Amlodipine besylate tablets and preparation method thereof

Abstract

The invention relates to an amlodipine besylate tablet and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The amlodipine besylate tablet comprises amlodipine besylate, a calcium carbonate starch complex, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, magnesium stearate, colloidal silicon dioxide, and pregelatinized starch, wherein the calcium carbonate starch complex is prepared by using calcium carbonate and pregelatinized starch in a certain mass ratio. The amlodipine besylate tablet prepared by the invention has the advantages of stable dissolution, simple operation, regular preparation surface, small dissolution change during stability, and the like.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to an amlodipine besylate tablet and a preparation method thereof. Background Art

[0002] Amlodipine besylate tablets are a calcium ion antagonist that works by selectively inhibiting the transmembrane entry of calcium ions into smooth muscle cells and cardiomyocytes, directly acting on vascular smooth muscle, reducing peripheral vascular resistance and thereby lowering blood pressure.

[0003] Amlodipine is unstable to light, moisture, heat, and acid. The current preparation method generally requires high temperature and high humidity conditions, which has a serious impact on the stability of this product. Amlodipine tablets contain anhydrous calcium hydrogen phosphate, microcrystalline cellulose and other excipients. The density difference between different excipients is large, which leads to uneven content problems during premixing or total mixing, further affecting product quality. Amlodipine besylate degrades in acidic media. The pH of the amlodipine besylate composition is about 7, and the pH of the amlodipine free base composition is about 9. Excipient preparations with a weakly alkaline pH are more suitable for the development of this preparation product. Calcium carbonate has a higher alkalinity than calcium hydrogen phosphate and is more suitable for use as an excipient for this product tablet.

[0004] Anhydrous calcium hydrogen phosphate was used in the original formulation of amlodipine besylate tablets, which had problems of incomplete dissolution and decreased dissolution during stability. Anhydrous calcium hydrogen phosphate excipients have better compressibility and fluidity than calcium carbonate, but the deformation mechanism of anhydrous calcium hydrogen phosphate during tableting is brittle fracture. Especially when the prescription volume is large, the tablets will have faults and top cracks, causing problems with the tablet surface regularity. Summary of the invention

[0005] The purpose of the present invention is to overcome the above shortcomings and defects and provide an amlodipine besylate tablet and a preparation method thereof. The preparation process of the method is simple and convenient to operate, has low requirements on production equipment, is suitable for industrial production, and the prepared amlodipine tablets have good stability and the dissolution curve will not change significantly during the stability period.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0007] An amlodipine besylate tablet and a preparation method thereof, characterized in that the amlodipine tablet comprises the following components by percentage of total weight:

[0008]

[0009] The calcium carbonate starch composite is obtained by using calcium carbonate and pregelatinized starch in a certain mass ratio, and is characterized in that the mass ratio of calcium carbonate to pregelatinized starch is 8 to 10:1.

[0010] The amlodipine besylate tablets and preparation method are characterized by comprising the following steps:

[0011] (1) adding calcium carbonate and pregelatinized starch in a certain mass ratio into a wet granulator, premixing, adding water to make a soft material, passing through a 40-mesh sieve to wet granulate, and then drying to prepare a calcium carbonate starch composite;

[0012] (2) The pretreated amlodipine besylate, calcium carbonate starch complex, and microcrystalline cellulose are sieved through a 60-mesh sieve respectively; colloidal silicon dioxide and pregelatinized starch are sieved through a 50-mesh sieve for later use;

[0013] (3) mixing the amlodipine besylate obtained in step (2) with 1 / 2 of the prescribed amount of microcrystalline cellulose to prepare a premix ①;

[0014] (4) mixing the colloidal silicon dioxide and pregelatinized starch obtained in step (2), as well as premix ①, cross-linked sodium carboxymethyl cellulose, and 1 / 2 of the prescribed amount of calcium carbonate starch complex for 2 minutes to obtain premix ②;

[0015] (5) The remaining 1 / 2 amount of microcrystalline cellulose and 1 / 2 amount of calcium carbonate starch complex were placed in a wet granulator for washing, and then the premix ② was added and mixed for 5 min, with stirring at 3 rpm and shearing at 10 rpm;

[0016] (6) adding the prescribed amount of magnesium stearate to step (5) and mixing for 5 minutes;

[0017] (7) The tablets are pressed using a punch with a length of 11.5 mm and a short length of 6.1 mm. The theoretical tablet weight is 250 mg and the hardness is controlled at 17 to 20 kg.

[0018] The amlodipine besylate tablet and preparation method are characterized in that the pretreated amlodipine besylate D90 is between 20 and 40 μm; the microcrystalline cellulose D90 is between 120 and 160 μm; and the magnesium stearate D90 is less than 200 μm.

[0019] The amlodipine besylate tablet and preparation method are characterized in that the premixing time of calcium carbonate and pregelatinized starch is 3 to 5 minutes, the soft material preparation time is 1 to 2 minutes; and the mixing time of amlodipine besylate and 1 / 2 of the prescription amount of microcrystalline cellulose is 1 to 2 minutes.

[0020] Beneficial Effects

[0021] 1. The amlodipine besylate tablets prepared by the present invention have a good dissolution fit with the original reference preparation, a simple preparation process, routine operation, and are suitable for industrial batch production. The process has good reproducibility and meets the quality standards of drugs.

[0022] 2. The present invention mixes calcium carbonate and pregelatinized starch in a specific ratio and performs wet granulation to obtain tablets with good appearance, excellent content and dissolution quality attributes, and no significant change in dissolution during the stability period, thereby improving the overall quality level of amlodipine tablets. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 Dissolution curve of amlodipine besylate tablets in pH 6.8 medium. DETAILED DESCRIPTION

[0024] In order to interpret and facilitate a deeper understanding of the present invention, the following examples are used to further illustrate the implementation methods of the claims, but it is worth noting that the protection scope of the present invention is not limited to the following implementation cases.

[0025] Example 1: Use of the present invention's prescription

[0026] Prescription composition:

[0027] mg / tablet % g / 1000 tablets Amlodipine Besylate 6.935 2.77 6.935 Calcium carbonate starch complex 100 40 100 Microcrystalline Cellulose 93.33 37.33 93.33 Croscarmellose Sodium 7.5 3 7.5 Magnesium Stearate 1.25 0.5 1.25 Colloidal Silica 1 0.4 1 Pregelatinized starch 40 16 40

[0028] Preparation process:

[0029] 1) Calcium carbonate and pregelatinized starch were added to a wet granulator at a mass ratio of 9:1, premixed for 5 minutes, and a binder was added to make a soft material for 1 minute. The wet granules were passed through a 40-mesh sieve and dried to prepare a calcium carbonate starch composite.

[0030] 2) Material pretreatment: The amlodipine API was crushed to a D90 of about 30 μm, and the calcium carbonate starch complex and microcrystalline cellulose excipients were dispersed through a 60-mesh sieve;

[0031] 3) Mixing amlodipine besylate API with half of the microcrystalline cellulose for 1 min to prepare a premix ①;

[0032] 4) The colloidal silicon dioxide and pregelatinized starch are mixed and passed through a 50-mesh sieve, and mixed with the premix ①, cross-linked sodium carboxymethyl cellulose and half of the calcium carbonate starch complex for 2 minutes to obtain premix ②;

[0033] 5) The remaining microcrystalline cellulose and calcium carbonate starch complex are placed in a wet granulator for washing, and then the premix ② is added and mixed for 5 minutes, with stirring at 3 rpm and shearing at 10 rpm.

[0034] 6) Mixing: weigh the prescribed amount of magnesium stearate and mix with the premixed material for 5 minutes;

[0035] 7) Tabletting: Use a 11.5mm long and 6.1mm short punch to tablet, the theoretical tablet weight is 250mg, and the hardness is controlled at 17-20kg.

[0036] Example 2: Anhydrous calcium hydrogen phosphate replaces calcium carbonate starch complex

[0037] Prescription composition:

[0038] mg / tablet % g / 2000 tablets Amlodipine Besylate 6.935 2.77 13.87 Anhydrous calcium hydrogen phosphate 100 40 200 Microcrystalline Cellulose 93.33 37.33 186.66 Croscarmellose Sodium 7.5 3 15 Magnesium Stearate 1.25 0.5 2.5 Colloidal Silica 1 0.4 2 Pregelatinized starch 40 16 80

[0039] Preparation process:

[0040] 1) Material pretreatment: The amlodipine API was crushed to a D90 of about 30 μm, and the anhydrous calcium hydrogen phosphate and microcrystalline cellulose excipients were dispersed through a 60-mesh sieve;

[0041] 2) Mixing amlodipine besylate API, anhydrous calcium hydrogen phosphate and half of the prescribed amount of microcrystalline cellulose for 1 minute to prepare a premix ①;

[0042] 3) The colloidal silicon dioxide and pregelatinized starch are mixed and passed through a 50-mesh sieve, and mixed with the premix ① and cross-linked sodium carboxymethyl cellulose for 2 minutes to obtain a premix ②;

[0043] 4) Add the remaining microcrystalline cellulose to the premix ② and mix for 5 minutes, stirring at 3 rpm and shearing at 10 rpm.

[0044] 5) Mixing: weigh the prescribed amount of magnesium stearate and mix with the premixed material for 5 minutes;

[0045] 6) Tabletting: Use a 11.5mm long and 6.1mm short punch to make tablets. The theoretical tablet weight is 250mg and the hardness is controlled at 17-20kg.

[0046] Example 3: Balance the formula with microcrystalline cellulose so that pregelatinized starch: microcrystalline cellulose = 1:1 (comparative case)

[0047] Prescription composition:

[0048] mg / tablet % g / 2000 tablets Amlodipine Besylate 6.935 2.77 13.85 Microcrystalline Cellulose 116.66 46.67 233.32 Croscarmellose Sodium 7.5 3 15 Magnesium Stearate 1.25 0.5 2.5 Colloidal Silica 1 0.4 2 Pregelatinized starch 116.66 46.67 233.32

[0049] Preparation process:

[0050] 1) Material pretreatment: The amlodipine API was crushed to a D90 of about 30 μm, and the microcrystalline cellulose excipient was sieved through a 60-mesh sieve;

[0051] 2) Mixing amlodipine besylate API and half of the prescribed amount of microcrystalline cellulose for 1 minute to prepare premix ①;

[0052] 3) The colloidal silicon dioxide and pregelatinized starch are mixed and passed through a 50-mesh sieve, and mixed with the premix ① and cross-linked sodium carboxymethyl cellulose for 2 minutes to obtain a premix ②;

[0053] 4) Add the remaining microcrystalline cellulose to the premix ② and mix for 5 minutes, stirring at 3 rpm and shearing at 10 rpm.

[0054] 5) Mixing: weigh the prescribed amount of magnesium stearate and mix with the premixed material for 5 minutes;

[0055] 6) Tabletting: Use a 11.5mm long and 6.1mm short punch to make tablets. The theoretical tablet weight is 250mg and the hardness is controlled at 17-20kg.

[0056] Example 4: Pregelatinized starch replaces calcium carbonate starch complex (comparative case)

[0057] Prescription composition:

[0058] mg / tablet % g / 2000 tablets Amlodipine Besylate 6.935 2.77 13.85 Microcrystalline Cellulose 93.33 37.33 186.67 Croscarmellose Sodium 7.5 3 15 Magnesium Stearate 1.25 0.5 2.5 Colloidal Silica 1 0.4 2 Pregelatinized starch 140 56 280 total 250 100 500

[0059] Preparation process:

[0060] 1) Material pretreatment: The amlodipine API was crushed to a D90 of about 30 μm, and the microcrystalline cellulose excipient was sieved through a 60-mesh sieve;

[0061] 2) Mixing amlodipine besylate API and half of the prescribed amount of microcrystalline cellulose for 1 minute to prepare premix ①;

[0062] 3) The colloidal silicon dioxide and pregelatinized starch are mixed and passed through a 50-mesh sieve, and mixed with the premix ① and cross-linked sodium carboxymethyl cellulose for 2 minutes to obtain a premix ②;

[0063] 4) Add the remaining microcrystalline cellulose to the premix ② and mix for 5 minutes, stirring at 3 rpm and shearing at 10 rpm.

[0064] 5) Mixing: weigh the prescribed amount of magnesium stearate and mix with the premixed material for 5 minutes;

[0065] 6) Tabletting: Use a 11.5mm long and 6.1mm short punch to make tablets. The theoretical tablet weight is 250mg and the hardness is controlled at 17-20kg.

[0066] Dissolution test:

[0067] Determination method: Take samples in each implementation case, and select 37°C, pH6.8 paddle method (sinking basket 50rpm), 0.01M hydrochloric acid + EDTA (75rpm), pH4.5 paddle method (50rpm), aqueous medium paddle method (50rpm), and 900mL to evaluate the fitting of the dissolution curve of the self-made product. And take samples at the corresponding time points, detect and calculate the dissolution amount of each tablet. The inspection results are shown in the table. The dissolution experiment method refers to the 2020 edition of the Chinese Pharmacopoeia 0931 Dissolution and Release Determination Method to calculate the cumulative dissolution. The dissolution results show that in each implementation case, except for the pH6.8 paddle method (sinking basket 50rpm) medium, the remaining implementation cases are rapidly dissolved in each medium (greater than 85% in 15 minutes), so only the dissolution data of the key medium of pH6.8 paddle method (sinking basket 50rpm) are explained and presented in detail.

[0068] Table 1 Dissolution curve of amlodipine tablets in pH 6.8 paddle method (sinking basket 50 rpm)

[0069] Time (min) Example 1 Example 2 Example 3 Example 4 Reference preparation 5 52 65 82 76 55 10 67 68 89 86 69 15 71 70 90 88 73 20 75 73 91 88 75 30 79 73 90 89 79 45 81 75 92 89 84 60 83 77 92 88 87 90 85 77 92 90 92 120 89 81 93 89 96 180 90 83 93 91 98 f2 72 50 39 43

[0070] The test results show that Examples 1 and 2 can dissolve consistently with the original formulation in a pH 6.8 paddle method (sinking basket 50 rpm) dissolution medium; however, the degree of similarity between Example 1 and the reference is much higher than that between Example 2. The dissolution behavior of Examples 3 and 4 is inconsistent with that of the reference formulation.

[0071] Dissolution change test during stability period:

[0072] The samples of Examples 1 and 2 of the present invention and the reference preparation samples were taken for accelerated stability study according to the guidelines for stability testing of pharmaceutical preparations in the 2020 edition of the Chinese Pharmacopoeia. The conditions were 40°C ± 2°C, RH 75% ± 5%, and samples were taken at 0 month, 1 month, 2 month, 3 month and 6 month after placement to examine the dissolution changes during the stability period. The results are shown in Table 2.

[0073] Table 2 Dissolution of amlodipine tablets during stability in pH 6.8 medium

[0074]

[0075] The test results show that the dissolution changes of the samples prepared by the present invention during the stability period are good, which is basically consistent with the dissolution changes of the original preparation samples during the stability period; in implementation case 2, the dissolution dropped or slowed down significantly during the stability period. Since the dissolution results of implementation cases 3 and 4 were not ideal, the dissolution changes during the stability period were not investigated.

Claims

1. An amlodipine besylate tablet, characterized in that: The amlodipine besylate tablets comprise the following components by percentage of total weight: Amlodipine besylate 2~3wt% Calcium carbonate starch complex 30~50wt% Microcrystalline cellulose 30~50wt% Cross-linked sodium carboxymethyl cellulose 1-5wt% Magnesium stearate 0.5~2wt% Colloidal silicon dioxide 0.2~0.6wt% Pregelatinized starch 10-20wt% The calcium carbonate starch composite is prepared by using calcium carbonate and pregelatinized starch in a certain mass ratio, wherein the mass ratio of calcium carbonate to pregelatinized starch is 8 to 10:1; The preparation method of the amlodipine besylate tablets comprises the following steps: (1) adding calcium carbonate and pregelatinized starch in a mass ratio of 8 to 10:1 into a wet granulator, premixing, adding water to make a soft material, passing through a 40-mesh sieve to wet granulate, and then drying to prepare a calcium carbonate starch composite; (2) The pretreated amlodipine besylate, calcium carbonate starch complex, and microcrystalline cellulose are sieved through a 60-mesh sieve respectively; colloidal silicon dioxide and pregelatinized starch are sieved through a 50-mesh sieve for later use; (3) mixing the amlodipine besylate obtained in step (2) with 1 / 2 of the prescribed amount of microcrystalline cellulose to prepare a premix ①; (4) mixing the colloidal silicon dioxide and pregelatinized starch obtained in step (2), as well as premix ①, cross-linked sodium carboxymethyl cellulose, and 1 / 2 of the prescribed amount of calcium carbonate starch complex for 2 minutes to obtain premix ②; (5) The remaining 1 / 2 amount of microcrystalline cellulose and 1 / 2 amount of calcium carbonate starch complex were placed in a wet granulator for washing, and then the premix ② was added and mixed for 5 min, with stirring at 3 rpm and shearing at 10 rpm; (6) adding the prescribed amount of magnesium stearate to step (5) and mixing for 5 minutes; (7) The tablets are pressed using a punch with a length of 11.5 mm and a short length of 6.1 mm. The theoretical tablet weight is 250 mg and the hardness is controlled at 17 to 20 kg.

2. The amlodipine besylate tablets according to claim 1, characterized in that: The D90 of pretreated amlodipine besylate is between 20 and 40 μm; the D90 of microcrystalline cellulose is between 120 and 160 μm; and the D90 of magnesium stearate is less than 200 μm.

3. The amlodipine besylate tablets according to claim 1, characterized in that: The premixing time of calcium carbonate and pregelatinized starch is 3 to 5 minutes, and the soft material preparation time is 1 to 2 minutes; the mixing time of amlodipine besylate and 1 / 2 of the prescribed amount of microcrystalline cellulose is 1 to 2 minutes.

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