Crystalline form of N-butyldeoxygalactonojirimycin
The invention relates to a crystalline form of [(2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)-piperidine-3,4,5-triol, processes for the preparation thereof, pharmaceutical compositions containing such a crystalline form, and its use as a medicament, especially as glycolipid biosynthesis inhibitor.
1. A crystalline form of the compound f(2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol:
characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 5.6°, 17.7°, and 21.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.
2. A crystalline form of the compound according to claim 1 , characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 5.6° 12.4°, 14.8°, 17.7°, and 21.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.
3. A crystalline form of the compound according to claim 1 , characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 5.6° 12.4°, 13.4°, 14.8°, 16.8°, 17.7°, 19.4°, 21.5°, 22.1°, and 24.2°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.
4. A crystalline form of the compound according to claim 1 , which essentially shows the X-ray powder diffraction pattern as depicted in FIG. 1 .
5. A crystalline form of the compound according to claim 1 , wherein said crystalline form shows endothermal melting with a peak at about 130° C. as determined by differential scanning calorimetry.
6. A crystalline form of the compound according to claim 1 , wherein said crystalline form consists essentially of particles having a particle size distribution, wherein D50 is equal or greater than about 50 μm.
7. A crystalline form of the compound according to claim 1 , wherein said crystalline form consists essentially of particles having a particle size distribution, wherein
D50 is from about 50 μm to about 150 μm; and
D90 is from about 100 μm to about 400 μm.
8. A process for the preparation of the crystalline form of the compound according to claim 1 , wherein said process comprises:
I) Step 1 comprising:
i. Preparing a solution of (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol in isopropanol, wherein preferably about 100 ww % to 140 ww % of isopropanol with respect to the weight of (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol is used;
ii. Warming up the solution to about 45° C. to 60° C.;
iii. Adding anhydrous acetone, wherein about 450 ww % to 550 ww % with respect to the weight of (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol is added, and wherein said acetone is added during about 30 min;
iv. Cooling the obtained solution to about −5° C. to +5° C. at a constant rate;
v. Agitating at about 0° C. for 1 to 3 hours;
vi. Isolating the product by solid-liquid separation;
vii. Washing the solid with anhydrous acetone, wherein about 250 ww % to 300 ww % of acetone with respect to the weight of (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol is used; and
viii. Drying; and
II) Step 2 comprising:
i. Dissolving the product of the first crystallization step at about 45° C. in about 200 ww % to 250 ww % methanol with respect to the weight of (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol;
ii. Filtering over activated carbon;
iii. Washing the activated carbon with about 90 ww % of methanol with respect to the weight of (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol;
iv. Concentrating the solution under vacuum;
v. Dissolving the distillation residue of the previous step in about 60 ww % to 65 ww % methanol and about 4 ww % to 8 ww % water with respect to the weight of (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol;
vi. Warming up the solution to about 55° C. to 58° C.
vii. Adding about 200 ww % to 220 ww % ethyl acetate during about 25 min to 45 min while keeping the temperature between about 55° C. to 58° C.;
viii. Cooling the resulting suspension down to about −5 to +5° C. at a constant rate;
ix. Agitating at about 0° C. for 1.5 to 3 hours;
x. Isolating the product by solid-liquid separation;
xi. Washing the solid twice with ethyl acetate; and
xii. Drying.
9. A pharmaceutical composition comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 1 ; and
from about 24 ww % to about 44 ww % of one or more diluents selected from a group consisting of lactose anhydrous, silicified microcrystalline cellulose, microcrystalline cellulose, calcium hydrogen phosphate and isomalt;
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof;
where the total ww % of said pharmaceutical composition is 100.
10. A pharmaceutical composition according to claim 9 , comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 1 ;
from about 24 ww % to about 44 ww % of lactose anhydrous; and
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof,
where the total ww % of said pharmaceutical composition is 100.
11. A capsule comprising the pharmaceutical composition according to claim 9 .
12. A method of reducing or eliminating symptoms of Niemann-Pick type C disease; Gaucher disease types 1, 2 and 3; Tay-Sachs disease, Sandhoff disease, GM2 gangliosidosis AB variant; GM1 gangliosidosis; Fabry disease; Schindler disease; Smith-Lemly-Opitz syndrome; Tangier disease; mucolipidosis IV; mucopolysaccharidoses; GbA1-synucleopathies and syndromes thereof; Huntington's disease; polycystic kidney disease; Darier's disease; or Guillain-Barré syndrome the method comprising administering to a patient in need thereof a pharmaceutically effective amount of the crystalline form of the compound according to claim 1 .
13. A method of reducing or eliminating symptoms of Fabry disease, comprising administering to a patient in need thereof an effective amount of a crystalline form of the compound according to claim 1 .
14. A crystalline form of the compound according to claim 1 , wherein said crystalline form consists essentially of particles having a particle size distribution, wherein D50 is from about 50 μm to about 300 μm.
15. A crystalline form of the compound according to claim 1 , wherein said crystalline form has a total impurity amount of less than about 0.5%.
16. A crystalline form of the compound according to claim 2 , wherein said crystalline form shows endothermal melting with a peak at about 130° C. as determined by differential scanning calorimetry.
17. A crystalline form of the compound according to claim 2 , wherein said crystalline form consists essentially of particles having a particle size distribution, wherein D50 is equal or greater than about 50 μm.
18. A crystalline form of the compound according to claim 2 , wherein said crystalline form consists essentially of particles having a particle size distribution wherein D50 is equal or greater than about 70 μm.
19. A crystalline form of the compound according to claim 2 , wherein said crystalline form consists essentially of particles having a particle size distribution, wherein D50 is from about 50 μm to about 300 μm.
20. A crystalline form of the compound according to claim 2 , wherein said crystalline form consists essentially of particles having a particle size distribution, wherein D50 is from about 70 μm to about 250 μm.
21. A crystalline form of the compound according to claim 2 , wherein said crystalline form consists essentially of particles having a particle size distribution, wherein
D50 is from about 50 μm to about 300 μm; and
D90 is from about 100 μm to about 400 μm.
22. A crystalline form of the compound according to claim 2 , wherein said crystalline form consists essentially of particles having a particle size distribution, wherein
D50 is from about 50 μm to about 300 μm; and
D90 is from about 100 μm to about 400 μm;
and D10 is from about 3 μm to about 12 μm.
23. A crystalline form of the compound according to claim 3 , wherein said crystalline form consists essentially of particles having a particle size distribution, wherein D50 is equal or greater than about 50 μm.
24. A crystalline form of the compound according to claim 3 , wherein said crystalline form consists essentially of particles having a particle size distribution, wherein D50 is from about 50 μm to about 300 μm.
25. A crystalline form of the compound according to claim 3 , wherein said crystalline form consists essentially of particles having a particle size distribution, wherein D50 is from about 70 μm to about 250 μm.
26. A crystalline form of the compound according to claim 3 , wherein said crystalline form consists essentially of particles having a particle size distribution, wherein
D50 is from about 50 μm to about 300 μm; and
D90 is from about 100 μm to about 400 μm.
27. A pharmaceutical composition according to claim 10 , wherein the tapped density of said pharmaceutical composition is at least 0.64 g/mL.
28. A pharmaceutical composition comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 2 ; and
from about 24 ww % to about 44 ww % of one or more diluents selected from a group consisting of lactose anhydrous, silicified microcrystalline cellulose, microcrystalline cellulose, calcium hydrogen phosphate and isomalt; and
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof;
where the total ww % of said pharmaceutical composition is 100.
29. A pharmaceutical composition according to claim 28 , wherein the tapped density of said pharmaceutical composition is at least 0.64 g/mL.
30. A pharmaceutical composition comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 2 ;
from about 24 ww % to about 44 ww % of lactose anhydrous; and
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof where the total ww % of said pharmaceutical composition is 100.
31. A pharmaceutical composition according to claim 30 , wherein the tapped density of said pharmaceutical composition is at least 0.64 g/mL.
32. A pharmaceutical composition comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 17 ; and
from about 24 ww % to about 44 ww % of one or more diluents selected from a group consisting of lactose anhydrous, silicified microcrystalline cellulose, microcrystalline cellulose, calcium hydrogen phosphate and isomalt; and
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof;
where the total ww % of said pharmaceutical composition is 100.
33. A pharmaceutical composition according to claim 32 , wherein the tapped density of said pharmaceutical composition is at least 0.64 g/mL.
34. A pharmaceutical composition comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 17 ;
from about 24 ww % to about 44 ww % of lactose anhydrous; and
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof where the total ww % of said pharmaceutical composition is 100.
35. A pharmaceutical composition according to claim 34 , wherein the tapped density of said pharmaceutical composition is at least 0.64 g/mL.
36. A pharmaceutical composition comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 19 ;
from about 24 ww % to about 44 ww % of lactose anhydrous; and
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof where the total ww % of said pharmaceutical composition is 100.
37. A pharmaceutical composition comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 21 ;
from about 24 ww % to about 44 ww % of lactose anhydrous; and
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof where the total ww % of said pharmaceutical composition is 100.
38. A pharmaceutical composition according to claim 37 , wherein the tapped density of said pharmaceutical composition is at least 0.64 g/mL.
39. A pharmaceutical composition comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 23 ;
from about 24 ww % to about 44 ww % of lactose anhydrous; and
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof where the total ww % of said pharmaceutical composition is 100.
40. A pharmaceutical composition comprising:
from about 55 ww % to about 75 ww % of the crystalline form of the compound according to claim 24 ;
from about 24 ww % to about 44 ww % of lactose anhydrous; and
from 0 ww % to about 6 ww % of a component selected from a group consisting of talc, magnesium stearate, sodium stearyl fumarate, silicon dioxide, or a combination thereof where the total ww % of said pharmaceutical composition is 100.
41. A capsule comprising the pharmaceutical composition according to claim 28 .
42. A capsule comprising the pharmaceutical composition according to claim 29 .
43. A capsule comprising the pharmaceutical composition according to claim 30 .
44. A capsule comprising the pharmaceutical composition according to claim 31 .
45. A capsule according to claim 44 , wherein said capsule comprises said compound in an amount of about 250 mg of active ingredient per capsule.
46. A capsule according to claim 45 , wherein said capsule is a size 0 capsule.
47. A capsule comprising the pharmaceutical composition according to claim 32 .
48. A capsule comprising the pharmaceutical composition according to claim 33 .
49. A capsule according to claim 48 , wherein said capsule comprises said compound in an amount of about 250 mg of active ingredient per capsule.
50. A capsule according to claim 49 , wherein said capsule is a size 0 capsule.
51. A capsule comprising the pharmaceutical composition according to claim 34 .
52. A capsule according to claim 51 , wherein said capsule comprises said compound in an amount of about 250 mg of active ingredient per capsule.
53. A capsule according to claim 52 , wherein said capsule is a size 0 capsule.
54. A capsule comprising the pharmaceutical composition according to claim 35 .
55. A capsule according to claim 54 , wherein said capsule comprises said compound in an amount of about 250 mg of active ingredient per capsule.
56. A capsule according to claim 55 , wherein said capsule is a size 0 capsule.
57. A method of reducing or eliminating symptoms of Fabry disease, comprising administering to a patient in need thereof an effective amount of a crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol, wherein said compound is administered in the form of a capsule according to claim 42 .
58. A method of reducing or eliminating symptoms of Fabry disease, comprising administering to a patient in need thereof an effective amount of a crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol, wherein said compound is administered in the form of a capsule according to claim 43 .
59. A method of reducing or eliminating symptoms of Fabry disease, comprising administering to a patient in need thereof an effective amount of a crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol, wherein said compound is administered in the form of a capsule according to claim 44 .
60. A method of reducing or eliminating symptoms of Fabry disease, comprising administering to a patient in need thereof an effective amount of a crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol, wherein said compound is administered in the form of a capsule according to claim 48 .
61. A method of reducing or eliminating symptoms of Fabry disease, comprising administering to a patient in need thereof an effective amount of a crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol, wherein said compound is administered in the form of a capsule according to claim 51 .
62. A method of reducing or eliminating symptoms of Fabry disease, comprising administering to a patient in need thereof an effective amount of a crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol, wherein said compound is administered in the form of a capsule according to claim 54 .