Acetaminophen particles, acetaminophen tablets and preparation method thereof

Abstract

The invention relates to an acetaminophen granule, an acetaminophen tablet and a preparation method of the acetaminophen granule and the acetaminophen tablet. The preparation method of the acetaminophen granules comprises the following steps: (1) taking part of corn starch to prepare starch slurry with the mass concentration of 8-20%; (2) putting the acetaminophen and the starch slurry into a high-speed mixing granulator, stirring and mixing, stopping stirring, adding the rest of corn starch, dextrin and microcrystalline cellulose, stirring and mixing, and then starting a granulating knife for granulating to obtain wet granules; and (3) drying and sieving the wet granules to obtain the acetaminophen granules. The acetaminophen tablet is obtained by mixing the acetaminophen particles and talcum powder and then tabletting. Compared with the existing acetaminophen tablet product, the acetaminophen tablet prepared by the preparation method disclosed by the invention has the advantages that the dissolution rate is improved, the friability is reduced, the tabletting defect and the tablet weight difference are reduced, and meanwhile, the dosage of auxiliary materials is greatly reduced, and the production cost is reduced.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to acetaminophen granules, acetaminophen tablets and a preparation method thereof. Background Art

[0002] Acetaminophen tablets, a representative nonsteroidal anti-inflammatory drug (NSAID), offer significant antipyretic and analgesic effects with minimal side effects. They are widely used to treat colds, fevers, and mild to moderate pain. The wet granulation process is a key step in its preparation. This involves mixing the active ingredient with excipients, adding a binder to create a soft material, granulating, drying, sizing, and blending the tablets before final tablet compression.

[0003] Although traditional wet granulation technology is mature, it also has many problems. For example, the amount of excipients used is large, and 20%-30% of fillers (such as corn starch, microcrystalline cellulose), binders (such as starch slurry, hydroxypropyl cellulose) and disintegrants (such as cross-linked polyvinylpyrrolidone) need to be added, which increases production costs and affects drug dissolution. The uniformity of the particles is poor, and when the soft material is sieved, it is easy to appear "dry outside and wet inside" or the soluble components migrate, resulting in a wide particle size distribution (125-1400μm) and large differences in tablet weight during tableting (more than ±5%). The drying time is long, and the wet granules need to be dried at 60°C with forced air for 4-5 hours, which consumes high energy and may cause acetaminophen to decompose. Summary of the Invention

[0004] Based on this, the object of the present invention is to provide a new granulation method for acetaminophen tablets, wherein the acetaminophen tablets prepared by the method have higher solubility, lower friability and tablet weight variation.

[0005] The technical solutions for achieving the above-mentioned purpose include the following.

[0006] In a first aspect, the present invention provides a method for preparing acetaminophen granules, comprising the following steps:

[0007] (1) preparing a starch slurry with a mass concentration of 8% to 20% by weight using a portion of corn starch;

[0008] (2) placing acetaminophen and starch slurry into a high-speed mixing granulator, stirring and mixing, stopping stirring, adding the remaining corn starch, dextrin and microcrystalline cellulose, stirring and mixing, and then turning on the granulating knife to granulate to obtain wet granules;

[0009] (3) drying the wet granules and sieving them to obtain the acetaminophen granules;

[0010] The weight proportions of the components in the acetaminophen granules are as follows:

[0011]

[0012] The corn starch in step (1) accounts for 30%-60% of the total corn starch usage.

[0013] In a second aspect, the present invention provides acetaminophen granules prepared according to the preparation method.

[0014] In a third aspect, the present invention provides a paracetamol tablet, which is obtained by mixing the paracetamol particles of the present invention and talc and then tableting.

[0015] Compared with the traditional preparation method of acetaminophen tablets, the present invention has the following beneficial effects:

[0016] Traditional wet granulation uses a process of "dry powder mixing → binder spraying / drip addition → soft material preparation → drying". The binder is added to the dry powder in the form of discrete droplets, which can easily lead to local over-wetting or over-drying, and uneven distribution of the binder within the granules. The new granulation method of the present invention using paracetamol first prepares a binder slurry (continuous phase), then slowly immerses the dry powder (drug + excipients) into the slurry. Through high-speed shearing, the drug particles are evenly coated with the binder. The preparation method of the present invention makes the binder a "continuous coating phase", avoiding the problem of uneven distribution of "liquid bridges" in traditional processes, fundamentally optimizing granule quality, and reducing tableting defects and tablet weight differences.

[0017] Traditional wet granulation suffers from uneven binder distribution, large variations in particle density, and weak impact resistance, resulting in a friability of typically around 0.8%. The granulation method of the present invention allows the binder to evenly coat the drug particles, resulting in a more consistent particle density, reduced porosity after tableting, and a denser tablet structure. The resulting acetaminophen tablets have a friability of less than 0.6% (significantly lower than the 0.8% achieved with the traditional process), fully meeting pharmacopoeia requirements with ample margin.

[0018] Acetaminophen is a poorly soluble drug (solubility in water is approximately 1.4 mg / mL), and its dissolution rate directly affects its bioavailability. The 30-minute dissolution rate of acetaminophen tablets obtained by traditional wet granulation is typically between 75% and 95%. Due to uneven mixing, localized overwetting can occur, resulting in large dissolution rate deviations. However, the drug granules of the present invention are completely coated with a hydrophilic binder (such as starch slurry), forming a "drug-binder" composite structure. The binder rapidly swells in the dissolution medium, destroying the hydrophobic layer on the drug surface and increasing the contact area between the drug and the dissolution medium. This allows the resulting acetaminophen tablets to achieve a 30-minute dissolution rate of 91%-103%, a significant improvement over traditional processes and closer to the "rapid dissolution" standard (>85%). Furthermore, the dissolution rate is smaller, resulting in more stable clinical efficacy.

[0019] Furthermore, the acetaminophen tablets prepared by the preparation method of the present invention improve dissolution, reduce friability, and reduce tableting defects and tablet weight differences. Compared with existing acetaminophen tablet products, the amount of auxiliary materials used is greatly reduced, thereby reducing production costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The figure is a comparison of the dissolution rates of the acetaminophen tablets prepared in Examples 1-6.

[0021] Figure 2 This is a comparative diagram of the dissolution rates of acetaminophen tablets prepared in Examples 6-8.

[0022] Figure 3 The figure is a comparison of the dissolution rates of the acetaminophen tablets prepared in Example 6 and Comparative Example 1.

[0023] Figure 4 The figure is a comparison chart of the particle yields of the acetaminophen particles prepared in Examples 1-6.

[0024] Figure 5 This is a comparison chart of the particle yields of the acetaminophen granules prepared in Examples 6-8.

[0025] Figure 6 The figure is a comparison chart of the particle yield of the acetaminophen granules prepared in Example 6 and Comparative Example 1. DETAILED DESCRIPTION

[0026] To facilitate understanding of the present invention, the present invention will be described more fully below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the present disclosure more thorough and comprehensive.

[0027] In the following examples, the experimental methods without specific conditions are generally carried out under conventional conditions or conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art to which this invention pertains. The terms used in this specification are for the purpose of describing specific embodiments only and are not intended to limit the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0029] Furthermore, as used herein, the term "or" is inclusive and equivalent to the term "and / or," unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for being based on other factors not described, unless the context clearly dictates otherwise. Furthermore, throughout this specification, the meanings of "a," "an," and "the" include plural referents. The meaning of "in" includes "in" and "on."

[0030] Some embodiments thereof relate to a method for preparing acetaminophen granules, comprising the following steps:

[0031] (1) preparing a starch slurry with a mass concentration of 8% to 20% by weight using a portion of corn starch;

[0032] (2) placing acetaminophen and starch slurry into a high-speed mixing granulator, stirring and mixing, stopping stirring, adding the remaining corn starch, dextrin and microcrystalline cellulose, stirring and mixing, and then turning on the granulating knife to granulate to obtain wet granules;

[0033] (3) drying the wet granules and sieving them to obtain the acetaminophen granules;

[0034] The weight proportions of the components in the acetaminophen granules are as follows:

[0035]

[0036] The corn starch in step (1) accounts for 30%-60% of the total corn starch usage.

[0037] In some embodiments, the corn starch mass concentration of the starch slurry in step (1) is 10%-17%, more preferably 14%-16%, and more preferably 15%.

[0038] In some embodiments, the corn starch in step (1) accounts for 30%-55% of the total corn starch used, more preferably 52%-54%, and more preferably 53%-53.5%.

[0039] In some embodiments, the weight ratio of each component in the acetaminophen granules is as follows:

[0040]

[0041]

[0042] In some embodiments, the weight ratio of each component in the acetaminophen granules is as follows:

[0043]

[0044] In some embodiments, step (2) comprises: placing acetaminophen and starch slurry into a high-speed mixing granulator, adjusting the stirring paddle speed to 8 Hz-18 Hz (preferably 10 Hz-15 Hz, more preferably 11 Hz-13 Hz, more preferably 12 Hz), stirring and mixing for 3 minutes to 8 minutes, stopping stirring, adding the remaining corn starch, dextrin and microcrystalline cellulose, adjusting the stirring paddle speed to 10 Hz-15 Hz, stirring and mixing for 3 minutes to 8 minutes, and then turning on the granulating knife to granulate to obtain wet granules.

[0045] In some embodiments, step (2) includes: placing acetaminophen and starch slurry into a high-speed mixing granulator, adjusting the stirring paddle speed to 11 Hz-13 Hz and stirring and mixing for 4 minutes to 6 minutes, stopping stirring, adding the remaining corn starch, dextrin and microcrystalline cellulose, adjusting the stirring paddle speed to 11 Hz-13 Hz and stirring and mixing for 4 minutes to 6 minutes, and then turning on the granulating knife to granulate to obtain wet granules.

[0046] In some embodiments, the stirring paddle speed of the granulating knife for granulation in step (2) is 10 Hz-15 Hz and operates for 1-2 minutes.

[0047] In some embodiments, the stirring paddle speed of the granulating knife for granulation in step (2) is 11 Hz-13 Hz, and the operation is 1-1.5 minutes.

[0048] In some embodiments, the water content of the acetaminophen granules obtained in step (2) is less than 4%.

[0049] In some embodiments, the drying in step (3) comprises: placing the wet granules in a fluidized bed dryer, setting the air inlet temperature to 55° C.-65° C., and drying for 130 minutes-145 minutes.

[0050] In some embodiments, the drying in step (3) comprises: placing the wet granules in a fluidized bed dryer, setting the inlet air temperature to 55° C.-65° C., and drying for 135 minutes-145 minutes.

[0051] In some embodiments, the sieving in step (3) is through 14 mesh and 60 mesh sieves.

[0052] In some embodiments of the present invention, the present invention relates to acetaminophen particles prepared by the preparation method.

[0053] In some embodiments of the present invention, there is provided a paracetamol tablet, which is obtained by mixing the paracetamol granules of the present invention with talc and then tableting.

[0054] In some embodiments, the weight ratio of the talc powder to the acetaminophen is 5-7 parts:1500 parts.

[0055] In some embodiments, the weight ratio of the talc powder to the acetaminophen is 5.8-6.2 parts:1500 parts.

[0056] The present invention is further described in detail below with reference to specific embodiments.

[0057] The sources of raw materials used in the following examples are as follows:

[0058] Acetaminophen was purchased from Huludao Bofa Pharmaceutical Co., Ltd.

[0059] Corn starch was purchased from Shenyang Yian Pharmaceutical Excipients Co., Ltd.

[0060] Dextrin was purchased from Shenyang Yian Pharmaceutical Excipients Co., Ltd.

[0061] Microcrystalline cellulose was purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd.

[0062] Talc powder was purchased from Guangxi Longsheng Huamei Talc Development Co., Ltd.

[0063] Example 1 Preparation of Paracetamol Tablets of Prescription 1

[0064] The prescription composition of the acetaminophen tablets provided in this embodiment is shown in the following table.

[0065] Prescription 1 (5000 tablets in total)

[0066]

[0067]

[0068] The preparation method is as follows:

[0069] (1) Take 50g corn starch and prepare a starch slurry with a mass concentration of 10% by water.

[0070] (2) 1500 g of acetaminophen and starch slurry were pre-mixed in a USE177007 high-speed mixing granulator (manufacturer: Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., a Sino-foreign joint venture). The stirring blade was turned on and adjusted to 12 Hz for stirring and mixing for 5 minutes. The machine was stopped and 114 g of corn starch, 50 g of dextrin, and 180 g of microcrystalline cellulose were added. The stirring blade was turned on and adjusted to 12 Hz for stirring and mixing for 5 minutes. The granulating knife was turned on and adjusted to 12 Hz for operation for 1 minute. The material was discharged to obtain acetaminophen wet granules.

[0071] (3) The wet paracetamol granules were placed in a GFG40A high-efficiency boiling dryer (manufacturer: Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., a Sino-foreign joint venture), and the inlet air temperature was set to 60°C. The granules were dried for 135 minutes (the temperature change was recorded in real time every 15 minutes during the drying process. When the moisture content of the granules was measured to be within the range of 2%-3%, the heating was turned off. The inlet air temperature was allowed to cool to below 30°C. The stirring and the fan were turned off. After the air pressure was balanced, the bag was shaken 5-7 times. The air seal was closed and the material was discharged after 1 minute). The moisture content was measured to be 2.78% after discharge. The dry paracetamol granules were obtained.

[0072] (4) The acetaminophen dry granules were sieved through 14-mesh and 60-mesh sieves for granulation. The granulated material and 6 g of talc were then placed in an HD-50 multi-directional motion mixer (manufacturer: Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., a Sino-foreign joint venture) and mixed for 3 minutes (rotation speed of 50 r / min). The total amount of mixed granules was 1.693 kg. The granule yield was calculated as 89.11% according to the following formula.

[0073]

[0074] (5) The mixed material obtained in step (4) is tableted using a ZPK-17 fully automatic rotary tablet press (manufacturer: Zhejiang Canaan Kaixinlong Technology Co., Ltd.). After the equipment is installed, the material is added to the hopper and the hopper valve is opened. First, the filling knob is adjusted to make the weight of the acetaminophen tablets within the range of 0.38g±5% (0.361g-0.399g). After the weight test is qualified, the tablet thickness knob is adjusted to make the hardness of the acetaminophen tablets within the range of 35N-65N. After the hardness test is qualified, formal production is carried out.

[0075] The acetaminophen tablets prepared in this example were subjected to the following quality checks:

[0076] Tablet weight: Place a 50ml beaker into a calibrated JJ224BC 1 / 10,000 electronic balance (manufacturer: Changshu Shuangjie Testing Instrument Factory), press the tare key, randomly select 20 acetaminophen tablets and place them into the 50ml beaker, and measure the weight of each tablet one by one using the weight loss weighing method.

[0077] Hardness: Randomly select 10 acetaminophen tablets, pick up one tablet with tweezers and put it into the YD-Ⅱ Tablet Hardness Tester (manufacturer: Tianjin Jingtuo Instrument Technology Co., Ltd.), press the start button, and repeat 10 times.

[0078] Friability: Randomly select approximately 6.5 g of acetaminophen tablets and place them on a 14-mesh sieve. Use a hair dryer to blow off any powder floating on the surface. Then place them on a calibrated JJ224BC 1 / 10,000 electronic balance for precise weighing. Place them on the turntable of a CS-2A friability tester (manufacturer: Tianjin Jingtuo Instrument Technology Co., Ltd.) and set the rotation speed to 25 rpm. After rotating for 4 minutes, take out the tablets and place them on a 14-mesh sieve. Use a hair dryer to blow off any powder floating on the surface again. Accurately weigh the weight of the friability tester and calculate according to the formula: Friability (%) = (W1-W2) / W1×100%, where W1 is the weight before the test and W2 is the weight after the test.

[0079] Absorbance and dissolution: at first configure 6 parts of 1000ml 0.1mol / L dilute hydrochloric acid solution and 500ml0.04% sodium hydroxide solution, and pour the sodium hydroxide solution that 50ml configures into in 50ml volumetric flask for standby as blank solution.Open RC-3 dissolution tester (manufacturer: Tianjin Guoming Pharmaceutical Equipment Co., Ltd.) power supply, the dilute hydrochloric acid solution that configures is poured in the dissolution cup successively, put into thermometer, start equipment, preheat and balance temperature to 37 ℃, it is 100r / min that rotating speed is set, the time is 40min, randomly select 6 paracetamol tablets and clamp 1 and put into the dissolution cup with tweezers every 1min, draw dissolution solution with 10ml syringe successively when the tablet dissolution time reaches 30min, use the filter membrane filtration of 0.45 μ m, measure 1ml dissolution solution in 50ml volumetric flask with the pipette precision of 1ml again, with 0.04% sodium hydroxide solution constant volume, standby as sample liquid.

[0080] Turn on the power of the 752N UV-visible spectrophotometer (manufacturer: Shanghai Yidian Analytical Instrument Co., Ltd.), preheat for 30 minutes, set the unit to A, set the wavelength to 257nm, wash the cuvette with distilled water three times, rinse the cuvette with blank solution three times, then pour in the blank solution, absorb the liquid on the surface of the cuvette with absorbent paper, wipe the transparent surface of the cuvette with lens paper, place the cuvette filled with blank solution, press "100% / T / 0A", wait until Abs displays "0.000", and remove the cuvette filled with blank solution. Pour out the blank solution, wash the cuvette with distilled water three times, rinse the cuvette with sample solution 1 three times, then pour in sample solution 1, absorb the liquid on the surface of the cuvette with absorbent paper, wipe the transparent surface of the cuvette with lens paper, place the cuvette filled with sample solution 1, and read the absorbance value. Measure the absorbance values ​​of 6 sample solutions in sequence according to the above operation. According to the absorption coefficient of C8H9NO2 The dissolution amount of each tablet is 715. The calculation formula is:

[0081] The results are shown in Table 1.

[0082] Table 1 Quality test results of acetaminophen tablets of prescription 1

[0083]

[0084]

[0085] Example 2 Preparation of Paracetamol Tablets of Prescription 2

[0086] The prescription composition of the acetaminophen tablets provided in this embodiment is shown in the following table.

[0087] Prescription 2 (5000 tablets in total)

[0088] acetaminophen 1500g corn starch 90g dextrin 50g microcrystalline cellulose 180g talcum powder 6g Corn starch (to prepare 10% starch slurry) 74g

[0089] The preparation method is as follows:

[0090] (1) 74 g corn starch was mixed with water to prepare a starch slurry with a mass concentration of 10%.

[0091] (2) 1500 g of acetaminophen and starch slurry were pre-mixed in a USE177007 high-speed mixing granulator (manufacturer: Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., a Sino-foreign joint venture). The stirring blade was turned on and adjusted to 12 Hz for stirring and mixing for 5 minutes. The machine was stopped and 90 g of corn starch, 50 g of dextrin, and 180 g of microcrystalline cellulose were added. The stirring blade was turned on and adjusted to 12 Hz for stirring and mixing for 5 minutes. The granulating knife was turned on and adjusted to 12 Hz for operation for 1 minute. The material was discharged to obtain acetaminophen wet granules.

[0092] Steps (3), (4) and (5) are the same as those in Example 1. The total amount of particles after mixing obtained in step (4) is 1.726 kg, and the particle yield is calculated to be 90.84%.

[0093] The acetaminophen tablets prepared in this example were quality checked using the method of Example 1. The results are shown in Table 2.

[0094] Table 2 Quality test data of acetaminophen tablets of prescription 2

[0095]

[0096] Example 3 Preparation of Paracetamol Tablets of Prescription 3

[0097] The prescription composition of the acetaminophen tablets provided in this embodiment is shown in the following table.

[0098] Prescription 3 (5000 tablets in total)

[0099]

[0100]

[0101] The preparation method is as follows:

[0102] (1) 114 g corn starch was mixed with water to prepare a starch slurry with a mass concentration of 10%.

[0103] (2) 1500 g of acetaminophen and starch slurry were pre-mixed in a USE177007 high-speed mixing granulator (manufacturer: Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., a Sino-foreign joint venture). The stirring blade was turned on and adjusted to 12 Hz for stirring and mixing for 5 minutes. The machine was stopped and 50 g of corn starch, 50 g of dextrin, and 180 g of microcrystalline cellulose were added. The stirring blade was turned on and adjusted to 12 Hz for stirring and mixing for 5 minutes. The granulating knife was turned on and adjusted to 12 Hz for operation for 1 minute. The material was discharged to obtain acetaminophen wet granules.

[0104] Steps (3), (4) and (5) are the same as those in Example 1. The total amount of particles after mixing obtained in step (4) is 1.789 kg, and the particle yield is calculated to be 94.16%.

[0105] The acetaminophen tablets prepared in this example were quality checked using the method of Example 1. The results are shown in Table 3.

[0106] Table 3 Quality test data of acetaminophen tablets of prescription 3

[0107]

[0108]

[0109] Example 4 Preparation of Paracetamol Tablets of Prescription 4

[0110] The prescription composition of the acetaminophen tablets provided in this embodiment is shown in the following table.

[0111] Prescription 4 (5000 tablets in total)

[0112] acetaminophen 1500g corn starch 84g dextrin 50g microcrystalline cellulose 180g talcum powder 6g Corn starch (to prepare 15% starch slurry) 80g

[0113] The preparation method is as follows:

[0114] (1) 80 g corn starch was mixed with water to prepare a starch slurry with a mass concentration of 15%.

[0115] (2) 1500 g of acetaminophen and starch slurry were pre-mixed in a USE177007 high-speed mixing granulator (manufacturer: Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., a Sino-foreign joint venture). The stirring blade was turned on and adjusted to 12 Hz for stirring and mixing for 5 minutes. The machine was stopped and 84 g of corn starch, 50 g of dextrin, and 180 g of microcrystalline cellulose were added. The stirring blade was turned on and adjusted to 12 Hz for stirring and mixing for 5 minutes. The granulating knife was turned on and adjusted to 12 Hz for operation for 1 minute. The material was discharged to obtain acetaminophen wet granules.

[0116] Steps (3), (4) and (5) are the same as those in Example 1. The total amount of particles after mixing obtained in step (4) is 1.815 kg, and the particle yield is calculated to be 95.53%.

[0117] The acetaminophen tablets prepared in this example were quality checked using the method of Example 1. The results are shown in Table 4.

[0118] Table 4 Quality test data of acetaminophen tablets of prescription 4

[0119]

[0120] Example 5 Preparation of Paracetamol Tablets of Prescription 5

[0121] The prescription composition of the acetaminophen tablets provided in this embodiment is shown in the following table.

[0122] Prescription 5 (5000 tablets in total)

[0123]

[0124]

[0125] The preparation method is as follows:

[0126] (1) Take 70g corn starch and prepare a starch slurry with a mass concentration of 15% with water.

[0127] (2) 1500 g of acetaminophen and starch slurry were pre-mixed in a USE177007 high-speed mixing granulator (manufacturer: Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., a Sino-foreign joint venture). The stirring blade was turned on and adjusted to 12 Hz for stirring and mixing for 5 minutes. The machine was stopped and 94 g of corn starch, 50 g of dextrin, and 180 g of microcrystalline cellulose were added. The stirring blade was turned on and adjusted to 12 Hz for stirring and mixing for 5 minutes. The granulating knife was turned on and adjusted to 12 Hz for operation for 1 minute. The material was discharged to obtain acetaminophen wet granules.

[0128] Steps (3), (4) and (5) are the same as those in Example 1. The total amount of particles after mixing obtained in step (4) is 1.748 kg, and the particle yield is calculated to be 92.00%.

[0129] The acetaminophen tablets prepared in this example were quality checked using the method of Example 1. The results are shown in Table 5.

[0130] Table 5 Quality test data of acetaminophen tablets of prescription 5

[0131]

[0132]

[0133] Example 6 Preparation of Paracetamol Tablets of Prescription 6

[0134] The prescription composition of the acetaminophen tablets provided in this embodiment is shown in the following table.

[0135] Prescription 6 (5000 tablets in total)

[0136] acetaminophen 1500g corn starch 77g dextrin 50g microcrystalline cellulose 180g talcum powder 6g Corn starch (to prepare 15% starch slurry) 87g

[0137] The preparation method is as follows:

[0138] (1) 87 g corn starch was mixed with water to prepare a starch slurry with a mass concentration of 15%.

[0139] (2) 1500 g of acetaminophen and starch slurry were pre-mixed in a USE177007 high-speed mixing granulator (manufacturer: Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., a Sino-foreign joint venture). The stirring paddle was turned on and stirred for 5 minutes (12 Hz). The machine was stopped and 77 g of corn starch, 50 g of dextrin, and 180 g of microcrystalline cellulose were added. The stirring paddle was turned on and adjusted to 12 Hz and mixed for 5 minutes. The granulating knife was turned on and adjusted to 12 Hz and operated for 1 minute. The material was discharged to obtain acetaminophen wet granules.

[0140] (3) The wet paracetamol granules were placed in a GFG40A high-efficiency boiling dryer (manufacturer: Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., a Sino-foreign joint venture), and the inlet air temperature was set to 60°C for drying for 135 minutes (the temperature change was recorded in real time every 15 minutes during the drying process. When the moisture content of the granules was measured to be within the range of 2%-3%, the heating was turned off, and the inlet air temperature was allowed to cool below 30°C. The stirring and the fan were turned off. After the air pressure was balanced, the bag was shaken 5-7 times, the air seal was closed, and the material was discharged). The moisture content after discharge was measured to be 2.62%, and the paracetamol dry granules were obtained.

[0141] (4) The acetaminophen dry granules were sieved through 14-mesh and 60-mesh sieves. The granules were then mixed with 6 g of talc in an HD-50 multi-directional motion mixer (manufactured by the Sino-foreign joint venture Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd.) for 3 minutes (at a speed of 50 r / min). The total amount of granules obtained after mixing in step (4) was 1.825 kg, and the granule yield was calculated to be 96.05%.

[0142] (5) The mixed material obtained in step (4) is tableted using a ZPK-17 fully automatic rotary tablet press (manufacturer: Zhejiang Canaan Kaixinlong Technology Co., Ltd.). After the equipment is installed, the material is added to the hopper and the hopper valve is opened. First, the filling knob is adjusted to make the weight of the acetaminophen tablets within the range of 0.38g±5% (0.361g-0.399g). After the weight test is qualified, the tablet thickness knob is adjusted to make the hardness of the acetaminophen tablets within the range of 35N-65N. After the hardness test is qualified, formal production is carried out.

[0143] The acetaminophen tablets prepared in this example were quality checked using the method of Example 1. The results are shown in Table 6.

[0144] Table 6 Quality inspection results of acetaminophen tablets of prescription 6

[0145]

[0146]

[0147] Example 7 Preparation of Acetaminophen Tablets at Different Stirring Speeds

[0148] The prescription composition of the acetaminophen tablets provided in this embodiment is the same as that in Example 6.

[0149] The preparation method is as follows:

[0150] (1) 87 g corn starch was mixed with water to prepare a starch slurry with a mass concentration of 15%.

[0151] (2) 1500 g of acetaminophen and starch slurry were pre-mixed in a USE177007 high-speed mixing granulator (manufacturer: Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., a Sino-foreign joint venture). The stirring paddle was turned on and stirred for 5 minutes (15 Hz). The machine was stopped and 77 g of corn starch, 50 g of dextrin, and 180 g of microcrystalline cellulose were added. The stirring paddle was turned on and adjusted to 12 Hz and mixed for 5 minutes. The granulating knife was turned on and adjusted to 12 Hz and operated for 1 minute. The material was discharged to obtain acetaminophen wet granules.

[0152] Steps (3), (4) and (5) are the same as those in Example 1. The total amount of particles after mixing obtained in step (4) is 1.737 kg, and the particle yield is calculated to be 91.42%.

[0153] The acetaminophen tablets prepared in this example were subjected to dissolution testing according to the method of Example 1. The results are shown in Table 7.

[0154] Table 7

[0155]

[0156] Example 8 Preparation of Acetaminophen Tablets at Different Stirring Speeds

[0157] The prescription composition of the acetaminophen tablets provided in this embodiment is the same as that in Example 6.

[0158] The preparation method is as follows:

[0159] (1) 87 g corn starch was mixed with water to prepare a starch slurry with a mass concentration of 15%.

[0160] (2) 1500 g of acetaminophen and starch slurry were pre-mixed in a USE177007 high-speed mixing granulator (manufacturer: Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., a Sino-foreign joint venture). The stirring paddle was turned on and stirred for 5 minutes (10 Hz). The machine was stopped and 77 g of corn starch, 50 g of dextrin, and 180 g of microcrystalline cellulose were added. The stirring paddle was turned on and adjusted to 12 Hz and mixed for 5 minutes. The granulating knife was turned on and adjusted to 12 Hz and operated for 1 minute. The material was discharged to obtain acetaminophen wet granules.

[0161] Steps (3), (4) and (5) are the same as those in Example 1. The total amount of particles after mixing obtained in step (4) is 1.725 kg, and the particle yield is calculated to be 90.79%.

[0162] The acetaminophen tablets prepared in this example were subjected to dissolution testing according to the method of Example 1. The results are shown in Table 8.

[0163] Table 8

[0164]

[0165] Comparative Example 1 Preparation of Acetaminophen Tablets by Traditional Wet Granulation

[0166] The prescription composition of the acetaminophen tablets provided in this comparative example is the same as that in Example 6.

[0167] The preparation method is as follows:

[0168] (1) 87 g corn starch was mixed with water to prepare a starch slurry with a mass concentration of 15%.

[0169] (2) Add 1500 g of acetaminophen, 77 g of corn starch, 50 g of dextrin, and 180 g of microcrystalline cellulose to a USE177007 high-speed mixer granulator (manufacturer: Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., a Sino-foreign joint venture). Turn on the stirring paddle and adjust it to 12 Hz and stir for 15 minutes. Slowly add 15% starch slurry, adjust it to 12 Hz and stir for 5 minutes. Turn on the granulating knife and adjust it to 12 Hz and run for 1 minute. Discharge the material to obtain acetaminophen wet granules.

[0170] (3) The wet paracetamol granules were placed in a GFG40A high-efficiency boiling dryer (manufacturer: Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., a Sino-foreign joint venture), and the inlet air temperature was set to 60°C. The granules were dried for 135 minutes. The water content of the sample was measured to be 5.53%. The granules were dried for 105 minutes at an inlet air temperature of 60°C (the temperature change was recorded in real time every 15 minutes during the drying process. When the water content of the granules was measured to be within the range of 2%-3%, the heating was turned off. The inlet air temperature was allowed to cool to below 30°C. The stirring and the fan were turned off. After the air pressure was balanced, the bag was shaken 5-7 times. The air seal was closed and the material was discharged after 1 minute. The water content was measured to be 2.79% after discharge. The dry paracetamol granules were obtained.

[0171] (4) The acetaminophen dry granules were sieved through 14-mesh and 60-mesh sieves, and then the granulated material and 6 g of talc were placed in an HD-50 multi-directional motion mixer (manufacturer: Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., a Sino-foreign joint venture) and mixed for 3 minutes (the speed was 50 r / min). The total amount of granules after mixing was 1.671 kg, and the granule yield was calculated to be 87.95%.

[0172] (5) The mixed material obtained in step (4) is tableted using a ZPK-17 fully automatic rotary tablet press (manufacturer: Zhejiang Canaan Kaixinlong Technology Co., Ltd.). After the equipment is installed, the material is added to the hopper and the hopper valve is opened. First, the filling knob is adjusted to make the weight of the acetaminophen tablets within the range of 0.38g±5% (0.361g-0.399g). After the weight test is qualified, the tablet thickness knob is adjusted to make the hardness of the acetaminophen tablets within the range of 35N-65N. After the hardness test is qualified, formal production is carried out.

[0173] The acetaminophen tablets prepared in this comparative example were subjected to quality inspection according to the method of Example 1. The results are shown in Table 9.

[0174] Table 9 Quality inspection results of acetaminophen tablets

[0175]

[0176] The comparative experimental results of the above Examples 1-8 and Comparative Example 1 show that the present invention significantly improves the friability, tablet dissolution and production efficiency of acetaminophen tablets by adjusting the order of adding materials and integrating the mixing and granulation processes (the traditional wet granulation method is to first mix the raw materials and auxiliary materials for 15 minutes, then add the starch slurry and mix for 5 minutes; while the method of the present invention is to first mix acetaminophen with the starch slurry for 5 minutes, then add other auxiliary materials and mix for 5 minutes, the mixing time is reduced from 20 minutes to 10 minutes, and the drying time is shorter, which reduces the energy consumption of the equipment; at the same time, the acetaminophen tablets pressed out of the granules prepared by the method of the present invention are more gentle than the acetaminophen tablets pressed out by the traditional wet granulation method. Figure 3 ), smaller deviation, higher dissolution rate, reflecting a significant improvement in production efficiency). Compared with traditional wet granulation, the advantages of the preparation method of the present invention are: (1) better granule flowability, compressibility and uniformity, reducing tableting defects and tablet weight differences; (2) higher dissolution rate with small deviation, good stability, and guaranteed clinical efficacy; (3) significantly improved tablet friability and dissolution rate while reducing production costs.

[0177] The preparation process parameters of Examples 1-6 were the same, and the starch dosage and concentration of the starch slurry were adjusted. The results showed that, under the same preparation process parameters, the acetaminophen granules prepared by using Prescription 6 had less fine powder, a higher granule yield, and higher compressibility than the acetaminophen granules prepared by using Prescriptions 1-5 ( Figure 4 ). According to the dissolution comparison curve ( Figure 1 ) It can be seen that the dissolution comparison curve of the acetaminophen tablets pressed from the granules prepared by prescription 6 is significantly flatter, and the tablet weight difference and friability are smaller, indicating that the acetaminophen tablets prepared by this prescription are more uniform, the quality difference between different tablets is smaller, and the quality is more uniform and stable.

[0178] The recipes of Examples 6-8 were the same, but the stirring parameters for mixing acetaminophen with starch slurry were adjusted. The acetaminophen granules prepared in Example 6 (stirring speed was 12 Hz) had less fine powder, a higher yield of granules, and better compressibility ( Figure 5 ); The dissolution comparison curve of the acetaminophen tablets prepared in Example 6 is smoother than that in Examples 7 and 8 (stirring speeds of 15 Hz and 10 Hz, respectively) ( Figure 2 ), indicating that the stirring uniformity under this condition is better, the uniformity of the prepared acetaminophen tablets is better, the quality difference between different tablets is smaller, and the quality is more uniform and stable.

[0179] A comparison of the auxiliary material cost prices of the acetaminophen tablets of the present invention and those of acetaminophen tablets of other manufacturers (estimated) is shown in Table 10: Compared with acetaminophen tablets produced by other manufacturers, the production cost of the acetaminophen tablets of the present invention is significantly reduced.

[0180] Table 10 Comparison of auxiliary material cost prices

[0181]

[0182]

[0183]

[0184]

[0185] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.

Claims

1. A method for preparing acetaminophen granules, characterized in that: The steps include: (1) preparing a starch slurry with a mass concentration of 8% to 20% by weight using a portion of corn starch; (2) placing acetaminophen and starch slurry into a high-speed mixing granulator, stirring and mixing, stopping stirring, adding the remaining corn starch, dextrin and microcrystalline cellulose, stirring and mixing, and then turning on the granulating knife to granulate to obtain wet granules; (3) drying the wet granules and sieving them to obtain the acetaminophen granules; The weight proportions of the components in the acetaminophen granules are as follows: The corn starch in step (1) accounts for 30%-60% of the total corn starch usage.

2. The method for preparing acetaminophen granules according to claim 1, wherein The corn starch mass concentration of the starch slurry in step (1) is 10%-17%, more preferably 14%-16%, more preferably 15%; And / or, the corn starch in step (1) accounts for 30%-55% of the total corn starch usage, more preferably 52%-54%, more preferably 53%-53.5%.

3. The method for preparing acetaminophen granules according to claim 1, wherein The weight proportions of the components in the acetaminophen granules are as follows:

4. The method for preparing acetaminophen granules according to claim 1, wherein Step (2) comprises: placing acetaminophen and starch slurry into a high-speed mixing granulator, adjusting the stirring speed of the paddle to 8 Hz-18 Hz and stirring and mixing for 3 minutes-8 minutes, stopping stirring, adding the remaining corn starch, dextrin and microcrystalline cellulose, adjusting the stirring speed of the paddle to 10 Hz-15 Hz and stirring and mixing for 3 minutes-8 minutes, and then turning on the granulator to granulate to obtain wet granules; Preferably, acetaminophen and starch slurry are placed in a high-speed mixing granulator, and the stirring and mixing speed is 10 Hz-15 Hz, more preferably 11 Hz-13 Hz, and more preferably 12 Hz.

5. The method for preparing acetaminophen granules according to claim 4, wherein Step (2) comprises: placing acetaminophen and starch slurry into a high-speed mixing granulator, adjusting the stirring paddle speed to 11 Hz-13 Hz and stirring and mixing for 4 minutes to 6 minutes, stopping stirring, adding the remaining corn starch, dextrin and microcrystalline cellulose, adjusting the stirring paddle speed to 11 Hz-13 Hz and stirring and mixing for 4 minutes to 6 minutes, and then turning on the granulating knife to granulate to obtain wet granules.

6. The method for preparing the acetaminophen granules according to any one of claims 1 to 5, characterized in that: In step (2), the stirring paddle for granulating with the granulating knife is turned on at a speed of 10 Hz to 15 Hz and is operated for 1 to 2 minutes.

7. The method for preparing acetaminophen granules according to any one of claims 1 to 5, characterized in that: The drying in step (3) comprises: placing the wet granules in a fluidized bed dryer, setting the air inlet temperature to 55° C. to 65° C., and drying for 130 minutes to 145 minutes; And / or, the sieving in step (3) is through 14 mesh and 60 mesh sieves.

8. Paracetamol granules prepared according to the preparation method according to any one of claims 1 to 7.

9. A paracetamol tablet, characterized in that: The acetaminophen granules according to claim 8 are mixed with talcum powder and then tabletted.

10. The acetaminophen tablet according to claim 9, characterized in that The weight ratio of the talc powder to the acetaminophen is 5-7 parts:1500 parts.

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