(19)
`
`(12)
`
`(45) Date of publication and mention
`of the grant of the patent:
`01.08.2007 Bulletin 2007/31
`
`EUROPEAN PATENT SPECIFICATION
`(51) Int Cl.:(cid:3)
`C07C215/54(2006.01)
`A61P13/00(2006.01)
`
`(cid:6)(cid:27)&(cid:11)(cid:11)(cid:12)(cid:17)(cid:12) (cid:11)(cid:14)(cid:24)(cid:12)(cid:6)
`EP 1 612 203 B1
`
`(11)
`
`A61K31/135(2006.01)
`
`(21) Application number: 04015091.4
`
`(22) Date of filing: 28.06.2004
`(54) Crystalline forms of (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol
`hydrochloride
`Kristalline Formen von (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)Dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochlorid
`Formes cristallines de chlorhydrate de (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)diméthylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)méthylpropyl)-phénol
`
`(84) Designated Contracting States:
`AT BE BG CH CY CZ DE DK EE ES FI FR GB GR
`HU IE IT LI LU MC NL PL PT RO SE SI SK TR
`Designated Extension States:
`LT LV
`
`(43) Date of publication of application:
`04.01.2006 Bulletin 2006/01
`
`(73) Proprietor: Grünenthal GmbH
`52099 Aachen (DE)(cid:3)
`
`(72) Inventors:
`• Fischer, Andreas, Dr.(cid:3)
`52393 Hürtgenwald (DE)(cid:3)
`• Buschmann, Helmut, Dr.(cid:3)
`08960 Sant Just Desvern Barcelona (ES)(cid:3)
`• Gruss, Michael, Dr.(cid:3)
`52080 Aachen (DE)(cid:3)
`• Lischke, Dagmar
`52459 Inden-(cid:3)Altdorf (DE)(cid:3)
`
`(56) References cited:
`EP-(cid:3)B- 0 693 475
`
`Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give
`notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in
`a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art.
`99(1) European Patent Convention).
`
`Printed by Jouve, 75001 PARIS (FR)
`
`EP1 612 203B1
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`RS 1022 - 000001
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`EP 1 612 203 B1
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`Description
`(cid:3)[0001] This invention relates to solid crystalline forms of (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phe-
`nol hydrochloride, methods of producing same, methods of use, use as analgesics and pharmaceutical compositions
`containing same.
`(cid:3)[0002] The treatment of pain conditions is of great importance in medicine. There is currently a world-(cid:3)wide need for
`additional pain therapy. The pressing requirement for a target-(cid:3)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.
`(cid:3)[0003] The underlying object of the present invention was to find new solid forms of (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-
`1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride useful in the treatment of pain.
`(cid:3)[0004] US 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,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride in example 25. As
`proven by X-(cid:3)ray diffraction the 1R,(cid:3)2R configuration as shown in the drawing of the structure in example 25 is correct
`although the configuration is reported as (-)-(1R,(cid:3)2S) in US 6,248,737 and (-)-(1 S,(cid:3)2S) in US 6,344,558 as well as in EP
`693 475 B1.
`(cid:3)[0005]
`It has now been surprisingly found that (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydro-
`chloride can be produced in a reproducible manner in two different crystalline forms. The present invention provides a
`new form (Form A) of (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride which is different
`from the form already known (Form B) obtained by the procedure described in example 25 of US 6,248,737 and US
`6,344,558 as well as EP 693 475 B1. This new Form A of (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol
`hydrochloride is very stable at ambient conditions and therefore useful for producing a pharmaceutical composition.
`(cid:3)[0006] The new crystalline Form A of (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride
`can be identified by X-(cid:3)ray powder diffraction. The X-(cid:3)ray diffraction ("XRPD") pattern is shown in Fig. 1 with the peak
`listing shown as Table 1.
`(cid:3)[0007] The most important X-(cid:3)ray lines (2-(cid:3)theta values) in terms of intensity characterizing Form A of (-)-(1R,(cid:3)2R)-(cid:3)3-(3-
`dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride showing one or a combination of the following in a powder
`diffraction measurement when measured using Cu Ka radiation at ambient temperature are 14.5(cid:25) 0.2, 18.2(cid:25)0.2,
`20.4(cid:25)0.2, 21.7(cid:25)0.2 and 25.5(cid:25)0.2.
`(cid:3)[0008] To discriminate crystalline Form A of (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydro-
`chloride from Form B it is more advantageous to look at the unique peaks in the X-(cid:3)ray diffraction diagram, i.e. e. the
`lines with sufficient intensity at 2-(cid:3)theta values, where Form B does not show lines with significant intensity. Such char-
`acteristic X-(cid:3)ray lines (2-(cid:3)theta values) for Form A in a powder diffraction pattern when measured using CuKa radiation
`at ambient temperature are: 15.1(cid:25)0.2, 16.0(cid:25)0.2, 18.9(cid:25)0.2, 20.4(cid:25)0.2, 22.5(cid:25)0.2, 27.3(cid:25)0.2. 29.3(cid:25)0.2 and 30.4(cid:25)0.2
`(cid:3)[0009] Another method to identify crystalline Form A of (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol
`hydrochloride is IR-(cid:3)spectroscopy. The IR-(cid:3)Spectrum of Form A is shown as Fig. 2 with the peak listing shown in comparism
`to Form B as Table 2.
`(cid:3)[0010]
`In the IR-(cid:3)spectrum it is characteristic for crystalline Form A of (-)-(1 R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)meth-
`ylpropyl)-phenol hydrochloride to show a combination of the following IR bands: 3180(cid:25)4 cm-1, 2970(cid:25)4 cm-1, 2695(cid:25)4
`cm-1 , 2115(cid:25)4 cm-1, 1698(cid:25)4 cm-1, 1462(cid:25)4 cm-1, 1032(cid:25)4 cm-1 and/or 972(cid:25)4 cm-1.
`(cid:3)[0011] RAMAN technique can also be used to identify of the crystalline Form A of (-)-(1 R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-
`ethyl-(cid:3)2-(cid:3)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.
`(cid:3)[0012] Crystal structure analysis of Form A of (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydro-
`chloride showed monoclinic crystals with the following parameters of the elemental cell (length of side and angle):(cid:3)
`
`a: 7,11 Å
`b: 11,62 Å
`c: 17,43 Å
`b : 95,00°.
`(cid:3)[0013] The elemental cell of the crystal of crystalline Form A has a volume of 1434 (cid:25) 2 Å3 and a calculated density
`of 1.19 (cid:25) 0.01 g/cm3.
`(cid:3)[0014] The Invention further relates to processes for the preparation of crystalline Form A of (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimeth-
`ylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride.
`(cid:3)[0015] The process starts from crystalline Form B of (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol
`hydrochloride prepared according to US Pat. Nos. 6,248,737 or 6,344,558 or European Patent EP 693 475 B1 incorpo-
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`RS 1022 - 000002
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`EP 1 612 203 B1
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`rated herein by reference.
`(cid:3)[0016]
`In one embodiment of the process (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochlo-
`ride of crystalline Form A is produced by dissolving the (-)-(1 R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)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 (-)-(1 R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hy-
`drochloride of crystalline Form A preferably by filtering again.
`(cid:3)[0017]
`If acetone or acetonitrile is used 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 (-)-(1 R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-
`1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride is dissolved per ml solvent.
`(cid:3)[0018] The use of isopropanol is preferred, if seed crystals of (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpro-
`pyl)-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,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)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.
`(cid:3)[0019] Optionally it is possible to reduce the solvent by evaporation, preferably in an evaporator under reduced pres-
`sure. Preferably the remaining volume of the solution after evaporation should not be less than 20 % of the volume at
`the beginning of the process. Optionally it is also possible to add active carbon to the solution originally prepared.
`(cid:3)[0020]
`In a preferred embodiment of the invention the (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)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.
`(cid:3)[0021]
`It is preferred that in the last crystallization step the temperature is maintained at £ 15°C, more preferably £
`10°C and especially £ 5 °C.
`(cid:3)[0022]
`In a further embodiment of the process according to the invention (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-
`methylpropyl)-phenol hydrochloride of crystalline Form A is produced in the solid state by cooling (-)-(1R,(cid:3)2R)-(cid:3)3-(3-
`dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride of crystalline Form B between 24 h and 168 h to a temper-
`ature 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 24h and 72 h, especially between 24 h and 48h.
`(cid:3)[0023] This invention further relates to a new Crystalline Form A of (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methyl-
`propyl)-phenol hydrochloride obtainable by dissolving (-)-(R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hy-
`drochloride 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,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)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,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride of
`Form A to crystallize.
`(cid:3)[0024] 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.
`(cid:3)[0025] Therefore the invention further relates to a pharmaceutical composition containing as active ingredient (-)-(1R,
`2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride of crystalline Form A according to the invention
`and at least one suitable additive and/or auxiliary substance.
`(cid:3)[0026] Such pharmaceutical composition according to the invention contains, in addition to crystalline Form A (-)-(1R.
`2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride, one or more suitable additive and/or auxiliary
`substance such as for example carrier materials, fillers, solvents, diluents, colouring agents and/or binders, and may be
`administered as liquid medicament preparations in the form of injectable solutions, drops or juices, as semi-(cid:3)solid med-
`icament preparations in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols. 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, intradermally, 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 tablets, sugar-(cid:3)coated pills, capsules, granules, droplets, juices and syrups, while for
`parenteral, topical and inhalative application suitable forms are solutions, suspensions, readily reconstitutable dry prep-
`arations, 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 admin-
`istered orally or percutaneously can provide for the delayed release of crystalline Form A according to the invention. In
`principle further active constituents known to the person skilled in the art may be added to the medicaments according
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`to the invention.
`(cid:3)[0027] Preferred formulations for crystalline Form A (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol
`hydrochloride according to the invention are presented in the PCT-(cid:3)application WO 03/035054 incorporated herein by
`reference.
`(cid:3)[0028] 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.
`(cid:3)[0029] Preferably, 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.
`(cid:3)[0030] Additionally 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.
`(cid:3)[0031] The following Examples shall further illustrate the invention without limiting it thereto.
`
`Example 1: Master Recipe for Preparation of Form A
`(cid:3)[0032] The master recipe is valid for a 50 ml scale.(cid:3)
`Charge 1.9 g (-)-(1 R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride prepared according to ex-
`ample 25 of European Patent EP 693 475 B1 to a 50 ml glass round bottom vessel with 3-(cid:3)blade overhead stirrer with
`baffles. Charge 25 ml isopropanol and 0.5 % (v/v) water
`Stir at 800 rpm
`Heat to 80 °C
`Hold temperature while stirring for 10 minutes
`Cool to 65 °C
`Charge 0.056 g seeds (Mean Sq. Wt. CL = 58 Pm2, Median No Wt. CL = 22 Pm)(cid:3)
`Cool to 0 °C over 1 h
`Filter slurry through PTFE filter column (5 Pm pore size)(cid:3)
`Dry solid material under slight vacuum until constant weight (approx. 24 h)(cid:3)
`Repeat the same procedure with the dry solid material obtained
`
`Example 2: Preparation of Form A (1)
`(cid:3)[0033]
`(cid:3)(-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride was prepared according to ex-
`ample 25 of European Patent EP 693 475 B1. 32.2 mg of the thus synthesized (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-
`2-(cid:3)methylpropyl)-phenol hydrochloride was - by slight heating up to 40°C and/or agitating on an orbital shaker for 30 min
`- dissolved in 20 ml acetone. Following that the solution was filtered through a nylon syringe filter having a mesh of 0.20
`Pm and the solution was left to crystallize by slow evaporation of the solvent. Crystalline Form A of (-)-(1R,(cid:3)2R)-(cid:3)3-(3-
`dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride was generated as proven by X-(cid:3)ray powder diffraction and
`by RAMAN microscopic analysis.
`
`Example 3: Preparation of Form A (2)
`(cid:3)[0034]
`(cid:3)(-)-(1 R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride was prepared according to ex-
`ample 25 of European Patent EP 693 475 B1. 32.2 mg of the thus synthesized (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-
`2-(cid:3)methylpropyl)-phenol hydrochloride was - if necessary by agitating for e.g. 30 min - dissolved in 20 ml acetone.
`Following that the solution was filtered with a nylon syringe filter having a mesh of 0.20 Pm and the solution was left to
`crystallize by slow evaporation of the solvent. In no step after and including the dissolving the temperature was allowed
`to rise above +25°C. Crystalline Form A of (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride
`was generated as proven by X-(cid:3)ray powder diffraction experiment and by RAMAN microscopic analysis.
`
`Example 4: Preparation of Form A (3)
`(cid:3)[0035]
`(cid:3)(-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride was prepared according to ex-
`ample 25 of European Patent EP 693 475 B1. 350 mg of the thus synthesized (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-
`2-(cid:3)methylpropyl)-phenol hydrochloride were dissolved in 50 ml acetonitrile in a 250 ml flask. The mixture was stirred for
`1.5 h on a water bath heated to 37°C (cid:25) 1°C. Any insoluble residue was removed by filtering. Of the clear solution 35
`ml was removed on a rotation evaporator at 70-80 mbar and a temperature of the water bath of 30°C (cid:25) 1°C. The
`precipitated solid compound was filtered by vacuum. Crystalline Form A of (-)-(1 R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-
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`EP 1 612 203 B1
`methylpropyl)-phenol hydrochloride was generated as proven by X-(cid:3)ray powder diffraction and by RAMAN microscopic
`analysis.
`
`Example 5: Preparation of Form A (4)
`(cid:3)[0036]
`(cid:3)(-)-(1 R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride was prepared according to ex-
`ample 25 of European Patent EP 693 475 B1. The thus synthesized (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methyl-
`propyl)-phenol hydrochloride was stored for 72 h at - 40°C. Crystalline Form A of (-)-(R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-
`2-(cid:3)methylpropyl)-phenol hydrochloride was generated as proven by X-(cid:3)ray powder diffraction and by RAMAN microscopic
`analysis.
`
`Example 6: Preparation of Form A (5)
`(cid:3)[0037]
`
`(cid:3)[0038]
`(cid:3)(-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride was prepared according to ex-
`ample 25 of European Patent EP 693 475 B1. 370 mg of the thus synthesized (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-
`2-(cid:3)methylpropyl)-phenol hydrochloride were added to 40 ml acetonitrile and 100 mg active carbon in a 100 ml flask and
`heated to the boiling point. The active carbon was filtered off from the hot solution by means of a paper filter and the
`filtrate concentrated to a volume of approx. 10 ml in a rotation evaporator at 150 (cid:25) 10 mbar and 50°C. The solution was
`slowly rotated for 30 minutes at room temperature. Following that the solution was allowed to stand for 30 minutes at
`room temperature and than for 1 hour at 4°C. The Crystals are filtered by vacuum through a glass filter (276 mg yield).(cid:3)
`266 mg of these Crystals were dissolved at room temperature in 45 ml acetonitrile, insoluble residues were removed by
`filtration and the solution was rotated for 1.5 h at 35-40°C at atmospheric pressure in a rotation evaporator. Than the
`solution was concentrated at 50°C and 150 (cid:25) 10 mbar to a volume of approx. 10 ml and then slowly rotated for 30
`minutes at room temperature. Following that the flask was allowed to stand for 12 h at 4°C.(cid:3)
`The precipitated solid is filtered by vacuum through a glass filter and dried in the air.
`
`Yield:
`(cid:3)[0039]
`
`151 mg (40.8% of the theory in relation to used educt), white microcrystalline solid form
`
`Example 7: Preparation of Form B (1)
`(cid:3)[0040]
`(cid:3)(- )-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride was prepared according to ex-
`ample 25 of European Patent EP 693 475 B1. Crystalline Form B of (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methyl-
`propyl)-phenol hydrochloride was generated as proven by X-(cid:3)ray powder diffraction and by RAMAN microscopic analysis.
`
`Example 8: Preparation of Form B (2)
`(cid:3)[0041]
`(cid:3)(-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethy)-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride prepared according to one of the
`examples 1 to 5 was milled for at least 20 min. Then it was kept at 130°C in an oven for 80 min. Crystalline Form B of
`(-)-(1 R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride was generated as proven by X-(cid:3)ray powder
`diffraction and by RAMAN microscopic analysis.
`
`5
`
`RS 1022 - 000005
`
`

`
`EP 1 612 203 B1
`
`Example 9: Preparation of Form B (3)
`(cid:3)[0042]
`(cid:3)(-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride prepared according to one of the
`examples 1 to 5 was cryogrinded for at least 15 min. Then it was kept at 125°C in a TGA for 30 min. Crystalline Form
`B of (-)-(1 R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride was generated as proven by X-(cid:3)ray
`powder diffraction and by RAMAN microscopic analysis.
`
`Example 10: Powder diffraction patterns of Forms A (1) and B (1)
`(cid:3)[0043] Powder Data Collection was done with the Shimadzu Powder Diffractometer. For the investigations of the
`reflection intensity the samples were determined with a Shimadzu powder diffractometer. The ground and sieved powders
`were prepared as flat samples. As source of the beam a copper X-(cid:3)ray tube with monochromatized Cu Ka 1 (l = 1.54051
`Å) radiation generated at 40 kV and 30 mA was used. The 2q area for the measurement was 5° - 50°. The used step
`width was 0.01 degrees. The data were collected at a temperature of 23 (cid:25) 1°.
`(cid:3)[0044] The X-(cid:3)ray pattern for Form A is shown in Fig. 1, the X-(cid:3)ray pattern for Form B in Fig. 4. The data are shown in
`Table 1.
`
`Table 1:
`Peak and Relative Intensity Listing (°2q , peaks with I/I1 value of 10 and over)
`Ba
`Aa
`I/I1
`I/I1
`Peak No.
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`14.58
`
`15.08
`
`15.24
`
`15.78
`
`16.00
`
`17.04
`
`18.02
`
`18.29
`
`18.93
`
`20.07
`
`20.44
`
`21.71
`
`100
`
`21
`
`12
`
`16
`
`27
`
`21
`
`12
`
`86
`
`17
`
`23
`
`58
`
`60
`
`14.26
`
`14.52
`
`15.38
`
`15.74
`
`16.77
`
`17.99
`
`19.55
`
`20.12
`
`20.95
`
`21.41
`
`21.94
`
`24.70
`
`12
`
`100
`
`17
`
`22
`
`13
`
`62
`
`40
`
`36
`
`21
`
`14
`
`79
`
`57
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`22.58
`
`24.32
`
`25.50
`
`25.90
`
`26.06
`
`27.36
`
`27.67
`
`28.20
`
`28.33
`
`29.12
`
`29.35
`
`29.81
`
`30.37
`
`24.88
`
`25.11
`
`25.62
`
`25.76
`
`26.25
`
`27.73
`
`28.12
`
`29.22
`
`29.38
`
`29.72
`
`29.84
`
`31.07
`
`33.13
`
`21
`
`19
`
`29
`
`25
`
`17
`
`29
`
`73
`
`20
`
`11
`
`14
`
`21
`
`33
`
`10
`
`43
`
`30
`
`63
`
`25
`
`31
`
`22
`
`34
`
`10
`
`22
`
`11
`
`25
`
`16
`
`21
`
`6
`
`RS 1022 - 000006
`
`

`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`EP 1 612 203 B1
`
`(continued)
`Peak and Relative Intensity Listing (°2q , peaks with I/I1 value of 10 and over)
`Ba
`Aa
`I/I1
`I/I1
`Peak No.
`
`26
`
`27
`
`28
`
`29
`
`30
`
`31
`
`32
`
`30.75
`
`31.72
`
`34.40
`
`16
`
`14
`
`17
`
`33.86
`
`34.00
`
`34.36
`
`35.74
`
`35.84
`
`36.27
`
`39.02
`
`15
`
`14
`
`10
`
`11
`
`12
`
`11
`
`14
`
`Example 11: Powder diffraction patterns of Forms A (2) and B (2)
`(cid:3)[0045] Powder Data Collection was done with the Huber Guinier Powder Diffractometer. For the investigations of the
`reflection intensity the samples were determined with a Philips PW 1820 guinier powder diffractometer. The ground and
`sieved powders were prepared as flat samples. As source of the beam a copper X-(cid:3)ray tube with monochromatized Cu
`Ka 1 (l = 1.54051 Å) radiation generated at 40 kV and 30 mA was used. The 2q area for the measurement was 5° - 50°.
`The used step width was 0.01 degrees. The data were collected at a temperature of 23 (cid:25) 1°.
`(cid:3)[0046] The X-(cid:3)ray pattern for Form A is shown in Fig. 7, the X-(cid:3)ray pattern for Form B in Fig. 8.
`
`Example 12: IR spectrum of Forms A and B
`(cid:3)[0047] 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. A Spectra-(cid:3)Tech, Inc. diffuse
`reflectance accessory was utilized for sampling. Each spectrum represents 256 co-(cid:3)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. Subsequently, a Log 1/R (R=Reflectance) spectrum was acquired by rationing the two data sets
`against each other. The spectrophotometer was calibrated (wavelength) with polystyrene at the time of use.
`(cid:3)[0048] The spectrum for Form A is shown in Fig. 2. The spectrum for Form B is shown in Fig. 5.
`(cid:3)[0049] The data are shown in Table 2.
`
`Table 2:
`
`IR Peak Listing
`
`Form A
`
`Form B
`
`Peak Pos. (cm-1)
`
`Intensity (log 1/R)
`
`Peak Pos. (cm-1)
`
`Intensity (log 1/R)
`
`3180.4
`
`2970
`
`1462.1
`
`2695.2
`
`1600.9
`
`1281.6
`
`1378.3
`
`1219.9
`
`1181.2
`
`1503.6
`
`1256.5
`
`2.196
`
`1.791
`
`2.098
`
`1.945
`
`2.116
`
`1.242
`
`1.246
`
`1.201
`
`1.236
`
`2.138
`
`1.755
`
`1.878
`
`1.856
`
`1.848
`
`1.841
`
`1.838
`
`1.771
`
`1.763
`
`1.754
`
`1.748
`
`1.743
`
`1.734
`
`3170.2
`
`3013.1
`
`2962.5
`
`2933.4
`
`2682
`
`1940.5
`
`1870.7
`
`1801.7
`
`1749.5
`
`1598.1
`
`1503.2
`
`7
`
`RS 1022 - 000007
`
`

`
`5
`
`10
`
`15
`
`20
`
`25
`
`EP 1 612 203 B1
`
`(continued)
`IR Peak Listing
`
`Form A
`
`Form B
`
`Peak Pos. (cm-1)
`
`Intensity (log 1/R)
`
`Peak Pos. (cm-1)
`
`Intensity (log 1/R)
`
`712.6
`
`879.8
`
`684.7
`
`798.7
`
`1313.6
`
`1005.1
`
`731.2
`
`1090.9
`
`810.2
`
`971.5
`
`842.6
`
`831.7
`
`1111.5
`
`1049.8
`
`1136.5
`
`1.725
`
`1.713
`
`1.692
`
`1.681
`
`1.673
`
`1.655
`
`1.63
`
`1.626
`
`1.622
`
`1.588
`
`1.576
`
`1.574
`
`1.55
`
`1.534
`
`1.498
`
`1451.5
`
`1417.2
`
`1396.3
`
`1377.1
`
`1353.2
`
`1313.2
`
`1280.7
`
`1254.8
`
`1217.6
`
`1177.5
`
`1154.6
`
`1136.4
`
`1111.3
`
`1090.3
`
`1065.9
`
`2.164
`
`1.89
`
`1.843
`
`1.864
`
`1.726
`
`1.661
`
`1.977
`
`1.973
`
`2.015
`
`1.868
`
`1.597
`
`1.431
`
`1.512
`
`1.625
`
`1.425
`
`1.52
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`461.3
`
`1065.8
`
`495.1
`
`542.1
`
`595.8
`
`527.9
`
`912.4
`
`1032.4
`
`416.9
`
`1698.3
`
`1940.5
`
`1870.6
`
`1749.4
`
`1801.6
`
`2115.5
`
`1.476
`
`1.457
`
`1.438
`
`1.408
`
`1.384
`
`1.327
`
`1.304
`
`1.3
`
`1.287
`
`1.282
`
`1.279
`
`1.277
`
`1.268
`
`1.208
`
`1.061
`
`1.813
`
`1.855
`
`1.735
`
`1.292
`
`1.951
`
`1.657
`
`1.664
`
`1.715
`
`1.892
`
`1.855
`
`2.04
`
`1.917
`
`1.439
`
`1.497
`
`1.425
`
`1.663
`
`1.622
`
`1.439
`
`1049.9
`
`1004.6
`
`958.7
`
`946.6
`
`912.5
`
`877.8
`
`842.7
`
`831.4
`
`810.7
`
`795.2
`
`730.6
`
`711.7
`
`683.4
`
`595.6
`
`542.1
`
`527.7
`
`495.1
`
`464.4
`
`416.7
`
`8
`
`RS 1022 - 000008
`
`

`
`EP 1 612 203 B1
`
`Example 12: Single Crystal Structure Analysis of Form A
`(cid:3)[0050] A colourless crystal of (-)-(1R,(cid:3)2R)-(cid:3)3-(3-(cid:3)dimethylamino-(cid:3)1-(cid:3)ethyl-(cid:3)2-(cid:3)methylpropyl)-phenol hydrochloride prepared
`according to one of the examples 2 to 6 having approximate dimensions of 0.6 x 0.60 x 0.50 mm was mounted on a
`glass fiber in random orientation. Preliminary examination and data collection were performed with Cu Ka radiation
`(1.54184 Å) on a Enraf-(cid:3)Nonius CAD4 computer controlled kappa axis diffractometer equipped with a graphite crystal,
`incident beam monochromator.
`(cid:3)[0051] Cell constants and an orientation matrix for data collection were obtained from least-(cid:3)squares refinement using
`the setting angles of 25 reflections in the range 16° < q < 24°, measured by the computer controlled diagonal slit metzhod
`of centering. The monoclinic cell parameters and calculated volume are:(cid:3)
`a = 7.110(cid:3)(3), b = 11.615(cid:3)(4), c = 17.425(cid:3)(6) Å, b = 95.00(cid:3)(3), V = 1433.5(cid:3)(10) Å3. For Z = 4 and formula weight of 257.79
`the calculated density is 1.20 g cm-3. The space group was determined to be P21 (No. 19).
`(cid:3)[0052] The data were collected at a temperature of 23 (cid:25) 1 °C using w
`-(cid:3)q scan technique. The scan rate varied from 4
`to 20°/min (in w
`). 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 2q of 75.11°. The scan range (in°.) was determined as a function of q to correct for the seperation of the
`Ka
` doublet. The scan width was calculated as follows:
`
`(cid:3)[0053] Moving-(cid:3)crystal moving-(cid:3)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:(cid:3)1. The counter aperture was also
`adjusted as a function of q . The horizontal aperture width ranged from 2.4 to 2.5 mm; the vertical aperture was set at
`4.0 mm.
`(cid:3)[0054] The data for Form A as collected in a commonly known ".cif"-(cid:3)document for complete reference of distances
`within the molecule are shown in Table 3.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`9
`
`RS 1022 - 000009
`
`

`
`EP1612203B1
`EP 1 612 203 B1
`
`Table 3:
`
`_audit_creation_method
`_chemica1_name_systematic
`
`SHELXL-97
`
`'?
`
`_chemical_name_common
`_chemica1_me1ting_point
`_chemica1_formula_moiety
`_chemical_formu1a_sum
`’C14 H24 C1 N 0'
`
`?
`?
`?
`
`_chemica1_formula_weight
`
`257.79
`
`loop_
`_atom_type_symbol
`_atom_type_description
`_atom_type_scat_dispersion_real
`_atom_type_scat_dispersion_imag
`_atom_type_scat_source
`0.7018
`'C1'
`‘C1’
`0.3639
`‘International Tables Vol C Tables 4.2.6.8
`'0'
`'0'
`0.0492
`0.0322
`‘International Tables Vol C Tables 4.2.6