shown in the table below.
[0047] Table 3 Results of content uniformity assessment after granulation process
[0048]
[0049] (7) Mixing: Add the granulated particles to the mixer hopper and mix with the prescribed amount of cross-linked sodium carboxymethyl cellulose (added) and colloidal silica for 15 min; then add behenicol glyceryl to the mixer hopper for total mixing for 5 min. After total mixing, measure the uniformity of intermediate particle content. The test results are shown in the table below.
[0050] Table 4 Results of content uniformity evaluation after mixing process
[0051]
[0052] (8) Tableting: The total content of acetaminophen and ibuprofen after mixing is relatively close. The tablet weight calculated based on acetaminophen is 463mg to 512mg, and the tablet weight calculated based on ibuprofen is 462mg to 510mg. The intersection is 463mg to 510mg, which is a wide range and easier to compress. Tableting is carried out according to this range. After tableting, the uniformity of the dose unit is tested. The results are shown in the table below.
[0053] Table 5 Results of dose uniformity after tableting process
[0054]
[0055]
[0056] According to the test results, the samples prepared using Example 1 showed good uniformity in the content of acetaminophen and ibuprofen, and the content difference after total mixing was small, which reduced the difficulty of tableting. The content uniformity after tableting was good, the quality was stable, and it was suitable for large-scale production.
[0057] Comparative Example 1:
[0058] Acetaminophen was purchased from Hebei Jiheng (Group) Pharmaceutical Co., Ltd.; ibuprofen was purchased from Hubei Hengdi Pharmaceutical Co., Ltd.; pregelatinized starch was purchased from Carbohydrate; hydroxypropyl methylcellulose was purchased from Nutrition & Biosciences USA 1, LLC; croscarmellose sodium was purchased from International N&H USA, Inc.; colloidal silica was purchased from Evonik Operations GmbH; and behenate glyceride was purchased from GATTEFOSSE SAS. The formulation composition is shown in the table below.
[0059] Table 6 Prescription Composition
[0060]
[0061]
[0062] Note: The particle size D of acetaminophen is... 90 The particle size of ibuprofen is 99.75 μm. 90 It is 80.65μm.
[0063] Brief description of the preparation process and intermediate test results:
[0064] (1) Weighing of raw materials and auxiliary materials: Weigh hydroxypropyl methylcellulose, pregelatinized starch, croscarmellose sodium (added internally), croscarmellose sodium (added externally), colloidal silica, behenicol glyceride, ibuprofen and acetaminophen in sequence.
[0065] (2) Pretreatment: The prescribed amounts of acetaminophen, ibuprofen, pregelatinized starch and croscarmellose sodium (added internally) are added to a mobile granulator for mixing and sieving; the external excipients croscarmellose sodium, colloidal silica and behenicol glyceryl ester are passed through a 60-mesh stainless steel sieve.
[0066] (3) Preparation of adhesive solution: Add hydroxypropyl methylcellulose to purified water (0.14g / tablet) and stir to dissolve.
[0067] (4) Granulation: The pretreated acetaminophen, ibuprofen, pregelatinized starch and croscarmellose sodium (added internally) are added to a wet granulator for mixing. The prepared binder solution is added to the wet granulator for granulation. The binder is added for 30 seconds and the granulation time is 60 seconds.
[0068] (5) Drying: The granules are dried using a multi-functional fluidized bed granulator.
[0069] (6) Granulation: The dried acetaminophen ibuprofen tablets are granulated.
[0070] (7) Mixing: Add the granulated particles to the mixer hopper and mix with the prescribed amount of cross-linked sodium carboxymethyl cellulose (added) and colloidal silica for 15 min; then add behenicol glyceryl to the mixer hopper for total mixing for 5 min. After total mixing, measure the uniformity of intermediate particle content. The test results are shown in the table below.
[0071] Table 7 Results of content uniformity assessment after mixing process
[0072]
[0073]
[0074] (8) Tableting: The total content of acetaminophen and ibuprofen after mixing showed a large difference. The tablet weight calculated based on acetaminophen ranged from 470mg to 520mg, while the tablet weight calculated based on ibuprofen ranged from 493mg to 544mg. The intersection was taken as 493mg to 520mg. The range is narrow, and tableting is quite difficult.
[0075] Comparative Example 2:
[0076] Acetaminophen was purchased from Hebei Jiheng (Group) Pharmaceutical Co., Ltd.; ibuprofen was purchased from Hubei Hengdi Pharmaceutical Co., Ltd.; pregelatinized starch was purchased from Carbohydrate; hydroxypropyl methylcellulose was purchased from Nutrition & Biosciences USA 1, LLC; croscarmellose sodium was purchased from International N&H USA, Inc.; colloidal silica was purchased from Evonik Operations GmbH; and behenate glyceride was purchased from GATTEFOSSE SAS. The formulation composition is shown in the table below.
[0077] Table 8 Prescription Composition
[0078]
[0079] Note: The particle size D of acetaminophen is... 90 The particle size of ibuprofen is 46.25 μm. 90 It is 127.9 μm.
[0080] Brief description of the preparation process and intermediate test results:
[0081] (1) Weighing of raw materials and auxiliary materials: Weigh hydroxypropyl methylcellulose, pregelatinized starch, croscarmellose sodium (added internally), croscarmellose sodium (added externally), colloidal silica, behenicol glyceride, ibuprofen and acetaminophen in sequence.
[0082] (2) Pretreatment: The prescribed amounts of acetaminophen, ibuprofen, pregelatinized starch and croscarmellose sodium (internal addition) are added to a mobile granulator and sieved separately; the external excipients croscarmellose sodium, colloidal silica and behenicol glyceryl ester are sieved through a 60-mesh stainless steel screen.
[0083] (3) Preparation of adhesive solution: Add hydroxypropyl methylcellulose to purified water (0.14g / tablet) and stir to dissolve.
[0084] (4) Granulation: The pretreated acetaminophen, ibuprofen, pregelatinized starch and croscarmellose sodium (added internally) are added to a wet granulator for mixing. The prepared binder solution is added to the wet granulator for granulation. The binder is added for 30 seconds and the granulation time is 60 seconds.
[0085] (5) Drying: The granules are dried using a multi-functional fluidized bed granulator. After drying, the material on the inner wall of the fluidized bed and the filter bag is collected in the dried granules.
[0086] (6) Granulation: The dried acetaminophen ibuprofen tablets were granulated and the content uniformity was tested. The test results are shown in the table below.
[0087] Table 9 Results of content uniformity assessment after granulation process
[0088]
[0089] The large RSD of the particle content uniformity test result after granulation indicates poor mixing uniformity.
[0090] Obviously, the above embodiments are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. Their purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly, and they should not be used to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.
Claims
1. An acetaminophen-ibuprofen tablet, characterized in that... This tablet is made from acetaminophen, ibuprofen, and pharmaceutical excipients, including acetaminophen with D... 90 Particle size and D of ibuprofen 90 The particle size difference is greater than 20 μm and less than or equal to 50 μm.
2. The acetaminophen-ibuprofen tablet according to claim 1, wherein the D of acetaminophen 90 Particle size and D of ibuprofen 90 The particle size difference is greater than 20 μm and less than or equal to 30 μm.
3. The acetaminophen ibuprofen tablet according to claim 1, wherein the pharmaceutical excipients include fillers, binders, disintegrants, flow aids, and lubricants.
4. An acetaminophen-ibuprofen tablet according to claim 3, comprising 250 parts by weight of acetaminophen, 125 parts by weight of ibuprofen, 60-70 parts by weight of filler, 5-15 parts by weight of binder, 15-25 parts by weight of internal disintegrant, 10-20 parts by weight of external disintegrant, 8-12 parts by weight of flow aid, and 4-6 parts by weight of lubricant.
5. The acetaminophen ibuprofen tablet according to claim 4, wherein the amount of purified water added to the binder is greater than 0.15 g / tablet and less than or equal to 0.20 g / tablet, and the granulation time for adding the binder shall not be less than 2 min.
6. The acetaminophen-ibuprofen tablets according to any one of claims 1-5, characterized in that, The preparation method of this tablet includes the following process steps: pretreatment, granulation (dry mixing, granulation), drying, sizing, mixing, and tableting.
7. An acetaminophen ibuprofen tablet according to claim 6, wherein in the preparation method: after dry mixing in the granulation process, the mixing uniformity is measured, and granulation is performed after confirming that the mixing is uniform.
8. An acetaminophen-ibuprofen tablet according to claim 6, characterized in that, During the granulation process, controlling the granulation parameters ensures that the material is fully wetted during granulation, reducing the amount of fine powder.
9. An acetaminophen-ibuprofen tablet according to claim 6, characterized in that, After drying, the material on the inner wall of the fluidized bed and the filter bag needs to be collected into the dried granules.
10. The acetaminophen-ibuprofen tablet according to claim 6, characterized in that, The mixing time for the mixing process shall not be less than 10 minutes.