A method for preparing apatinib tablets

Abstract

The application belongs to the technical field of pharmaceutical preparations and relates to a preparation method of apaziquone tablets. The preparation method comprises the following steps: (1) preparing a solution containing apaziquone and hydroxypropyl methyl cellulose acetate succinate; (2) using part of microcrystalline cellulose as a substrate, one-step granulation is performed on the solution to obtain granules; (3) the granules are crushed to obtain fine granules; and (4) the fine granules, the remaining microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate are mixed and then compressed into a tablet core. According to the preparation method, on the basis of a selected prescription, a spray drying device or a hot melt extrusion device does not need to be introduced, dry granulation or drug particle size control does not need to be performed, one-step granulation is performed on a fluidized bed, the process is highly accessible, the cost is lower, and the product has a dissolution curve basically consistent with that of an original drug.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and specifically relates to a method for preparing apalutamide tablets. Background Technology

[0002] Apaltamethamide, chemical name: 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thio-5,7-diazaspiro[3,4]oct-5-yl]-2-fluoro-N-methylbenzamide; molecular formula: C 21 H 15 F4N5O2S; Molecular weight: 477.43; Chemical structural formula as follows:

[0003]

[0004] Apalutamide is practically insoluble in the pH range of 1-12. In the original chemistry review, apalutamide was classified as a BCS II drug. The original manufacturer used solid dispersion technology to improve the oral bioavailability of apalutamide. The solid dispersion technology used by the original manufacturer was spray drying or hot melt extrusion.

[0005] The original formulation patent (CN106999431B) uses dichloromethane / methanol or acetone as solvents and employs spray drying technology to prepare apaltadamine solid dispersions, with a solid content of approximately 5%, utilizing a large amount of organic solvents. Due to limitations of the spray drying process, increasing the solid content is difficult, and the spray-dried particles are relatively loose, requiring further addition of other excipients for dry granulation to obtain particles with better flowability before compression into tablets. The entire process cycle is lengthy, and the spray drying equipment requires supporting plant facilities, necessitating additional plant modifications; all costs (labor, materials, equipment, etc.) are high. The original formulation patent also mentions using hot-melt extrusion equipment to prepare solid dispersions. Apaltadamine has a high melting point of 194-196℃, which places higher demands on the performance of the hot-melt extruder. The hot-melt extruded solid dispersions are elongated strips, harden upon cooling, and possess strong toughness, making grinding and pulverization difficult. Furthermore, the dissolution rate cannot meet the dissolution standard after sieving through a 250μm sieve.

[0006] The following are currently published patent applications related to apalutamide tablets:

[0007] The invention patent application with publication number CN117838645A describes the preparation of apalutamide tablets using a hot-melt extrusion process. This process optimizes the particle size of the active pharmaceutical ingredient (API), carrier type, solid dispersion particle size, hot-melt process, and pulverization process. The hot-melt extrusion process requires strict control of the API particle size; otherwise, the quality of the solid dispersion prepared by hot-melt extrusion will be affected. Summary of the Invention

[0008] To address the shortcomings of existing technologies, this invention provides a novel method for preparing apalutamide tablets. This invention uses conventional excipient microcrystalline cellulose (e.g., microcrystalline cellulose 101) as a substrate and granulates the apalutamide-hydroxypropyl methylcellulose acetate succinate drug-containing system. It avoids spray drying and hot-melt extrusion, eliminates the need for particle size control of the active pharmaceutical ingredient, and allows for a solid content increase of 30-40% in the apalutamide-hydroxypropyl methylcellulose acetate succinate drug-containing system. This significantly reduces the use of organic solvents, shortens production time, and controls material and labor costs.

[0009] The present invention provides a method for preparing apalutamide tablets, wherein the tablet core comprises: 50-70 parts by weight of apalutamide, 160-200 parts by weight of hydroxypropyl methylcellulose acetate succinate, 400-420 parts by weight of microcrystalline cellulose, 30-40 parts by weight of croscarmellose sodium, 7-10 parts by weight of colloidal silica, and 2-5 parts by weight of magnesium stearate.

[0010] The preparation method includes the following steps:

[0011] (1) Prepare a solution containing apaltadamine and hydroxypropyl methylcellulose succinate;

[0012] (2) Using a portion of microcrystalline cellulose as a substrate, granulation was performed in one step using the above solution to obtain granules;

[0013] (3) Crush the above particles to obtain fine particles;

[0014] (4) The fine particles are mixed with the remaining microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, colloidal silica and magnesium stearate, and then pressed into a core.

[0015] Preferably, in step (1), the solvent of the solution is dichloromethane and methanol in a weight ratio of 1:1-2; the solid content of the solution (i.e., the weight of apatamide and hydroxypropyl methylcellulose acetate accounts for 30-40% of the weight of the solution) is 30-40%.

[0016] More preferably, in step (1), the solvent of the solution is dichloromethane and methanol in a weight ratio of 1:1.5; and the solid content of the solution is 33-37%.

[0017] Preferably, in step (2), the air inlet temperature is controlled at 60-75℃, the peristaltic pump speed is controlled at 6-25rpm, and the atomization pressure is controlled at 0.2-0.6Mpa.

[0018] More preferably, in step (2), during the one-step granulation, the inlet air temperature is controlled at 60-70℃, the peristaltic pump speed is controlled at 10-25rpm, and the atomization pressure is controlled at 0.2-0.6Mpa;

[0019] More preferably, in step (2), the air inlet temperature is controlled at 62-67°C, the peristaltic pump speed is controlled at 15-20 rpm, and the atomization pressure is controlled at 0.3-0.5 MPa.

[0020] Preferably, in step (2), the one-step granulation is carried out in a fluidized bed.

[0021] Preferably, in step (2), the mass of the partial microcrystalline cellulose is about 5-10% of the total mass.

[0022] More preferably, in step (2), the portion of microcrystalline cellulose is microcrystalline cellulose 101, which accounts for about 5-8% of the total mass.

[0023] Preferably, in step (3), the pulverizing speed is 3500-4500 rpm, the pulverizing times are 1-2 times, and the screen aperture is 0.3-0.5 mm.

[0024] More preferably, in step (3), the pulverizing speed is 4000-4500 rpm, the pulverizing time is 2 times, and the screen aperture is 0.3-0.4 mm.

[0025] Preferably, in step (3), the pulverization is carried out using a high-efficiency pulverizer.

[0026] Preferably, in step (4), the remaining microcrystalline cellulose accounts for about 90-95% of the total mass.

[0027] More preferably, in step (4), the remaining microcrystalline cellulose is microcrystalline cellulose 102, which accounts for about 92-95% of the total mass.

[0028] The microcrystalline cellulose 101 has a small particle size and a large specific surface area, making it easy for hydroxypropyl methylcellulose acetate succinate and apaltamethamide to spread and adhere to its surface, thus facilitating particle formation. The microcrystalline cellulose 102 has a large particle size and good flowability, which is beneficial for subsequent mixing and tableting, and will not cause uniformity problems.

[0029] Preferably, the core comprises: 55-65 parts by weight of apalutamide, 170-190 parts by weight of hydroxypropyl methylcellulose succinate, 405-420 parts by weight of microcrystalline cellulose, 32-38 parts by weight of croscarmellose sodium, 8-10 parts by weight of colloidal silica, and 3-5 parts by weight of magnesium stearate.

[0030] More preferably, the core comprises: 60 parts by weight of apaltadamine, 180 parts by weight of hydroxypropyl methylcellulose succinate, 412.4 parts by weight of microcrystalline cellulose, 35 parts by weight of croscarmellose sodium, 9.1 parts by weight of colloidal silica, and 3.5 parts by weight of magnesium stearate.

[0031] Preferably, the preparation method includes: step (5) coating the core with a thin film coating layer.

[0032] Preferably, the weight of the film coating layer is 1.5% to 5% of the weight of the tablet core; more preferably, the weight of the film coating layer is 3% of the weight of the tablet core.

[0033] Specifically, the preparation method includes the following steps:

[0034] (1) Disperse the active ingredient apaltamethasone in a mixed solvent of dichloromethane and methanol, clarify it, add hydroxypropyl methylcellulose succinate acetate, and stir until clear to obtain a solution;

[0035] (2) Microcrystalline cellulose 101 was placed in a fluidized bed as a substrate and granulated in one step using the above solution to obtain granules;

[0036] (3) The above particles are crushed using a universal pulverizer to obtain fine particles;

[0037] (4) After the above fine particles are mixed evenly with microcrystalline cellulose 102, cross-linked sodium carboxymethyl cellulose, colloidal silica and magnesium stearate, they are pressed into a core.

[0038] The apalutamide tablets prepared by the method of this invention, when tested using the detection method in the imported registration standard, exhibit a dissolution curve similar to that of the reference formulation.

[0039] The present invention has the following beneficial effects:

[0040] (1) No need to control the particle size of the active pharmaceutical ingredient.

[0041] (2) The process is relatively simple.

[0042] (3) The amount of solvent used is about 1 / 6 of that of the original drug, saving costs.

[0043] (4) The prepared apaltamethasone tablets have good dissolution stability.

[0044] The preparation method of the present invention, based on the selected formulation, does not require the introduction of spray drying equipment or hot melt extrusion equipment, nor does it require dry granulation or control of the particle size of the active pharmaceutical ingredient. It adopts one-step fluidized bed granulation, which has high process accessibility, lower cost, and the product has a dissolution curve that is basically consistent with the original drug. Attached Figure Description

[0045] Figure 1 The dissolution curves of apalutamide tablets and reference formulations prepared for the examples and comparative examples are shown.

[0046] Figure 2 Accelerated stability dissolution curve of apalutamide tablets prepared for the example. Detailed Implementation

[0047] To better understand and illustrate the present invention, the following illustrative description of the preparation method of apalutamide tablets provided by the present invention is given, but it should not be construed as a limitation on the content of the present invention.

[0048] The instruments used in the following examples mainly include: FBL experimental fluidized bed, GFSJ-8A high-efficiency granulator, BSL-25 mixer, ZP-10A tablet press, BGB-5F high-efficiency coating machine; RC806 dissolution apparatus, and Agilent 1260 high-performance liquid chromatograph.

[0049] Example 1

[0050] (1) The prescription is shown in Table 1:

[0051] Table 1 Prescription

[0052]

[0053] (2) Preparation method:

[0054] The active ingredient apaltamethasone was dispersed in a mixed solvent of dichloromethane and methanol. After clarification, hydroxypropyl methylcellulose succinate was added and stirred until clear to obtain a drug-containing polymeric carrier solution.

[0055] Microcrystalline cellulose 101 was placed in a fluidized bed, with the inlet air temperature controlled at 62-67℃, the peristaltic pump speed controlled at 15-20 rpm, and the atomization pressure controlled at 0.3-0.5 MPa. The above-mentioned drug-containing polymer carrier solution was sprayed into the fluidized bed for granulation.

[0056] Control the grinding speed (rotation speed) of the high-efficiency pulverizer to 4000-4500 rpm, screen aperture 0.4 mm, and grind twice.

[0057] The resulting fine particles are mixed evenly with cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose 102, colloidal silica, and magnesium stearate, and then pressed into a core.

[0058] After dispersing Opadry, it is coated with a film to achieve a 3% weight gain.

[0059] Comparative Example 1

[0060] (1) The prescription is shown in Table 2:

[0061] Table 2 Prescriptions

[0062]

[0063] (2) Preparation method:

[0064] Solid dispersions containing apaltamethamide and hydroxypropyl methylcellulose acetate succinate were prepared using a hot melt extrusion apparatus.

[0065] The above solid dispersion was pulverized using a high-efficiency pulverizer and passed through a 100-mesh sieve (sieve aperture approximately 150 μm).

[0066] The resulting granules are mixed evenly with cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose 102, colloidal silica, and magnesium stearate, and then pressed into a core sheet.

[0067] After dispersing Opadry, it is coated with a film to achieve a 3% weight gain.

[0068] Comparative Example 2

[0069] (1) The prescription is shown in Table 3:

[0070] Table 3 Prescriptions

[0071]

[0072] (2) Preparation method:

[0073] Apaltamethasone was pulverized to a D50 of 10 μm using an air jet mill.

[0074] Solid dispersions containing apaltamethamide and hydroxypropyl methylcellulose acetate succinate were prepared using a hot melt extrusion apparatus.

[0075] The above solid dispersion was pulverized using a high-efficiency pulverizer and passed through a 100-mesh sieve (sieve aperture approximately 150 μm).

[0076] The resulting granules are mixed evenly with cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose 102, colloidal silica, and magnesium stearate, and then pressed into a core sheet.

[0077] After dispersing Opadry, it is coated with a film to achieve a 3% weight gain.

[0078] Comparative Example 3

[0079] (1) The prescription is shown in Table 4:

[0080] Table 4 Prescriptions

[0081]

[0082] (2) Preparation method:

[0083] Hydroxypropyl methylcellulose succinate was pulverized using a high-efficiency pulverizer and then passed through an 80-mesh sieve (sieve aperture approximately 178 μm).

[0084] Apaltamethasone was pulverized to a D50 of 10 μm using an air jet mill.

[0085] Solid dispersions containing apaltamethamide and hydroxypropyl methylcellulose acetate succinate were prepared using a hot melt extrusion apparatus.

[0086] The above solid dispersion was pulverized using a high-efficiency pulverizer and passed through a 100-mesh sieve (sieve aperture approximately 150 μm).

[0087] The resulting granules are mixed evenly with cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose 102, colloidal silica, and magnesium stearate, and then pressed into a core sheet.

[0088] After dispersing Opadry, it is coated with a film to achieve a 3% weight gain.

[0089] Experimental Example 1: Dissolution Curve Determination

[0090] Dissolution profiles of tablets prepared in Examples 1, 1, 2, and 3 of this invention were analyzed (pH 4.5 + 0.25% SDS, paddle method at 75 rpm). The results are shown in [Figure number missing]. Figure 1 .

[0091] Figure 1 Dissolution results showed that the tablets prepared in Example 1 of this invention had a dissolution curve similar to the reference formulation (original drug); the dissolution curves of the tablets prepared in Comparative Examples 1, 2, and 3 were all slower than those of the reference formulation, and none achieved complete dissolution; the dissolution rate of the tablets prepared in Comparative Example 2 was faster than that of the tablets prepared in Comparative Example 1, indicating that controlling the particle size of the active pharmaceutical ingredient in the hot-melt extrusion process helps with product dissolution. The dissolution rate of the tablets prepared in Comparative Example 3 was faster than that of the tablets prepared in Comparative Example 2, indicating that controlling the particle size of the polymer carrier in the hot-melt extrusion process helps with product dissolution.

[0092] In summary, the hot melt extrusion process requires strict control of the particle size of the active pharmaceutical ingredient and the polymer carrier (hydroxypropyl methylcellulose acetate succinate).

[0093] Experimental Example 2: Dissolution Stability Study

[0094] The tablets prepared in Example 1 were subjected to accelerated stability testing. Dissolution profiles of the accelerated stability samples were analyzed (pH 4.5 + 0.25% SDS, paddle method at 75 rpm). The results are shown in [Figure Number]. Figure 2 .

[0095] Figure 2 The dissolution results show that the apaltamethasone tablets prepared in this invention have good stability.

[0096] The apalutamide tablets prepared by the method described in this invention have significantly reduced the amount of organic solvent used, do not require control of the particle size of the active pharmaceutical ingredient, and do not require control of the particle size of the polymer carrier (hydroxypropyl methylcellulose acetate succinate). The preparation process is relatively simple, and the prepared apalutamide tablets have a similar dissolution curve to the original drug. All key properties meet the import registration standards, and the tablets exhibit good stability.

[0097] Based on the above description of the invention, those skilled in the art can fully apply the present invention, and all similar modifications and principles used should be considered within the scope of the present invention.

Claims

1. A method for preparing apalutamide tablets, wherein the tablet core comprises: 50-70 parts by weight of apalutamide, 160-200 parts by weight of hydroxypropyl methylcellulose acetate succinate, 400-420 parts by weight of microcrystalline cellulose, 30-40 parts by weight of croscarmellose sodium, 7-10 parts by weight of colloidal silica, and 2-5 parts by weight of magnesium stearate; The preparation method includes the following steps: (1) Prepare a solution containing apaltadamine and hydroxypropyl methylcellulose succinate; (2) Using a portion of microcrystalline cellulose as a substrate, granulation was performed in one step using the above solution to obtain granules; (3) Crush the above particles to obtain fine particles; (4) The fine particles are mixed with the remaining microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, colloidal silica and magnesium stearate, and then pressed into a core.

2. The method for preparing apalutamide tablets according to claim 1, wherein, In step (1), the solvent of the solution is dichloromethane and methanol in a weight ratio of 1:1-2; the solid content of the solution is 30-40%. Preferably, in step (1), the solvent of the solution is dichloromethane and methanol in a weight ratio of 1:1.5; the solid content of the solution is 33-37%.

3. The method for preparing apalutamide tablets according to claim 1, wherein, In step (2), during the one-step granulation, the inlet air temperature is controlled at 60-75℃, the peristaltic pump speed is controlled at 6-25rpm, and the atomization pressure is controlled at 0.2-0.6Mpa. Preferably, in step (2), during the one-step granulation, the inlet air temperature is controlled at 60-70℃, the peristaltic pump speed is controlled at 10-25rpm, and the atomization pressure is controlled at 0.2-0.6Mpa; More preferably, in step (2), the air inlet temperature is controlled at 62-67°C, the peristaltic pump speed is controlled at 15-20 rpm, and the atomization pressure is controlled at 0.3-0.5 MPa.

4. The method for preparing apalutamide tablets according to claim 1, wherein, In step (2), the mass of the microcrystalline cellulose is approximately 5-10% of the total mass; Preferably, in step (2), the microcrystalline cellulose is microcrystalline cellulose 101, and its mass is about 5-8% of the total mass.

5. The method for preparing apalutamide tablets according to claim 1, wherein, In step (3), the pulverizing speed is 3500-4500 rpm, the pulverizing times are 1-2 times, and the screen aperture is 0.3-0.5 mm; Preferably, in step (3), the pulverizing speed is 4000-4500 rpm, the pulverizing time is 2 times, and the screen aperture is 0.3-0.4 mm.

6. The method for preparing apalutamide tablets according to claim 1, wherein, In step (4), the remaining microcrystalline cellulose accounts for approximately 90-95% of the total mass; Preferably, in step (4), the remaining microcrystalline cellulose is microcrystalline cellulose 102, which accounts for about 92-95% of the total mass.

7. The method for preparing apalutamide tablets according to claim 1, wherein, The core comprises: 55-65 parts by weight of apaltadamine, 170-190 parts by weight of hydroxypropyl methylcellulose acetate succinate, 405-420 parts by weight of microcrystalline cellulose, 32-38 parts by weight of croscarmellose sodium, 8-10 parts by weight of colloidal silica, and 3-5 parts by weight of magnesium stearate. Preferably, the core comprises: 60 parts by weight of apaltadamine, 180 parts by weight of hydroxypropyl methylcellulose succinate, 412.4 parts by weight of microcrystalline cellulose, 35 parts by weight of croscarmellose sodium, 9.1 parts by weight of colloidal silica, and 3.5 parts by weight of magnesium stearate.

8. The method for preparing apalutamide tablets according to claim 1 further comprises the following steps: (5) Coat the core film with a thin film coating.

9. The method for preparing apalutamide tablets according to claim 8, wherein, The weight of the film coating is 1.5% to 5% of the weight of the core. Preferably, the weight of the film coating is 3% of the weight of the core.

10. The method for preparing apalutamide tablets according to claim 1, comprising the following steps: (1) Disperse the active ingredient apaltamethasone in a mixed solvent of dichloromethane and methanol, clarify it, add hydroxypropyl methylcellulose succinate acetate, and stir until clear to obtain a solution; (2) Microcrystalline cellulose 101 was placed in a fluidized bed as a substrate and granulated in one step using the above solution to obtain granules; (3) The above particles are crushed using a universal pulverizer to obtain fine particles; (4) After the above fine particles are mixed evenly with microcrystalline cellulose 102, cross-linked sodium carboxymethyl cellulose, colloidal silica and magnesium stearate, they are pressed into a core.

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