A method for preparing a brivaracetam solution and a brivaracetam solution

Abstract

The present application discloses a method for preparing a brivaracetam solution and the brivaracetam solution thereof, belonging to the field of medical technology. The method for preparing the brivaracetam solution comprises the following steps: (1) preparing solution 1: mixing a mixture including sodium carboxymethylcellulose and glycerol with purified water and stirring to obtain solution 1; (2) preparing solution 2: mixing purified water, methylparaben, sodium malate, malic acid, sucralose, crystalline sorbitol solution, brivaracetam, and glycerol and stirring to obtain an intermediate solution, mixing the intermediate solution with essence and stirring to obtain solution 2; (3) mixing solution 1, solution 2 and purified water, stirring, and filtering to obtain a brivaracetam solution. The method improves the clarity of the solution by controlling the order and temperature of addition of each auxiliary material, and the obtained brivaracetam solution has good stability and is free of precipitation and degradation impurities.

Description

Technical Field

[0001] The present application relates to a preparation method of a brivaracetam solution and the brivaracetam solution thereof, belonging to the field of medical technology. Background Art

[0002] Brivaracetam is a third-generation antiepileptic drug and a structural analog of the antiepileptic drug levetiracetam. As a third-generation AED, it has a unique mechanism of action compared to previous AEDs, significantly enhancing its antiepileptic activity through high affinity for SV2A (synaptic vesicle protein 2A) and sodium channel inhibition. Brivaracetam oral solution is a convenient liquid formulation indicated as an adjunctive treatment for partial-onset seizures in patients 16 years of age and older with epilepsy.

[0003] The preparation of brivaracetam solutions inevitably involves the use of excipients that have poor solubility in water and tend to precipitate over time. Furthermore, aqueous solutions of brivaracetam are unstable, prone to degradation and impurities, and exhibit poor stability. Summary of the Invention

[0004] According to one aspect of the present application, a method for preparing a brivaracetam solution is provided. The method improves the clarity of the solution by controlling the order and temperature of addition of each excipient. The obtained brivaracetam solution has good stability and is free of precipitation and degradation impurities.

[0005] The preparation method of the brivaracetam solution described in the present application comprises the following steps:

[0006] (1) Preparation of Solution 1: A mixture comprising sodium carboxymethylcellulose and glycerol I is mixed with purified water I and stirred to obtain Solution 1;

[0007] (2) Preparation of Solution 2: Purified water II, methylparaben, sodium malate, malic acid, sucralose, crystalline sorbitol solution, brivaracetam, and glycerol II were mixed and stirred to obtain an intermediate solution. The intermediate solution and flavor were mixed and stirred to obtain Solution 2;

[0008] (3) Solution 1, solution 2 and purified water III are mixed, stirred, and filtered to obtain a brivaracetam solution.

[0009] Optionally, the step (1) comprises: mixing sodium carboxymethyl cellulose and glycerol I, stirring I, then adding purified water I, and stirring II.

[0010] Optionally, in step (1), the stirring time of I is 25-35 min; preferably, in step (1), the stirring time of I is 30 min.

[0011] Optionally, in step (1), the stirring time of II is 10-20 min; preferably, the stirring time of II in step (1) is 15 min.

[0012] Optionally, the preparation temperature of the (1) solution 1 is 20-30°C.

[0013] Optionally, in step (1), the weight ratio of sodium carboxymethyl cellulose to glycerol I is 1:(15-18); preferably, in step (1), the weight ratio of sodium carboxymethyl cellulose to glycerol I is 1:16.5.

[0014] Optionally, in step (1), the weight ratio of sodium carboxymethyl cellulose to purified water I is 1:(8-12); preferably, in step (1), the weight ratio of sodium carboxymethyl cellulose to purified water I is 1:10.

[0015] Optionally, in step (2), the preparation temperature of the intermediate solution is 70-80°C; preferably, in step (2), the preparation temperature of the intermediate solution is 75°C.

[0016] Optionally, in step (2), the temperature at which the intermediate solution and the essence are mixed is 20-30°C; preferably, in step (2), the temperature at which the intermediate solution and the essence are mixed is 25°C.

[0017] Optionally, in step (2), the weight ratio of purified water II, methylparaben, and sucralose is (290-375):1:40; preferably, in step (2), the weight ratio of purified water II, methylparaben, and sucralose is 330:1:40.

[0018] Optionally, in the step (2), the weight ratio of the crystalline sorbitol solution, brivaracetam, glycerol II and methylparaben is (15-18):1:(6-8):0.1; wherein the crystalline sorbitol solution is calculated based on the sorbitol content; preferably, in the step (2), the weight ratio of the crystalline sorbitol solution, brivaracetam, glycerol II and methylparaben is 16.8:1:7:0.1, wherein the crystalline sorbitol solution is calculated based on the sorbitol content.

[0019] Optionally, in step (2), the weight ratio of the essence to brivaracetam is (0.5-0.6):1; preferably, in step (2), the weight ratio of the essence to brivaracetam is 0.53:1.

[0020] In the present application, sodium malate and malic acid are used to adjust the pH of the solution so that the pH of the final oral solution is 5.4.

[0021] Optionally, in step (3), the stirring time is 2-3 hours; preferably, in step (3), the stirring time is 2 hours.

[0022] Optionally, in step (3), the pore size of the filtration is 250-350 mesh; preferably, in step (3), the pore size of the filtration is 300 mesh.

[0023] Optionally, in step (3), the weight ratio of purified water III to brivaracetam is (34-36):1; preferably, in step (3), the weight ratio of purified water III to brivaracetam is 35:1.

[0024] Optionally, the weight ratio of sodium carboxymethyl cellulose to brivaracetam is 1:(1.5-2.5); preferably, the weight ratio of sodium carboxymethyl cellulose to brivaracetam is 1:2.

[0025] In another aspect, the present application provides a brivaracetam solution prepared by the preparation method of the brivaracetam solution.

[0026] The beneficial effects of this application include:

[0027] 1. The present application pre-disperses sodium carboxymethyl cellulose in a specified amount of glycerol at 20-30° C. and then mixes it with a specified amount of purified water, thereby improving the clarity of the brivaracetam solution to a clarity of less than 0.5. While reducing the dissolution time, the destruction of the sodium carboxymethyl cellulose structure is avoided.

[0028] 2. In the present application, sodium carboxymethyl cellulose and glycerol are first mixed and dispersed, then mixed with purified water, and then mixed and stirred with solution 2. After this process, the dissolution process of carboxymethyl cellulose promotes the dissolution compatibility between the various excipients and avoids the generation of precipitation caused by the solubility of the excipients.

[0029] 3. the application is in advance mixed dispersion of sodium carboxymethylcellulose and glycerol at 20-30 DEG C, then mixed with purified water, obtain solution 1, then methylparaben, purified water, glycerol etc. are mixed, obtain solution 2, solution 1 and solution 2 are mixed, this kind of technique, solves the dissolution problem of sodium carboxymethylcellulose and methylparaben, improves the stability of oral liquid, it may be that sodium carboxymethylcellulose is present in glycerol with minimum microparticle, by later stage adding purified water, makes carboxymethylcellulose microparticle rapidly contact water molecule and disperse, when later stage solution 1 and solution 2 are mixed, promote the dispersion of materials such as methylparaben on the contrary. In addition, the method simplifies production process, does not need to carry out dissolution treatment such as glycerol to methylparaben separately, and methylparaben stability is high in the oral liquid obtained.

[0030] 4. The present application controls the addition ratio of purified water, methylparaben, and glycerol in step (2), thereby further improving the solubility of methylparaben in the brivaracetam solution and reducing the dissolution time of methylparaben.

[0031] 5. The process of this application solves the problem of easy degradation and impurity generation of brivaracetam aqueous solution and has high stability.

[0032] 6. This application uses a 250-350 mesh filter membrane to filter the brivaracetam solution intermediate, and the filtration is smooth and there is no clogging. DETAILED DESCRIPTION

[0033] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.

[0034] Unless otherwise specified, the raw materials in the examples of this application were purchased through commercial channels.

[0035] Example 1

[0036] Example 1 provides a method for preparing the brivaracetam solution, which is as follows:

[0037] (1) Preparation of solution 1: Mix sodium carboxymethyl cellulose and glycerol I at 25°C, stir for 30 minutes, then add purified water I and stir for 15 minutes;

[0038] (2) Preparation of Solution 2: Mix purified water II, methylparaben, sodium malate, malic acid, sucralose, crystalline sorbitol solution, brivaracetam, and glycerol II at 75°C and stir until completely dissolved; when cooled to 25°C, add the flavoring and stir until completely dissolved.

[0039] (3) Solution 1, solution 2 and purified water III were mixed, stirred for 2 h, and filtered (300 mesh).

[0040] In step (1), the added amounts of sodium carboxymethyl cellulose, glycerol I, and purified water I are 1:16.5:10.

[0041] In step (2), the weight ratio of purified water II, methylparaben, and sucralose is 330:1:40; the weight ratio of crystalline sorbitol solution, brivaracetam, glycerol II, and methylparaben is 16.8:1:7:0.1, wherein the crystalline sorbitol solution is calculated based on the sorbitol content. The weight ratio of flavor to brivaracetam is 0.53:1.

[0042] Sodium malate and malic acid were used to adjust the pH of the final oral solution to 5.4.

[0043] In step (3), the weight ratio of purified water III to brivaracetam is 35:1.

[0044] In this embodiment, the amount of brivaracetam added is 10 g, and the amount of sodium carboxymethyl cellulose added is 5 g.

[0045] Comparative Example 1

[0046] Comparative Example 1 provides a method for preparing the brivaracetam solution, which is as follows:

[0047] 75 ℃, add 365g purified water, 1g methylparaben, sodium malate, malic acid, 5g sodium carboxymethyl cellulose, 40g sucralose in sequence, stir for 47min, stop heating and add 168g non-crystallized sorbitol solution (calculated as sorbitol), 10g brivaracetam, 152.5g glycerin in sequence, stir, add 5.3g flavor after cooling to 25 ℃, then add 365g purified water, stir, and filter through a 300 mesh sieve.

[0048] The addition amount of each substance in Comparative Example 1 is the same as that in Example 1, and the addition amount of each material is the total amount of the corresponding substance added in Example 1. Sodium malate and malic acid are used to adjust the pH of the final oral solution to 5.4.

[0049] The solution obtained by this preparation method has poor clarity, with a clarity exceeding 0.5. The inventors speculate that the reason is that the structure of sodium carboxymethyl cellulose is destroyed. However, the preparation process of Example 1 of the present application obtains a solution with a clarity of less than 0.5, which solves the problem of destruction of the structure of sodium carboxymethyl cellulose and reduces the dissolution time.

[0050] Comparative Example 2

[0051] A preparation method of brivaracetam solution is as follows:

[0052] (1) Preparation of solution 1: At 25°C, mix 5 g of sodium carboxymethyl cellulose and 70 g of glycerol, stir for 30 min, then add 62.5 g of purified water and stir for 15 min;

[0053] (2) Preparation of Solution 2: Mix 317.5 g of purified water, 82.5 g of glycerin, 1 g of methylparaben, sodium malate, malic acid, 40 g of sucralose, 168 g of crystalline sorbitol solution (calculated as sorbitol), and 10 g of brivaracetam at 75°C and stir until completely dissolved; when the temperature drops to 25°C, add 5.3 g of flavor and stir until completely dissolved.

[0054] (3) Solution 1, solution 2 and 350 g of purified water were mixed, stirred for 2 h, and filtered through a 300-mesh sieve.

[0055] Sodium malate and malic acid were used to adjust the pH of the final oral solution to 5.4.

[0056] The clarity of the brivaracetam oral solution obtained by this preparation method is poor, with a clarity greater than 0.5. The inventors speculate that this is caused by incomplete dissolution of sodium carboxymethylcellulose and methylparaben. This proves that under the temperature and operating conditions determined in this application, the preparation process of Comparative Example 2 cannot meet the requirements.

[0057] Comparative Example 3

[0058] Comparative Example 3 provides a method for preparing the brivaracetam solution, which is as follows:

[0059] (1) Preparation of solution 1: Mix 5 g of sodium carboxymethyl cellulose and 95 g of glycerol at 25°C, stir for 30 min, then add 37.5 g of purified water and stir for 15 min;

[0060] (2) Preparation of Solution 2: Mix 342.5 g of purified water, 1 g of methylparaben, sodium malate, malic acid, 40 g of sucralose, 168 g of crystalline sorbitol solution (calculated as sorbitol), 10 g of brivaracetam, and 57.5 g of glycerin at 75°C and stir until completely dissolved; when the temperature drops to 25°C, add 5.3 g of flavor and stir until completely dissolved.

[0061] (3) Solution 1, solution 2 and 350 g of purified water were mixed, stirred for 2 h, and filtered through a 300-mesh sieve.

[0062] Sodium malate and malic acid were used to adjust the pH of the final oral solution to 5.4.

[0063] The brivaracetam oral solution obtained by this preparation method has poor clarity, with a clarity greater than 0.5. After being placed for a period of time, there is a slight sediment at the bottom. The inventors speculate that this is due to the poor compatibility between the various excipients.

[0064] Comparative Example 4

[0065] Comparative Example 4 provides a method for preparing a brivaracetam solution, and the specific implementation method is the same as that of Example 1, except that, step (1): preparation of solution 1: sodium carboxymethyl cellulose, glycerol, and purified water are mixed at 25° C. and stirred for 45 min.

[0066] The brivaracetam oral liquid obtained by the preparation method has extremely poor clarity, and after being left for a period of time, obvious precipitation is formed at the bottom.

[0067] Comparative Examples 2 to 4 demonstrate that the present application requires that sodium carboxymethyl cellulose and a specified content of glycerol be first mixed, and then mixed with a specified content of purified water. At the same time, a specified content of glycerol is added during the preparation of solution 2, which solves the solubility problem of sodium carboxymethyl cellulose and methylparaben and improves the stability of the oral solution. This may be because sodium carboxymethyl cellulose is present in glycerol as extremely small particles. By adding purified water later, the carboxymethyl cellulose particles quickly contact water molecules and disperse, and when solution 1 and solution 2 are mixed later, the dispersion of materials such as methylparaben is promoted.

[0068] Comparative Example 5

[0069] Comparative Example 5 provides a method for preparing a brivaracetam solution, which is as follows:

[0070] (1) Preparation of solution 1: Mix 5 g of sodium carboxymethyl cellulose and 50 g of purified water at 25°C and stir for 45 min.

[0071] (2) Preparation of Solution 2: Mix 330 g of purified water, 1 g of methylparaben, sodium malate, malic acid, 40 g of sucralose, 168 g of crystalline sorbitol solution (calculated as sorbitol), 10 g of brivaracetam, and 152.5 g of glycerin at 75°C and stir until completely dissolved; when the temperature drops to 25°C, add 5.3 g of flavor and stir until completely dissolved.

[0072] (3) Solution 1, solution 2 and 350 g of pure water were mixed, stirred for 2 h, and filtered (300 mesh).

[0073] The clarity of the solution obtained by this method is still poor, with a clarity exceeding 0.5.

[0074] Comparative Example 6

[0075] Comparative Example 6 provides a method for preparing the brivaracetam solution, and its specific implementation method is the same as that of Example 1, except that the filtration pore size is different, as shown in Table 1.

[0076] Table 1

[0077]

[0078] From the test results in Table 1, it can be seen that the brivaracetam solution intermediate is subject to filtration risks when filtered through 1250-mesh, 625-mesh and 500-mesh filter membranes.

[0079] The stability of the brivaracetam solution obtained in Example 1 was tested under the following conditions: 60°C, naked exposure (5000 lx), and accelerated exposure (40°C / 75% RH). The test results are shown in Table 2. Methylparaben was determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0512).

[0080] Table 2

[0081]

[0082]

[0083] The test results of reference preparation batch 350156 are shown in Tables 3 and 4.

[0084] Table 3

[0085]

[0086] Table 4

[0087]

[0088] As can be seen from Table 2 to Table 4, the preparation method of the present application has good stability under the premise of simplifying the operation process, and solves the dissolution problem of hydroxybenzyl and sodium carboxymethyl cellulose.

[0089] The brivaracetam solution prepared in Example 1 was detected for related substances, and the test conditions were as follows: mobile phase A: 0.1% phosphoric acid aqueous solution; mobile phase B: acetonitrile, chromatographic column: Waters XBridge C18; detection wavelength was 210 nm; flow rate of mobile phase was 1.0 ml / min; column temperature was 40°C; elution gradient was as follows:

[0090]

[0091]

[0092] The test results are shown in Table 5.

[0093] Table 5

[0094]

[0095] Impurity A: (R)-2-((R)-2-oxo-4-propylpyrrolidin-1-yl)butyramide; the structure is as follows:

[0096]

[0097] Impurity B: (S)-2-((S)-2-oxo-4-propylpyrrolidin-1-yl)butyramide; the structure is as follows:

[0098]

[0099] Impurity C: (R)-2-((S)-2-oxo-4-propylpyrrolidin-1-yl)butyramide; the structure is as follows:

[0100]

[0101] Impurity E: (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butyric acid; the structure is as follows:

[0102]

[0103] The above descriptions are merely a few embodiments of the present application and do not constitute any form of limitation to the present application. Although the present application discloses the preferred embodiments as above, they are not intended to limit the present application. Any technical personnel familiar with the present 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 method for preparing a brivaracetam solution, characterized in that: The following steps are included: (1) Preparation of solution 1: Mix sodium carboxymethyl cellulose and glycerol I at 25°C, stir for 30 minutes, then add purified water I and stir for 15 minutes; (2) Preparation of Solution 2: Mix purified water II, methylparaben, sodium malate, malic acid, sucralose, crystalline sorbitol solution, brivaracetam, and glycerol II at 75°C and stir until completely dissolved; when cooled to 25°C, add the flavoring and stir until completely dissolved; (3) Solution 1, solution 2, and purified water III were mixed, stirred for 2 h, and filtered to obtain a brivaracetam solution; In step (1), the addition amount of sodium carboxymethyl cellulose, glycerol I, and purified water I is 1:16.5:10; In step (2), the weight ratio of purified water II, methylparaben, and sucralose is 330:1:40; the weight ratio of crystalline sorbitol solution, brivaracetam, glycerol II, and methylparaben is 16.8:1:7:0.1; the crystalline sorbitol solution is calculated based on sorbitol content; the weight ratio of flavor and brivaracetam is 0.53:1; Sodium malate and malic acid were used to adjust the pH of the final oral solution to 5.4; In step (3), the weight ratio of purified water III to brivaracetam is 35:1; The amount of brivaracetam added is 10 g, and the amount of sodium carboxymethyl cellulose added is 5 g.

2. The method for preparing the brivaracetam solution according to claim 1, characterized in that: In the step (3), the pore size of the filtration is 250-350 mesh.

3. A brivaracetam solution prepared according to the preparation method of the brivaracetam solution according to any one of claims 1 to 2.

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