SOLID DISPERSION AND PREPARATION METHOD THEREFOR

Abstract

Solid dispersion and a preparation method therefor. In a specific embodiment, the solid dispersion contains an active ingredient (R)-4-amino-1-(1-(but-2-ynyl)pyrrolidin-3-yl))-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one or a salt thereof, and a carrier material, and the pH value is adjusted; employing a method that adds an appropriate amount of acid effectively inhibits an emulsification phenomenon in a reverse solvent process, thereby obtaining solid dispersion having a moderate particle size and uniform content.

Claims

1. A method for preparing a solid dispersion, comprising the steps of dissolving a carrier material and the active ingredient (R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one or a pharmaceutically acceptable salt thereof in a good solvent to obtain a solution, adding the resulting solution to a poor solvent, and adjusting the pH to 1.0 to 6.0; or, comprising the steps of dissolving a carrier material and the active ingredient in a good solvent to obtain a solution, and adding the resulting solution to a poor solvent, wherein the pH of the poor solvent is 1.0 to 6.0.

2. The method according to claim 1, wherein the good solvent is at least one selected from the group consisting of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, ethanol, tetrahydrofuran and methanol.

3. The method according to claim 1, wherein the poor solvent is at least one selected from the group consisting of diethyl ether, n-hexane, petroleum ether and water.

4. The method according to claim 1, wherein the reagent used to adjust pH is at least one selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid and phosphoric acid.

5. The method according to claim 1, wherein the addition to the poor solvent is accompanied by a stirring process, the stirring rate is selected from the group consisting of 20 to 1000 rpm.

6. The method according to claim 1, wherein the temperature for the precipitation of solid is selected from the group consisting of 0 to 40° C.

7. The method according to claim 1, comprising: method 1: a) dissolving the carrier material and the active ingredient (R)-4-amino-1-(1-(but-2-Preliminary Amendment ynoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one or the pharmaceutically acceptable salt thereof in a good solvent, wherein the good solvent is at least one selected from the group consisting of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, ethanol, tetrahydrofuran and methanol, b) adding the solution obtained in step a) to a poor solvent, and adjusting the pH to 1.0 to 6.0, wherein the poor solvent is at least one selected from the group consisting of diethyl ether, n-hexane, petroleum ether and water; or, method 2: a) dissolving the carrier material and the active ingredient (R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one or the pharmaceutically acceptable salt thereof in a good solvent, wherein the good solvent is at least one selected from the group consisting of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, ethanol, tetrahydrofuran and methanol, b) adding the solution obtained in step a) to a poor solvent, wherein the poor solvent is selected from the group consisting of water and a mixed solution of water with one or more of ether, n-hexane and petroleum ether, and the pH of the poor solvent is 1.0 to 6.0.

8. The method according to claim 1, wherein the carrier material is at least one selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, polyvinylpyrrolidone, hydroxypropyl methylcellulose phthalate and polyvinylpyrrolidone.

9. The method according to claim 1, wherein the weight ratio of the carrier material to the active ingredient is 0.5:1 to 4:1, and preferably 0.8:1 to 3.

10. The method according to claim 1, wherein the solid dispersion is consisting of the active ingredient (R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one or the pharmaceutically acceptable salt thereof and the carrier material.

11. (canceled)

12. (canceled)

13. (canceled)

14. A method for preparing a solid dispersion, comprising the steps of dissolving a carrier material and an active ingredient in a good solvent to obtain a solution, adding the resulting solution to a poor solvent, and adjusting the pH to 1.0 to 6.0; or, comprising the steps of dissolving a carrier material and an active ingredient in a good solvent to obtain a solution, and adding the resulting solution to a poor solvent, wherein the pH of the poor solvent is 1.0 to 6.0.

15. A solid dispersion comprising the active ingredient (R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one or the salt thereof and a carrier material, wherein the particle size D90 of the solid dispersion is 50 μm to 2000 μm.

16. The solid dispersion according to claim 15, wherein the particle size D50 of the solid dispersion is 20 μm to 500 μm.

17. The solid dispersion according to claim 15, wherein the particle size D10 of the solid dispersion is 1 μm to 100 μm.

18. The solid dispersion according to claim 15, wherein the carrier material is at least one selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, polyvinylpyrrolidone, hydroxypropyl methylcellulose phthalate and polyvinylpyrrolidone.

19. The solid dispersion according to claim 15, wherein the weight ratio of the carrier material to the active ingredient is 0.5:1 to 4:1.

20. The solid dispersion according to claim 15, wherein the solid dispersion is consisting of the active ingredient (R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one or the pharmaceutically acceptable salt thereof and the carrier material.

21. A solid formulation comprising the solid dispersion prepared by the method according to claim 1 and optionally at least one excipient selected from the group consisting of disintegrant, filler, binder and lubricant.

22. The solid formulation according to claim 21, wherein the disintegrant is at least one selected from the group consisting of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, starch, pregelatinized starch and alginic acid; the binder is at least one selected from the group consisting of polyvinylpyrrolidone, starch, methyl cellulose, carboxy cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and alginate; and the lubricant is at least one selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax and sodium stearyl fumarate.

23. The solid formulation according to claim 21, comprising: 1) 10 mg to 500 mg of the active ingredient, 2) 5 to 15% by weight of the disintegrant, 3) 30 to 90% by weight of the filler, 4) 0.5 to 10% by weight of the binder, 5) 0.1 to 5% by weight of the lubricant.

24. The solid formulation according to claim 21, wherein the dissolution rate of the active ingredient determined according to the second method (paddle method) of the dissolution rate test described in general rule of volume IV of Chinese Pharmacopoeia 2015 Edition, using 0.15% aqueous solution of SDS as a dissolution medium, at 37±0.5° C., and at a paddle speed of 50 rpm, is no less than 85%.

Description

DESCRIPTION OF THE DRAWINGS

[0092] The above and other objects and features of the present disclosure will become apparent with reference to the following drawings, which respectively represent:

[0093] FIG. 1: SEM image of the sample of Example 3

[0094] FIG. 2: SEM image of the sample of Example 4

DETAILED DESCRIPTION

[0095] The present disclosure will be further described in detail with reference to the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only, and should not be considered as limiting the scope of the present disclosure.

Example 1

[0096] 1 g of (R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (abbreviated as compound A) and 1 g of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were added to 15 ml of dimethylacetamide, and stirred to dissolve. The resulting solution was added dropwise into 100 ml of water at a rate of 4 g/min or 2 g/min, and stirred for about 1 hour. The resulting suspension was filtered. Agglomeration was observed initially, filtration (or suction filtration) was difficult, and the suction filtrate appeared milky.

Example 2

[0097] 1 g of compound A and 1 g of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were added to 15 ml of dimethylacetamide, and stirred to dissolve. The resulting solution was added dropwise at a rate of 4 g/min into 100 ml of water with different pH (shown in Table 1), and stirred for about 1 hour. The resulting suspension was filtered to obtain solid. The observed phenomena are as follows:

TABLE-US-00001 TABLE 1 Active Experimental Powder ingredient example pH Acid type appearance Phenomenon content % XRPD 1 2   98% Fluffy Evenly dispersed, 47.39% Amorphous sulfuric acid easy to filter, and the filtrate was clear 2 2   85% Fluffy Evenly dispersed, 50.88% Amorphous phosphoric easy to filter, and acid the filtrate was clear 3 3 Glacial Fluffy Evenly dispersed, 47.25% Amorphous acetic acid easy to filter, and the filtrate was clear 4 3   98% Fluffy Evenly dispersed, 50.75% Amorphous sulfuric acid easy to filter, and the filtrate was clear 5 3 36.5% Tight Evenly dispersed, 46.35% Amorphous hydrochloric easy to filter, and acid the filtrate was clear

[0098] Conclusion: The solid dispersion prepared with phosphoric acid or sulfuric acid has low residual ion content. For example, when using phosphoric acid, the phosphorus content in the obtained solid dispersion is about 20 μg/g; and when using sulfuric acid, the sulfur content in the obtained solid dispersion is 10 μg/g.

[0099] The samples obtained in Experimental Examples 1, 4 and 5 were placed at 93%, 60° C., 40° C./75% RH, 25° C./60% RH conditions respectively to investigate the physical and chemical stability. Data are shown as follows:

TABLE-US-00002 Conditions Humidity (%) Temperature (°C) 1 4 5 Day 7 60 25 99.42% 99.40% 99.37% 75 40 99.41% 99.38% 99.38% 93 / 99.42% 99.40% 99.39% / 60 99.42% 99.39% 99.38% Day 14 60 25 99.41% 99.39% 99.43% 75 40 99.40% 99.40% 99.40% 93 / 99.39% 99.41% 99.42% / 60 99.39% 99.40% 99.41%

Example 3

[0100] 1 g of compound A and 1 g of HPMC-AS were dissolved in 15 ml of N,N-dimethylacetamide. The resulting solution was added dropwise at a rate of 4 g/min into 100 ml of water solution (adjusted to pH=2 with 36.5% hydrochloric acid), and stirred for 30 minutes. The resulting suspension was filtered, and the filter cake was rinsed with water. The resulting solid was dried overnight at 40° C., and subjected to SEM determination.

[0101] SEM result shows that the obtained sample is microsphere-like and has uniformly distribution, see FIG. 1.

Example 4

[0102] 1 g of compound A and 1 g of HPMC-AS were dissolved in 15 ml of N,N-dimethylacetamide. The resulting solution was added dropwise at a rate of 4 g/min into 100 ml of water and stirred. The sample obtained with water as the dispersion medium was used for particle size determination. The resulting suspension was filtered, the suction filtrate appeared milky, and the filter cake was rinsed with water. The resulting solid was dried overnight at 40° C., and subjected to SEM determination.

[0103] Particle size of the sample obtained with water as the dispersion medium: D10=7.6 μm, D50=27.2 μm, D90=86 D [4,3]=39.4 μm.

[0104] SEM result shows that the obtained sample is granular with uneven particle size, see FIG. 2.

Example 5

[0105] A certain amount of compound A and HPMC-AS-LF were weighed and dissolved in 15 ml of N,N-dimethylacetamide (DMAC). The resulting solution was added dropwise at a rate of 4 g/min into 100 ml of water (adjusted to pH=2 with 36.5% hydrochloric acid) and stirred. The specific parameters are shown in the table below:

TABLE-US-00003 Test Stirring Compound HPMC-AS pH Temperature Stirring rate Example method (g) (g) value (°C) (rpm) 6 Mechanical 1 1 2 25 300 stirring 7 Mechanical 1 1 2 15 300 stirring 8 Mechanical 1 1 2 10 300 stirring 9 Mechanical 1 1 2 5 300 stirring 10 Mechanical 1 1 2 0 300 stirring

[0106] The samples obtained with water as the dispersion medium were subjected to particle size determination respectively. The specific data are as follows:

TABLE-US-00004 Test D10 D50 D90 D Example (μm) (μm) (μm) (μm) 6 19.9 165 497 223 7 21.6 209 746 349 8 17.5 151 477 203 9 19.3 163 460 204 10 33.1 268 1430 501

Example 6

[0107] A solid dispersion comprising compound A and hydroxypropyl methylcellulose acetate succinate was prepared by the method of Test Example 9. A prescription amount of the solid dispersion, lactose, microcrystalline cellulose and croscarmellose sodium were weighed according to the formulation specified as follows. The mixture was poured into a granulating tank, mixed well, and polyvinylpyrrolidone was added as the binder to prepare granules. The wet and soft material was wet-milled and dried, and then the dry granules (water content less than 3%) were dry-milled. Extragranular auxiliary materials were added, and mixed well with the granules. The resulting total mixed granules were compressed into tablets. Specific prescription ratios are shown in Table 2.

TABLE-US-00005 TABLE 2 Experimental Example (mg/tablet) Ingredients 11 12 Compound A 100 100 Hydroxypropyl methylcellulose 100 200 acetate succinate Lactose monohydrate 175 175 Microcrystalline cellulose 101 60 60 Croscarmellose sodium 25 25 (intragranularly) Polyvinylpyrrolidone K30 20 20 Croscarmellose sodium 15 15 (extragranularly) Magnesium stearate 5.0 5.6 Total (mg) 500 600

[0108] Dissolution Test

[0109] The dissolution rates of the tablets of Experimental Examples 11 and 12 were determined according to the second method (paddle method) of the dissolution rate test described in general rule of volume IV of Chinese Pharmacopoeia 2015 Edition. The dissolution test was carried out using 1000 ml of 0.15% aqueous solution of SDS as a dissolution medium, at 37±0.5° C., and at a paddle speed of 50 rpm.

TABLE-US-00006 TABLE 3 Dissolution Time rate (%) (min) 11 12 5 60.3 63.2 15 80.2 82.9 45 97.8 98.2