Low hygroscopic aripiprazole drug substance and processes for the preparation thereof

Patent metadata

Field	Value
Publication number	US-9359302-B2
Application number	US-201314049777-A
Country	US
Kind code	B2
Filing date	Oct 9, 2013
Priority date	Sep 25, 2001
Publication date	Jun 7, 2016
Grant date	Jun 7, 2016

Abstract

The present invention provides low hygroscopic forms of aripiprazole and processes for the preparation thereof which will not convert to a hydrate or lose their original solubility even when a medicinal preparation containing the anhydrous aripiprazole crystals is stored for an extended period.

First claim

The invention claimed is:

1. Anhydrous aripiprazole crystals having low hygroscopicity, wherein said low hygroscopicity is defined as a moisture content of 0.40% or less when the anhydrous aripiprazole crystals are placed for 24 hours in a dessicator maintained at a temperature of 60° C. and a humidity level of 100%,
wherein the anhydrous aripiprazole crystals have one or more of the following properties:
a powder x-ray diffraction spectrum comprising characteristic peaks at 2θ=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°, using a Cu K α x-ray;
an infrared absorption spectrum comprising infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm −1 on the IR (KBr) spectrum;
an endothermic curve comprising an endothermic peak at about 141.5° C. in a thermogravimetric or differential thermal analysis (heating rate 5° C./min); and
an endothermic curve comprising an endothermic peak at about 140.7° C. in a differential scanning calorimetry analysis (heating rate 5° C./min).

2. The anhydrous aripiprazole crystals according to claim 1 , wherein the anhydrous aripiprazole crystals have a mean particle size of 50 μm or less.

3. The anhydrous aripiprazole crystals according to claim 1 , wherein the anhydrous aripiprazole crystals have a mean particle size of 50 μm or less, wherein the mean particle size is measured using a laser diffraction particle size analyzer.

4. The anhydrous aripiprazole crystals according to claim 1 , wherein the anhydrous aripiprazole crystals have a mean particle size of 50 μm or less, wherein the mean particle size is measured using a laser diffraction particle size analyzer by suspending 0.1 g of said anhydrous aripiprazole crystals in a 20 mL n-hexane solution of 0.5 g soy lecithin.

5. The anhydrous aripiprazole crystals according to claim 1 , wherein the anhydrous aripiprazole crystals have a mean particle size of 30 μm or less.

6. The anhydrous aripiprazole crystals according to claim 1 , wherein the anhydrous aripiprazole crystals have a mean particle size of 30 μm or less, wherein the mean particle size is measured using a laser diffraction particle size analyzer.

7. The anhydrous aripiprazole crystals according to claim 1 , wherein the anhydrous aripiprazole crystals have a mean particle size of 30 μm or less, wherein the mean particle size is measured using a laser diffraction particle size analyzer by suspending 0.1 g of said anhydrous aripiprazole crystals in a 20 mL n-hexane solution of 0.5 g soy lecithin.

8. The anhydrous aripiprazole crystals according to claim 1 , wherein the anhydrous aripiprazole crystals have a powder x-ray diffraction spectrum comprising characteristic peaks at 2θ=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°, using a Cu K α x-ray.

9. The anhydrous aripiprazole crystals according to claim 1 , wherein the anhydrous aripiprazole crystals have an infrared absorption spectrum comprising infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm −1 on the IR (KBr) spectrum.

10. The anhydrous aripiprazole crystals according to claim 1 , wherein the anhydrous aripiprazole crystals have an endothermic curve comprising an endothermic peak at about 141.5° C. in a thermogravimetric or differential thermal analysis (heating rate 5° C./min).

11. The anhydrous aripiprazole crystals according to claim 1 , wherein the anhydrous aripiprazole crystals have an endothermic curve comprising an endothermic peak at about 140.7° C. in a differential scanning calorimetry analysis (heating rate 5° C./min).

12. Anhydrous aripiprazole crystals having low hygroscopicity, wherein said low hygroscopicity is defined as a moisture content of 0.40% or less when the anhydrous aripiprazole crystals are placed for 24 hours in a dessicator maintained at a temperature of 60° C. and a humidity level of 100%,
wherein the anhydrous aripiprazole crystals have a powder x-ray diffraction spectrum which is substantially the same as the powder x-ray diffraction spectrum shown in FIG. 5 using a Cu K α x-ray.

13. The anhydrous aripiprazole crystals according to claim 12 , wherein the anhydrous aripiprazole crystals have a mean particle size of 50 μm or less.

14. The anhydrous aripiprazole crystals according to claim 12 , wherein the anhydrous aripiprazole crystals have a mean particle size of 50 μm or less, wherein the mean particle size is measured using a laser diffraction particle size analyzer.

15. The anhydrous aripiprazole crystals according to claim 12 , wherein the anhydrous aripiprazole crystals have a mean particle size of 50 μm or less, wherein the mean particle size is measured using a laser diffraction particle size analyzer by suspending 0.1 g of said anhydrous aripiprazole crystals in a 20 mL n-hexane solution of 0.5 g soy lecithin.

16. The anhydrous aripiprazole crystals according to claim 12 , wherein the anhydrous aripiprazole crystals have a mean particle size of 30 μm or less.

17. The anhydrous aripiprazole crystals according to claim 12 , wherein the anhydrous aripiprazole crystals have a mean particle size of 30 μm or less, wherein the mean particle size is measured using a laser diffraction particle size analyzer.

18. The anhydrous aripiprazole crystals according to claim 12 , wherein the anhydrous aripiprazole crystals have a mean particle size of 30 μm or less, wherein the mean particle size is measured using a laser diffraction particle size analyzer by suspending 0.1 g of said anhydrous aripiprazole crystals in a 20 mL n-hexane solution of 0.5 g soy lecithin.

19. Anhydrous aripiprazole crystals having low hygroscopicity, wherein said low hygroscopicity is defined as a moisture content of 0.10% or less when the anhydrous aripiprazole crystals are placed for 24 hours in a dessicator maintained at a temperature of 60° C. and a humidity level of 100%,
wherein the anhydrous aripiprazole crystals have one or more of the following properties:
a powder x-ray diffraction spectrum comprising characteristic peaks at 2θ=11.0°, 16.6°, 19.3°, 20.3°, and 22.1°, using a Cu K α x-ray;
an infrared absorption spectrum comprising infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm −1 on the IR (KBr) spectrum;
an endothermic curve comprising an endothermic peak at about 141.5° C. in a thermogravimetric or differential thermal analysis (heating rate 5° C./min); and
an endothermic curve comprising an endothermic peak at about 140.7° C. in a differential scanning calorimetry analysis (heating rate 5° C./min).

20. The anhydrous aripiprazole crystals according to claim 19 , wherein the anhydrous aripiprazole crystals have a mean particle size of 50 μm or less.

21. The anhydrous aripiprazole crystals according to claim 19 , wherein the anhydrous aripiprazole crystals have a mean particle size of 50 μm or less, wherein the mean particle size is measured using a laser diffraction particle size analyzer.

22. The anhydrous aripiprazole crystals according to claim 19 , wherein the anhydrous aripiprazole crystals have a mean particle size of 50 μm or less, wherein the mean particle size is measured using a laser diffraction particle size analyzer by suspending 0.1 g of said anhydrous aripiprazole crystals in a 20 mL n-hexane solution of 0.5 g soy lecithin.

23. The anhydrous aripiprazole crystals according to claim 19 , wherein the anhydrous aripiprazole crystals have a mean particle size of 30 μm or less.

24. The anhydrous aripiprazole crystals according to

Assignees

• Otsuka Pharma Co Ltd

Inventors

• Bando Takuji
• Aoki Satoshi
• Kawasaki Junichi
• Ishigami Makoto
• Taniguchi Youichi
• Yabuuchi Tsuyoshi
• Fujimoto Kiyoshi
• Nishioka Yoshihiro
• Kobayashi Noriyuki
• Fujimura Tsutomu
• Takahashi Masanori
• Abe Kaoru
• Nakagawa Tomonori
• Shinhama Koichi
• Utsumi Naoto
• Tominaga Michiaki
• Ooi Yoshihiro
• Yamada Shohei
• Tomikawa Kenji

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P25/06

  Antimigraine agents · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title