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 capsule comprising a pharmaceutical composition, wherein said pharmaceutical composition comprises:
from about 55 ww % to about 75 ww % of a crystalline form of the compound (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° 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°;
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;
wherein said capsule is an HPMC capsule.
2. The capsule according to claim 1 , wherein said crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol is 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°.
3. The capsule according to claim 1 , wherein said crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol consists essentially of particles having a particle size distribution, wherein D50 is equal or greater than about 50 μm.
4. The capsule according to claim 1 , wherein said crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol 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.
5. The capsule according to claim 1 , wherein the tapped density of said pharmaceutical composition is at least 0.64 g/mL.
6. The capsule according to claim 1 , wherein said pharmaceutical composition comprises:
from about 55 ww % to about 75 ww % of the crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol;
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.
7. The capsule according to claim 6 , wherein the tapped density of said pharmaceutical composition is at least 0.64 g/mL.
8. The capsule according to claim 7 , wherein said capsule comprises the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol in an amount of about 250 mg per capsule.
9. The capsule according to claim 7 , wherein said capsule is a size 0 capsule.
10. The capsule according to claim 6 , wherein said crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol consists essentially of particles having a particle size distribution, wherein D50 is equal or greater than about 50 μm.
11. The capsule according to claim 6 , wherein said crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol consists essentially of particles having a particle size distribution, wherein D50 is from about 50 μm to about 300 μm.
12. The capsule according to claim 6 , wherein said crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol consists essentially of particles having a particle size distribution, wherein D50 is from about 70 μm to about 250 μm.
13. The capsule according to claim 6 , wherein said crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol 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.
14. The capsule according to claim 6 , wherein said crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol consists essentially of particles having a particle size distribution, wherein
D50 is from about 50 μm to about 300 μm;
D90 is from about 100 μm to about 400 μm; and
D10 is from about 3 μm to about 12 μm.
15. The capsule according to claim 6 , wherein said crystalline form of the compound (2R,3S,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol has a total impurity amount of less than about 0.5%.
16. A process for preparing the capsule according to claim 1 , wherein the process comprises preparing a pharmaceutical composition by admixing:
from about 55 ww % to about 75 ww % of a crystalline form of the compound (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° 12.4°, 14.8°, 17.7°, and 21.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kaα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°;
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;
and filling the pharmaceutical composition into an HPMC capsule.
17. A process for preparing the capsule according to claim 6 , wherein the process comprises preparing a pharmaceutical composition by admixing:
from about 55 ww % to about 75 ww % of the crystalline form of the compound (2R,3S,4R, 5S)-1-butyl-2-(hydroxymethyl)piperidine-3 ,4, 5-triol;
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;
and filling the pharmaceutical composition into an HPMC capsule.
18. A method of reducing 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;
GbAl-synucleopathies and syndromes thereof; Huntington's disease; polycystic kidney disease;
Darier's disease; or Guillain-Barré syndrome, wherein the method comprises administering to a patient in need thereof the capsule according to claim 1 .
19. A method for reducing the amount of glycolipids in a patient having a glycolipid storage disease or related disorder, wherein the method comprises administering to a patient in need thereof the capsule according to claim 1 .
20. A method of reducing symptoms of Fabry disease, wherein the method comprises administering to a patient in need thereof the capsule according to claim 1 .
21. A method of reducing symptoms of Niemann-Pick type C disease; Gaucher disease types 1, 2, and 3; Tay-Sachs disease; Sandhoff disease; GM2 gangliosidosis AB variant; GM 1 gangliosidosis; Fabry disease; Schindler disease; Smith-Lemly-Opitz syndrome; Tangier disease; mucolipidosis IV; mucopolysaccharidoses; GbAl-synucleopathies and syndromes thereof; Huntington's disease; polycystic kidney disease; Darier's disease; or Guillain-Barré syndrome, wherein the method comprises administering to a patient in need thereof the capsule according to claim 6 .
22. A method for reducing the amount of glycolipids in a patient having a glycolipid storage disease or related disorder, wherein the method comprises administering to a patient in need thereof the capsule according to claim 6 .
23. A method of reducing or eliminating symptoms of Fabry disease, wherein the method comprises administering to a patient in need thereof the capsule according to claim 6 .
24. A method of reducing 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; GbAl-synucleopathies and syndromes thereof; Huntington's disease; polycystic kidney disease;
Darier's disease; or Guillain-Barré syndrome, wherein the method comprises administering to a patient in need thereof the capsule according to claim 8 .
25. A method for reducing the amount of glycolipids in a patient having a glycolipid storage disease or related disorder, wherein the method comprises administering to a patient in need thereof the capsule according to claim 8 .
26. A method of reducing symptoms of Fabry disease, wherein the method comprises administering to a patient in need thereof the capsule according to claim 8 .