CN107951849B - Amlodipine besylate tablet and preparation method thereof - Google Patents

Abstract

The invention provides an amlodipine besylate tablet and a preparation method thereof. The amlodipine besylate tablet comprises the following components in parts by weight: 1-5 parts of amlodipine besylate, 0.3-0.6 part of superfine silica gel powder, 30-70 parts of microcrystalline cellulose, 20-50 parts of anhydrous calcium hydrophosphate, 1-3 parts of magnesium stearate and 0.4-0.6 part of sodium carboxymethyl starch; the method specifically comprises the following steps: firstly, mixing amlodipine besylate and silica gel micropowder to obtain a mixed material A; dissolving microcrystalline cellulose and anhydrous calcium hydrophosphate in an organic solvent, and drying to obtain a mixed material B; placing A, B and magnesium stearate in a high-efficiency wet mixing granulator to obtain a mixed material C; granulating C by a dry method to obtain granules I; and (3) uniformly mixing the I, magnesium stearate and sodium carboxymethyl starch to obtain granules II, and tabletting to obtain the amlodipine besylate tablets. The amlodipine besylate tablet prepared by the method has higher dissolution rate and better stability.

Description

Amlodipine besylate tablet and preparation method thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to an amlodipine besylate tablet and a preparation method thereof.

Background

Amlodipine besylate is a dihydropyridine calcium antagonist, mainly inhibits the calcium storage capacity of cell membranes of cardiac muscle and vascular smooth muscle and the capacity of combining with calcium ions, and achieves the effect of reducing blood pressure by expanding vascular arterioles and reducing peripheral resistance.

In the preparation process of the amlodipine besylate tablet, due to the fact that materials are in contact with and collide with the wall surface of a device, an electrostatic effect is easy to generate, on one hand, particles are promoted to be mutually aggregated to block sieve pores, and sieving is slow and difficult; on the other hand, particles adhere to the inner wall surface of the apparatus, resulting in a low yield and an increase in cost. Meanwhile, the amlodipine besylate is easy to generate electrostatic action, so that the amlodipine besylate as the main drug is easy to accumulate into groups in the mixing process with other auxiliary materials, and the dissolution and the content uniformity of the main drug are influenced.

Because amlodipine besylate is unstable to light, moisture and heat, a preparation obtained by a general preparation method is easy to degrade under the action of high temperature, high moisture and strong light, so that the stability of the medicament is influenced.

At present, anhydrous calcium hydrophosphate and microcrystalline cellulose are commonly used as auxiliary materials for preparing amlodipine besylate tablets, but the anhydrous calcium hydrophosphate is heavy, and the microcrystalline cellulose is light, so that materials are difficult to uniformly mix, the dissolution rate of a product is influenced, and the drug effect is reduced. Therefore, research and development of a method for preparing amlodipine besylate tablets capable of ensuring the yield, uniformity and dissolution rate of the product and improving the drug effect are urgently needed.

Disclosure of Invention

The technical problem to be solved by the invention is to overcome the defects and shortcomings in the background art, provide a preparation method of amlodipine besylate tablets, which ensures the product yield and dissolution rate, has simple process and high production efficiency, and also provide amlodipine besylate tablets with high dissolution rate prepared by the method.

In order to solve the technical problems, the technical scheme provided by the invention is as follows:

the amlodipine besylate tablet comprises the following components in parts by weight:

the amlodipine besylate tablet takes amlodipine besylate as a main drug, silica gel micropowder as an antistatic agent, microcrystalline cellulose and anhydrous calcium hydrogen phosphate as fillers, magnesium stearate as a lubricant and sodium carboxymethyl starch as an adhesive, and the content of each component is controlled within the scope of the tablet, so that the cost is reduced while the drug effect is ensured through the synergistic effect of the components.

Preferably, the magnesium stearate comprises 1.0-2.0 parts by weight of magnesium stearate and 0.5-1.5 parts by weight of magnesium stearate.

Preferably, the amlodipine besylate tablet comprises the following components in parts by weight:

the amlodipine besylate tablet is preferably that the particle size of the anhydrous calcium hydrophosphate is D10 less than 30 μm, and D90 less than 100 μm; the grain size of the microcrystalline cellulose is D10 less than 30 μm, and D90 less than 150 μm. The particle size of the anhydrous calcium hydrophosphate and the microcrystalline cellulose is controlled within the range of the invention, so that the rapid dissolution of the anhydrous calcium hydrophosphate and the microcrystalline cellulose in an organic solvent can be promoted.

The amlodipine besylate tablet is preferably that the particle size of the sodium carboxymethyl starch is D10 < 40 μm, and D90 < 180 μm; the particle size of the magnesium stearate is D10 less than 40 mu m, and D90 less than 180 mu m; the particle size of the micropowder silica gel is D10 less than 30 μm, and D90 less than 150 μm. The particle sizes of the sodium carboxymethyl starch, the magnesium stearate and the superfine silica powder are controlled within the range of the invention, so that the main drug and the auxiliary materials can be uniformly distributed when being mixed.

In the amlodipine besylate tablet, the particle size of the amlodipine besylate is preferably D10 less than 30 μm, and D90 less than 150 μm. The particle size of the amlodipine besylate serving as the main drug is controlled within the range of the invention, so that the phenomenon that the main drug and the auxiliary materials are aggregated due to electrostatic action in the mixing process can be avoided, the uniform distribution of the main drug during mixing is ensured, and the dissolution rate of the main drug is improved.

As a general inventive concept, the present invention also provides a preparation method of the above amlodipine besylate tablet, comprising the steps of:

(1) uniformly mixing amlodipine besylate and silica gel micropowder to obtain a mixed material A;

(2) dissolving microcrystalline cellulose and anhydrous calcium hydrogen phosphate in an organic solvent, stirring for accelerating dissolution, and then drying to obtain a mixed material B;

(3) the dosage of the main drug is small, the dosage of the auxiliary materials is large, and all the raw and auxiliary materials are fine powder, so that electrostatic effect is easily generated and the raw and auxiliary materials are agglomerated to influence the dissolution rate, and the mixed material A, the mixed material B and the magnesium stearate are required to be placed in a high-efficiency wet mixing granulator, and stirred and mixed to obtain a mixed material C; the magnesium stearate added in the step (3) is the magnesium stearate added in the step (3);

(4) adding the mixed material C into a dry granulating machine for granulation, wherein the fine powder has poor flowability, so that the amount of the fine powder flowing into a die hole is large and small during tabletting, so that the tablet has large difference and uneven content distribution, dust is easy to fly in the tabletting process, the tablets prepared after tabletting are easy to have the phenomena of cracking, sticking, die drawing and the like, the fine powder needs to be screened out, and the fine powder is re-granulated until the particle size of the particles is 200-300 mu m to obtain particles I;

(5) uniformly mixing the granules I, magnesium stearate and sodium carboxymethyl starch to obtain granules II; magnesium stearate added in the step (5) is added magnesium stearate;

(6) and tabletting the granules II to obtain the amlodipine besylate tablets.

In the above method for preparing amlodipine besylate tablets, preferably, the step (1) further comprises the following steps: and (3) sieving the mixed material A by a sieve of 100-120 meshes, sieving anhydrous calcium hydrophosphate by a sieve of 150-200 meshes, sieving microcrystalline cellulose by a sieve of 100-120 meshes, and sieving sodium carboxymethyl starch and magnesium stearate by a sieve of 80-100 meshes.

Preferably, in the preparation method of amlodipine besylate tablets, the drying treatment in the step (2) is spray drying, and in the spray drying process, the temperature of an air inlet is controlled to be 80-100 ℃;

the mixing process in the step (3) is carried out in a high-efficiency wet mixing granulator, the stirring speed is controlled to be 79-81 r/min, the cutter speed is controlled to be 79-81 r/min, the stirring time is 0.5-1 min, then the stirring speed is controlled to be 100-120 r/min, the cutter speed is controlled to be 100-120 r/min, and the continuous stirring time is 3-5 min; the amlodipine besylate is light and easy to generate static electricity, and the stirring time is too long or the stirring speed is too high in the mixing process, so that the static electricity is easy to generate by high-speed collision of particles, and the mixing is not uniform, so that the parameters of the mixing process in the step (3) need to be controlled within the range of the invention.

And (5) carrying out the mixing process in a three-dimensional motion mixer, controlling the rotating speed to be 10-15 r/min, and mixing for 15-30 min.

In the above preparation method of amlodipine besylate tablets, preferably, the organic solvent in the step (2) is absolute ethyl alcohol; and (4) sieving fine powder by using a 60-mesh sieve in the step (4).

Compared with the prior art, the invention has the advantages that:

(1) according to the method, the amlodipine besylate and the micropowder silica gel are uniformly mixed and sieved, so that the adsorption of the amlodipine besylate on the surface of a sieve can be reduced in the sieving process, and the yield is improved; on the other hand, the aggregation effect of the amlodipine besylate in the preparation process can be reduced, and the content uniformity and dissolution of the product can be improved.

(2) The method of the invention adopts dry granulation and powder direct compression, avoids the amlodipine besylate from contacting light, wet and hot environments, and is beneficial to improving the stability of the product.

(3) The method of the invention heats and dissolves anhydrous calcium hydrogen phosphate and microcrystalline cellulose in anhydrous ethanol according to the proportion of the prescription to prepare soluble solution, and then prepares the composite auxiliary material by spray drying, which is beneficial to uniformly mixing the anhydrous calcium hydrogen phosphate and the microcrystalline cellulose, thereby ensuring the dissolution rate of the product.

(4) According to the method, the raw materials and the auxiliary materials are mixed in the high-efficiency wet mixing granulator at a very high mixing speed, so that the materials are mixed into a vortex shape at a high speed to ensure that the materials are uniformly dispersed, the contained high-speed leaf pulp can thoroughly break up lumps, and the materials are free of particles after being mixed, so that the uniformity and the dissolution rate of the components of the medicine are ensured.

(5) The amlodipine besylate tablet prepared by the invention has higher dissolution rate and better stability.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.

FIG. 1 is a chromatogram of relevant substances of sample 1 in comparative example 1 of the present invention;

FIG. 2 is a chromatogram of relevant substances of sample 2 in comparative example 2 of the present invention;

FIG. 3 is a chromatogram of the relevant substances of sample 3 in example 1 of the present invention;

FIG. 4 is a chromatogram of related substances of amlodipine besylate as a starting material drug in the invention.

Detailed Description

In order to facilitate an understanding of the invention, the invention will be described more fully and in detail below with reference to the accompanying drawings and preferred embodiments, but the scope of the invention is not limited to the specific embodiments below.

Unless otherwise defined, all terms of art used hereinafter have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention.

Unless otherwise specifically stated, various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or can be prepared by existing methods.

Comparative example 1:

the amlodipine besylate tablet comprises the following components in percentage by weight:

the preparation method of the amlodipine besylate tablet of the comparative example comprises the following steps:

taking the raw and auxiliary materials in the formula, sieving amlodipine besylate with a 120-mesh sieve, sieving anhydrous calcium hydrophosphate with a 200-mesh sieve, sieving microcrystalline cellulose with a 100-mesh sieve, and sieving sodium carboxymethyl starch and magnesium stearate with a 80-mesh sieve; placing amlodipine besylate, microcrystalline cellulose PH101, anhydrous calcium hydrophosphate and magnesium stearate added in a high-efficiency wet mixing granulator, firstly stirring for 1min at a stirring speed of 80r/min and a cutter speed of 80r/min, and then continuously stirring for 4min at a stirring speed of 120r/min and a cutter speed of 120 r/min; adding the uniformly mixed raw and auxiliary materials into a dry-method granulator for granulation; adding the dosage of magnesium stearate and sodium carboxymethyl starch according to the yield conversion, placing the obtained mixture and the granulated particles in a three-dimensional motion mixer together, and uniformly mixing at a set rotating speed of 15r/min for 20 min; finally, the tablets were tabletted to obtain amlodipine besylate tablets (sample 1).

Comparative example 2:

the amlodipine besylate tablet comprises the following components in percentage by weight:

the preparation method of the amlodipine besylate tablet of the comparative example comprises the following steps:

taking the raw and auxiliary materials in the formula, sieving amlodipine besylate with a 120-mesh sieve, sieving anhydrous calcium hydrophosphate with a 200-mesh sieve, sieving microcrystalline cellulose with a 100-mesh sieve, and sieving sodium carboxymethyl starch and magnesium stearate with a 80-mesh sieve; placing amlodipine besylate, microcrystalline cellulose PH101, anhydrous calcium hydrophosphate and magnesium stearate added in a high-efficiency wet mixing granulator, firstly stirring for 1min at a stirring speed of 80r/min and a cutter speed of 80r/min, and then continuously stirring for 4min at a stirring speed of 120r/min and a cutter speed of 120 r/min; adding the uniformly mixed raw and auxiliary materials into 75% ethanol by mass, stirring and uniformly mixing, and performing wet granulation; adding the dosage of magnesium stearate and sodium carboxymethyl starch according to the yield conversion, placing the obtained mixture and the granulated particles in a three-dimensional motion mixer together, and uniformly mixing at a set rotating speed of 15r/min for 20 min; finally, tabletting was performed to obtain amlodipine besylate tablets (sample 2).

Example 1:

the amlodipine besylate tablet comprises the following components in percentage by weight:

in the amlodipine besylate tablet of the present example, the particle size of anhydrous calcium hydrogen phosphate in the selected components is D10 ═ 28 μm, D90 ═ 100 μm, the particle size of microcrystalline cellulose is D10 ═ 29 μm, D90 ═ 136 μm, the particle size of sodium carboxymethyl starch is D10 ═ 38 μm, D90 ═ 171 μm, the particle size of magnesium stearate (including magnesium stearate and magnesium stearate) is D10 ═ 38 μm, D90 ═ 159 μm, the particle size of colloidal silica is D10 ═ 28 μm, D90 ═ 127 μm, the particle size of amlodipine besylate is D10 ═ 28 μm, and D90 ═ 125 μm.

The preparation method of amlodipine besylate tablets of the embodiment comprises the following steps:

(1) taking the raw and auxiliary materials in the formula, uniformly mixing the amlodipine besylate and the silica gel micropowder to obtain a mixed material A, and sieving the mixed material A by a 120-mesh sieve; then, sieving anhydrous calcium hydrogen phosphate with a 200-mesh sieve, sieving microcrystalline cellulose with a 100-mesh sieve, and sieving sodium carboxymethyl starch and magnesium stearate with a 80-mesh sieve;

(2) dissolving microcrystalline cellulose and anhydrous calcium hydrogen phosphate in absolute ethyl alcohol, stirring to accelerate dissolution, and then performing spray drying, wherein the temperature of an air inlet is controlled to be 100 ℃, and the temperature of an air outlet is controlled to be 80 ℃ to obtain a mixed material B;

(3) placing the mixed material A, the mixed material B and magnesium stearate in an efficient wet mixing granulator, starting stirring for mixing, stirring for 1min at a stirring speed of 80r/min and a cutter speed of 80r/min, and continuing stirring for 4min at a stirring speed of 120r/min and a cutter speed of 120r/min to obtain a mixed material C;

(4) adding the mixed material C into a dry-method granulator for granulation, then sieving fine powder (more than 250 micrometers) by using a 60-mesh sieve, and re-granulating the fine powder until the particle size of the particles is 250-300 micrometers to obtain particles I;

(5) adding the granules I, magnesium stearate and sodium carboxymethyl starch into a three-dimensional motion mixer together, and uniformly mixing, wherein the rotating speed is controlled to be 15r/min, and the mixing time is 20min, so as to obtain granules II;

(6) the pellet ii was tabletted to obtain amlodipine besylate tablets (sample 3).

The related properties of the amlodipine besylate tablet samples prepared in comparative examples 1 and 2 and example 1 were examined by the following experiments:

1. and (3) comparing the content, yield, dissolution rate and content uniformity of related substances of the sample:

the content, yield, dissolution rate and content uniformity of related substances of the amlodipine besylate tablets prepared in comparative examples 1 and 2 and example 1 were tested, and the test results are shown in table 1.

Table 1 content, yield, dissolution rate and content of related substances of amlodipine besylate tablets in comparative examples 1 and 2 and example 1

Uniformity

As can be seen from table 1, compared with samples 1 and 2, the yield, dissolution rate and content uniformity of sample 3 are all significantly improved, while the content of related substances is relatively low; therefore, the amlodipine besylate tablet prepared by the method can obviously improve the yield, dissolution and content uniformity of the product and effectively reduce the content of related substances in the product.

2. High-temperature test:

the amlodipine besylate tablets prepared in comparative examples 1 and 2 and example 1 were placed in an incubator at 60 ℃ for 10 days, and sampled before (0d) and after (10d) the placement, respectively, to observe the change of the contents of the related substances, and the test results are shown in table 2.

TABLE 2 test results of the contents of substances (%)

As can be seen from table 2, when the pellet was placed for 0 day, the content of the related substances in sample 2 was higher than that in samples 1 and 3, which is mainly caused by the water intervention during the wet granulation process, and a part of amlodipine besylate was hydrolyzed to generate impurities; after being continuously placed for 10 days at a high temperature, the content of related substances in the sample 2 is obviously higher than that of the sample 1 and the sample 3, which is mainly caused by the fact that the amlodipine besylate is degraded to generate impurities due to the fact that the wet granulation needs to be dried at the high temperature; therefore, the amlodipine besylate tablet prepared by the method can effectively reduce the content of related substances in the product, and the content of the related substances is only slowly increased after the tablet is placed for a period of time under the high-temperature condition, which indicates that the product has good stability.

3. High humidity test:

samples of amlodipine besylate tablets prepared in comparative examples 1 and 2 and example 1 were placed in a constant temperature closed container having a relative humidity of 90% for 10 days, and sampled before (0d), after (5d) and after (10d) respectively, to observe changes in the contents of the relevant substances, and the test results are shown in table 3.

TABLE 3 test results of the respective samples for the content of the relevant substances in the high humidity test (%)

As can be seen from Table 3, the content of the related substances in sample 3 is significantly lower than that in samples 1 and 2 after being placed under high humidity for 0 day, 5 days and 10 days, and it can be seen that the content of the related substances in the product can be effectively reduced by adopting the method of the present invention to prepare amlodipine besylate tablets, and the content of the related substances is only slowly increased after being placed under high humidity for a period of time, which indicates that the product stability is good.

4. Strong light irradiation test:

the amlodipine besylate tablets prepared in comparative examples 1 and 2 and example 1 were placed under a light intensity of 4500Lx for 10 days, and sampled before (0d), after (5d) and after (10d) respectively, to observe the change of the contents of the substances, and the test results are shown in Table 4.

Table 4 test results of the content of the relevant substances (%) -of each sample in the hard light test

As can be seen from table 4, after being placed under a strong light condition for 0 day, 5 days and 10 days, the content of the related substances in the sample 3 is significantly lower than that of the sample 1 and the sample 2, and thus, the content of the related substances in the product can be effectively reduced by adopting the method for preparing the amlodipine besylate tablet, and the content of the related substances is only slowly increased after being placed under the strong light condition for a period of time, which indicates that the product has good stability.

5. And (3) stability test:

the amlodipine besylate tablet samples prepared in comparative examples 1 and 2 and example 1 are placed under the conditions of 40 ℃ +/-2 ℃ and 75% +/-5% relative humidity for 6 months, and then sampled in the sixth month respectively to observe the content change of related substances, wherein the chromatogram of the related substances of the sample 1 is shown in figure 1, the chromatogram of the related substances of the sample 2 is shown in figure 2, the chromatogram of the related substances of the sample 3 is shown in figure 3, and the chromatogram of the related substances of the starting raw material amlodipine besylate is shown in figure 4. As can be seen from fig. 1 to 4, the impurity species and the impurity content of sample 2 are the highest, and the impurity contents of samples 1 and 3 are significantly reduced compared to sample 2, wherein the impurity content of sample 3 is the lowest. Therefore, the amlodipine besylate tablet prepared by the method of the invention still keeps a good stable state after being placed for 6 months.

Claims (8)

1. The preparation method of the amlodipine besylate tablet is characterized in that the amlodipine besylate tablet comprises the following components in parts by weight:

1-5 parts of amlodipine besylate,

0.3 to 0.6 part of micro silica gel powder,

30-70 parts of microcrystalline cellulose,

20-50 parts of anhydrous calcium hydrophosphate,

1-3 parts of magnesium stearate,

0.4-0.6 part of sodium carboxymethyl starch;

the particle size of the anhydrous calcium hydrophosphate is D10=28 μm, and D90=100 μm; the microcrystalline cellulose has a particle size of D10=29 μm, D90=136 μm; the particle size of the micro silica gel powder is D10 less than 30 μm, and D90 less than 150 μm;

the preparation method of the amlodipine besylate tablet comprises the following steps:

(1) uniformly mixing amlodipine besylate and silica gel micropowder to obtain a mixed material A;

(2) dissolving microcrystalline cellulose and anhydrous calcium hydrogen phosphate in an organic solvent, stirring for accelerating dissolution, and then drying to obtain a mixed material B;

(3) placing the mixed material A, the mixed material B and magnesium stearate in an efficient wet mixing granulator, and stirring to mix to obtain a mixed material C; the mixing process in the step (3) is carried out in a high-efficiency wet mixing granulator, the stirring speed is controlled to be 79-81 r/min, the cutter speed is controlled to be 79-81 r/min, the stirring time is 0.5-1 min, then the stirring speed is controlled to be 100-120 r/min, the cutter speed is controlled to be 100-120 r/min, and the continuous stirring time is 3-5 min;

(4) adding the mixed material C into a dry-method granulator for granulation, then screening out fine powder, and re-granulating the fine powder until the particle size of the particles is 200-300 mu m to obtain particles I;

(5) uniformly mixing the granules I, magnesium stearate and sodium carboxymethyl starch to obtain granules II;

(6) and tabletting the granules II to obtain the amlodipine besylate tablets.

2. The method for preparing amlodipine besylate tablets according to claim 1, wherein the magnesium stearate comprises 1.0-2.0 parts by weight of magnesium stearate and 0.5-1.0 part by weight of magnesium stearate.

3. The method for preparing amlodipine besylate tablets according to claim 1 or 2, wherein the amlodipine besylate tablets comprise the following components in parts by weight:

2-3 parts of amlodipine besylate,

0.4 to 0.5 part of micro silica gel powder,

50-60 parts of microcrystalline cellulose,

30-40 parts of anhydrous calcium hydrophosphate,

2-3 parts of magnesium stearate,

0.5-0.6 part of sodium carboxymethyl starch.

4. The method for preparing amlodipine besylate tablets according to claim 1, wherein the particle size of said sodium carboxymethyl starch is D10 < 40 μm, D90 < 180 μm; the particle size of the magnesium stearate is D10 < 40 mu m, and D90 < 180 mu m.

5. The method for preparing amlodipine besylate tablets according to claim 1, wherein the particle size of amlodipine besylate is D10 < 30 μm and D90 < 150 μm.

6. The method for preparing amlodipine besylate tablets according to claim 1, wherein the step (1) further comprises the steps of: and (3) sieving the mixed material A by a sieve of 100-120 meshes, sieving anhydrous calcium hydrophosphate by a sieve of 150-200 meshes, sieving microcrystalline cellulose by a sieve of 100-120 meshes, and sieving sodium carboxymethyl starch and magnesium stearate by a sieve of 80-100 meshes.

7. The preparation method of amlodipine besylate tablets according to claim 1, wherein the drying treatment in the step (2) is spray drying, and the temperature of an air inlet is controlled to be 80-100 ℃ in the spray drying process;

and (5) carrying out the mixing process in a three-dimensional motion mixer, controlling the rotating speed to be 10-15 r/min, and mixing for 15-30 min.

8. The method for preparing amlodipine besylate tablets according to claim 1, wherein the organic solvent in the step (2) is absolute ethanol; and (4) sieving fine powder by using a 60-mesh sieve in the step (4).

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