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

Patent metadata

Field	Value
Publication number	US-2016122287-A1
Application number	US-201514930337-A
Country	US
Kind code	A1
Filing date	Nov 2, 2015
Priority date	Jun 28, 2004
Publication date	May 5, 2016
Grant date	—

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.

First claim

1 . 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.

2 . The process of claim 1 , 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.

3 . The process according to claim 1 , 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.

4 . The process of claim 3 , wherein said (−)-(1R,2R)-3-(3-dimethylamino-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.

5 . The process of claim 3 , wherein said mixture is cooled down to ≦10° C.

6 . The process of claim 3 , wherein said mixture is cooled down to ≦5° C.

7 . The process according to claim 1 , 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.

8 . The process of claim 7 , 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.

9 . The process of claim 7 , wherein during the step of allowing the solution to crystallize, the temperature is maintained at ≦15° C.

10 . The process of claim 7 , wherein during the step of allowing the solution to crystallize, the temperature is maintained at ≦10° C.

11 . The process of claim 7 , wherein during the step of allowing the solution to crystallize, the temperature is maintained at ≦5° C.

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

13 . A 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.

14 . A pharmaceutical composition comprising, as an active ingredient, a crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride 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, and
at least one suitable additive or auxiliary substance.

Assignees

• Gruenenthal Gmbh

Inventors

• Fischer Andreas
• Buschmann Helmut
• Gruss Michael
• Lischke Dagmar

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P13/00

  Drugs for disorders of the urinary system · CPC title

• A61P13/02

  of urine or of the urinary tract, e.g. urine acidifiers · CPC title