CN116120200A - Vigabatrin bulk drug, vigabatrin solid composition and preparation method thereof - Google Patents

Abstract

The invention provides a vigabatrin bulk drug and a preparation method thereof, and a vigabatrin solid composition and a preparation method thereof, wherein the particle size D90 of the vigabatrin bulk drug is 200-460 mu m, and the vigabatrin solid composition is needle-shaped. The vigabatrin crude drug is easy to form, and the vigabatrin solid composition prepared by using the vigabatrin crude drug is good in dispersibility and small in loading difference; the preparation method is simple to operate, high in yield and suitable for industrial production.

Description

Vigabatrin raw material drug, vigabatrin solid composition and preparation method thereof

technical field

The present invention relates to the field of medicine. Specifically, the present invention relates to a vigabatrin raw material drug, a vigabatrin solid composition and a preparation method thereof.

Background technique

The chemical name of Vigabatrin is 4-amino-5-hexenoic acid, the molecular formula is C ₆ H ₁₁ NO ₂ , and the molecular weight is 129.157. It is an analog of γ-aminobutyric acid (GABA), which can specifically It binds to GABA aminotransferase irreversibly, leading to an increase in the concentration of GABA in the brain, thereby exerting an antiepileptic effect. Vigabatrin can be used as an adjuvant therapy in patients who have not responded to other antiepileptic drugs, especially in patients with partial seizures (mainly for the control of complex partial seizures), and in West syndrome (infantile spasms) in babies. As an adjuvant drug, vigabatrin can obtain better curative effect. When used alone, it is effective in the treatment of newly diagnosed patients.

Currently, vigabatrin has only two dosage forms, oral tablets and powders. The existing technology for preparing vigabatrin raw material medicine has problems such as uneven particle size of the prepared vigabatrin, and further problems such as poor fluidity and large difference in loading amount in the preparation of vigabatrin powder.

Therefore, the current solid composition of vigabatrin and its preparation method still need to be studied.

Contents of the invention

The present invention aims to solve at least one of the technical problems existing in the prior art at least to a certain extent. For this reason, the present invention proposes a vigabatrin bulk drug and a preparation method thereof, a vigabatrin solid composition and a preparation method thereof, the vigabatrin bulk drug is easy to form, and the vigabatrin made from it The solid composition has good dispersibility and small difference in loading; the preparation method is simple in operation and high in yield, and is suitable for industrialized production.

In one aspect of the present invention, the present invention provides a raw material drug of vigabatrin. According to an embodiment of the present invention, the particle size D90 of the vigabatrin bulk drug is 200-460 μm, and is needle-shaped. The vigabatrin raw material drug of the invention is easy to form, and the vigabatrin solid composition prepared by using the vigabatrin solid composition has good dispersibility and small difference in loading amount.

It should be noted that the "particle size D90" described in the present invention refers to the corresponding particle size when the cumulative particle size distribution number of a sample reaches 90%. Specifically, "the particle diameter D90 is 200 to 460 μm" means that 90% of the particles have an average particle diameter of 200 to 460 μm.

According to an embodiment of the present invention, the purity of the vigabatrin raw material drug is not less than 98%. In some preferred embodiments, the purity of the vigabatrin raw material drug is not less than 99%.

In another aspect of the invention, the present invention provides a method for preparing the aforementioned vigabatrin bulk drug. According to an embodiment of the present invention, the method includes: step 1: mixing crude vigabatrin with water, filtering the resulting mixture, and collecting the filtrate; step 2: mixing the filtrate with alcohols, heat preservation, cooling and crystallization, and crystal collection to obtain the vigabatrin raw material; wherein, in the step 1, the mass ratio of the water to the crude vigabatrin is (1.8-2.5):1.

The inventors have found that the ratio between water and the crude product of vigabatrin will significantly affect the morphology and particle size distribution of the finally formed crystals. Furthermore, the inventors have found through a large number of experiments that when the quality of the crude product of water and vigabatrin When the ratio is (1.8-2.5):1, the morphology of the obtained vigabatrin crystals is needle-like, and the particle size distribution is D90=200-460 μm.

According to an embodiment of the present invention, in the step 1, the purity of the crude vigabatrinic acid is 80-88%. Thus, the formation of crystals is facilitated.

According to an embodiment of the present invention, in the step 2, the alcohols are selected from 1-6 alcohols. In some preferred embodiments, the alcohol is ethanol or isopropanol.

According to an embodiment of the present invention, the mass ratio of the alcohols to the crude vigabatrin is (8-12):1. The inventors have found that the mass ratio of the alcohols to the crude vigabatrin will affect the morphology and particle size distribution of the finally formed crystals. Furthermore, the inventors have found through a large number of experiments that when the alcohols and the crude vigabatrin When the mass ratio is (8-12):1, the morphology of the obtained vigabatrin crystals is needle-like, and the particle size distribution is D90=200-460 μm.

According to an embodiment of the present invention, the crystallization is carried out at 0-20°C. Thereby, precipitation of vigabatrin crystals is facilitated, and needle-shaped crystals having a particle diameter D90 of 200 to 460 μm can be obtained.

According to an embodiment of the present invention, the mixing is performed by adding the filtrate dropwise into the alcohol substance. Thus, it is helpful to obtain needle-shaped crystals with a particle diameter D90 of 200-460 μm, and the obtained vigabatrin raw material drug has high purity.

According to an embodiment of the present invention, the dropping rate is 10-30 mL/min. This contributes to obtaining needle-shaped crystals with a particle diameter D90 of 200 to 460 μm.

In yet another aspect of the present invention, the present invention provides a vigabatrin solid composition. According to an embodiment of the present invention, the vigabatrin solid composition includes: the aforementioned vigabatrin raw material drug and pharmaceutically acceptable auxiliary materials. Therefore, the vigabatrin solid composition according to the embodiment of the present invention has good dispersibility and small difference in loading.

According to an embodiment of the present invention, the dosage form of the vigabatrin solid composition is selected from tablet or powder.

According to an embodiment of the present invention, the auxiliary material includes povidone. Povidone has properties such as adhesion, thickening, dispersion, film formation, and complexation, and can be used as a binder in solid compositions.

In yet another aspect of the present invention, the present invention proposes a method for preparing the aforementioned vigabatrin solid composition. According to an embodiment of the present invention, the method includes: mixing, granulating and drying the vigabatrin bulk drug and pharmaceutically acceptable excipients to obtain the vigabatrin solid composition. Therefore, the vigabatrin solid composition prepared according to the method of the embodiment of the present invention has good dispersibility and small difference in loading. The preparation method is simple in operation and high in yield, and is suitable for industrial production.

According to an embodiment of the present invention, the vigabatrin bulk drug is obtained by the above-mentioned method for preparing the vigabatrin bulk drug.

According to an embodiment of the present invention, the method further includes: mixing the vigabatrin raw material drug, alcohols and pharmaceutically acceptable excipients to obtain a mixture; granulating the mixture to obtain Granules: sizing the granules, drying the granules obtained, sieving the granules obtained after drying, and collecting the granules to obtain the vigabatrin solid composition. Thus, the prepared vigabatrin solid composition has good dispersibility and little difference in loading.

Additional aspects and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.

Description of drawings

The above and/or additional aspects and advantages of the present invention will become apparent and understandable from the description of the embodiments in conjunction with the following drawings, wherein:

Fig. 1 shows the topography of the vigabatrin bulk drug prepared according to Example 3 of the present invention;

Figure 2 shows the morphology of the vigabatrin bulk drug prepared according to Comparative Example 3 of the present invention.

Detailed ways

The solutions of the present invention will be explained below in conjunction with examples. Those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be considered as limiting the scope of the present invention. If no specific technique or condition is indicated in the examples, it shall be carried out according to the technique or condition described in the literature in this field or according to the product specification. The reagents or instruments used were not indicated by the manufacturer, and they were all commercially available conventional products.

Example 1

In this example, formamido-5-vinyl-2-pyrrolidone was reacted in concentrated hydrochloric acid and acetic acid to obtain the crude product of vigabatrin, the reaction formula is as follows:

1.5 grams of 3-formamido-5-vinyl-2-pyrrolidone was added to a three-necked flask, a mixture of 20 milliliters of concentrated hydrochloric acid and 10 milliliters of glacial acetic acid was added and heated under reflux for 16 hours, and then the reaction solution was evaporated to dryness under reduced pressure. The residue was dissolved in water, extracted with ether, and the aqueous phase was retained, treated with activated carbon, and neutralized by adding 2M ammonia water. The neutral solution was passed through Amberlite I.R.120 column, and the product was eluted with 2M ammonia water. Evaporate under reduced pressure to obtain a residual solid, which was recrystallized by adding acetone aqueous solution to obtain a crude product of vigabatrin with a yield of 46.9%. The purity of the crude product is 84.68%.

The obtained crude product of vigabatrin was subjected to follow-up experiments.

Example 2

In this embodiment, adopt following method to prepare vigabatrin bulk drug:

Weigh 10 g of crude vigabatrin, add it into 18 g of purified water, dissolve at 50° C., and then filter with suction. Transfer the filtrate to a three-neck flask, add 80 g of isopropanol dropwise at a rate of 10 ml/min, keep it at 50°C for 1 hour, then slowly cool down to 10°C, keep it warm for crystallization for 2 hours, suction filter, wash, and dry to obtain ammonia Acrylic acid API products. The particle size D90 of the vigabatrin product is 201.5 μm, and the shape is needle-like. The purity is 98.53%.

Example 3

In this embodiment, adopt following method to prepare vigabatrin bulk drug:

Weigh 10 g of crude vigabatrin, add it into 20 g of purified water, dissolve it at 50° C., and then filter it with suction. Transfer the filtrate to a three-necked flask, add 40g of isopropanol dropwise at a rate of 30ml/min, keep it warm at 50°C for 1h, then slowly cool down to 0°C, keep it warm for crystallization for 2h, suction filter, wash, and dry to obtain ammonia Acrylic acid API products. The particle size D90 of the vigabatrin product is 316.5 μm, and its appearance is needle-like, as shown in Figure 1. The purity is 98.27%.

Example 4

In this embodiment, adopt following method to prepare vigabatrin bulk drug:

Weigh 10 g of crude vigabatrin, add it into 25 g of purified water, dissolve at 50° C., and then filter with suction. Transfer the filtrate to a three-necked flask, add 120 g of isopropanol dropwise at a rate of 20 ml/min, keep it warm at 50°C for 1 hour, then slowly cool down to 20°C, keep it warm for crystallization for 2 hours, suction filter, wash, and dry to obtain ammonia Acrylic acid API products. The particle size D90 of the vigabatrin product is 456.8 μm, and its shape is needle-like. The purity is 99.88%.

Example 5

In this embodiment, adopt following method to prepare vigabatrin bulk drug:

Weigh 10 g of crude vigabatrin, add it into 20 g of purified water, dissolve it at 50° C., and then filter it with suction. Transfer the filtrate to a three-neck flask, add 100g of ethanol dropwise at a rate of 20ml/min, keep it warm at 50°C for 1h, then slowly cool down to 10°C, keep it warm for crystallization for 2h, suction filter, wash, and dry to obtain vigabatrin API products. The particle size D90 of the vigabatrin product is 278.3 μm, and the shape is needle-like. The purity is 99.86%.

Comparative example 1

In this comparative example, adopt following method to prepare vigabatrin bulk drug:

Weigh 10 g of the crude product of vigabatrin, add it into 16 g of purified water, dissolve at 50° C., and then filter with suction. Transfer the filtrate to a three-neck flask, add 80 g of isopropanol dropwise at a rate of 10 ml/min, keep it at 50°C for 1 hour, then slowly cool down to 10°C, keep it warm for crystallization for 2 hours, suction filter, wash, and dry to obtain ammonia Acrylic acid API products. The particle size D90 of the vigabatrin product is 158.8 μm, and its appearance is needle-like. The purity is 93.97%.

Thus, it is shown that the mass ratio of water to the crude product of vigabatrin is too low, which will cause the particle size D90 of the crude drug of vigabatrin to be low.

Comparative example 2

In this comparative example, adopt following method to prepare vigabatrin bulk drug:

Weigh 10 g of crude vigabatrin, add it into 18 g of purified water, dissolve at 50° C., and then filter with suction. Transfer the filtrate to a three-neck flask, add 140 g of isopropanol dropwise at a rate of 10 ml/min, keep it warm at 50°C for 1 hour, then slowly cool down to 10°C, keep it warm for crystallization for 2 hours, suction filter, wash, and dry to obtain ammonia Acrylic acid API products. The particle size D90 of the vigabatrin product is 329.7 μm, and the shape is spherical. The purity is 99.89%.

Thus, it is shown that the mass ratio of the alcohol to the crude product of vigabatrin is too high, and the needle-shaped vigabatrin bulk drug cannot be obtained.

Comparative example 3

In this comparative example, adopt following method to prepare vigabatrin bulk drug:

Weigh 10 g of crude vigabatrin, add it into 18 g of purified water, dissolve at 50° C., and then filter with suction. Transfer the filtrate to a three-necked flask, add 80 g of isopropanol dropwise at a rate of 8 ml/min, keep it warm at 50°C for 1 hour, then slowly cool down to 10°C, keep it warm for crystallization for 2 hours, suction filter, wash, and dry to obtain ammonia Acrylic acid API products. The particle size D90 of the vigabatrin product is 386.4 μm, and the morphology is columnar, as shown in Figure 2. The purity is 97.34%.

Thus, it was shown that the dripping speed of the filtrate was too low, and the needle-like vigabatrin bulk drug could not be obtained.

Example 6

The consumption of each raw material of the vigabatrin powder of the present embodiment is as follows:

Raw materials Quantity for 1000 packs (g) Proportion Raw material of vigabatrin 500 99.01% povidone 5 0.99% gross weight 505 100%

Wherein, the particle size D90 of the vigabatrin raw material used is 201.5 μm, and the vigabatrin is needle-shaped (prepared in Example 2).

Preparation method of vigabatrin powder:

(1) slurry preparation: take 50g ethanol, add the povidone (PVP) of recipe quantity and stir until dissolving completely, as adhesive;

(2) Granulation: Put the vigabatrin raw material drug in the prescribed amount into a wet granulator, and wet granulate to obtain wet granules;

(3) Wet granulation: wet granules are wet sized with 30 mesh;

(4) Drying: use a fluidized bed for drying.

(5) Dry granulation: the dried material is dry granulated with 40 mesh.

(6) Filling: Filling at 505mg/bag.

The bulk density, tap density, angle of repose, and Carr index of the dried granules obtained in the detection step (5) are calculated to calculate the Hausner ratio and evaluate the fluidity. The results were: the Hausner ratio was 1.15, the angle of repose was 33.24°, the Carr index was 13.4%, and the fluidity was evaluated as good.

Take 10 bags of the filling test product obtained in step (6), accurately weigh the weight of the contents of each bag respectively, compare the filling amount of each bag with the marked filling amount, and calculate the difference in loading amount. The results are shown in Table 1.

Combined with the requirements of the four general rules of the Chinese Pharmacopoeia 2020 edition [Variance in Loading Volume], the average loading volume or marked loading volume is more than 0.5g to 1.5g, and the loading volume difference limit (traditional Chinese medicine, chemical medicine) is ±8%. There shall be no more than 2 bags of powder that exceed the limit of difference in filling volume, and no one bag shall exceed 1 times the limit of difference in filling volume.

It can be seen from Table 1 that the difference in the volume of the powder obtained by using the above formula meets the requirements of the item [Variance in Loading Volume] in the General Rules of Part Four of the Chinese Pharmacopoeia 2020 Edition.

Table 1 Loading difference detection results

Example 7

The consumption of each raw material of the vigabatrin powder of the present embodiment is as embodiment 6.

Wherein, the particle size D90 of the vigabatrin raw material used is 316.5 μm, and the vigabatrin is needle-shaped (prepared in Example 3).

The preparation method of vigabatrin powder is the same as in Example 6.

The bulk density, tap density and angle of repose of the dry granules obtained in the detection step (5) are calculated, the Hausner ratio is calculated, and the fluidity is evaluated. The results were: the Hausner ratio was 1.12, the angle of repose was 31.43°, the Carr index was 11.0%, and the fluidity was evaluated as good.

Take 10 bags of the filling test product obtained in step (6), accurately weigh the weight of the contents of each bag respectively, compare the filling amount of each bag with the marked filling amount, and calculate the difference in loading amount. The results are shown in Table 2.

Combined with the requirements of the four general rules of the Chinese Pharmacopoeia 2020 edition [Variance in Loading Volume], the average loading volume or marked loading volume is more than 0.5g to 1.5g, and the loading volume difference limit (traditional Chinese medicine, chemical medicine) is ±8%. There shall be no more than 2 bags of powder that exceed the limit of difference in filling volume, and no one bag shall exceed 1 times the limit of difference in filling volume.

It can be seen from Table 2 that the difference in the volume of the powder obtained by using the above formula meets the requirements of the item [Variance in Loading Volume] in the General Rules of Part Four of the Chinese Pharmacopoeia 2020 Edition.

Table 2 Loading difference detection results

Example 8

The consumption of each raw material of the vigabatrin powder of the present embodiment is as embodiment 6.

Wherein, the particle size D90 of the vigabatrin raw material used is 456.8 μm, and the vigabatrin is needle-shaped (prepared in Example 4).

The preparation method of vigabatrin powder is the same as in Example 6.

The bulk density, tap density and angle of repose of the dry granules obtained in the detection step (5) are calculated, the Hausner ratio is calculated, and the fluidity is evaluated. The results were: the Hausner ratio was 1.13, the angle of repose was 31.89°, the Carr index was 11.8%, and the fluidity was evaluated as good.

Take 10 bags of the filling test product obtained in step (6), accurately weigh the weight of the contents of each bag respectively, compare the filling amount of each bag with the marked filling amount, and calculate the difference in loading amount. The results are shown in Table 3.

Combined with the requirements of the four general rules of the Chinese Pharmacopoeia 2020 edition [Variance in Loading Volume], the average loading volume or marked loading volume is more than 0.5g to 1.5g, and the loading volume difference limit (traditional Chinese medicine, chemical medicine) is ±8%. There shall be no more than 2 bags of powder that exceed the limit of difference in filling volume, and no one bag shall exceed 1 times the limit of difference in filling volume.

It can be seen from Table 3 that the difference in the volume of the powder obtained by using the above formula meets the requirements of the item [Variance in Loading Volume] in the General Rules of Part Four of the Chinese Pharmacopoeia 2020 Edition.

Table 3 Loading difference detection results

Comparative example 4

The consumption of each raw material of the vigabatrin powder of the present embodiment is as embodiment 6.

Wherein, the particle size D90 of the vigabatrin raw material used is 386.4 μm, and the vigabatrin is columnar (prepared in Comparative Example 4).

The preparation method of vigabatrin powder is the same as in Example 6.

The bulk density, tap density and angle of repose of the dry granules obtained in the detection step (5) are calculated, the Hausner ratio is calculated, and the fluidity is evaluated. The results were: Hausner ratio was 1.21, angle of repose was 32.35°, Carr index was 17.6%, and mobility was assessed as fair.

Take 10 bags of the filling test product obtained in step (6), accurately weigh the weight of the contents of each bag respectively, compare the filling amount of each bag with the marked filling amount, and calculate the difference in loading amount. The test results are shown in Table 5.

Combined with the requirements of the four general rules of the Chinese Pharmacopoeia 2020 edition [Variance in Loading Volume], the average loading volume or marked loading volume is more than 0.5g to 1.5g, and the loading volume difference limit (traditional Chinese medicine, chemical medicine) is ±8%. There shall be no more than 2 bags of powder that exceed the limit of difference in filling volume, and no one bag shall exceed 1 times the limit of difference in filling volume.

It can be seen from Table 4 that the difference in the volume of the powder obtained by using the above formula does not meet the requirements of the item [Variance in Loading Volume] in the General Rules of Part Four of the Chinese Pharmacopoeia 2020 Edition.

Table 4 Loading difference detection results

Comparative example 5

The consumption of each raw material of the vigabatrin powder of the present embodiment is as embodiment 6.

Wherein, the particle size D90 of the vigabatrin raw material used is 173.4 μm, and the vigabatrin is needle-shaped (prepared in Comparative Example 1).

The preparation method of vigabatrin powder is the same as in Example 6.

The bulk density, tap density and angle of repose of the dry granules obtained in the detection step (5) are calculated, the Hausner ratio is calculated, and the fluidity is evaluated. The results were: Hausner ratio was 1.18, angle of repose was 33.23°, Carr index was 15.5%, and mobility was assessed as fair.

Take 10 bags of the filling test product obtained in step (6), accurately weigh the weight of the contents of each bag respectively, compare the filling amount of each bag with the marked filling amount, and calculate the difference in loading amount. The test results are shown in Table 6.

Combined with the requirements of the four general rules of the Chinese Pharmacopoeia 2020 edition [Variance in Loading Volume], the average loading volume or marked loading volume is more than 0.5g to 1.5g, and the loading volume difference limit (traditional Chinese medicine, chemical medicine) is ±8%. There shall be no more than 2 bags of powder that exceed the limit of difference in filling volume, and no one bag shall exceed 1 times the limit of difference in filling volume.

It can be seen from Table 5 that the difference in the volume of the powder obtained by using the above formula does not meet the requirements of the item [Variance in Loading Volume] in the Four General Rules of the Chinese Pharmacopoeia 2020 Edition.

Table 5 Loading difference detection results

In the description of this specification, descriptions referring to the terms "one embodiment", "some embodiments", "example", "specific examples", or "some examples" mean that specific features described in connection with the embodiment or example , structure, material or characteristic is included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the described specific features, structures, materials or characteristics may be combined in any suitable manner in any one or more embodiments or examples. In addition, those skilled in the art can combine and combine different embodiments or examples and features of different embodiments or examples described in this specification without conflicting with each other.

Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention, those skilled in the art can make the above-mentioned The embodiments are subject to changes, modifications, substitutions and variations.

Claims (10)

1. The vigabatrin bulk drug is characterized in that the particle size D90 of the vigabatrin bulk drug is 200-460 mu m, and the vigabatrin bulk drug is needle-shaped.

2. The vigabatrin unit dose of claim 1, wherein the vigabatrin unit dose has a purity of not less than 98%, preferably not less than 99%.

3. A method of preparing the vigabatrin unit dosage of claim 1, comprising:

step 1: mixing the crude product of vigabatrin with water, filtering the obtained mixed solution, and collecting filtrate;

step 2: mixing the filtrate with alcohol substances, preserving heat, cooling and crystallizing, and collecting crystals to obtain the vigabatrin crude drug;

in the step 1, the mass ratio of the water to the crude product of vigabatrin is (1.8-2.5): 1.

4. the method according to claim 3, wherein in the step 1, the crude vigabatrin has a purity of 80 to 88%;

optionally, in the step 2, the alcohol is selected from 1-6 alcohols, preferably, the alcohol is ethanol or isopropanol;

optionally, the mass ratio of the alcohol substance to the crude product of vigabatrin is (8-12): 1, a step of;

optionally, the crystallization is performed at 0 to 20 ℃.

5. A method according to claim 3, wherein said mixing is performed by dropping said filtrate into said alcohol;

optionally, the dropping speed is 10-30 mL/min.

6. A solid composition of vigabatrin comprising: the vigabatrin unit dosage of claim 1 and pharmaceutically acceptable excipients.

7. The solid composition of vigabatrin according to claim 6, characterized in that the solid composition of vigabatrin is in a dosage form selected from the group consisting of a tablet and a powder;

optionally, the adjuvant comprises povidone.

8. A method of preparing the solid vigabatrin composition of claim 6 or 7, comprising:

mixing, granulating and drying the vigabatrin crude drug and pharmaceutically acceptable auxiliary materials to obtain the vigabatrin solid composition.

9. The method according to claim 8, wherein the starting material of vigabatrin is obtained by the method of preparing a starting material of vigabatrin according to any one of claims 3-6.

10. The method as recited in claim 8, further comprising:

mixing the vigabatrin crude drug, the alcohol substances and pharmaceutically acceptable auxiliary materials to obtain a mixture;

granulating the mixture to obtain granules;

and (3) finishing the particles, drying the obtained particles, sieving the dried particles, and collecting the obtained particles to obtain the solid vigabatrin composition.

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