US20070213405A1 - Crystalline forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride - Google Patents

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

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US20070213405A1
US20070213405A1 US11/646,232 US64623206A US2007213405A1 US 20070213405 A1 US20070213405 A1 US 20070213405A1 US 64623206 A US64623206 A US 64623206A US 2007213405 A1 US2007213405 A1 US 2007213405A1
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methylpropyl
dimethylamino
ethyl
phenol hydrochloride
crystalline form
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Abandoned
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Andreas Fischer
Helmut Buschmann
Michael Gruss
Dagmar Lischke
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Gruenenthal GmbH
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Gruenenthal GmbH
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Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Assigned to GRUENENTHAL GMBH reassignment GRUENENTHAL GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BUSCHMANN, HELMUT, FISCHER, ANDREAS, GRUSS, MICHAEL, LISCHKE, DAGMAR
Publication of US20070213405A1 publication Critical patent/US20070213405A1/en
Priority to US12/274,747 priority Critical patent/US20090186947A1/en
Priority to US12/634,777 priority patent/US7994364B2/en
Priority to US13/172,009 priority patent/US20110294898A1/en
Priority to US13/565,867 priority patent/US20120302643A1/en
Priority to US13/923,891 priority patent/US20140011886A1/en
Priority to US14/304,313 priority patent/US20140296346A1/en
Priority to US14/930,337 priority patent/US20160122287A1/en
Priority to US15/428,613 priority patent/US20170166515A1/en
Priority to US15/725,967 priority patent/US20180029976A1/en
Priority to US15/951,838 priority patent/US20180230082A1/en
Priority to US16/172,100 priority patent/US20190062263A1/en
Priority to US16/600,884 priority patent/US20200102261A1/en
Priority to US16/909,123 priority patent/US20200385334A1/en
Priority to US17/194,717 priority patent/US20210261492A1/en
Priority to US18/103,410 priority patent/US20230174458A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • This invention relates to solid crystalline forms of ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride compounds, methods of producing these compounds, and related treatments, including use as analgesics as well as pharmaceutical compositions containing these compounds.
  • One object of the present invention is to provide new solid forms of ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride useful in the treatment or inhibition of pain.
  • U.S. Pat. Nos. 6,248,737 and 6,344,558 as well as European Patent EP 693 475 B1 disclose the substance and the synthesis of ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride in example 25.
  • the 1R,2R configuration as shown in the drawing of the structure in example 25 is correct although the configuration is reported as ( ⁇ )-(1R,2S) in U.S. Pat. No. 6,248,737 and ( ⁇ )-(1S,2S) in U.S. Pat. No. 6,344,558 as well as in EP 693 475 B1.
  • the present invention provides a new form (Form A) of ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride which is different from the form already known (Form B) obtained by the procedure described in example 25 of U.S. Pat. No. 6,248,737 and U.S. Pat. No. 6,344,558 as well as EP 693 475 B1.
  • This new Form A of ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride is very stable at ambient conditions and therefore useful for producing a pharmaceutical composition.
  • FIG. 1 shows an X-ray diffraction pattern
  • FIG. 2 shows an infrared spectrum
  • FIG. 3 shows a RAMAN spectrum
  • FIG. 4 shows an X-ray diffraction pattern
  • FIG. 5 shows an infrared spectrum
  • FIG. 6 shows a RAMAN spectrum
  • FIG. 7 shows an X-ray diffraction pattern
  • FIG. 8 shows an X-ray diffraction pattern
  • the new crystalline Form A of ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride can be identified by X-ray powder diffraction.
  • the X-ray diffraction (“XRPD”) pattern is shown in FIG. 1 with the peak listing shown as Table 1.
  • RAMAN technique can also be used to identify of the crystalline Form A of ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride. Especially the range between 800 cm ⁇ 1 and 200 cm ⁇ 1 , which is shown in FIG. 3 , is advantageously used also by way of RAMAN microscopy.
  • the elemental cell of the crystal of crystalline Form A has a volume of 1434 ⁇ 5 ⁇ 3 and a calculated density of 1.20 ⁇ 0.01 g/cm 3 .
  • the invention further relates to processes for the preparation of crystalline Form A of ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride.
  • ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A is produced by dissolving the ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form B in acetone, acetonitrile or isopropanol, optionally followed by filtering, leaving the solution to crystallize and isolating the crystals of ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A preferably by filtering again.
  • acetone or acetonitrile it is preferred that during this process the temperature is kept below +40° C., more preferably below +25° C., especially after filtering. It is further preferred that in this process between 5 mg and 1 mg, more preferably between 2.5 mg and 1.4 mg, especially between 2.0 mg and 1.4 mg ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride is dissolved per ml solvent.
  • isopropanol is preferred, if seed crystals of ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A are available.
  • the isopropanol used preferably contains about 0.5% per volume of water.
  • the dissolution of the ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form B in isopropanol is performed at temperatures above room temperature, preferably above 65° C. but not exceeding 80° C. After complete dissolution the heat is turned of and the seed crystals are added during a first cooling phase. Thereafter the resulting mixture is cooled down to ⁇ 15° C., preferably ⁇ 10° C. and especially ⁇ 5° C.
  • the solvent by evaporation, preferably in an evaporator under reduced pressure.
  • the remaining volume of the solution after evaporation should not be less than 20% of the volume at the beginning of the process.
  • active carbon it is also possible to add active carbon to the solution originally prepared.
  • the ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A obtained by the process described above is redesolved in acetone acetonitrile or isopropanol, preferably in the solvent already used in the first step, optionally is filtered to remove any insoluble residue and, optionally after reducing the amount of solvent by evaporation, is left to crystallize.
  • the temperature is maintained at ⁇ 15° C., more preferably ⁇ 10° C. and especially ⁇ 5° C.
  • ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A is produced in the solid state by cooling ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form B between 24 h and 168 h to a temperature between ⁇ 4° C. and ⁇ 80° C. It is preferred that in this process the cooling temperature is between ⁇ 10° C. and ⁇ 60° C., preferably between ⁇ 15° C. and ⁇ 50° C., especially between ⁇ 25° C. and ⁇ 40° C. and the cooling is carried out for a time between 24h and 120 h, preferably between 24 h and 72 h, especially between 24 h and 48 h.
  • This invention further relates to a new Crystalline Form A of ( ⁇ )-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride obtainable by 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 crystals so obtained in acetonitrile, removing insoluble residue by filtering and removing part of the solvent leaving ( ⁇ )-(1R,2
  • Crystalline Form A according to the invention has the same pharmacological activity as Form B but is more stable under ambient conditions. It can be advantageously used as active ingredient in pharmaceutical compositions.
  • the invention further relates to a pharmaceutical composition containing as active ingredient ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A according to the invention and at least one suitable additive and/or auxiliary substance.
  • Such pharmaceutical composition according to the invention contains, in addition to crystalline Form A ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride, one or more suitable additive and/or auxiliary substance such as for example carrier materials, fillers, solvents, diluents, coloring agents and/or binders, and may be administered as liquid medicament preparations in the form of injectable solutions, drops or juices, as semi-solid medicament preparations in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols.
  • suitable additive and/or auxiliary substance such as for example carrier materials, fillers, solvents, diluents, coloring agents and/or binders
  • auxiliary substances etc., as well as the amounts thereof to be used depend on whether the medicament is to be administered orally, per orally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or topically, for example to the skin, the mucous membranes or the eyes.
  • suitable preparations are in the form of tablets, sugar-coated pills, capsules, granules, droplets, juices and syrups
  • parenteral, topical and inhalative application suitable forms are solutions, suspensions, readily reconstitutable dry preparations, as well as sprays.
  • Form A in a depot form, in dissolved form or in a plaster, optionally with the addition of agents promoting skin penetration, are suitable percutaneous application preparations.
  • Preparation forms that can be administered orally or percutaneously can provide for the delayed release of crystalline Form A according to the invention.
  • further active constituents known to the person skilled in the art may be added to the medicaments according to the invention.
  • the amount of active constituent to be administered to the patient varies depending on the patient's weight, on the type of application, medical indication and severity of the condition. Normally 0.005 to 1000 mg/kg, preferably 0.05 to 5 mg/kg of crystalline Form A according to the invention are administered.
  • the crystalline Form A according to the invention is used for the treatment of pain or the treatment of urinary incontinence. Accordingly the invention also relates to the use of crystalline Form A according to the invention for the treatment of pain or the treatment of urinary incontinence.
  • the invention relates to a method of treatment using a sufficient amount of crystalline Form A according to the invention for the treatment of a disease, especially pain or urinary incontinence.
  • the master recipe is valid for a 50 ml scale.
  • Crystalline Form A of ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was generated as proven by X-ray powder diffraction and by RAMAN microscopic analysis.
  • Crystalline Form A of ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was generated as proven by X-ray powder diffraction experiment and by RAMAN microscopic analysis.
  • Crystalline Form A of ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was generated as proven by X-ray powder diffraction and by RAMAN microscopic analysis.
  • the precipitated solid is filtered by vacuum through a glass filter and dried in the air.
  • Powder Data Collection was performed with a STOE Stadi P Transmission Powder Diffractometer equipped with a curved germanium monochromator and a linear position sensitive detector. The very carefully ground powders were prepared as flat samples.
  • the X-ray pattern for Form A is shown in FIG. 1 , the X-ray pattern for Form B in FIG. 4 .
  • the mid IR spectra were acquired on a Nicolet model 860 Fourier transform IR spectrophotometer equipped with a globar source, Ge/KBr beamsplitter, and deterated triglycine sulfate (DTGS) detector.
  • DTGS deterated triglycine sulfate
  • a Spectra-Tech, Inc. diffuse reflectance accessory was utilized for sampling. Each spectrum represents 256 co-added scans at a spectral resolution of 4 cm ⁇ 1 .
  • a background data set was then acquired with an alignment mirror in place.
  • a single beam sample data set was then acquired.
  • the spectrophotometer was calibrated (wavelength) with polystyrene at the time of use.
  • the spectrum for Form A is shown in FIG. 2 .
  • the spectrum for Form B is shown in FIG. 5 .
  • a colorless crystal of ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride prepared according to one of the examples 2 to 6 having approximate dimensions of 0.6 ⁇ 0.60 ⁇ 0.50 mm was mounted on a glass fiber in random orientation. Preliminary examination and data collection were performed with Cu K ⁇ radiation (1.54184 ⁇ ) on a Enraf-Nonius CAD4 computer controlled kappa axis diffractometer equipped with a graphite crystal, incident beam monochromator.
  • Cell constants and an orientation matrix for data collection were obtained from least-squares refinement using the setting angles of 25 reflections in the range 16° ⁇ 24°, measured by the computer controlled diagonal slit method of centering.
  • the monoclinic cell parameters and calculated volume are:
  • the data were collected at a temperature of ⁇ 103 ⁇ 5° C. using ⁇ - ⁇ scan technique.
  • the scan rate varied from 4 to 20°/min (in ⁇ ).
  • the variable scan rate allows rapid data collection for intense reflections where a fast scan rate is used and assures good counting statistics for weak reflections where a slow scan rate is used.
  • Data were collected to a maximum of 2 ⁇ of 75.110.
  • the scan range (in°) was determined as a function of ⁇ to correct for the separation of the K ⁇ doublet.
  • Moving-crystal moving-counter background counts were made by scanning an additional 25% above and below this range. Thus the ratio of peak counting time to background counting time was 2:1.
  • the counter aperture was also adjusted as a function of ⁇ .
  • the horizontal aperture width ranged from 2.4 to 2.5 mm; the vertical aperture was set at 4.0 mm.
  • the weighted R-factor wR and goodness of fit S are based on F ⁇ circumflex over ( ) ⁇ 2 ⁇ circumflex over ( ) ⁇
  • conventional R-factors R are based on F, with F set to zero for negative F ⁇ circumflex over ( ) ⁇ 2 ⁇ circumflex over ( ) ⁇ .
  • the threshold expression of F ⁇ circumflex over ( ) ⁇ 2 ⁇ circumflex over ( ) ⁇ > 2sigma(F ⁇ circumflex over ( ) ⁇ 2 ⁇ circumflex over ( ) ⁇ ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement.
  • R-factors based on F ⁇ circumflex over ( ) ⁇ 2 ⁇ circumflex over ( ) ⁇ are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.
  • H20B H 0.7521 0.3445 1.0166 0.054 Uiso 1 1 calc R . . H20C H 0.8179 0.2384 1.0710 0.054 Uiso 1 1 calc R . . C21 C 0.4877(7) 0.1235(5) 1.0570(3) 0.0410(11) Uani 1 1 d . . . H21A H 0.4403 0.1642 1.1006 0.053 Uiso 1 1 calc R . . H21B H 0.5842 0.0677 1.0760 0.053 Uiso 1 1 calc R . . H21C H 0.3833 0.0830 1.0281 0.053 Uiso 1 1 calc R . .
  • Cell constants and an orientation matrix for data collection were obtained from least-squares refinement using the setting angles of 6172 reflections in the range 5 ⁇ 27°.
  • the calculated density is 1.15 g ⁇ cm ⁇ 3 .
  • the refined mosaicity from DENZO/SCALEPACK was 0.680 ( ⁇ 1 mod, ⁇ 2 poor) indicating moderate crystal quality.
  • the space group was determined by the program ABSEN. From the systematic presence of:
  • _diffrn_ambient_temperature 343 (2) _diffrn_radiation_wavelength 0.71073 _diffrn_radiation_type MoK ⁇ a _diffrn_radiation_source ‘fine-focus sealed tube’ _diffrn_radiation_monochromator graphite _diffrn_measurement_device_type ? _diffrn_measurement_method ? _diffrn_detector_area_resol_mean ? _diffrn_standards_number ? _diffrn_standards_interval_count ? _diffrn_standards_interval_time ?
  • the weighted R-factor wR and goodness of fit S are based on F ⁇ circumflex over ( ) ⁇ 2 ⁇ circumflex over ( ) ⁇
  • conventional R-factors R are based on F, with F set to zero for negative F ⁇ circumflex over ( ) ⁇ 2 ⁇ circumflex over ( ) ⁇ .
  • the threshold expression of F ⁇ circumflex over ( ) ⁇ 2 ⁇ circumflex over ( ) ⁇ > 2sigma(F ⁇ circumflex over ( ) ⁇ 2 ⁇ circumflex over ( ) ⁇ ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement.
  • R-factors based on F ⁇ circumflex over ( ) ⁇ 2 ⁇ circumflex over ( ) ⁇ are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.
  • Form A and B were investigated using RAMAN spectroscopy.
  • the RAMAN spectrometer used was a Bruker Raman FT 100.
  • the RAMAN Microscope was a Renishaw 1000 System, 20 ⁇ Obj. Long working distance, diode laser 785 nm.
  • Raman spectroscopy was able to distinguish clearly between Forms A and B. Differences between the spectra of the two forms appear in the whole spectral range (3200-50 cm ⁇ 1 ), but the difference in the range between 800-200 cm-1 were most significant.
  • a variable temperature X-ray powder diffraction experiment was run thereby producing Form B from Form A.
  • Form A converted to Form B from 40-50° C. during the experiment.
  • the result is reversible with Form B changing over into Form A at lower temperature.

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US11/646,232 2004-06-28 2006-12-28 Crystalline forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride Abandoned US20070213405A1 (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
US12/274,747 US20090186947A1 (en) 2004-06-28 2008-11-20 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US12/634,777 US7994364B2 (en) 2004-06-28 2009-12-10 Crystalline forms of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US13/172,009 US20110294898A1 (en) 2004-06-28 2011-06-29 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol Hydrochloride
US13/565,867 US20120302643A1 (en) 2004-06-28 2012-08-03 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol Hydrochloride
US13/923,891 US20140011886A1 (en) 2004-06-28 2013-06-21 Crystalline Forms of (-)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US14/304,313 US20140296346A1 (en) 2004-06-28 2014-06-13 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US14/930,337 US20160122287A1 (en) 2004-06-28 2015-11-02 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US15/428,613 US20170166515A1 (en) 2004-06-28 2017-02-09 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US15/725,967 US20180029976A1 (en) 2004-06-28 2017-10-05 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US15/951,838 US20180230082A1 (en) 2004-06-28 2018-04-12 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US16/172,100 US20190062263A1 (en) 2004-06-28 2018-10-26 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US16/600,884 US20200102261A1 (en) 2004-06-28 2019-10-14 Crystalline forms of (-)-(1r,2r)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US16/909,123 US20200385334A1 (en) 2004-06-28 2020-06-23 Crystalline forms of (-)-(1r,2r)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US17/194,717 US20210261492A1 (en) 2004-06-28 2021-03-08 Crystalline forms of (-)-(1r,2r)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US18/103,410 US20230174458A1 (en) 2004-06-28 2023-01-30 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride

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EP04015091A EP1612203B1 (de) 2004-06-28 2004-06-28 Kristalline Formen von (-)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochlorid
EP04015091.4 2004-06-28
PCT/EP2005/006884 WO2006000441A2 (en) 2004-06-28 2005-06-27 Crystalline forms of (-)-(1r,2r)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride

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US11/646,232 Abandoned US20070213405A1 (en) 2004-06-28 2006-12-28 Crystalline forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US12/274,747 Abandoned US20090186947A1 (en) 2004-06-28 2008-11-20 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US12/634,777 Active US7994364B2 (en) 2004-06-28 2009-12-10 Crystalline forms of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US13/172,009 Abandoned US20110294898A1 (en) 2004-06-28 2011-06-29 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol Hydrochloride
US13/565,867 Abandoned US20120302643A1 (en) 2004-06-28 2012-08-03 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol Hydrochloride
US13/923,891 Abandoned US20140011886A1 (en) 2004-06-28 2013-06-21 Crystalline Forms of (-)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US14/304,313 Abandoned US20140296346A1 (en) 2004-06-28 2014-06-13 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US14/930,337 Abandoned US20160122287A1 (en) 2004-06-28 2015-11-02 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US15/428,613 Abandoned US20170166515A1 (en) 2004-06-28 2017-02-09 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US15/725,967 Abandoned US20180029976A1 (en) 2004-06-28 2017-10-05 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US15/951,838 Abandoned US20180230082A1 (en) 2004-06-28 2018-04-12 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US16/172,100 Abandoned US20190062263A1 (en) 2004-06-28 2018-10-26 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US16/600,884 Abandoned US20200102261A1 (en) 2004-06-28 2019-10-14 Crystalline forms of (-)-(1r,2r)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US16/909,123 Abandoned US20200385334A1 (en) 2004-06-28 2020-06-23 Crystalline forms of (-)-(1r,2r)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US17/194,717 Abandoned US20210261492A1 (en) 2004-06-28 2021-03-08 Crystalline forms of (-)-(1r,2r)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US18/103,410 Pending US20230174458A1 (en) 2004-06-28 2023-01-30 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride

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US12/274,747 Abandoned US20090186947A1 (en) 2004-06-28 2008-11-20 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US12/634,777 Active US7994364B2 (en) 2004-06-28 2009-12-10 Crystalline forms of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US13/172,009 Abandoned US20110294898A1 (en) 2004-06-28 2011-06-29 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol Hydrochloride
US13/565,867 Abandoned US20120302643A1 (en) 2004-06-28 2012-08-03 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol Hydrochloride
US13/923,891 Abandoned US20140011886A1 (en) 2004-06-28 2013-06-21 Crystalline Forms of (-)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US14/304,313 Abandoned US20140296346A1 (en) 2004-06-28 2014-06-13 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US14/930,337 Abandoned US20160122287A1 (en) 2004-06-28 2015-11-02 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US15/428,613 Abandoned US20170166515A1 (en) 2004-06-28 2017-02-09 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US15/725,967 Abandoned US20180029976A1 (en) 2004-06-28 2017-10-05 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US15/951,838 Abandoned US20180230082A1 (en) 2004-06-28 2018-04-12 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US16/172,100 Abandoned US20190062263A1 (en) 2004-06-28 2018-10-26 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US16/600,884 Abandoned US20200102261A1 (en) 2004-06-28 2019-10-14 Crystalline forms of (-)-(1r,2r)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US16/909,123 Abandoned US20200385334A1 (en) 2004-06-28 2020-06-23 Crystalline forms of (-)-(1r,2r)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US17/194,717 Abandoned US20210261492A1 (en) 2004-06-28 2021-03-08 Crystalline forms of (-)-(1r,2r)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride
US18/103,410 Pending US20230174458A1 (en) 2004-06-28 2023-01-30 Crystalline Forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride

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