Dry granulation process for briracetam
Through the premixture of briocetam with disintegrant, binder and diluent and the dry granulation process, the preparation difficulties caused by briocetam viscous are solved, and the effect of simplifying the process, improving efficiency and reducing costs is achieved.
Patent Information
- Application Number
- CN202510097062.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-22
- Publication Date
- 2025-04-08
AI Technical Summary
The raw materials of bulicetam have a high viscosity, which affects the preparation process, is difficult to tablet, and the existing technology is complex, requiring additional glidants.
The tablets are prepared by premixing briocetam, disintegrant, binder and diluent by premixing the briocetam, the disintegrant is avoided and the process flow is simplified.
The problem of adhesion-free has been solved, the equipment requirements are not high, the premix time is short, the efficiency is high, the tablet content is stable, the cost is low, and it is suitable for large-scale production.
Smart Images
Figure BDA0005253137330000041 
Figure BDA0005253137330000051 
Figure BDA0005253137330000052
Abstract
Description
Technical Field
[0001] The present application relates to a process for dry granulation of brivaracetam, belonging to the technical field of dry granulation. Background Art
[0002] Brivaracetam is a new third-generation anti-epileptic drug with few side effects and little interaction with other anti-epileptic drugs. However, the brivaracetam raw material has high viscosity, which affects the preparation process and makes tableting difficult.
[0003] Chinese Patent 2020109892071 provides a method for improving adhesion during the preparation of brivaracetam tablets, by mixing brivaracetam and a glidant, sieving the mixture, and then mixing the mixture with a disintegrant, a filler, etc., and dry granulating the mixture. In this process, a glidant is used to treat brivaracetam to disperse the brivaracetam and reduce adhesion, and the process is complicated. Summary of the invention
[0004] According to one aspect of the present application, a process for dry granulation of brivaracetam is provided, which does not require the use of additional glidants to treat brivaracetam, has no adhesion problems during the preparation process, has low requirements on equipment, has a short premixing time, is highly efficient, has stable tablet content, and is low in cost, and can be mass-produced.
[0005] The process for dry granulation of brivaracetam described in the present application comprises the following steps:
[0006] (1) premixing brivaracetam, disintegrant I, binder and diluent I to obtain a premixed powder;
[0007] (2) placing the premixed powder in a feeder of a dry granulator for dry granulation;
[0008] (3) After dry granulation, disintegrant II, lubricant and diluent II are added and mixed;
[0009] (4) tableting;
[0010] (5) coating;
[0011] In step (1), the premixing conditions are: rotation speed 5-15 rpm, time 8-12 min.
[0012] Optionally, in step (1), the mixing conditions are: rotation speed is 10 rpm; time is 10 min.
[0013] Optionally, during dry granulation, the feeding rate is 5-6 rpm.
[0014] Optionally, during dry granulation, the granulation pressure is 0.7-1.5 MPa.
[0015] Optionally, during dry granulation, the granulation pressure is 0.7-1.0 MPa.
[0016] Optionally, during dry granulation, the granulation pressure is 1-1.5 MPa.
[0017] Optionally, during dry granulation, the granulation pressure is independently selected from any value of 0.7 MPa, 1 MPa, 1.2 MPa, 1.5 MPa, or a range between any two of the above values.
[0018] Optionally, during dry granulation, the roller speed is 10-15 rpm.
[0019] Optionally, during dry granulation, the roller speed is 12.3 rpm.
[0020] Optionally, the binder is cyclodextrin; preferably, the cyclodextrin is β-cyclodextrin.
[0021] Optionally, the binder accounts for 4-6wt% of the total materials; the total materials include: brivaracetam, disintegrant I, binder, diluent I, diluent II, disintegrant II and lubricant.
[0022] Optionally, the binder accounts for 5wt% of the total materials; the total materials include: brivaracetam, disintegrant I, binder, diluent I, diluent II, disintegrant II and lubricant.
[0023] Optionally, the disintegrant I is cross-linked sodium carboxymethyl cellulose.
[0024] Optionally, the disintegrant I accounts for 1.5-2.5wt% of the total materials; the total materials include: brivaracetam, disintegrant I, binder, diluent I, diluent II, disintegrant II and lubricant.
[0025] Preferably, the disintegrant I accounts for 2 wt% of the total materials; the total materials include: brivaracetam, disintegrant I, binder, diluent I, diluent II, disintegrant II and lubricant.
[0026] Optionally, the disintegrant II is cross-linked sodium carboxymethyl cellulose.
[0027] Optionally, the disintegrant II accounts for 1.5-2.5wt% of the total materials; the total materials include: brivaracetam, disintegrant I, binder, diluent I, diluent II, disintegrant II and lubricant.
[0028] Preferably, the disintegrant II accounts for 1.8 wt% of the total materials; the total materials include: brivaracetam, disintegrant I, binder, diluent I, diluent II, disintegrant II and lubricant.
[0029] Optionally, the lubricant is magnesium stearate.
[0030] Optionally, the lubricant accounts for 0.5-1.5wt% of the total materials; the total materials include: brivaracetam, disintegrant I, binder, diluent I, diluent II, disintegrant II and lubricant.
[0031] Preferably, the lubricant accounts for 1.2 wt% of the total materials; the total materials include: brivaracetam, disintegrant I, binder, diluent I, diluent II, disintegrant II and lubricant.
[0032] Optionally, the brivaracetam accounts for 15-20wt% of the total materials; the total materials include: brivaracetam, disintegrant I, binder, diluent I, diluent II, disintegrant II and lubricant.
[0033] Preferably, the brivaracetam accounts for 18 wt% of the total materials; the total materials include: brivaracetam, disintegrant I, binder, diluent I, diluent II, disintegrant II and lubricant.
[0034] Optionally, the diluent I is lactose monohydrate and anhydrous lactose.
[0035] Optionally, in the diluent I, the mass ratio of lactose monohydrate to anhydrous lactose is 1:(1-2); preferably, in the diluent I, the mass ratio of lactose monohydrate to anhydrous lactose is 1:1.5.
[0036] Optionally, the diluent II is anhydrous lactose.
[0037] Optionally, the mass ratio of the total amount of anhydrous lactose to lactose monohydrate is (2.5-4.5):1;
[0038] The total amount of anhydrous lactose includes the mass of anhydrous lactose in diluent I and the mass of anhydrous lactose in diluent II.
[0039] Preferably, the mass ratio of the total amount of anhydrous lactose to lactose monohydrate is 3:1;
[0040] The total amount of anhydrous lactose includes the mass of anhydrous lactose in diluent I and the mass of anhydrous lactose in diluent II.
[0041] The beneficial effects of this application include:
[0042] 1. In the present application, brivaracetam, a binder, a disintegrant I and a diluent I are first mixed, and the diluent I is controlled to be lactose monohydrate and lactose anhydrous, and the mass ratio between the two is 1: (1-2); at this time, a relatively uniform mixture can be mixed at a lower speed and a shorter mixing time, while in the prior art, it takes 20 minutes to mix evenly. In addition, the inventors found that when the binder is β-cyclodextrin, the mass ratio of lactose monohydrate and lactose anhydrous in the diluent I is controlled, and there is no astringency problem during the granulation process.
[0043] 2. The inventor found in the study that when the granulation pressure is 0.7-1.5Mpa, the appearance, hardness and disintegration time can meet the requirements, and when the granulation pressure is 1-1.5Mpa, the particle size distribution of the total mixed powder is significantly improved, the fluidity is improved, and the tablet compressibility is good. However, when the inventor conducted the content test, he found that the tablet content was low. The inventor adjusted the speed of the roller, and the problem of low tablet content has not been significantly improved. After research, the inventor adjusted the granulation pressure. When the granulation pressure was 0.7-1.0Mpa and the roller speed was 12.3rpm, the tablet content was effectively solved.
[0044] In the present application, the inventors reduced the granulation pressure, controlled the roller speed and increased the tablet content without significantly reducing the fluidity and affecting other properties of the tablet.
[0045] 3. The process of the present application is simple and easy to operate. No additional flow aid is required to treat brivaracetam. No adhesion problem occurs during the preparation process using the process of the present application. The equipment requirements are not high, the cost is low, and large-scale production is possible. The brivaracetam tablets obtained using the process of the present application have stable quality and meet the requirements. DETAILED DESCRIPTION
[0046] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.
[0047] Unless otherwise specified, the raw materials in the examples of this application were purchased through commercial channels.
[0048] Example 1
[0049] The process of dry granulation of 3000 tablets of Brivaracetam is as follows:
[0050] (1) Brivaracetam was passed through a 60-mesh sieve, and then 18 wt% of brivaracetam, 2 wt% of disintegrant I (cross-linked carboxymethyl cellulose sodium), 5 wt% of binder (β-cyclodextrin), and 41.2 wt% of diluent I (lactose monohydrate and lactose anhydrous, mass ratio of 1:1) were premixed (10 rpm, 10 min) to obtain a premixed powder;
[0051] (2) placing the premixed powder in the feeder of a dry granulator and dry granulating the powder (feeding rate 5 rpm, granulation pressure 0.7-1.0 MPa, roller speed 12.3 rpm);
[0052] (3) adding 1.8 wt % of disintegrant II (crosslinked sodium carboxymethyl cellulose), 30.8 wt % of diluent II (anhydrous lactose) and 1.2 wt % of lubricant (magnesium stearate) to the mixture obtained in step (2) and mixing to obtain a total mixed powder;
[0053] (4) tableting;
[0054] (5) Coating.
[0055] The mixing uniformity of the premixed powder is shown in Table 1 below.
[0056] Table 1
[0057]
[0058]
[0059] Example 2
[0060] The process of dry granulation of brivaracetam is specifically the same as that of Example 1, except that the diluent I includes lactose monohydrate and anhydrous lactose in a mass ratio of 1:2; and the feeding rate is 6 rpm.
[0061] Example 3
[0062] The preparation process is the same as that of Example 1, except that the granulation pressure is 1-1.5 MPa.
[0063] The intermediate products of Example 1 and Example 3 were tested, and the test results are shown in Table 2 below.
[0064] Table 2
[0065]
[0066]
[0067] When the granulation pressure is 1-1.5Mpa, the particle size distribution of the total mixed powder is significantly improved, the fluidity is improved, and the tablet compressibility is good.
[0068] Example 4
[0069] The preparation process is the same as that of Example 1, except that the granulation pressure is 1-1.5 MPa and the roller speed is 8.0 rpm.
[0070] The test results of the uniformity of the total mixed powder content of Example 1 and Example 2 are shown in Table 3 below.
[0071] Table 3
[0072]
[0073]
[0074] The results of the uniformity test of the tablets of Example 1 are shown in Table 4 below.
[0075] Table 4
[0076]
[0077] The results of the uniformity test of the tablets of Example 4 are shown in Table 5 below.
[0078] Table 5
[0079]
[0080] Example 5
[0081] The preparation process is the same as that in Example 1, except that the speed of the pressing roller is 20 rpm.
[0082] The content uniformity test results of the tablets of Example 5 are shown in Table 6 below.
[0083] Table 6
[0084]
[0085]
[0086] Example 6
[0087] The preparation process is the same as that of Example 1, except that the diluent I is lactose monohydrate.
[0088] The problem of astringency occurs during the preparation process.
[0089] The above are only a few embodiments of the present application and do not constitute any form of limitation to the present application. Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the present application. Any technician familiar with the profession, without departing from the scope of the technical solution of the present application, using the technical content disclosed above to make slight changes or modifications are equivalent to equivalent implementation cases and fall within the scope of the technical solution.
Claims
1. A process for dry granulation of brivaracetam, characterized in that: The following steps are included: (1) premixing brivaracetam, disintegrant I, binder and diluent I to obtain a premixed powder; (2) placing the premixed powder in a feeder of a dry granulator for dry granulation; (3) After dry granulation, disintegrant II, diluent II and lubricant are added and mixed; (4) tableting; (5) coating; In step (1), the premixing conditions are: rotation speed 5-15 rpm, time 8-12 min.
2. The process for dry granulation of brivaracetam according to claim 1, characterized in that: During dry granulation, the feeding rate is 5-6 rpm.
3. The process for dry granulation of brivaracetam according to claim 1, characterized in that: During dry granulation, the granulation pressure is 0.7-1.5Mpa.
4. The process for dry granulation of brivaracetam according to claim 3, characterized in that: During dry granulation, the granulation pressure is 0.7-1.0Mpa.
5. The process for dry granulation of brivaracetam according to claim 1, characterized in that: During dry granulation, the roller speed is 10-15 rpm.
6. The process for dry granulation of brivaracetam according to claim 1, characterized in that: The binder is cyclodextrin.
7. The process for dry granulation of brivaracetam according to claim 1, characterized in that: The disintegrant I and disintegrant II are independently cross-linked sodium carboxymethyl cellulose.
8. The process for dry granulation of brivaracetam according to claim 1, characterized in that: The diluent I is lactose monohydrate and anhydrous lactose.
9. The process for dry granulation of brivaracetam according to claim 8, characterized in that: In the diluent I, the mass ratio of lactose monohydrate to anhydrous lactose is 1:(1-2).
10. The process for dry granulation of brivaracetam according to claim 1, characterized in that: The diluent II is anhydrous lactose.