WO2006089708A1 - Crystalline forms of (1rs,3rs,6rs)-6-dimethvlaminomethvl-1-(3-methoxv- phenyl)cyclohexane-1 ,3-diol hydrochloride - Google Patents

Crystalline forms of (1rs,3rs,6rs)-6-dimethvlaminomethvl-1-(3-methoxv- phenyl)cyclohexane-1 ,3-diol hydrochloride Download PDF

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Publication number
WO2006089708A1
WO2006089708A1 PCT/EP2006/001548 EP2006001548W WO2006089708A1 WO 2006089708 A1 WO2006089708 A1 WO 2006089708A1 EP 2006001548 W EP2006001548 W EP 2006001548W WO 2006089708 A1 WO2006089708 A1 WO 2006089708A1
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Prior art keywords
cyclohexane
phenyl
crystalline form
methoxy
dimethylaminomethyl
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PCT/EP2006/001548
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French (fr)
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WO2006089708A8 (en
Inventor
Michael Gruss
Helmut Buschmann
Andreas Fischer
Wolfgang Hell
Dagmar Lischke
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Grünenthal GmbH
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Priority claimed from DE102005009217A external-priority patent/DE102005009217A1/en
Priority claimed from EP05004183A external-priority patent/EP1695957A1/en
Priority to NZ560204A priority Critical patent/NZ560204A/en
Priority to US11/885,039 priority patent/US8309610B2/en
Priority to EP06707124A priority patent/EP1851192A1/en
Priority to JP2007556543A priority patent/JP2008531511A/en
Priority to CA002598579A priority patent/CA2598579A1/en
Priority to CN2006800062321A priority patent/CN101128417B/en
Application filed by Grünenthal GmbH filed Critical Grünenthal GmbH
Priority to AU2006218133A priority patent/AU2006218133B8/en
Priority to BRPI0606234-2A priority patent/BRPI0606234A2/en
Priority to MX2007010192A priority patent/MX2007010192A/en
Publication of WO2006089708A1 publication Critical patent/WO2006089708A1/en
Priority to IL185467A priority patent/IL185467A0/en
Publication of WO2006089708A8 publication Critical patent/WO2006089708A8/en
Priority to NO20074676A priority patent/NO20074676L/en
Priority to IL212292A priority patent/IL212292A0/en
Priority to IL212291A priority patent/IL212291A0/en

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    • 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
    • C07C217/74—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 rings other than six-membered aromatic rings being part of the carbon skeleton
    • 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
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • This invention relates to solid crystalline forms of (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride (1), methods of producing 1 , methods of use of 1 , use of 1 as analgesics and pharmaceutical compositions comprising 1.
  • the underlying object of the present invention was to find new solid forms of
  • (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3- methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride can be produced in several different crystalline forms.
  • the present invention provides the new forms form A, form B, form C, form D and form E of (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3- methoxy-phenyl)cyclohexane ⁇ 1 ,3-diol hydrochloride.
  • the compound (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol has the following structure:
  • the new crystalline forms can be identified by X-ray powder diffraction.
  • the X-ray powder diffraction ("XRPD") patterns are shown in Figure 1 , Figure 3, Figure 5, Figure 7 and Figure 9 with the peak listing shown in Table 1.
  • Ambient temperature and room temperature is defined as 23+3 0 C.
  • RAMAN technique can also be used to identify the crystalline form A of
  • Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride showing one or a combination of the following in a Raman spectrum when measured using a laser wave length of 632 nm are 227 + 4, 262 ⁇ 4, 643 ⁇ 4, 716 ⁇ 4, 813 ⁇ 4, 830 ⁇ 4, 970 ⁇ 4, 993 ⁇ 4, 1252 ⁇ 4, 2973 ⁇ 4 and 3273 ⁇ 4 cm "1 . 5
  • the present invention relates to a process for the production of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form A comprising precipitating the free base solution of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol 0 with concentrated hydrochloric acid, stirring and filtering off the liquid phase, drying of the solid at 40-60 0 C, preferred at 45-55°C, and reduced pressure of less than 300 mbar, preferred 150 mbar, for 20-40, preferred 20-28, hours, keeping the temperature at 120-140 0 C, preferred 125-135°C, for 60-80, preferred 70-74 hours at less than 150 mbar pressure, reducing the temperature to 50-70 0 C, preferred 55- 65°C, and drying
  • the very preferred process starts from a free base solution of (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol, which is precipitated with concentrated hydrochloric acid and allowed to stirr further for 24 hours.
  • the liquid phase is filtered off.
  • the solid is dried at 50°C ⁇ 5°C and reduced pressure of less than 150 mbar for 24 hours. After that the temperature is kept at 130 0 C for another 72 + 10 hours at less than 150 mbar pressure. Then the temperature is again reduced to 60 0 C and the product is dried for another 24 hours at 60 0 C and less than 150 mbar.
  • the obtained substance is (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form A.
  • the present invention further relates to crystalline form A of (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride obtainable by one of the processes described herein.
  • Crystalline form A of (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride has the advantage of having very high solubility in water and may easily be formulated into a medicament. Moreover, since form A is an anhydrous form, the moisture (water) content must not be taken into account during formulation. Moreover form A is resistant to water absorption of up to 60 % relative humidity at room temperature for prolonged periods of time, at least up to three weeks.
  • Form A is also stable in organic media such as chloroform, dioxane, ethyl acetate, hexane, tetrahydrofuran, toluene at room temperature or higher temperatures (e.g. up to 40 0 C), e.g. in chloroform and hexane.
  • organic media such as chloroform, dioxane, ethyl acetate, hexane, tetrahydrofuran, toluene at room temperature or higher temperatures (e.g. up to 40 0 C), e.g. in chloroform and hexane.
  • This invention further relates to a new crystalline form B of (1RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride.
  • Crystalline form B can be used as active ingredient in pharmaceutical compositions.
  • the invention further relates to a pharmaceutical composition containing as active ingredient (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form B according to the invention and at least one suitable additive and/or auxiliary substance.
  • Such characteristic X-ray lines (2-theta values) for form B in a powder diffraction pattern when measured using CuK ⁇ radiation at ambient temperature are: 9.7 ⁇ 0.2, 10.5 ⁇ 0.2, 13.6 ⁇ 0.2, 14.6 ⁇ 0.2, 20.6 ⁇ 0.2, 21.6+0.2, 27.2 ⁇ 0.2 and 29.6 ⁇ 0.2.
  • the present invention further relates to a process for the preparation of crystalline form B of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride comprising the steps of dissolving crystalline form A in ethanol and/or water, sonication and allowing evaporating at room temperature at atmospheric pressure.
  • the present invention relates to a process for the production of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 ⁇ (3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form B comprising the steps of dissolving crystalline form A in ethanol and/or water, preferred ratio range ethanol to water 9,5:0,5 to 0,5 to 9,5 (weight/weight), very preferred ethanol and water ratio 9:1 (weight/weight), sonication, filtering, and allowing evaporating at room temperature by atmospheric pressure.
  • the preferred process starts from crystalline form A of (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride.
  • (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3- methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form B is produced by dissolving 30 -50 mg (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form A in a mixture of about 100 ⁇ l ethanol and water (w : w; 9 : 1) of HPLC grade.
  • the present invention relates to crystalline form B of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride obtainable by a process as described herein.
  • Crystalline form B (hydrated form) has the advantage that even under high humidity it is not converted to another polymorph. Thus, this crystalline form is particularly suitable for use in wet granulation processes, which are widely used in the pharmaceutical industry.
  • This invention further relates to a new crystalline form C of (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride. Crystalline form C can be used as active ingredient in pharmaceutical compositions.
  • the invention further relates to a pharmaceutical composition containing as active ingredient (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form C according to the invention and at least one suitable additive and/or auxiliary substance.
  • RAMAN technique can also be used to identify of the crystalline form C of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride as shown in Fig. 6.
  • the invention further relates to a process for the preparation of crystalline form C of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride comprising the step of dissolving the free base (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol in isopropanol at a temperature above room temperature.
  • the present invention relates to a process for the production of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form C comprising the step of dissolving the free base of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol in isopropanol at 40- xx°C, wherein xx is the boiling point of isopropanol under the given conditions (approximately 82°C under ambient conditions), cooling and treatment of solution with hydrogenchloride.
  • Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol of crystalline form A Approximately 20 g are dissolved in isopropanol at an elevated temperature (approximately 45 0 C or higher) to reach complete dissolution. The samples were allowed to cool to ambient temperature before treatment with gaseous hydrogen chloride. A constant purge of nitrogen was bubbled through the clear solution while stirring. Anhydrous hydrogen chloride was introduced into the system through the purge stream. Addition of hydrogen chloride was stopped when precipitation was observed. (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride form C was recovered by vacuum filtration immediately after formation.
  • the present invention relates to a process for the production of form C comprising the steps of suspending crystalline form A in a liquid medium, stirring the resulting suspension and filtering off the liquid.
  • the liquid medium may preferably be selected from the group consisting of acetonitrile, a mixture of acetonitrile and water, ethanol, and a mixture of tetrahydrofuran and methanol.
  • the temperature is preferably kept at 15 ⁇ 75 0 C, more preferably 15-60 0 C, yet more preferably 20-45 0 C, most preferably 20-26 0 C.
  • the present invention relates to crystalline form C of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride obtainable by a process as described herein.
  • Polymorph C has the advantage that it has the lowest hygroscopicity of all known polymorphic forms. Moreover it has the highest thermodynamic stability of the known polymorphic forms at temperatures of 15-60 0 C, particulary of 15-35°C. These properties make polymorph C particularly useful for its formulation into a pharmaceutical composition and a medicament.
  • thermodynamic properties can be evaluated by measuring the equilibrium solubilities in the respective temperature range such as 15-6O 0 C and in particular 15- 35°C and graphical evaluation of the results via a van ' t Hoff Plot (solubility vs. 1/T) as described in the publications of W. Higuchi et al, J. Pharm. Sci. 1963, 52, 150-153 and S. R. Byrn., Solid State Chemistry of drugs, 2 nd edition, SSCI Inc., 1999. The respective parts of the descriptions are hereby incorporated by reference and form part of the present disclosure.
  • This invention further relates to a new crystalline form D of (1 RS,3RS,6RS)-6 ⁇ Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride.
  • Crystalline form D can be used as active ingredient in pharmaceutical compositions.
  • the invention further relates to a pharmaceutical composition containing as active ingredient (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form D according to the invention and at least one suitable additive and/or auxiliary substance.
  • the Invention further relates to a process for the preparation of crystalline form D of 15 (1 RS.SRS.eRSJ- ⁇ -Dimethylaminomethyl-i-CS-methoxy-phenyOcyclohexane-i ,3-diol hydrochloride comprising the step of heating crystalline form B to a temperature of at least 160 0 C.
  • the present invention related to a process for the production of 0 (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form D comprising heating form B to 160-185 0 C, preferred 175-185°C, for 20-50, preferred 30-40 minutes, and cooling to room temperature.
  • Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride form B A small sample is heated in a XRPD glass capillary to 180 0 C for approx. 35 minutes. After cooling down to ambient temperature (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride form 0 D was recovered.
  • Another aspect of the present invention relates to crystalline form D of
  • (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride obtainable by a process as described herein.
  • This invention further relates to a new crystalline form E of (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1 ⁇ (3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride.
  • Crystalline form E can be used as active ingredient in pharmaceutical compositions.
  • the invention further relates to a pharmaceutical composition containing as active ingredient (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form E according to the invention and at least one suitable additive and/or auxiliary substance.
  • RAMAN technique can also be used to identify of the crystalline form E of
  • the Invention further relates to a process for the preparation of crystalline form E of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride comprising the step of heating crystalline form B to 80-100 0 C.
  • the present invention relates to a process for the production of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3 ⁇ methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form E comprising the step of heating form B to 80- 100 0 C, preferred 85-95°C, for 20-40, preferred 25-35, minutes.
  • the very preferred process starts from the freshly prepared (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride form B.
  • a small sample is heated in a XRPD glass capillary to 90 0 C for approx. 30 minutes.
  • (1 RS,3RS,6RS)-6-Dimethylaminomethyl ⁇ 1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride form E was recovered.
  • form E is prepared by drying freshly prepared (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride form B at 60 0 C at ambient relative humidity for 2 to 6 weeks.
  • Another aspect of the present invention relates to crystalline form E of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride obtainable by a process as described herein.
  • the preferred crystalline form is form A.
  • the preferred crystalline form is form B.
  • the preferred crystalline form is form C.
  • the preferred crystalline form is form D.
  • the preferred crystalline form is form E.
  • the very preferred crystalline forms are A, B, C especially preferred form is C.
  • compositions comprising mixtures of crystalline forms according to the invention, preferred mixtures of crystalline forms comprising one or more members selected from the group of the forms A, B, C, very preferred comprising form C.
  • compositions comprising mixtures of crystalline forms according to the invention, preferred mixtures of crystalline forms comprising one or more members selected from the group of the forms A, B, C, very preferred comprising form C.
  • pharmaceutical composition containing as active ingredient a or a mixture of, preferred a, crystalline form(s) according to the invention and containing preferred at least one suitable additive and/or auxiliary substance.
  • the pain is selected from the group consisting of acute pain, chronic pain, visceral pain, neuropathic pain and inflammatory pain, more preferably preferred acute or chronic pain.
  • compositions according to the invention may preferably contain in addition to the crystalline forms (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3- methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride, one or more suitable additive and/or auxiliary substance such as for example carrier materials, fillers, solvents,
  • 15 diluents, colouring agents and/or binders may be administered as liquid medicament preparations in the form of injectable solutions, drops or juices, as semisolid or solid medicament preparations in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols.
  • 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, intradermal ⁇ , intramuscularly, intranasally, buccally, rectally or topically, for example to the skin, the mucous membranes or the eyes.
  • suitable preparations are in the form of 5 tablets, sugar-coated pills, capsules, granules, droplets, juices and syrups
  • suitable forms are solutions, suspensions, readily reconstitutable dry preparations, as well as sprays.
  • the multiparticulate forms such as pellets or crystals may, for example, be compressed into a tablet, filled into a capsule or suspended in a suitable liquid.
  • Crystalline forms 0 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 forms according to the invention.
  • further active constituents known to the person skilled in the art may be added to the medicaments/pharmaceutical compositions according to the present invention.
  • inventive pharmaceutical formulations / medicaments may be produced using materials, means, devices and processes that are well known in the prior art of pharmaceutical formulations, as described for example in "Remington's Pharmaceutical Sciences", A.R. Gennaro (ed.), 17 th edition Mack Publishing Company, Easton, Pa. (1985), in particular in part 8, chapters 76 to 93. The respective parts of the description are hereby incorporated by reference and form part of the disclosure.
  • 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 the crystalline forms according to the invention are administered.
  • the crystalline forms according to the invention are used for the treatment of pain, wherein the pain is preferably selected from the group of chronic pain, acute pain, visceral pain, neuropathic pain and inflammatory pain, more preferably the pain is chronic pain or acute pain.
  • the invention relates to a method of treatment using a sufficient amount of the crystalline forms according to the invention for the treatment of a disease, preferably for treating pain, urinary incontinence, depression or anxiety, preferably pain, more preferably pain selected from the group of chronic pain, acute pain, visceral pain, neuropathic pain and inflammatory pain, yet more preferably for the treatment of chronic pain or acute pain.
  • Example 1 Powder diffraction patterns of forms A, B and C
  • Powder Data Collection was done with a STOE Stadi P Powder Diffractometer equipped with a curved germanium monochromator and a linear position sensitive
  • the samples were prepared as flat samples.
  • the X-ray powder pattern for form A is shown in Figure 1
  • the X-ray powder pattern for form B is shown in Figure 3
  • the X-ray powder pattern for form C is shown in Figure 5.
  • Example 2 Powder diffraction patterns of forms D and E
  • Powder Data Collection was carried out on a Shimadzu XRD-6000 X-ray powder 0 diffractometer using Cu Ka radiation.
  • the instrument is equipped with a fine focus X- ray tube.
  • the tube voltage and amperage were set to 40 kV and 40 mA, respectively.
  • the divergence and scattering slits were set at 1 ° and the receiving slit was set at 0.15 mm.
  • Diffracted radiation was detected by a NaI scintillation detector.
  • a theta- two theta continuous scan at 3 7min (0.4 sec/0.02° step) from 2.5 to 40 °2 ⁇ was 5 used.
  • a silicon standard was analyzed each day to check the instrument alignment. The data were collected at a temperature of 23 ⁇ 1 ° .
  • the X-ray powder diffraction pattern for form D is shown in Figure 7 and the X-ray powder diffraction pattern for form E is shown in Figure 9. 0
  • Example 3 RAMAN spectra of forms A, B and C
  • the polymorphs of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride were investigated using RAMAN microscopy.
  • the RAMAN spectrometer used was a Jobin Yvon Horiba Labram.
  • the microscope was an Olympus BX40 System, 10Ox Obj., diode laser 632 nm.
  • Raman microscopy was able to distinguish between forms A, B, C and D. Differences between the spectra of the two forms appear in the whole spectral range (3500-150 cm "1 ).
  • the polymorphs of (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride were investigated using RAMAN spectroscopy
  • the Raman spectrum was acquired on a Raman accessory interfaced to a Nicolet Magna 960 Fourier transform infrared spectrometer using InGaAs detector.
  • the accessory utilizes an excitation wavelength of 1064 nm and approximately 0.45 W of Nd: YAG laser power.
  • the spectrum represents 256 co-added scans acquired at 4 cm-1 resolution.
  • the sample was prepared for analysis by placing a portion into a 5- mm diameter glass tube and positioning this tube in the spectrometer.
  • the spectrometer was calibrated (wavelength) with sulfur and cyclohexane at the time of use.
  • Variable temperature Powder Diffraction Data Collection was carried out on a Shimadzu XRD-6000 X-ray powder diffractometer using Cu Ka radiation.
  • the instrument is equipped with a fine focus X-ray tube.
  • the tube voltage and amperage were set to 40 kV and 40 mA, respectively.
  • the divergence and scattering slits were set at 1° and the receiving slit was set at 0.15 mm.
  • Diffracted radiation was detected by a NaI scintillation detector.
  • a theta-two theta continuous scan at 3 7min (0.4 sec/0.02° step) from 2.5 to 40 °2 ⁇ was used.
  • a silicon standard was analyzed each day to check the instrument alignment.
  • the instrument was equipped with an Anton Paar HTK 1200 high temperature stage and a ceramic sample holder
  • a variable temperature X-ray powder diffraction experiment was run thereby producing form E from form B.
  • form B converted to form E at 90 0 C after half an hour during the experiment.
  • Crystalline form C was also obtained when the process was carried out at 60 0 C.
  • Crystalline form B in an open glas container is stored in a humidity chamber at relative humidity of 35 % and room temperature. Samples were taken prior to storage and after 4, 14, 19 and 21 days of storage under these conditions. In all cases the samples were found to be crystalline form B only.
  • Crystalline form B in an open glas container is stored in a humidity chamber at relative humidity of 60 % and room temperature. Samples were taken prior to storage and after 7, 17 and 22 days of storage under these conditions. In all cases the samples were found to be crystalline form B only.
  • Example 12 Crystalline form B in an open glas container is stored in a humidity chamber at relative humidity of 75 % and room temperature. Samples were taken prior to storage and after 6, 13 and 23 days of storage under these conditions. In all cases the samples were found to be crystalline form B only.
  • Example 13 Example 13:

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Abstract

This invention relates to solid crystalline forms of (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride (1), methods of producing 1, methods of use of 1, use of 1 as analgesics and pharmaceutical compositions comprising 1.

Description

Crystalline forms of (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride
This invention relates to solid crystalline forms of (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride (1), methods of producing 1 , methods of use of 1 , use of 1 as analgesics and pharmaceutical compositions comprising 1.
The treatment of pain conditions is of great importance in medicine. There is currently a world-wide need for additional pain therapy. The pressing requirement for a target-oriented treatment of pain conditions which is right for the patient, which is to be understood as the successful and satisfactory treatment of pain for the patients, is documented in the large number of scientific works which have recently and over the years appeared in the field of applied analgesics or on basic research on nociception.
The underlying object of the present invention was to find new solid forms of
(1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride, preferably useful in the treatment of pain.
US Pat. Nos. RE 37355 E and 5,733,936 as well as European Patent EP 753 506 B1 disclose the substance and the synthesis of (1RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride in example 18.
It has now been surprisingly found that (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3- methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride can be produced in several different crystalline forms. The present invention provides the new forms form A, form B, form C, form D and form E of (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3- methoxy-phenyl)cyclohexane~1 ,3-diol hydrochloride. These new forms of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride are useful for producing pharmaceutical compositions. It is the first time to have access to the relevant polymorphs of this important pharmaceutical compound. The polymorph forms are important for evaluation of synthesis, stability and safety both of this compound and of the pharmaceutical formulation made from this compound. Furthermore each of the polymorph forms are important in terms of the different pharmaceutical formulation process that might be involved, in which each of the polymorphs are advantageous with their special physico-chemical properties.
The compound (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol has the following structure:
Figure imgf000003_0001
oder in a different notation:
Figure imgf000003_0002
The new crystalline forms can be identified by X-ray powder diffraction. The X-ray powder diffraction ("XRPD") patterns are shown in Figure 1 , Figure 3, Figure 5, Figure 7 and Figure 9 with the peak listing shown in Table 1. Ambient temperature and room temperature is defined as 23+30C. The most important X-ray lines (2-theta values) in terms of intensity characterizing form A of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride showing one or a combination of the following in a powder diffraction measurement when measured using Cu Ka radiation 5 at ambient temperature are 12.9+ 0.2, 17.5+0.2, 19.0±0.2, 19.3±0.2, 21.0±0.2 and 25.3±0.2.
To discriminate crystalline form A of (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3- methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride from the other forms it is more 0 advantageous to look at the unique peaks in the X-ray diffraction diagram, i.e. the lines with sufficient intensity at 2-theta values, where the other modifications do not show lines with significant intensity. Such characteristic X-ray lines (2-theta values) for form A in a powder diffraction pattern when measured using CuKa radiation at ambient temperature are: 11.0±0.2, 12.3±0.2, 12.9±0.2, 16.6±0.2, 17.9±0.2, [5 19.0±0.2 and 25.3±0.2.
RAMAN technique can also be used to identify the crystalline form A of
(1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride as shown in Fig. 2. The most important Raman wave numbers (cm"1)
20 in terms of intensity characterizing form A of (1 RS,3RS,6RS)-6-
Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride showing one or a combination of the following in a Raman spectrum when measured using a laser wave length of 632 nm are 227 + 4, 262 ± 4, 643 ± 4, 716 ± 4, 813 ± 4, 830 ± 4, 970 ± 4, 993 ± 4, 1252 ± 4, 2973 ± 4 and 3273 ± 4 cm"1. 5
In another aspect the present invention relates to a process for the production of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form A comprising precipitating the free base solution of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol 0 with concentrated hydrochloric acid, stirring and filtering off the liquid phase, drying of the solid at 40-60 0C, preferred at 45-55°C, and reduced pressure of less than 300 mbar, preferred 150 mbar, for 20-40, preferred 20-28, hours, keeping the temperature at 120-1400C, preferred 125-135°C, for 60-80, preferred 70-74 hours at less than 150 mbar pressure, reducing the temperature to 50-70 0C, preferred 55- 65°C, and drying the product for another 20-60, preferred 20-30, hours at 50-70, preferred 55-65°C, at less than 150 mbar.
The very preferred process starts from a free base solution of (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol, which is precipitated with concentrated hydrochloric acid and allowed to stirr further for 24 hours. The liquid phase is filtered off. The solid is dried at 50°C ± 5°C and reduced pressure of less than 150 mbar for 24 hours. After that the temperature is kept at 130 0C for another 72 + 10 hours at less than 150 mbar pressure. Then the temperature is again reduced to 60 0C and the product is dried for another 24 hours at 60 0C and less than 150 mbar. The obtained substance is (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form A.
The present invention further relates to crystalline form A of (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride obtainable by one of the processes described herein.
Crystalline form A of (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride has the advantage of having very high solubility in water and may easily be formulated into a medicament. Moreover, since form A is an anhydrous form, the moisture (water) content must not be taken into account during formulation. Moreover form A is resistant to water absorption of up to 60 % relative humidity at room temperature for prolonged periods of time, at least up to three weeks. Form A is also stable in organic media such as chloroform, dioxane, ethyl acetate, hexane, tetrahydrofuran, toluene at room temperature or higher temperatures (e.g. up to 40 0C), e.g. in chloroform and hexane.
This invention further relates to a new crystalline form B of (1RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride.
Crystalline form B can be used as active ingredient in pharmaceutical compositions.
Therefore the invention further relates to a pharmaceutical composition containing as active ingredient (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form B according to the invention and at least one suitable additive and/or auxiliary substance.
The most important X-ray lines (2-theta values) in terms of intensity characterizing 5 form B of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride showing one or a combination of the following in a powder diffraction measurement when measured using Cu Kα radiation at ambient temperature are 9.7+ 0.2, 13.6±0.2, 14.6±0.2, 16.3±0.2, 20.6±0.2 and 29.6±0.2. [0
To discriminate crystalline form B of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3- methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride from the other modifications it is more advantageous to look at the unique peaks in the X-ray diffraction diagram, i.e. the lines with sufficient intensity at 2-theta values, where the other modifications do 15 not show lines with significant intensity. Such characteristic X-ray lines (2-theta values) for form B in a powder diffraction pattern when measured using CuKα radiation at ambient temperature are: 9.7±0.2, 10.5±0.2, 13.6±0.2, 14.6±0.2, 20.6±0.2, 21.6+0.2, 27.2±0.2 and 29.6±0.2.
0 RAMAN technique can also be used to identify of the crystalline form B of
(I RS.SRS.ΘRSJ-δ-Dimethylaminomethyl-i-CS-methoxy-phenyOcyclohexane-i ,3-diol hydrochloride as shown in Fig. 4. Especially the range between 800 cm"1 and 200 cm"1 is advantageously used also by way of RAMAN microscopy. The most important Raman wave numbers (cm'1) in terms of intensity characterizing form B of 5 (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride showing one or a combination of the following in a Raman spectrum when measured using a laser wave length of 632 nm are 633 ± 4, 720 ± 4, 836 ± 4, 995 ± 4, 1109 ± 4, 1600 + 4, 2921 ± 4, and 2944 ± 4 cm"1.
0 The present invention further relates to a process for the preparation of crystalline form B of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride comprising the steps of dissolving crystalline form A in ethanol and/or water, sonication and allowing evaporating at room temperature at atmospheric pressure. In another aspect the present invention relates to a process for the production of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 ~(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form B comprising the steps of dissolving crystalline form A in ethanol and/or water, preferred ratio range ethanol to water 9,5:0,5 to 0,5 to 9,5 (weight/weight), very preferred ethanol and water ratio 9:1 (weight/weight), sonication, filtering, and allowing evaporating at room temperature by atmospheric pressure.
The preferred process starts from crystalline form A of (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride. In one embodiment of the process (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3- methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form B is produced by dissolving 30 -50 mg (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form A in a mixture of about 100 μl ethanol and water (w : w; 9 : 1) of HPLC grade. After sonication to assist dissolution the solution is filtered through a 0.2 micron filter attached to a syringe into a scintillation vial at ambient temperature. The solvent is allowed to evaporate at ambient temperature at athmospheric pressure. The remaining substance is (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride form B.
Alternatively instead of an ethanol and water (w : w; 9 : 1) mixture an ethanol and water mixture of w:w; 6:1 and HPLC grade can be used. Alternatively instead of an ethanol and water (w : w; 9 : 1) mixture water of HPLC grade can be used.
In another aspect the present invention relates to crystalline form B of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride obtainable by a process as described herein.
Crystalline form B (hydrated form) has the advantage that even under high humidity it is not converted to another polymorph. Thus, this crystalline form is particularly suitable for use in wet granulation processes, which are widely used in the pharmaceutical industry. This invention further relates to a new crystalline form C of (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride. Crystalline form C can be used as active ingredient in pharmaceutical compositions.
Therefore the invention further relates to a pharmaceutical composition containing as active ingredient (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form C according to the invention and at least one suitable additive and/or auxiliary substance.
The most important X-ray lines (2-theta values) in terms of intensity characterizing form C of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride showing one or a combination of the following in a powder diffraction measurement when measured using Cu Kα radiation at ambient temperature are 14.1± 0.2, 17.4±0.2, 19.5±0.2, 20.0±0.2, 23.4±0.2 and 26.6±0.2.
To discriminate crystalline form C of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3- methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride from the other modifications it is more advantageous to look at the unique peaks in the X-ray diffraction diagram, i.e. the lines with sufficient intensity at 2-theta values, where the other modifications do not show lines with significant intensity. Such characteristic X-ray lines (2-theta values) for form C in a powder diffraction pattern when measured using CuKα radiation at ambient temperature are: 11.9+0.2, 12.2±0.2, 12.6±0.2, 15.4±0.2, 17.3±0.2, 22.3±0.2, and 23.4±0.2.
RAMAN technique can also be used to identify of the crystalline form C of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride as shown in Fig. 6. The most important Raman wave numbers (cm'1) in terms of intensity characterizing form C of (1RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride showing one or a combination of the following in a Raman spectrum when measured using a laser wave length of 632 nm are 239 ± 4, 305 ± 4, 448 ± 4, 502 ± 4, 537 ± 4, 722 ± 4, 830 ± 4, 992 ± 4, 1094 ± 4, 1243 ± 4, 2928 ± 4 and 2945 ± 4 cm"1. The invention further relates to a process for the preparation of crystalline form C of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride comprising the step of dissolving the free base (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol in isopropanol at a temperature above room temperature.
In another aspect the present invention relates to a process for the production of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form C comprising the step of dissolving the free base of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol in isopropanol at 40- xx°C, wherein xx is the boiling point of isopropanol under the given conditions (approximately 82°C under ambient conditions), cooling and treatment of solution with hydrogenchloride.
The very preferred process starts from the free base of (1 RS,3RS,6RS)-6-
Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol of crystalline form A. Approximately 20 g are dissolved in isopropanol at an elevated temperature (approximately 45 0C or higher) to reach complete dissolution. The samples were allowed to cool to ambient temperature before treatment with gaseous hydrogen chloride. A constant purge of nitrogen was bubbled through the clear solution while stirring. Anhydrous hydrogen chloride was introduced into the system through the purge stream. Addition of hydrogen chloride was stopped when precipitation was observed. (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride form C was recovered by vacuum filtration immediately after formation.
In another aspect the present invention relates to a process for the production of form C comprising the steps of suspending crystalline form A in a liquid medium, stirring the resulting suspension and filtering off the liquid.
The liquid medium may preferably be selected from the group consisting of acetonitrile, a mixture of acetonitrile and water, ethanol, and a mixture of tetrahydrofuran and methanol. The temperature is preferably kept at 15τ75 0C, more preferably 15-600C, yet more preferably 20-450C, most preferably 20-260C. In another one of its aspects the present invention relates to crystalline form C of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride obtainable by a process as described herein.
Polymorph C has the advantage that it has the lowest hygroscopicity of all known polymorphic forms. Moreover it has the highest thermodynamic stability of the known polymorphic forms at temperatures of 15-600C, particulary of 15-35°C. These properties make polymorph C particularly useful for its formulation into a pharmaceutical composition and a medicament.
The thermodynamic properties can be evaluated by measuring the equilibrium solubilities in the respective temperature range such as 15-6O0C and in particular 15- 35°C and graphical evaluation of the results via a van't Hoff Plot (solubility vs. 1/T) as described in the publications of W. Higuchi et al, J. Pharm. Sci. 1963, 52, 150-153 and S. R. Byrn., Solid State Chemistry of drugs, 2nd edition, SSCI Inc., 1999. The respective parts of the descriptions are hereby incorporated by reference and form part of the present disclosure.
This invention further relates to a new crystalline form D of (1 RS,3RS,6RS)-6~ Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride.
Crystalline form D can be used as active ingredient in pharmaceutical compositions.
Therefore the invention further relates to a pharmaceutical composition containing as active ingredient (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form D according to the invention and at least one suitable additive and/or auxiliary substance.
The most important X-ray lines (2-theta values) in terms of intensity characterizing form D of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1~(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride showing one or a combination of the following in a powder diffraction measurement when measured using Cu Kα radiation at ambient temperature are 17.9+ 0.2, 18.6±0.2, 19.0±0.2, 19.9±0.2 and 25.7±0.2. To discriminate crystalline form D of (1RS,3RS,6RS)~6-Dimethylaminomethyl-1-(3- methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride from the other modifications it is more advantageous to look at the unique peaks in the X-ray diffraction diagram, i.e. the lines with sufficient intensity at 2-theta values, where the other modifications do 5 not show lines with significant intensity. Such characteristic X-ray lines (2-theta values) for form D in a powder diffraction pattern when measured using CuKα radiation at ambient temperature are: 10.3+0.2, 12.7±0.2, 13.0±0.2, 13.5±0.2, 18.6±0.2, 25.7±0.2 and 28.7±0.2.
[0 RAMAN technique can also be used to identify of the crystalline form D of
(1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride as shown in Fig. 8.
The Invention further relates to a process for the preparation of crystalline form D of 15 (1 RS.SRS.eRSJ-δ-Dimethylaminomethyl-i-CS-methoxy-phenyOcyclohexane-i ,3-diol hydrochloride comprising the step of heating crystalline form B to a temperature of at least 160 0C.
In another aspect the present invention related to a process for the production of 0 (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form D comprising heating form B to 160-1850C, preferred 175-185°C, for 20-50, preferred 30-40 minutes, and cooling to room temperature.
5 The very preferred process starts from the freshly prepared (1 RS,3RS,6RS)-6-
Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride form B. A small sample is heated in a XRPD glass capillary to 180 0C for approx. 35 minutes. After cooling down to ambient temperature (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride form 0 D was recovered.
Another aspect of the present invention relates to crystalline form D of
(1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride obtainable by a process as described herein. This invention further relates to a new crystalline form E of (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1 ~(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride. Crystalline form E can be used as active ingredient in pharmaceutical compositions.
5 Therefore the invention further relates to a pharmaceutical composition containing as active ingredient (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form E according to the invention and at least one suitable additive and/or auxiliary substance.
[0 The most important X-ray lines (2-theta values) in terms of intensity characterizing form E of (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride showing one or a combination of the following in a powder diffraction measurement when measured using Cu Kα radiation at ambient temperature are 9.7± 0.2, 14.9+0.2, 16.6±0.2, 19.2±0.2, 21.4±0.2 and
15 27.3+0.2.
To discriminate crystalline form E of (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3- methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride from the other modifications it is more advantageous to look at the unique peaks in the X-ray diffraction diagram, i.e. 0 the lines with sufficient intensity at 2-theta values, where the other modifications do not show lines with significant intensity. Such characteristic X-ray lines (2-theta values) for form D in a powder diffraction pattern when measured using CuKα radiation at ambient temperature are: 10.7± 0.2, 14.9±0.2, 21.4±0.2, 22.4±0.2, 24.2±0.2 and 28.9±0.2 5
RAMAN technique can also be used to identify of the crystalline form E of
(1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride as shown in Fig. 10.
0 The Invention further relates to a process for the preparation of crystalline form E of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride comprising the step of heating crystalline form B to 80-1000C. In another aspect the present invention relates to a process for the production of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3~methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form E comprising the step of heating form B to 80- 1000C, preferred 85-95°C, for 20-40, preferred 25-35, minutes.
The very preferred process starts from the freshly prepared (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride form B. A small sample is heated in a XRPD glass capillary to 90 0C for approx. 30 minutes. At this temperature (1 RS,3RS,6RS)-6-Dimethylaminomethyl~1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride form E was recovered.
Alternatively form E is prepared by drying freshly prepared (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride form B at 60 0C at ambient relative humidity for 2 to 6 weeks. Another aspect of the present invention relates to crystalline form E of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride obtainable by a process as described herein.
The preferred crystalline form is form A. The preferred crystalline form is form B. The preferred crystalline form is form C. The preferred crystalline form is form D. The preferred crystalline form is form E.
The very preferred crystalline forms are A, B, C especially preferred form is C.
Further objects of the invention are also different mixtures comprising one or more selected from the form A, B, C, D, E.
Further objects of the invention are compositions comprising mixtures of crystalline forms according to the invention, preferred mixtures of crystalline forms comprising one or more members selected from the group of the forms A, B, C, very preferred comprising form C. Further objects of the invention are pharmaceutical composition containing as active ingredient a or a mixture of, preferred a, crystalline form(s) according to the invention and containing preferred at least one suitable additive and/or auxiliary substance.
5 Further objects of the invention are the use of a or a mixture of, preferred a, crystalline form(s) according to the invention for the production of a medicament for treating pain. Preferably the pain is selected from the group consisting of acute pain, chronic pain, visceral pain, neuropathic pain and inflammatory pain, more preferably preferred acute or chronic pain.
[0
Pharmaceutical compositions according to the invention may preferably contain in addition to the crystalline forms (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3- methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride, one or more suitable additive and/or auxiliary substance such as for example carrier materials, fillers, solvents,
15 diluents, colouring agents and/or binders, and may be administered as liquid medicament preparations in the form of injectable solutions, drops or juices, as semisolid or solid medicament preparations in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols.
0 The choice of the 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, intradermal^, intramuscularly, intranasally, buccally, rectally or topically, for example to the skin, the mucous membranes or the eyes. For oral application suitable preparations are in the form of 5 tablets, sugar-coated pills, capsules, granules, droplets, juices and syrups, while for parenteral, topical and inhalative application suitable forms are solutions, suspensions, readily reconstitutable dry preparations, as well as sprays. The multiparticulate forms such as pellets or crystals may, for example, be compressed into a tablet, filled into a capsule or suspended in a suitable liquid. Crystalline forms 0 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 forms according to the invention. In principle further active constituents known to the person skilled in the art may be added to the medicaments/pharmaceutical compositions according to the present invention.
The inventive pharmaceutical formulations / medicaments may be produced using materials, means, devices and processes that are well known in the prior art of pharmaceutical formulations, as described for example in "Remington's Pharmaceutical Sciences", A.R. Gennaro (ed.), 17th edition Mack Publishing Company, Easton, Pa. (1985), in particular in part 8, chapters 76 to 93. The respective parts of the description are hereby incorporated by reference and form part of the disclosure.
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 the crystalline forms according to the invention are administered.
Preferably, the crystalline forms according to the invention are used for the treatment of pain, wherein the pain is preferably selected from the group of chronic pain, acute pain, visceral pain, neuropathic pain and inflammatory pain, more preferably the pain is chronic pain or acute pain.
Additionally the invention relates to a method of treatment using a sufficient amount of the crystalline forms according to the invention for the treatment of a disease, preferably for treating pain, urinary incontinence, depression or anxiety, preferably pain, more preferably pain selected from the group of chronic pain, acute pain, visceral pain, neuropathic pain and inflammatory pain, yet more preferably for the treatment of chronic pain or acute pain.
The following Examples shall further illustrate the invention without limiting it thereto. Example 1 : Powder diffraction patterns of forms A, B and C
Powder Data Collection was done with a STOE Stadi P Powder Diffractometer equipped with a curved germanium monochromator and a linear position sensitive
5 detector. The samples were prepared as flat samples. As source of the beam a copper X-ray tube with monochromatized Cu Kαi (λ = 1.54051 A) radiation generated at 50 kV and 30 mA was used. The 20 area for the measurement was 2° - 50°. The used step width was 0.05 degrees. The data were collected at a temperature of 23 ± 1°.
[0
The X-ray powder pattern for form A is shown in Figure 1 , the X-ray powder pattern for form B is shown in Figure 3 and the X-ray powder pattern for form C is shown in Figure 5.
15 The data are shown in Table 1.
Example 2: Powder diffraction patterns of forms D and E
Powder Data Collection was carried out on a Shimadzu XRD-6000 X-ray powder 0 diffractometer using Cu Ka radiation. The instrument is equipped with a fine focus X- ray tube. The tube voltage and amperage were set to 40 kV and 40 mA, respectively. The divergence and scattering slits were set at 1 ° and the receiving slit was set at 0.15 mm. Diffracted radiation was detected by a NaI scintillation detector. A theta- two theta continuous scan at 3 7min (0.4 sec/0.02° step) from 2.5 to 40 °2 Θ was 5 used. A silicon standard was analyzed each day to check the instrument alignment. The data were collected at a temperature of 23 ± 1°.
The X-ray powder diffraction pattern for form D is shown in Figure 7 and the X-ray powder diffraction pattern for form E is shown in Figure 9. 0
The data are shown in Table 1. Table 1:
Peak and Relative Intensity Listing (degree 2Θ, peaks with 1/11 value)
Figure imgf000017_0001
Example 3: RAMAN spectra of forms A, B and C
The polymorphs of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride were investigated using RAMAN microscopy. The RAMAN spectrometer used was a Jobin Yvon Horiba Labram. The microscope was an Olympus BX40 System, 10Ox Obj., diode laser 632 nm. Raman microscopy was able to distinguish between forms A, B, C and D. Differences between the spectra of the two forms appear in the whole spectral range (3500-150 cm"1).
The results for form A are shown in Figure 2, the results for form B in Figure 4, the results for form C in Figure 6.
Example 4: RAMAN spectra of forms D and E
The polymorphs of (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride were investigated using RAMAN spectroscopy The Raman spectrum was acquired on a Raman accessory interfaced to a Nicolet Magna 960 Fourier transform infrared spectrometer using InGaAs detector. The accessory utilizes an excitation wavelength of 1064 nm and approximately 0.45 W of Nd: YAG laser power. The spectrum represents 256 co-added scans acquired at 4 cm-1 resolution. The sample was prepared for analysis by placing a portion into a 5- mm diameter glass tube and positioning this tube in the spectrometer. The spectrometer was calibrated (wavelength) with sulfur and cyclohexane at the time of use.
The results for form D are shown in Figure 8, the results for form E in Figure 10. ,
Example 5: Variable Temperature X-ray powder diffraction experiment
Variable temperature Powder Diffraction Data Collection was carried out on a Shimadzu XRD-6000 X-ray powder diffractometer using Cu Ka radiation. The instrument is equipped with a fine focus X-ray tube. The tube voltage and amperage were set to 40 kV and 40 mA, respectively. The divergence and scattering slits were set at 1° and the receiving slit was set at 0.15 mm. Diffracted radiation was detected by a NaI scintillation detector. A theta-two theta continuous scan at 3 7min (0.4 sec/0.02° step) from 2.5 to 40 °2 θ was used. A silicon standard was analyzed each day to check the instrument alignment. The instrument was equipped with an Anton Paar HTK 1200 high temperature stage and a ceramic sample holder
A variable temperature X-ray powder diffraction experiment was run thereby producing form E from form B. form B converted to form E at 90 0C after half an hour during the experiment.
Example 6:
Several milligrams of crystalline form A were suspended in acetonitrile at room temperature and stirred at this temperature for several hours. The thus obtained residue of crystalline form C was filtered off.
Example 7:
a) Several milligrams of crystalline form A were suspended in a mixture of acetonitrile and water (99:1 weight/weight) at room temperature and stirred at this temperature for several hours. The thus obtained residue of crystalline form C was filtered off.
b) Crystalline form C was also obtained when the process was carried out at 6O0C.
Example 8:
a) Several milligrams of crystalline form A were suspended in ethanol at room temperature and stirred at this temperature for several hours. The thus obtained residue of crystalline form C was filtered off. b)
Crystalline form C was also obtained when the process was carried out at 600C.
Example 9:
Several milligrams of crystalline form A were suspended in a mixture of tetrahydrofuran and methanol (95:5 weight/weight) at room temperature and stirred at this temperature for several hours. The thus obtained residue of crystalline form C was filtered off.
Example 10:
Crystalline form B in an open glas container is stored in a humidity chamber at relative humidity of 35 % and room temperature. Samples were taken prior to storage and after 4, 14, 19 and 21 days of storage under these conditions. In all cases the samples were found to be crystalline form B only.
Example 11 :
Crystalline form B in an open glas container is stored in a humidity chamber at relative humidity of 60 % and room temperature. Samples were taken prior to storage and after 7, 17 and 22 days of storage under these conditions. In all cases the samples were found to be crystalline form B only.
Example 12: Crystalline form B in an open glas container is stored in a humidity chamber at relative humidity of 75 % and room temperature. Samples were taken prior to storage and after 6, 13 and 23 days of storage under these conditions. In all cases the samples were found to be crystalline form B only. Example 13:
Several milligrams of crystalline form A were suspended in mixtures of ethanol and water (95:5; 61.5:1 ; 18.3:1 , 8.3:1 , 3.8:1 and 1 : 2.8, in each case weight/weight) at room temperature and stirred at this temperature for several hours. Subsequently the ethanol/water mixture is removed under reduced pressure. The thus obtained residue of crystalline form B was filtered off.

Claims

Claims:
1. Crystalline form A of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy- phenyl)cyclohexane-1,3-diol hydrochloride showing at least X-ray lines (2-
5 theta values) in a powder diffraction pattern when measured using Cu Ka radiation at 12.9+0.2, 17.5±0.2, 19.0±0.2, 19.3±0.2, 21.0±0.2 and 25.3±0.2.
2. Crystalline form A of (1 RS,3RS,6RS)-6-DimethylaminomethyM -(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride according to claim 1 showing in
0 addition at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu Ka radiation at 11. O± 0.2, 12.3+0.2, 16.6±0.2 and 17.9±0.2.
3. Crystalline form A of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy- 5 phenyl)cyclohexane-1 ,3-diol hydrochloride showing an X-ray pattern (2-theta values) in a powder diffraction when measured using Cu Ka radiation essentially as in Fig. 1.
4. Crystalline form A of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- >0 phenyl)cyclohexane-1 ,3-diol hydrochloride characterized by at least the following bands in a RAMAN spectrum when measured using a laser wave length of 632 nm at 227 ± 4, 262 ± 4, 643 ± 4, 716 ± 4, 813 ± 4, 830 ± 4, 970 ± 4, 993 ± 4, 1252 ± 4, 2973 ± 4 and 3273 + 4 cm"1.
5 5. Crystalline form A of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride showing a RAMAN spectrum when measured using a laser wave length of 632 nm essentially as in Fig. 2.
0
6. A process for the production of crystalline form A of (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride according to one or more of claims 1-5 comprising the steps of precipitating the free base solution of (1 RS,3RS,6RS)-6-
5 Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol with hydrochloric acid, isolating the thus obtained solid, drying of the solid at 40-60 0C and reduced pressure of less than 300 mbar for 20-40, hours, then keeping the temperature at 120-1400C for 60-80 hours at less than 150 mbar pressure, followed by reducing the temperature to 50-70 0C, and drying the
0 product for another 20-60 hours at 50-70 0C and less than 150 mbar.
7. A process according to claim 6 comprising the steps of precipitating the free base solution of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy~ phenyl)cyclohexane-1 ,3-diol with hydrochloric acid, stirring and filtering, drying
5 of the thus obtained solid at 45-55°C, and reduced pressure of less than 150 mbar for 20-28, hours, then keeping the temperature at 125-135°C for 70-74, hours at less than 150 mbar pressure, followed by reducing the temperature to 55-65°C, and drying the product for another 20-30 hours at 55-65°C at less than 150 mbar. >0
8. A process according to claim 6 or 7 comprising the steps of precipitating the free base solution of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol with concentrated hydrochloric acid, stirring for 24 hours, filtering off the liquid phase, drying the thus obtained solid at 45-55 0C
25 and reduced pressure of less than 150 mbar for 24 hours, keeping the temperature at 130 0C for 62-82 hours and subsequently reducing the temperature to 6O0C and drying for another 24 hours at 60°C and less than 150 mbar.
0 9. Crystalline form A of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride obtainable by a process according to one or more of claims 6-8.
10. Crystalline form B of (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride showing at least X-ray lines (2- theta values) in a powder diffraction pattern when measured using Cu Ka radiation at 9.7±0.2, 13.6±0.2, 14.6±0.2, 16.3±0.2, 20.6±0.2 and 29.6±0.2.
5
11. Crystalline form B of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride according to claim 10 showing in addition at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu Ka radiation at 10.5±0.2, 21.6±0.2 and 27.2±0.2.
[0
12. Crystalline form B of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride showing an X-ray pattern (2-theta values) in a powder diffraction when measured using Cu Ka radiation essentially as in Fig. 3.
15
13. Crystalline form B of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride characterized by at least the following bands in a RAMAN spectrum when measured using a laser wave length of 632 nm at 633 ± 4, 720 ± 4, 836 ± 4, 995 ± 4, 1 109 ± 4, 1600 ± 4, 0 2921 ± 4 and 2944 ± 4 cm"1.
14. Crystalline form B of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride showing a RAMAN spectrum when measured using a laser wave length of 632 nm essentially as in Fig. 4. 5
15. A process for the production of crystalline form B of (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride according to one or more of claims 10-14 comprising the steps of dissolving crystalline form A in ethanol and/or water, sonication and 0 allowing for evaporation at room temperature under atmospheric pressure.
16. A process according to claim 15 comprising the steps of dissolving crystalline form A in ethanol and/or water, preferred ratio range ethanol to water 9,5:0,5 to 0,5 to 9,5, very preferred ethanol and water ratio 9:1 , sonication , filtering, and allowing evaporating at room temperature by atmospheric pressure.
5
17. A process according to claim 15 or 16 comprising the steps of dissolving crystalline form A in a mixture of ethanol and water ratio 9:1 , sonication , filtering, and allowing evaporating at room temperature by atmospheric pressure.
0
18.A process according to any of claims 15-17 comprising the steps of dissolving 30-50 mg (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride of crystalline form A in a mixture of about 100 μl ethanol and water (weight/weight 9 : 1) of HPLC grade,
[5 sonication, filtering the mixture through a 0.2 micron filter attached to a syringe into a scintillation vial at ambient temperature and allowing the solvent to evaporate at ambient temperature and at athmospheric pressure.
19. Crystalline form B of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- 0 phenyl)cyclohexane-1 ,3-diol hydrochloride obtainable by a process according to one or more of claims 15-18.
20. Crystalline form C of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1~(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride showing at least X-ray lines (2- 5 theta values) in a powder diffraction pattern when measured using Cu Ka radiation at 14.1 ±0.2, 17.4±0.2, 19.5±0.2, 20.0±0.2, 23.4±0.2 and 26.6±0.2.
21. Crystalline form C of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride according to claim 20 showing in 0 addition at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu Ka radiation at 1 1 .9± 0.2, 12.2±0.2, 12.6±0.2, 15.4±0.2, 17.3±0.2 and 22.3±0.2.
22. Crystalline form C of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride showing an X-ray pattern (2-theta values) in a powder diffraction when measured using Cu Ka radiation essentially as in Fig. 5.
5
23. Crystalline form C of (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride characterized by at least the following bands in a RAMAN spectrum when measured using a laser wave length of 632nm: 239 ± 4, 305 ± 4, 448 ± 4, 502 ± 4, 537 ± 4, 722 ± 4, 830 ±
0 4, 992 ± 4, 1094 ± 4, 1243 ± 4 , 2928 ± 4 and 2945 ± 4 cm'1.
24. Crystalline form C of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride showing a RAMAN spectrum when measured using a laser wave length of 632 nm essentially as in Fig. 6.
5
25. A process for the production of form C according to any of claims 20-24 comprising the steps of dissolving the free base (1RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1 ,3-diol in isopropanol at a temperature above room temperature.
»0
26.A process according to claim 25 comprising the steps of dissolving the free base (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy- phenyl)cyclohexane-1 ,3-diol in isopropanol at a temperature of 40 0C to xx 0C, wherein xx°C is the boiling point of isopropanol under the given conditions, 5 cooling and treating the solution with hydrochloride.
27.A process according to claim 25 or 26 comprising the steps of dissolving the free base (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol in isopropanol at a temperature of 45 0C to xx 0C, 0 wherein xx°C is the boiling point of isopropanol under the given conditions, cooling of the resulting solution to ambient temperature and treating the solution with gaseous, anhydrous hydrogen chloride.
28. A process for the production of form C according to any of claims 20-24 comprising the steps of suspending crystalline form A in a liquid medium, stirring the resulting suspension and filtration.
5 29.A process according to claim 28, characterized in that the liquid medium is acetonitrile, a mixture of acetonitril and water, ethanol or a mixture of tetrahydrofuran and methanol.
30. A process according to claim 28 or 29, characterized that it is carried out at a 0 temperature of 15-75 0C, preferably 15-600C, more preferably 20-450C, yet more preferably 20-26°C.
31. Crystalline form C of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride obtainable by a process according
5 to one or more of claims 25-30.
32. Crystalline form D of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride showing at least X-ray lines (2- theta values) in a powder diffraction pattern when measured using Cu Ka
>0 radiation at 17.9±0.2, 18.6±0.2, 19.0±0.2, 19.9±0.2 and 25.7±0.2.
33. Crystalline form D of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride according to claim 32 showing in addition at least X-ray lines (2-theta values) in a powder diffraction pattern
25 when measured using Cu Ka radiation at 10.3± 0.2, 12.7±0.2, 13.0+0.2,
13.5±0.2 and 28.7±0.2.
34. Crystalline form D of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride showing an X-ray pattern (2-theta 0 values) in a powder diffraction when measured using Cu Ka radiation essentially as in Fig. 7.
35. Crystalline form D of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride showing a RAMAN spectrum when measured using a laser wave length of 632 nm essentially as in Fig. 8.
36. A process for the production of crystalline form D of (1 RS,3RS,6RS)-6-
Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride according to one or more of claims 32-35 comprising the step of heating crystalline form B to a temperature of at least 160 0C.
37.A process according to claim 36 comprising the step of heating form B to 160-
185°C, preferred 175-1850C, for 20-50, preferred 30-40 minutes, and cooling to room temperature.
38. A process according to claim 36 or 37 comprising the step of heating form B to 175-1850C for 30-40 minutes, and cooling to room temperature.
39. Crystalline form D of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride obtainable by a process according to one or more of claims 36-38.
40. Crystalline form E of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride showing at least X-ray lines (2- theta values) in a powder diffraction pattern when measured using Cu Kα radiation at 9.7±0.2, 14.9±0.2, 16.6±0.2, 19.2±0.2, 21.4±0.2 and 27.3±0.2.
41. Crystalline form E of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride according to claim 40 showing in addition at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu Ka radiation at 10.7± 0.2, 14.9±0.2, 21.4±0.2, 22.4±0.2, 24.2+0.2 and 28.9±0.2.
42. Crystalline form E of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride showing a X-ray pattern (2-theta values) in a powder diffraction when measured using Cu Ka radiation essentially as in Fig. 9.
43. Crystalline form E of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride showing a RAMAN spectrum when measured using a laser wave length of 632 nm essentially as in Fig. 10.
44. A process for the production of crystalline form E of (1 RS,3RS,6RS)-6-
Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride according to one or more of claims 40-43 comprising the step of heating crystalline form B to 80-1000C.
45. A process according to claims 44 comprising the step of heating crystalline form B to 80-1000C , preferred 85-95°C, for 20-40, preferred 25-35, minutes.
46. A process according to claim 44 or 45 comprising the step of heating crystalline form B to 85-950C for 25-35, minutes.
47.A process for the production of Crystalline form E of (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1 -(3-methoxy-phenyl)cyclohexane-1 ,3-diol hydrochloride according to claim 40-43 comprising the step of drying crystalline form B at 60 0C at ambient relative humidity for 2 to 6 weeks.
48.A process according to one or more of claims 44-47, wherein the crystalline form B is freshly prepared.
49. Crystalline form E of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1,3-diol hydrochloride obtainable by a process according to one or more of claims 44-48.
50. Composition comprising mixtures of one or more crystalline forms according to one or more of claims 1-5, 9-14, 19-24, 31-35, 39-43 and 49, preferably mixtures of crystalline forms comprising one or more members selected from the group of the forms A, B, C, more preferably a composition comprising form 5 A.
5 I . Pharmaceutical composition containing as active ingredient a or a mixture of, preferred a, crystalline form(s) according to one or more of claims 1-5, 9-14, 19-24, 31-35, 39-43 and 49 and containing preferably at least one suitable 0 additive and/or auxiliary substance.
52. Medicament containing as active ingredient a or a mixture of, preferred a, crystalline form(s) according to claims 1-5, 9-14, 19-24, 31-35, 39-43 and 49 and containing preferably at least one suitable additive and/or auxiliary
.5 substance.
53. Medicament according to claim 52 for the treatment and/or prophylaxis of one or more selected from the group consisting of pain, urinary incontinence, depression and anxiety.
>0
54. Medicament according to claim 53, wherein the pain is selected from the group consisting of chronic pain, acute pain, neuopathic pain, visceral pain and inflammatory pain, more preferably the pain is chronic pain or acute pain.
25 55. Use of a or a mixture of, preferred a, form(s) according to claim 1-5, 9-14, 19-
24, 31-35, 39-43 and 49 for the production of a medicament for treating pain, urinary incontinence, depression or anxiety.
56. Use according to claim 55, wherein the pain is selected from the group 0 consisting of chronic pain, acute pain, neuopathic pain, visceral pain and inflammatory pain, preferably the pain is chronic pain or acute pain.
PCT/EP2006/001548 2005-02-25 2006-02-21 Crystalline forms of (1rs,3rs,6rs)-6-dimethvlaminomethvl-1-(3-methoxv- phenyl)cyclohexane-1 ,3-diol hydrochloride WO2006089708A1 (en)

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BRPI0606234-2A BRPI0606234A2 (en) 2005-02-25 2006-02-21 (1rs, 3rs, 6rs) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) cyclohexane-1,3-diol hydrochloride forms
MX2007010192A MX2007010192A (en) 2005-02-25 2006-02-21 Crystalline forms of (1rs,3rs,6rs)-6-dimethvlaminomethvl-1-(3- methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride.
AU2006218133A AU2006218133B8 (en) 2005-02-25 2006-02-21 Crystalline forms of (1RS,3RS,6RS)-6-Dimethvlaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1 ,3-diol hydrochloride
EP06707124A EP1851192A1 (en) 2005-02-25 2006-02-21 Crystalline forms of (1rs,3rs,6rs)-6-dimethvlaminomethvl-1-(3-methoxv- phenyl)cyclohexane-1 ,3-diol hydrochloride
JP2007556543A JP2008531511A (en) 2005-02-25 2006-02-21 Crystalline form of (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) cyclohexane-1,3-diol hydrochloride
CA002598579A CA2598579A1 (en) 2005-02-25 2006-02-21 Crystalline forms of (1rs,3rs,6rs)-6-dimethvlaminomethvl-1-(3-methoxv- phenyl)cyclohexane-1 ,3-diol hydrochloride
CN2006800062321A CN101128417B (en) 2005-02-25 2006-02-21 Crystalline forms of (1rs,3rs,6rs)-6-dimethvlaminomethvl-1-(3-methoxv- phenyl)cyclohexane-1 ,3-diol hydrochloride
NZ560204A NZ560204A (en) 2005-02-25 2006-02-21 Crystalline forms of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxy- phenyl)cyclohexane-1,3-diol hydrochloride
US11/885,039 US8309610B2 (en) 2005-02-25 2006-02-21 Crystalline forms of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexane-1,3-diol hydrochloride
IL185467A IL185467A0 (en) 2005-02-25 2007-08-23 Crystalline forms of (1rs,3rs,6rs)-6-dimethylaminomethyl-1-(3-methoxy-phenyl) cyclohexane-1,3-diol hydrochloride
NO20074676A NO20074676L (en) 2005-02-25 2007-09-13 Crystalline forms of (1 RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxyphenyl) cyclohexane-1,3-diol hydrochloride
IL212292A IL212292A0 (en) 2005-02-25 2011-04-13 Crystalline form of (1rs,3rs,6rs)-6-dimethylaminomethyl-1-(3-methoxy-phenyl) cyclohexane-1,3-diol hydrochloride, a proess, for its preparation and pharmaceutical compositions comprising it
IL212291A IL212291A0 (en) 2005-02-25 2011-04-13 Crystalline form of (1rs,3rs,6rs)-6-dimethylaminomethyl-1-(3-methoxy-phenyl) cyclohexane-1,3-diol hydrochloride, pharmaceutical compositions comprising it and a process for its preparation

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EP05004183.9 2005-02-25
DE102005009217A DE102005009217A1 (en) 2005-02-25 2005-02-25 New phosphoric acid salts of 6-dimethylaminomethyl -1-(3-methoxyphenyl)-1,3-dihydroxycyclohexane useful to treat e.g. pain, migraine, depressions, neurodegenerative illnesses, cognitive illnesses, fear conditions and epilepsy
EP05004183A EP1695957A1 (en) 2005-02-25 2005-02-25 Crystalline forms of (1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)cyclohexane-1,3-diol hydrochloride
DE102005009217.9 2005-02-25

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WO2008138558A1 (en) * 2007-05-11 2008-11-20 Grünenthal GmbH Axomadol for treating pain from arthritis
US20110060053A1 (en) * 2002-09-09 2011-03-10 Gruenenthal Gmbh Crystalline Modifications of 6-Dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol
WO2012000667A1 (en) * 2010-06-30 2012-01-05 Grünenthal GmbH Axomadol or metabolite thereof for use in the treatment of irritable bowel syndrome

Families Citing this family (1)

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Publication number Priority date Publication date Assignee Title
JP5488956B2 (en) * 2008-11-25 2014-05-14 株式会社Ｄｎｐファインケミカル宇都宮 (±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride mixed crystal of Form I and Form II crystals

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EP0753506A1 (en) * 1995-07-11 1997-01-15 Grünenthal GmbH 6-Dimethylaminomethyl-1-phenyl-cyclo-hexane compounds as pharmaceutical agents
WO2005009329A2 (en) * 2003-07-24 2005-02-03 Grünenthal GmbH Medicament containing 6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol with delayed release of active ingredients

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EP0753506A1 (en) * 1995-07-11 1997-01-15 Grünenthal GmbH 6-Dimethylaminomethyl-1-phenyl-cyclo-hexane compounds as pharmaceutical agents
US5733936A (en) * 1995-07-11 1998-03-31 Gruenenthal Gmbh 6-dimethylaminomethyl-1-phenyl-cyclohexane compounds as pharmaceutical active ingredients
USRE37355E1 (en) * 1995-07-11 2001-09-04 Gruenenthal Gmbh 6-dimethylaminomethyl-1-phenyl-cyclohexane compounds as pharmaceutical active ingredients
WO2005009329A2 (en) * 2003-07-24 2005-02-03 Grünenthal GmbH Medicament containing 6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol with delayed release of active ingredients

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110060053A1 (en) * 2002-09-09 2011-03-10 Gruenenthal Gmbh Crystalline Modifications of 6-Dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol
WO2008138558A1 (en) * 2007-05-11 2008-11-20 Grünenthal GmbH Axomadol for treating pain from arthritis
WO2012000667A1 (en) * 2010-06-30 2012-01-05 Grünenthal GmbH Axomadol or metabolite thereof for use in the treatment of irritable bowel syndrome

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WO2006089708A8 (en) 2007-09-07
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JP2008531511A (en) 2008-08-14
EP1851192A1 (en) 2007-11-07
US20110306673A1 (en) 2011-12-15
US8309610B2 (en) 2012-11-13
AU2006218133A1 (en) 2006-08-31
IL185467A0 (en) 2008-01-06
AU2006218133B2 (en) 2011-09-08
IL212292A0 (en) 2011-06-30
CN101128417B (en) 2012-02-29
MX2007010192A (en) 2007-09-07
BRPI0606234A2 (en) 2009-06-09
NZ560204A (en) 2011-01-28
CA2598579A1 (en) 2006-08-31
CN101128417A (en) 2008-02-20
KR20070112812A (en) 2007-11-27
RU2007135270A (en) 2009-03-27
AU2006218133B8 (en) 2011-09-29

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