Crystalline forms of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride

• US 7,994,364 B2
• Filed: 12/10/2009
• Issued: 08/09/2011
• Est. Priority Date: 06/28/2004
• Status: Active Grant

• Current Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Original Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Inventors: Fischer, Andreas, Buschmann, Helmut, Lischke, Dagmar, Gruss, Michael
• Primary Examiner(s): Sullivan; Daniel
• Assistant Examiner(s): BROOKS, CLINTON A
• Application Number:
  US12/634,777
• Publication Number:
  US 20100160447A1
• Time in Patent Office: 607 Days
• Field of Search: None
• US Class Current: 564/336
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 7/12 Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07C 213/10 Separation; Purification; Stabilisation; Use of additives
• CPC Class Codes: C07C 215/54 linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring

Abstract

A hitherto unknown crystalline form of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride, pharmaceutical compositions containing the new crystalline form, methods of producing the new crystalline form, and a related method of use including treatment of, e.g., pain and/or urinary incontinence.

Claims

1. A crystalline Form A of (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K_α

radiation at 15.1±

0.2, 16.0±

0.2, 18.9±

0.2, 20.4±

0.2, 22.5±

0.2, 27.3±

0.2, 29.3±

0.2 and 30.4±

0.2.

2. The crystalline Form A of (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride according to claim 1 exhibiting at least X-ray lines (2-theta values) in a powder diffraction when measured using Cu K_α

radiation at 14.5±

0.2, 18.2±

0.2, 20.4±

0.2, 21.7±

0.2 and 25.5±

0.2.

3. The crystalline Form A of (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride according to claim 1 exhibiting an X-ray pattern (2-theta values) in a powder diffraction when measured using Cu K_α

radiation essentially the same as that provided in FIG. 1.

4. The crystalline Form A of (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride according to claim 1 wherein the crystal has a monoclinic form.

24. A crystalline Form A of (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride according to claim 1, produced by the process of;

dissolving (−

) (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form B in acetonitrile together with active carbon,

heating the solution to the boiling point,

removing the active carbon by filtering,

stirring the solution at a temperature below 40°

C.,

removing insoluble residue by filtering and removing part of the solvent,

leaving (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form A to crystallize,

redissolving the resulting crystals in acetonitrile,

removing insoluble residue by filtering and removing part of the solvent, and

leaving (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form A to crystallize.

5. A process for producing a (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A, said process comprising;

dissolving a (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form B in acetone, acetonitrile or isopropanol to form a solution;

leaving the solution to crystallize and

isolating crystals of (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A;

wherein during the process the temperature is kept below +40°

C.

6. The process for producing a (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A according to claim 5 wherein during the process the temperature is kept below +25°

C.

7. The process of claim 5 wherein said (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form B is dissolved in acetonitrile, and further comprising the steps of;

stirring the solution;

removing insoluble residue by filtering and

evaporating the acetonitrile leaving (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form A to crystallize.

8. The process according to claim 5 wherein said (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form B is dissolved in isopropanol at temperatures above room temperature, and after complete dissolution no further heat is provided and further comprising;

adding seed crystals of (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A and then cooling the mixture down to ≦

15°

C.

9. The process of claim 8, wherein said (−

)-(1R,2R)-3-(3-dimethyl-amino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form B is dissolved in isopropanol at a temperature above 65°

C. but not exceeding 80°

C.

10. The process of claim 8, wherein said mixture is cooled down to ≦

10°

C.

11. The process of claim 8, wherein said mixture is cooled down to ≦

5°

C.

12. The process according to claim 5 further comprising redissolving the (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A in a solvent selected from acetone, acetonitrile and isopropanol, then optionally filtering the solution to remove any insoluble residue and optionally reducing the amount of solvent by evaporation, then allowing the solution to crystallize.

13. The process of claim 12, wherein said solvent is the same as that used to form the (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A before the step of redissovling.

14. The process of claim 12, wherein during the step of allowing the solution to crystallize, the temperature is maintained at ≦

15°

C.

15. The process of claim 12, wherein during the step of allowing the solution to crystallize, the temperature is maintained at ≦

10°

C.

16. The process of claim 12, wherein during the step of allowing the solution to crystallize, the temperature is maintained at ≦

5°

C.

17. A process for producing crystalline Form A of (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride comprising the step of cooling (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-hydrochloride phenol of Form B for a time between 24 hours and 168 hours at a temperature of between −

4°

C. and −

80°

C.

18. The process of claim 17 wherein the cooling temperature is between −

10°

C. and −

60°

C.

19. The process of claim 17, wherein the cooling temperature is between −

15°

C. and −

50°

C.

20. The process of claim 17, wherein the cooling temperature is between −

25°

C. and −

40°

C.

21. The process of claim 17, wherein the cooling is carried out for a time between 24 hours and 120 hours.

22. The process of claim 17, wherein the cooling is carried out for a time between 24 hours and 72 hours.

23. The process of claim 17, wherein the cooling is carried out for a time between 24 hours and 48 hours.

25. A solid pharmaceutical composition comprising, as an active ingredient, a crystalline Form A of (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K_α

radiation at 15.1±

0.2, 16.0±

0.2, 18.9±

0.2, 20.4±

0.2, 22.5±

0.2, 27.3±

0.2, 29.3±

0.2 and 30.4±

0.2, and at least one suitable additive or auxiliary substance.

26. A solid pharmaceutical composition comprising, as an active ingredient, a crystalline Form A of (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride according to claim 25, produced by the process of;

dissolving (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form B in acetonitrile together with active carbon,

heating the solution to the boiling point,

removing the active carbon by filtering,

stirring the solution at a temperature below 40°

C.,

removing insoluble residue by filtering and removing part of the solvent,

leaving (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form A to crystallize, and

redissolving the resulting crystals in acetonitrile,

removing insoluble residue by filtering and removing part of the solvent, and

leaving (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form A to crystallize, and

at least one suitable additive or auxiliary substance.

27. A method of treating or inhibiting pain or urinary incontinence, said method comprising the step of administering a pharmaceutically effective amount of a crystalline Form A of (−

)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu K_α

radiation at 15.1±

0.2, 16.0±

0.2, 18.9±

0.2, 20.4±

0.2, 22.5±

0.2, 27.3±

0.2, 29.3±

0.2 and 30.4±

0.2 to a subject in need thereof.