Low hygroscopic aripiprazole drug substance and processes for the preparation thereof

• US 8,399,469 B2
• Filed: 04/26/2007
• Issued: 03/19/2013
• Est. Priority Date: 09/25/2001
• Status: Expired due to Term

• Current Assignee: Otsuka Pharmaceutical Company Limited (Otsuka Holdings Company Limited)
• Original Assignee: Otsuka Pharmaceutical Company Limited (Otsuka Holdings Company Limited)
• 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
• Primary Examiner(s): Wilson, James O
• Assistant Examiner(s): SACKEY, EBENEZER O
• Application Number:
  US11/790,604
• Publication Number:
  US 20070212421A1
• Time in Patent Office: 2,154 Days
• Field of Search: 514/252.13, 544/363
• US Class Current: 514/252.13
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 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 Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 215/22 attached in position 2 or 4
• CPC Class Codes: C07D 215/227 only one oxygen atom which is attached in position 2
• CPC Class Codes: Y10T 428/2982 Particulate matter [e.g., sphere, flake, etc.]

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.

Claims

1. Hydrate A of aripiprazole characterized by one or more of the properties chosen from:

a powder x-ray diffraction spectrum comprising characteristic peaks at 20=12.6°

, 15.4°

, 17.3°

, 18.0°

, 18.6°

, 22.5° and

24.8°

using a Cu K_α

x-ray;

an infrared absorption spectrum comprising infrared absorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and 784 cm^-1 on the IR (KBr) spectrum; and

an endothermic trace comprising an endothermic peak at about 71°

C. and a second endothermic peak around 60°

C. to 120°

C. in a thermogravimetric or differential thermal analysis (heating rate 5°

C/min).

2. Hydrate A of aripiprazole according to claim 1, wherein said Hydrate has a mean particle size of 50 μ

m or less.

3. Hydrate A of aripiprazole accoding to claim 2, wherein said Hydrate has a mean particle size range of 36 to 14 μ

m.

8. Hydrate A of aripiprazole according to claim 2, wherein said hydrate has a mean particle size of 20 μ

m or less.

9. Hydrate A of aripiprazole according to claim 2, wherein the mean particle size is measured using a laser diffraction particle size analyzer.

10. Hydrate A of aripiprazole according to claim 3, wherein the mean particle size is measured using a laser diffraction particle size analyzer.

11. Hydrate A of aripiprazole according to claim 8, wherein the mean particle size is measured using a laser diffraction particle size analyzer.

14. Hydrate A of aripiprazole according to any one of claims 9, 10, or 11, wherein the mean particle size is measured by suspending 0.1 g of the Hydrate A of aripiprazole in a 20 mL n-hexane solution of 0.5 g soy lecithin.

4. A process for preparing Hydrate A of aripiprazole wherein said process comprises milling Aripiprazole Hydrate characterized by one or more of the properties chosen from:

a powder x-ray diffraction spectrum comprising characteristic peaks at 2θ

=12. 6°

, 15.1°

, 17.4°

, 18.2°

, 18.7°

, 24.8° and

27.5°

using a Cu K_α

x-ray; and

an endothermic trace comprising endothermic peaks at 75.0°

C., 123.5°

C. and 140. 5°

C. in a thermogravimetric or differential thermal analysis (heating rate 5°

C./min)

to a mean particle size of 50 μ

m or less.

5. A process according to claim 4, wherein said milling is performed by an atomizer using a rotational speed of 5000-15000 rpm for the main axis, a feed rotation of 10-30 rpm and a screen hole size of 1-5 mm.

12. The process according to claim 4, wherein the Hydrate A of aripiprazole is characterized by one or more properties chosen from:

a powder x-ray diffraction spectrum comprising characteristic peaks at 2θ

=12.6°

, 15.4°

, 17.3°

, 18.0°

, 18.6°

, 22.5° and

24.8°

using a Cu K_θ

x-ray;

an infrared absorption spectrum comprising infrared absorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and 784 cm^-1 on the IR (KBr) spectrum;

an endothermic trace comprising an endothermic peak at about 71°

C. and a second endothermic peak around 60°

C. to 120°

C. in a thermogravimetric or differential thermal analysis (heating rate 520 C./min); and

a mean particle size of 50 μ

m or less.

16. The process according to any one of claim 4 or 12, wherein the mean particle size is measured by suspending 0.1 g of the Hydrate A of aripiprazole in a 20 mL n-hexane solution of 0.5 g soy lecithin using a laser diffraction particle size analyzer.

6. Hydrate A of aripiprazole made by a pocess comprising milling Aripiprazole Hydrate characterized by one or more of the properties chosen from:

a powder x-ray diffraction spectrum having characteristic peaks at 2θ

=12.6°

, 15.1°

, 17.4°

, 18.2°

, 18.7°

, 24.8° and

27.5°

using a Cu K_α

x-ray; and

an endothermic trace comprising endothermic peaks at 75.0°

C., 123.5°

C. and 140. 5°

C. in a thermogravimetric or differential thermal analysis (heating rate 5°

C/min)

to a mean particle size of 50 μ

m or less.

7. Hydrate A of aripiprazole according to claim 6, wherein said milling is performed by an atomizer using a rotational speed of 5000-15000 rpm for the main axis, a feed rotation of 10-30 rpm and a screen hole size of 1-5 mm.

13. Hydrate A of aripiprazole according to claim 6, wherein the Hydrate A of aripiprazole is characterized by one or more properties chosen from:

a powder x-ray diffraction spectrum comprising characteristic peaks at 2θ

=12.6°

, 15.4°

, 17.3°

, 18.0°

, 18.6°

, 22.5° and

24.8°

using a Cu K_α

x-ray;

an infrared absorption spectrum comprising infrared absorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and 784 cm^-1 on the IR (KBr) spectrum;

an endothermic trace comprising an endothermic peak at about 71°

C. and a second endothermic peak around 60°

C. to 120°

C. in a thermogravimetric or differential thermal analysis (heating rate 5°

C./min); and

a mean particle size of 50 μ

m or less.

15. Hydrate A of aripiprazole according to any one of claims 6, 7, or 13, wherein the mean particle size is measured by suspending 0.1 g of the Hydrate A of aripiprazole in a 20 mL n-hexane solution of 0.5 g soy lecithin using a laser diffraction particle size analyzer.