Atenolol tablet and preparation method thereof

Abstract

The invention discloses atenolol tablets and a preparation method thereof. The atenolol tablets are prepared from the following raw materials in parts by mass: 25 to 50 parts of atenolol, 55 to 65 parts of microcrystalline cellulose, 2 to 4 parts of povidone K30, 4 to 8 parts of carboxymethyl starch sodium and 1 to 2 parts of magnesium stearate. The preparation method comprises the following steps: preparing the following raw materials: atenolol, microcrystalline cellulose, povidone K30, carboxymethyl starch sodium and magnesium stearate, wherein the microcrystalline cellulose is divided into internally added microcrystalline cellulose and externally added microcrystalline cellulose; mixing internally added microcrystalline cellulose, povidone K30 and atenolol, and carrying out wet particle preparation, wet size stabilization, drying and dry size stabilization to obtain dry particles; and mixing the dry particles, carboxymethyl starch sodium and additional microcrystalline cellulose, adding magnesium stearate, mixing, and tabletting. The atenolol tablet intermediate particles prepared by the invention are good in flowability and compressibility, and the atenolol tablet is excellent in appearance, qualified in quality and stable in property.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical production, and particularly relates to an atenolol tablet and a preparation method thereof. Background Art

[0002] Atenolol, chemical name: 4-[3-(2-hydroxy-3-isopropylamino)propoxy]benzeneacetamide, molecular formula: C 14 H 22 N2O3, molecular weight 266.34, chemical structural formula:

[0003] Atenolol is a β-adrenergic receptor blocker, mainly used for the treatment of hypertension, angina pectoris, and acute myocardial infarction. The peak effect is reached 2-4 hours after administration, and the action duration is relatively long, with a half-life of 6-7 hours. It is mainly excreted unchanged in the urine. Commercially available atenolol drugs are mostly tablets. The preparation of tablets generally involves mixing raw materials and auxiliary additives, granulating, drying, and tabletting. The existing preparation methods have the disadvantages of poor particle fluidity and difficulty in tabletting, resulting in inconsistent drug quality.

[0004] The information disclosed in this background art section is only intended to enhance the overall understanding of the present invention and should not be regarded as an admission or any form of suggestion that this information constitutes prior art already known to those of ordinary skill in the art. Summary of the Invention

[0005] The purpose of the present invention is to provide an atenolol tablet and a preparation method thereof, which solve the problems of poor fluidity of intermediate particles, difficulty in tabletting, and non-compliance of the appearance of the tablets with quality requirements during the preparation of atenolol tablets, and the drug quality is consistent with the reference preparation.

[0006] In order to achieve the above purpose, the technical solution provided by a specific embodiment of the present invention is as follows:

[0007] An atenolol tablet, comprising the following raw materials in parts by mass: 25-50 parts of atenolol, 55-65 parts of microcrystalline cellulose, 2-4 parts of polyvinylpyrrolidone K30, 4-8 parts of sodium carboxymethyl starch, and 1-2 parts of magnesium stearate.

[0008] In one or more embodiments of the present invention, the D10 of the atenolol is less than or equal to 30 μm, the D50 is 30 μm - 60 μm, and the D90 is less than or equal to 120 μm.

[0009] The technical solution provided by another specific embodiment of the present invention is as follows:

[0010] A preparation method of an atenolol tablet, comprising the following steps:

[0011] Prepare raw materials atenolol, microcrystalline cellulose, polyvinylpyrrolidone K30, sodium carboxymethyl starch and magnesium stearate. Divide the microcrystalline cellulose into internal addition microcrystalline cellulose and external addition microcrystalline cellulose. The weight portion of the internal addition microcrystalline cellulose is 10 - 20 parts, and the weight portion of the external addition microcrystalline cellulose is 40 - 50 parts;

[0012] Mix the internal addition microcrystalline cellulose, polyvinylpyrrolidone K30 and atenolol, and carry out wet granulation, wet screening, drying, and dry screening to obtain dry granules;

[0013] Mix the dry granules, sodium carboxymethyl starch and external addition microcrystalline cellulose, and then add magnesium stearate and mix, followed by tabletting.

[0014] In one or more embodiments of the present invention, when wet granulating, first add atomized water under the conditions of stirring frequency of 15 - 30 Hz and chopping frequency of 4 - 8 Hz. After adding, then granulate for 3 - 5 min under the conditions of stirring frequency of 15 - 30 Hz and chopping frequency of 25 - 35 Hz.

[0015] In one or more embodiments of the present invention, the drying is carried out at 60°C - 70°C until the water content is less than 1.5%.

[0016] In one or more embodiments of the present invention, the wet screening is carried out using a 18 - 25 mesh sieve for screening.

[0017] In one or more embodiments of the present invention, the dry screening is carried out using a 18 - 25 mesh sieve for screening.

[0018] Compared with the prior art, the present invention optimizes the raw material ratio and preparation process, and divides the microcrystalline cellulose into internal addition and external addition, improves the fluidity of the material, enhances the compressibility of the material, the prepared atenolol tablets have excellent appearance, the tablets meet the quality requirements, and the process is stable. Specific Embodiments

[0019] In order to enable those skilled in the art to better understand the technical solutions in the present invention, the technical solutions in the embodiments of the present invention are clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0020] A specific embodiment of the present invention provides an atenolol tablet, including the following raw materials in parts by mass: 25 - 50 parts of atenolol, 55 - 65 parts of microcrystalline cellulose, 2 - 4 parts of polyvinylpyrrolidone K30, 4 - 8 parts of sodium carboxymethyl starch, and 1 - 2 parts of magnesium stearate.

[0021] Specifically, microcrystalline cellulose has good fluidity, can be uniformly mixed with other raw materials, improve the mixing uniformity, enhance the compressibility of the material, and promote tablet formation. Polyvinylpyrrolidone K30 can effectively bind various raw materials, contribute to tablet formation, and improve compressibility. Sodium carboxymethyl starch has good water absorption and swelling properties, can promote rapid disintegration of tablets and drug dissolution; and to a certain extent, it can also improve the fluidity of the material, enhance the mixing uniformity and compressibility. Magnesium stearate can improve the fluidity of the material, increase the mixing uniformity of the raw materials, and at the same time, its lubricating effect can also improve compressibility.

[0022] Further, the D10 of atenolol is less than or equal to 30 μm, the D50 is 30 μm - 60 μm, and the D90 is less than or equal to 120 μm.

[0023] Specifically, by controlling the particle size of atenolol, it can be rapidly dissolved.

[0024] Another specific embodiment of the present invention provides a method for preparing atenolol tablets, including steps 1 - 3.

[0025] Step 1, prepare the raw materials atenolol, microcrystalline cellulose, polyvinylpyrrolidone K30, sodium carboxymethyl starch, and magnesium stearate.

[0026] Specifically, prepare the above raw materials according to the raw material ratio. At the same time, divide the microcrystalline cellulose into internal addition microcrystalline cellulose and external addition microcrystalline cellulose. The weight portion of the internal addition microcrystalline cellulose is 10 - 20 parts, and the weight portion of the external addition microcrystalline cellulose is 40 - 50 parts.

[0027] Step 2, mix the internal addition microcrystalline cellulose, polyvinylpyrrolidone K30, and atenolol, and perform wet granulation, wet screening, drying, and dry screening to obtain dry granules.

[0028] Specifically, place the internal addition microcrystalline cellulose, polyvinylpyrrolidone K30, and atenolol in a wet granulator and mix evenly. Wet granulation: Set the stirring frequency to 15 - 30 Hz, the chopping frequency to 4 - 8 Hz, atomize and spray purified water into it, the spraying time shall not exceed 3 min. After the spraying ends, keep the stirring frequency unchanged, set the chopping frequency to 25 - 35 Hz, and continue granulation for 3 - 5 min. Wet screening is carried out using a 18 - 25 - mesh sieve for screening, drying is carried out at 60℃ - 70℃ until the water content is less than 1.5%, and dry screening is carried out using a 18 - 25 - mesh sieve for screening.

[0029] Step 3, mix the dry granules, sodium carboxymethyl starch, and external addition microcrystalline cellulose, and then add magnesium stearate and mix, and press tablets.

[0030] Specifically, microcrystalline cellulose is divided into internal addition and external addition parts for addition, which can improve the mobile phase and compressibility of the intermediate product. At the same time, controlling the amount of externally added microcrystalline cellulose to be greater than that of internally added microcrystalline cellulose increases the fluidity of the material particles, which is more conducive to improving the compressibility of the material.

[0031] The present invention will be further described in detail below in conjunction with specific embodiments.

[0032] Example 1

[0033] The formula of raw and auxiliary materials for atenolol tablets in this example (prescription amount for 1000 tablets), the composition of raw and auxiliary materials: atenolol 50 g, microcrystalline cellulose (internally added) 15.1 g, polyvinylpyrrolidone K30 3 g, microcrystalline cellulose (externally added) 45.9 g, sodium carboxymethyl starch 4.8 g, magnesium stearate 1.2 g, purified water 18 g.

[0034] The preparation process of the atenolol tablets in this example is as follows:

[0035] (1) Place the microcrystalline cellulose (internally added), polyvinylpyrrolidone K30 and atenolol in a wet granulator and mix evenly.

[0036] (2) Prepare wet granules: Set the stirring frequency to 20 Hz and the chopping frequency to 6 Hz, atomize and spray purified water into it, and the spraying time should not exceed 3 min. After the spraying is completed, keep the stirring frequency unchanged, set the chopping frequency to 30 Hz, and continue granulation for 3.5 min.

[0037] (3) Screen the wet granules produced using a rocking granulator (the sieve is a 20-mesh nylon sieve).

[0038] (4) Place the wet-screened granules in a fluidized bed dryer for drying. Stop drying when the moisture content < 1.5%. Discharge to obtain the dried granules.

[0039] (5) Screen the dried granules using a rocking granulator (the sieve is a 20-mesh nylon sieve) to obtain the dry-screened granules.

[0040] (6) Add the dry-screened granules, sodium carboxymethyl starch and microcrystalline cellulose (externally added) to a mixer and mix evenly. Then add magnesium stearate to the mixer and mix evenly.

[0041] (7) Press the drug granules after mixing in step (6) using a 7-mm diameter round single-sided scored flat punch to obtain tablets.

[0042] Appearance of tablets: The tablets have uniform thickness, smooth surfaces, uniform color, no foreign matter, no sticking to the punch, no obvious mottling, no chipping, and no loose tablets.

[0043] Weight difference: ±5%; Friability: ≤1.0%; Disintegration time limit: ≤5 min.

[0044] Example 2

[0045] The formulation of raw and auxiliary materials for the atenolol tablets described in this example (prescription amount for 1000 tablets), the composition of raw and auxiliary materials: atenolol 50 g, microcrystalline cellulose (added internally) 15.1 g, polyvinylpyrrolidone K30 2.5 g, microcrystalline cellulose (added externally) 45.9 g, sodium carboxymethyl starch 4.8 g, magnesium stearate 1.2 g, purified water 18 g.

[0046] The preparation process of the atenolol tablets described in this example is as follows:

[0047] (1) Place microcrystalline cellulose (added internally), polyvinylpyrrolidone K30 and atenolol in a wet granulator and mix evenly.

[0048] (2) Prepare wet granules: Set the stirring frequency at 20 Hz and the chopping frequency at 6 Hz, atomize and spray purified water into it, the spraying time shall not exceed 3 min. After the spraying is completed, keep the stirring frequency unchanged, set the chopping frequency at 30 Hz, and continue granulating for 3.5 min.

[0049] (3) Screen the prepared wet granules with a rocking granulator (the sieve is a 20-mesh nylon sieve).

[0050] (4) Place the wet-screened granules in a fluidized bed dryer for drying. Stop drying when the moisture content is < 1.5%. Discharge to obtain the dried granules.

[0051] (5) Add the dried granules to a rocking granulator for screening (the sieve is a 20-mesh nylon sieve) to obtain the dried-screened granules.

[0052] (6) Add the dried-screened granules, sodium carboxymethyl starch and microcrystalline cellulose (added externally) to a mixer and mix evenly. Then add magnesium stearate to the mixer and mix evenly.

[0053] (7) Press the drug granules after mixing in step (6) with a 7-mm diameter round single-sided scored flat punch to obtain tablets.

[0054] Appearance of tablets: The tablets have uniform thickness, smooth surfaces, uniform color, no foreign matter, no sticking to the punch, no obvious mottling, chipping or loose tablets.

[0055] Weight variation: ±5%; Friability: ≤1.0%; Disintegration time limit: ≤5 min.

[0056] Example 3

[0057] The raw and auxiliary material formula of atenolol tablets in this example (prescription amount for 1000 tablets), the composition of raw and auxiliary materials: atenolol 25g, microcrystalline cellulose (added internally) 10g, polyvinylpyrrolidone K30 2g, microcrystalline cellulose (added externally) 45g, sodium carboxymethyl starch 4g, magnesium stearate 1g, purified water 18g.

[0058] The preparation process of the atenolol tablets described in this example is as follows:

[0059] (1) Place microcrystalline cellulose (added internally), polyvinylpyrrolidone K30 and atenolol in a wet granulating mixer and mix evenly.

[0060] (2) Prepare wet granules: Set the stirring frequency at 15 Hz and the chopping frequency at 4 Hz, atomize and spray purified water into it, the spraying time should not exceed 3 min. After the spraying is completed, keep the stirring frequency unchanged, set the chopping frequency at 25 Hz, and continue granulating for 3.5 min.

[0061] (3) Screen the prepared wet granules using a vibrating granulator (the sieve is a 20-mesh nylon sieve).

[0062] (4) Place the wet-screened granules in a fluidized bed dryer for drying. Stop drying when the moisture content is < 1.5%. Discharge to obtain the dried granules.

[0063] (5) Screen the dried granules using a vibrating granulator (the sieve is a 20-mesh nylon sieve) to obtain the dried and screened granules.

[0064] (6) Add the dried and screened granules, sodium carboxymethyl starch and microcrystalline cellulose (added externally) to a mixer and mix evenly. Then add magnesium stearate to the mixer and mix evenly.

[0065] (7) Press the drug granules after mixing in step (6) using a round single-sided scored flat punch with a diameter of 7 mm to obtain tablets.

[0066] Appearance of tablets: The thickness of the tablet shape is consistent, the tablet surface is smooth, the color and luster are uniform, there are no foreign matters, no sticking to the punch, no obvious mottling, no chipping, and no loose tablets.

[0067] Weight variation: ±5%; Friability: ≤1.0%; Disintegration time limit: ≤5 min.

[0068] Example 4

[0069] The raw and auxiliary material formula of atenolol tablets in this example (prescription amount for 1000 tablets), the composition of raw and auxiliary materials: atenolol 40g, microcrystalline cellulose (added internally) 20g, polyvinylpyrrolidone K30 4g, microcrystalline cellulose (added externally) 40g, sodium carboxymethyl starch 8g, magnesium stearate 2g, purified water 18g.

[0070] The preparation process of the atenolol tablets described in this example is as follows:

[0071] (1) Put microcrystalline cellulose (added internally), polyvinylpyrrolidone K30 and atenolol into a wet granulating mixer and mix evenly.

[0072] (2) Prepare wet granules: Set the stirring frequency at 30 Hz and the chopping frequency at 8 Hz, atomize and spray purified water into it, the spraying time shall not exceed 3 min. After the spraying is completed, keep the stirring frequency unchanged, set the chopping frequency at 35 Hz, and continue granulating for 3.5 min.

[0073] (3) Screen the prepared wet granules using a vibrating granulator (the sieve is a 20-mesh nylon sieve).

[0074] (4) Put the wet-screened granules into a fluidized bed dryer for drying. Stop drying when the moisture content is < 1.5%. Discharge the material to obtain the dried granules.

[0075] (5) Put the dried granules into a vibrating granulator for screening (the sieve is a 20-mesh nylon sieve) to obtain the dried and screened granules.

[0076] (6) Put the dried and screened granules, sodium carboxymethyl starch and microcrystalline cellulose (added externally) into a mixer and mix evenly. Then add magnesium stearate and mix evenly in the mixer.

[0077] (7) Press the drug granules after mixing in step (6) using a round single-sided scored flat punch with a diameter of 7 mm to prepare tablets.

[0078] Appearance of tablets: The thickness of the tablet shape is consistent, the tablet surface is smooth, the color and luster are uniform, there are no foreign matters, no sticking to the punch, no obvious mottling, chipping, or loose tablets.

[0079] Weight variation: ±5%; Friability: ≤1.0%; Disintegration time limit: ≤5 min.

[0080] Example 5

[0081] The formula of raw and auxiliary materials for the atenolol tablets in this example (prescription amount for 1000 tablets), the composition of raw and auxiliary materials: 35 g of atenolol, 15 g of microcrystalline cellulose (added internally), 3 g of polyvinylpyrrolidone K30, 50 g of microcrystalline cellulose (added externally), 5 g of sodium carboxymethyl starch, 1 g of magnesium stearate, 18 g of purified water.

[0082] The preparation process of the atenolol tablets in this example is as follows:

[0083] (1) Put microcrystalline cellulose (added internally), polyvinylpyrrolidone K30 and atenolol into a wet granulating mixer and mix evenly.

[0084] (2) Wet granulation: Set the stirring frequency at 20 Hz and the chopping frequency at 6 Hz. Atomize and spray purified water into it, and the spraying time shall not exceed 3 min. After the spraying is completed, keep the stirring frequency unchanged, set the chopping frequency at 30 Hz, and continue granulation for 3.5 min.

[0085] (3) Screen the wet granules produced using a vibrating granulator (the sieve is a 20-mesh nylon sieve).

[0086] (4) Place the wet-screened granules in a fluidized bed dryer for drying. Stop drying when the moisture content is < 1.5%. Discharge the material to obtain the dried granules.

[0087] (5) Screen the dried granules using a vibrating granulator (the sieve is a 20-mesh nylon sieve) to obtain the dried and screened granules.

[0088] (6) Add the dried and screened granules, sodium carboxymethyl starch, and microcrystalline cellulose (externally added) to a mixer and mix evenly. Then add magnesium stearate to the mixer and mix evenly.

[0089] (7) Press the drug granules after mixing in step (6) using a round single-sided scored flat punch with a diameter of 7 mm to obtain tablets.

[0090] Appearance of tablets: The thickness of the tablet shape is consistent, the tablet surface is smooth, the color is uniform, there are no foreign matters, no sticking to the punch, no obvious mottling, no chipping, and no loose tablets.

[0091] Weight variation: ±5%; Friability: ≤1.0%; Disintegration time limit: ≤5 min.

[0092] Comparative Example 1

[0093] The difference between this comparative example and Example 1 is that in step (1), all the microcrystalline cellulose is placed in a wet granulator together with povidone K30 and atenolol at one time, mixed evenly, and then the subsequent steps such as wet granulation are carried out.

[0094] Comparative Example 2

[0095] The difference between this comparative example and Example 1 is that all the microcrystalline cellulose is added to a mixer together with the dried and screened granules and sodium carboxymethyl starch in step (6), mixed evenly. Then magnesium stearate is added to the mixer and mixed evenly, and then pressed into tablets.

[0096] Comparative Example 3

[0097] The difference between this comparative example and Example 1 is that for the raw and auxiliary material formula (prescription amount for 1000 tablets) of this comparative example of atenolol tablets, the composition of the raw and auxiliary materials is: atenolol 50 g, microcrystalline cellulose (internally added) 45.9 g, povidone K30 3 g, microcrystalline cellulose (externally added) 15.1 g, sodium carboxymethyl starch 4.8 g, magnesium stearate 1.2 g, purified water 18 g.

[0098] Comparative Example 4

[0099] The difference between this comparative example and Example 1 lies in the raw and auxiliary material formula (prescription amount for 1000 tablets) of the atenolol tablets in this comparative example. The composition of the raw and auxiliary materials is as follows: 50 g of atenolol, 7 g of microcrystalline cellulose (added internally), 3 g of polyvinylpyrrolidone K30, 35 g of microcrystalline cellulose (added externally), 4.8 g of sodium carboxymethyl starch, 0.7 g of magnesium stearate, and 18 g of purified water.

[0100] The dissolution curves of the atenolol tablets prepared in Example 1 and Example 2 were compared. The reference preparation was sourced from Almatica Pharma LLC, the medium was pH 1.2 hydrochloric acid solution, and the dissolution conditions were 900 ml, 50 rpm, paddle method. The results are shown in Table 1.

[0101] Table 1 Dissolution data of atenolol tablets

[0102]

[0103] As can be seen from Table 1, in Example 1 and Example 2, the dosage of polyvinylpyrrolidone K30 was adjusted, and the dissolution curve results of the obtained tablets all belonged to rapid dissolution, similar to the reference preparation, meeting the quality requirements. When the dosage of polyvinylpyrrolidone K30 increased, the prepared granules had better formability, and the disintegration time limit of the samples showed a trend of slowing down. Considering the granule properties and the dissolution curve results of the samples, granules with better formability and not affecting the dissolution rate were selected. Therefore, it was determined that the optimal dosage of polyvinylpyrrolidone K30 was 3 g per 1000 tablets containing polyvinylpyrrolidone K30.

[0104] In addition, by observing the appearance of the tablets in Comparative Examples 1 - 4, it was found that there were situations of inconsistent thickness, concave and convex points on the tablet surface, mottling, chipping, and loose tablets in Comparative Examples 1 - 4, and the friability was greater than 1%, showing poor compressibility. By comparison, the granules in the examples of the present invention had better fluidity and excellent compressibility, and the obtained tablets had excellent appearance, meeting the quality requirements.

[0105] For those skilled in the art, it is obvious that the present invention is not limited to the details of the above - mentioned exemplary embodiments, and without departing from the spirit or basic characteristics of the present invention, the present invention can be implemented in other specific forms. Therefore, from any point of view, the embodiments should be regarded as exemplary and non - restrictive. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be encompassed within the present invention.

[0106] In addition, it should be understood that although this specification is described according to embodiments, not every embodiment only contains an independent technical solution. This narrative way of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. An atenolol tablet, characterized in that, It comprises the following raw materials in parts by mass: 25 - 50 parts of atenolol, 55 - 65 parts of microcrystalline cellulose, 2 - 4 parts of polyvinylpyrrolidone K30, 4 - 8 parts of sodium carboxymethyl starch, and 1 - 2 parts of magnesium stearate.

2. The atenolol tablet according to claim 1, characterized in that, The D10 of the atenolol is less than or equal to 30 μm, the D50 is 30 μm - 60 μm, and the D90 is less than or equal to 120 μm.

3. The preparation method of the atenolol tablets according to any one of claims 1-2, characterized in that, It comprises the following steps: Prepare the raw materials of atenolol, microcrystalline cellulose, polyvinylpyrrolidone K30, sodium carboxymethyl starch, and magnesium stearate. Divide the microcrystalline cellulose into internal addition microcrystalline cellulose and external addition microcrystalline cellulose. The weight of the internal addition microcrystalline cellulose is 10 - 20 parts, and the weight of the external addition microcrystalline cellulose is 40 - 50 parts; Mix the internal addition microcrystalline cellulose, polyvinylpyrrolidone K30, and atenolol, and carry out wet granulation, wet screening, drying, and dry screening to obtain dry granules; Mix the dry granules, sodium carboxymethyl starch, and external addition microcrystalline cellulose, and then add magnesium stearate and mix them, and then press tablets.

4. The preparation method of atenolol tablets according to claim 3, characterized in that, When carrying out wet granulation, first add atomized water under the conditions of a stirring frequency of 15 - 30 Hz and a chopping frequency of 4 - 8 Hz. After adding, then carry out granulation for 3 - 5 min under the conditions of a stirring frequency of 15 - 30 Hz and a chopping frequency of 25 - 35 Hz.

5. The preparation method of atenolol tablets according to claim 3, characterized in that, The drying is carried out at 60°C - 70°C until the water content is less than 1.5%.

6. The preparation method of atenolol tablets according to claim 3, characterized in that, The wet screening is carried out using a 18 - 25 - mesh sieve for screening.

7. The preparation method of the atenolol tablet according to claim 3, characterized in that, The dry screening is carried out using a 18 - 25 - mesh sieve for screening.

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