HK1235765A1

HK1235765A1 - Crystalline modifications of (1r, 2r) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) - phenol

Info

Publication number: HK1235765A1
Application number: HK17109696.9A
Authority: HK
Inventors: Michael Gruss
Original assignee: Grünenthal GmbH
Priority date: 2007-12-07
Filing date: 2011-04-19
Publication date: 2018-03-16

Abstract

The invention relates to crystalline modifications of (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, pharmaceutical preparations containing said modifications, and the use thereof.

Description

The invention relates to crystalline modifications of (1R,2R) 3- ((3-Dimethylamino-1-ethyl-2-methyl-propyl) phenol, pharmaceutical formulations containing these modifications and their uses.

(1R,2R) 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl) phenol is a synthetic analgesic used to treat severe to very severe, acute and chronic pain. The compound can be used as its free base or as pharmaceutically compatible salts and solvates. The manufacture of the compound and its salts is known from EP-A-0 693 475, where the compound is usually obtained in the form of its salt, e.g. its hydrochloride.

One of the tasks underlying the present invention was to make the compound (1R,2R)-3- ((3-dimethylamino-1-ethyl-2-methylpropyl) phenol available as such, i.e. in the form of the free base, with good yield and good purity.

This task was solved by the subject matter of the claims.

Surprisingly, it was found that under appropriate conditions the compound (1R,2R) -3- ((3-Dimethylamino-1-ethyl-2-methyl-propyl) -phenol can be obtained in crystalline form, in particular in the form of the polymorphs A, B and C described below.

These crystalline forms allow the compound (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl) phenol to be obtained in the form of the free base with good yield and purity, and are also characterised by good handling and facilitate precise dosing of the active substance.

In addition, different polymorphs of the same pharmaceutical active substance differ fundamentally in their properties, which may result in further advantages.

On the one hand, the advantages may be due to a specific physical property of a particular modification, for example in its processing and storage, such as thermodynamic stability; crystal morphology, in particular shape, size, colour; density; bulk density; hardness; deformability; calorimetric behaviour, in particular melting point; solubility properties; in particular intrinsic solubility rate and equilibrium solubility; hygroscopicity; relative humidity profile; adhesion, etc.

On the other hand, crystalline modification can also have improved chemical properties, for example, it is known that lower hygroscopicity can lead to improved chemical stability and longer shelf life of chemical compounds.

One of the objects of the present invention concerns a crystalline modification of (1R,2R) 3-dimethylamino-1-ethyl-2-methyl-propyl) phenol.

A further subject matter of the present invention concerns a crystalline modification A of (1R,2R) 3- ((3-dimethylamino-1-ethyl-2-methyl-propyl) phenol.

This crystalline modification A of the invention has an X-ray diffraction reflex of 15,58 ± 0,20 (2Θ).

Preferably, the crystalline modification A of the invention may additionally include at least one X-ray diffraction reflector selected from the group consisting of 28,37±0,20 (2Θ) and 34,45±0,20 (2Θ).

The crystalline modification A according to the invention may also be characterized by the addition of an X-ray diffraction reflex at 15,58 ± 0,20 (2Θ) and one or more X-ray diffraction reflexes, if any, selected from the group consisting of 28,37 ± 0,20 (2Θ) and 34,45 ± 0,20 (2Θ), in addition to at least one X-ray diffraction reflex selected from the group consisting of 13,71 ± 10,20 (2Θ), 14,80 ± 0,20 (2Θ), 16,89 ± 0,20 (2Θ), 17,79 ± 0,20 (2Θ), 18,45 ± 0,20 (2Θ), 20,20 ± 0,20 (2Θ), 20,20 ± 0,20 (2Θ), 20,92 ± 0,20 (2), 22,50 ± 0,20 (2Θ), 24,37 ± 0,20 (2Θ) and 25,33 ± 0,20 (2Θ).

Furthermore, the crystalline modification A according to the invention may be characterised by the addition of an X-ray diffraction reflection at 15,58 ± 0,20 (2Θ) and one or more X-ray diffraction reflections selected from the group consisting of 28,37 ± 0,20 (2Θ) and 34,45 ± 0,20 (2Θ) and one or more X-ray diffraction reflections selected from the group consisting of 13,71 ± 0,20 (2Θ), 14,80 ± 0,20 (2Θ), 16,89 ± 0,20 (2Θ), 17,79 ± 0,20 (2Θ), 18,45 ± 0,20 (2Θ), 20,20 ± 0,20 (2Θ), 20,92 ± 0,20 (2Θ), 22,50 ± 0,20 (2Θ), 24,37 ± 0,20 (2Θ) and 25,33 ± 0,20 (2Θ) in addition to at least one X-ray diffraction reflection selected from the group consisting of 27,07 ± 0,11 (2Θ), 27,07 ± 0,20 (2Θ), 19,20 ± 0,20 (2Θ), 20,20 ± 0,20 (2Θ), 27,20 ± 0,20 (2Θ), 20,20 ± 0,20 (2Θ), 20,20 ± 0,20 (2Θ), 20,20 ± 0,20 (2Θ), 20,220, ± 20,220, ± 20,220, ± 20,220, ± 20,220, ± 20,220, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20, ± 20,

The crystalline modification A according to the invention may also be characterised by the addition of an X-ray diffraction reflection at 15,58 ± 0,20 (2Θ) and one or more X-ray diffraction reflections, if any, from the group consisting of 28,37 ± 0,20 (2Θ) and 34,45 ± 0,20 (2Θ) and one or more X-ray diffraction reflections, if any, from the group consisting of 13,71 ± 0,20 (2Θ), 14,80 ± 0,20 (2Θ), 16,89 ± 0,20 (2Θ), 17,79 ± 0,20 (2Θ), 18,45 ± 0,20 (2Θ), 20,20 ± 0,20 (2Θ), 20,20 ± 0,20 (2Θ), 20,92 ± 0,20 (2Θ), 22,50 ± 0,20 (2Θ), 24,04 ± 0,20 (2Θ), 29,20 ± 0,20 (2Θ), 30,20 ± 0,20 (2Θ), 29,04 ± 0,20 (2Θ), and 31,20 ± 0,20 (2Θ), and a further X-ray diffraction selection, if any, from the group consisting of at least one X-ray diffraction, consisting of a group consisting of (2, 20,20 ± 0,20), 32,20 ± 0,20 (2Θ), 32,20 ± 0,20 (2Θ, 20, (220 ± 0,20 (2Θ), 22,20 ± 0,20 (220, (220, ± 0,20 (220, ± 0,20), 22,20 ± 0,20 (220, ± 0,20 (220, ± 0,20), (220, ± 0,20), (220, ± 0,20 ± 0,20), (20,0,0,0,0,0, 0,20 (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (20, 0,20), (2

Preferably, the crystalline modification A of the invention may also be characterized by not including one or more of the following X-ray diffraction reflections selected from the group consisting of 10,93±0,20 (2Θ), 12,41±0,20 (2Θ) and 26,22±0,20 (2Θ).

It is also preferable that the crystalline modification A of the invention be further characterized by not including one or more of the following X-ray diffraction reflectors selected from the group consisting of 8,10±0,20 (2Θ), 10,93±0,20 (2Θ), 11,83±0,20 (2Θ), 12,41±0,20 (2Θ), 26,22±0,20 (2Θ), 26,54±0,20 (2Θ) and 26,72±0,20 (2Θ).

Figure 1 shows an X-ray powder diffractogram of modification A.

The crystalline modification A according to the invention has, in DSC studies, an endothermic peak temperature of 75-84 °C, preferably 76-83 °C, even more preferably 77-82 °C and particularly 78-81 °C.

The crystalline form A according to the invention can also be characterized by the inclusion of one or more Raman bands selected from the group consisting of 104±2 cm-1, 249±2 cm-1, 536±2 cm-1, 724±2 cm-1, 830±2 cm-1, 999±2 cm-1, 1283±2 cm-1, 1462±2 cm-1, 1584±2 cm-1, 2790±2 cm-1, 2839±2 cm-1, 2873±2 cm-1, 2933±2 cm-1, 2965±2 cm-1 and 3045±2 cm-1.

The present invention relates to a process for the production of the crystalline modification A, including the steps (a) Concentrate a solution of (1R,2R) 3-dimethylamino-1-ethyl-2-methylpropyl) phenol and (b) store the residue obtained in accordance with step (a) at a temperature > 5 °C.

Preferably a solution of (1R,2R) 3- ((3-dimethylamino-1-ethyl-2-methylpropyl) phenol is first fully compressed to produce crystalline modification A.

The solvents in such a solution are common organic solvents known to the professional, in particular alcohols such as methanol, ethanol, 1-propanol and 2-propanol, esters such as acetic esters, ketones such as acetone and ethyl methyl ketone, diethyl ether, tert-butyl methyl ether, 1,4-dioxane and tetrahydrofuran, nitrile such as acetonitrile, chlorinated hydrocarbons such as dichloromethane, aromatic hydrocarbons such as toluene, and dimethyl formamide and dimethyl sulfoxide.

The solution may also be compressed by conventional methods known to the professional, for example by rotary evaporation or inert gas flow, especially argon flow or nitrogen flow.

The resulting residue is usually preferably oily, which crystallizes at > 5°C as modification A. A storage period of 24 hours is generally sufficient.

Further processing, if necessary, may also be carried out by usual methods known to the professional, such as filtration, washing and/or drying.

Another subject matter of the invention concerns a crystalline modification A of (1R,2R)-3- ((3-dimethylamino-1-ethyl-2-methyl-propyl) phenol which is obtained by the process described above.

A further subject of the present invention is the crystalline modification B of (1R,2R) 3- ((3-dimethylamino-1-ethyl-2-methyl-propyl) phenol.

This crystalline modification B of (1R,2R)-3- ((3-dimethylamino-1-ethyl-2-methylpropyl) phenol according to the invention has an X-ray diffraction reflex of 29,06 ± 0,20 (2Θ).

Preferably, the crystalline modification B according to the invention may additionally include at least one X-ray diffraction reflector selected from the group consisting of 19,50±0,20 (2Θ), 35,49±0,20 (2Θ) and 40,01±0,20 (2Θ).

The crystalline modification B according to the invention may also be characterized by the addition of an X-ray diffraction reflection at 29,06 ± 0,20 (2Θ) and one or more X-ray diffraction reflections, if any, selected from the group consisting of 19,50 ± 0,20 (2Θ), 35,49 ± 0,20 (2Θ) and 40,01 ± 0,20 (2Θ), in addition to at least one X-ray diffraction reflection selected from the group consisting of 14,11 ± 0,20 (2Θ), 14,44 ± 0,20 (2Θ), 16,08 ± 0,20 (2Θ), 17,17 ± 0,20 (2Θ), 17,43 ± 0,20 (2Θ), 18,81 ± 0,20 (2Θ), 20,24 ± 0,20 (2Θ), 20,80 ± 0,20 (2Θ), 22,00 ± 0,20 (2Θ), 24,49 ± 0,20 (2Θ), 23,40 ± 0,20 (2Θ), 24,50 ± 0,15 (2Θ), 29,20 ± 0,20 (2Θ), 29,20 ± 0,20 (2Θ), and 20,20 ± 0,20 (2Θ), respectively.

Furthermore, the crystalline modification B according to the invention may be characterised by having, in addition to the X-ray diffraction reflex at 29,06 ± 0,20 (2Θ) and one or more X-ray diffraction reflexes, selected from the group consisting of 19,50 ± 0,20 (2Θ), 35,49 ± 0,20 (2Θ) and 40,01 ± 0,20 (2Θ) and one or more X-ray diffraction reflexes, selected from the group consisting of 14,11 ± 0,20 (2Θ), 14,44 ± 20,20 (2Θ), 16,08 ± 0,20 (2Θ), 17,17 ± 0,20 (2Θ), 17,43 ± 0,20 (2Θ), 18,81 ± 0,20 (2Θ), 20,24 ± 0,20 (2Θ), 20,80 ± 0,20 (2Θ), 22,20 ± 0,20 (2Θ), 25,00 ± 0,20 (2Θ), 31,00 ± 0,20 (2Θ), 22,00 ± 0,20 (2Θ), 22,20 ± 0,20 (2Θ), 24,20 ± 0,20 (2Θ), 24,20 ± 0,20 (2Θ), 24,20 ± 0,20 (2Θ), and 27,20 ± 0,20 (2Θ), comprising at least one additional group (2,20 ± 0,20 (2Θ), including the selected X-ray diffraction.

The crystalline modification B according to the invention may also be characterised by the addition of an X-ray diffraction reflector at 29,06±0,20 (2Θ) and one or more X-ray diffraction reflectors, if any, selected from the group consisting of 19,50±0,20 (2Θ), 35,49±0,20 (2Θ) and 40,01±0,20 (2Θ) and one or more X-ray diffraction reflectors, if any, selected from the group consisting of 14,11±0,20 (2Θ), 14,44±0,20 (2Θ), 16,08±0,20 (2Θ), 17,170,20 (2Θ), 17,430,20 (2Θ), 18,81±0,20 (2Θ), 20,24±0,20 (2Θ), 20,20±0,20 (2Θ), 30,20±0,20 (2Θ), 22,20±0,20 (2Θ), 30,20±0,20 (2Θ), 31,20±0,20, 31,20±0,25,20 (2Θ), 25,20±0,25,20 (2Θ), 24,20±0,25,20 (2Θ), 24,20±0,25,20 (2Θ), 32,20±0,20 (2Θ), 32,20±0,20 (2Θ), 32,20±0,20 (2Θ), 32,20±0,20 (2Θ), 22,20±0,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,20,

Preferably, the crystalline modification B of the invention may also be characterized by not including one or more of the following X-ray diffraction reflections selected from the group consisting of 10,93±0,20 (2Θ), 12,41±0,20 (2Θ) and 26,22±0,20 (2Θ).

It is also preferable that the crystalline modification B of the invention be characterized by not including one or more of the following X-ray diffraction reflectors selected from the group consisting of 8,10±0,20 (2Θ), 10,93±0,20 (2Θ), 11,83±0,20 (2Θ), 12,41±0,20 (2Θ), 26,22±0,20 (2Θ), 26,54±0,20 (2Θ) and 26,72±0,20 (2Θ).

Figure 3 shows an X-ray powder diffractogram of the form B.

The crystalline modification B according to the invention has an endothermic peak temperature of 87-93 °C, preferably 88-92 °C, and even more preferably 89-91 °C in DSC studies.

The crystalline form B of the invention may also be characterized by the inclusion of one or more Raman bands selected from the group consisting of 91±2 cm-1, 112±2 cm-1, 259±2 cm-1, 381±2 cm-1, 535±2 cm-1, 535±2 cm-1, 730±2 cm-1, 829±2 cm-1, 999±2 cm-1, 1088±2 cm-1, 1173±2 cm-1, 1288±2 cm-1, 1445±2 cm-1, 1585±2 cm-1, 2790±2 cm-1, 2838±2 cm-1, 28692 cm-1, 2925±2 cm-1, 2952±2 cm-1, 2980-1 and 3059±2 cm-1.

The present invention relates to a process for the production of the crystalline modification B, including the steps (a) Concentrate a solution of (1R,2R) 3- ((3-Dimethylamino-1-ethyl-2-methyl-propyl) phenol and (b) store the residue obtained in accordance with step (a) at a temperature ≤ 5 °C, or (b) suspend the residue obtained in accordance with step (a) and stir the suspension.

Preferably a solution of (1R,2R) 3- ((3-dimethylamino-1-ethyl-2-methylpropyl) phenol is first fully compressed to produce crystalline modification B.

The solvents in such a solution are common organic solvents known to the professional, in particular alcohols such as methanol, ethanol, 1-propanol and 2-propanol, esters such as acetic esters, ketones such as acetone and ethyl methyl ketone, ethers such as diethyl ether, tert-butyl methyl ether, 1,4-dioxane and tetrahydrofuran, nitriles such as acetonitrile, chlorinated hydrocarbons such as dichloromethane, aromatic hydrocarbons such as toluene, and dimethyl formamide and dimethyl sulfoxide.

The resulting residue is usually preferably oily, which crystallizes as modification B after storage at ≤ 5°C. A storage period of 24 hours is generally sufficient.

Alternatively, the preferably oily residue may be incorporated into an appropriate suspension medium and stirred for some time, in particular by mixing one of the above solvents with water or a saturated hydrocarbon, in particular n-pentane, n-hexane or n-heptane, and the proportion of the solvent should be chosen so that the residue does not dissolve completely. The temperature in step (b) can vary over a wide range, in particular between 5 and 25°C, as can the agitation time, which can range from a few minutes to several weeks, in particular up to one week.

The present invention relates to a process for the production of the crystalline modification B, including the step

(a) Precipitation of (1R,2R) 3-dimethylamino-1-ethyl-2-methylpropyl) phenol from solution.

For the preparation of the solution of (1R,2R) 3-(3-Dimethylamino-1-ethyl-2-methylpropyl) phenol, the usual organic solvents known to the professional are suitable, in particular alcohols such as methanol, ethanol, 1-propanol and 2-propanol, esters such as acetic esters, ketones such as acetone and ethyl methyl ketone, ethers such as diethyl ether, tert-butyl methyl ether, 1,4-dioxane and tetrahydrofuran, nitrile such as acetonitrile, chlorinated hydrocarbons such as dihydrochloromethane, aromatic hydrocarbons such as toluene, and dimethylformamide and dimethylfoxide.

Precipitation of (1R,2R) 3- ((3-Dimethylamino-1-ethyl-2-methyl-propyl) phenol from the solution is then carried out with the aid of media in which this compound is poorly soluble, such as saturated hydrocarbons such as n-pentane, n-hexane and n-heptane, and water.

The crystalline modification B can also be obtained by cooling a crystalline modification A melt.

A further subject matter of the invention concerns a crystalline modification B of (1R,2R)-3- ((3-dimethylamino-1-ethyl-2-methyl-propyl) phenol which is obtained by the processes described above.

Modification A is usually obtained by faster crystallization and/or at higher temperatures (likely via the amorphous form as an intermediate). Modification B is usually obtained by slower crystallization and/or at lower temperatures (likely by direct crystallization).

Thermodynamic stability is important, since the use of the most stable modification in a medicinal product can ensure that no polymorphic transformation of the active substance in the pharmaceutical formulation takes place during storage. This is advantageous, as otherwise the transformation from a less stable modification to a more stable modification may result in a change in the properties of the medicinal product. In terms of the pharmacological properties of a dosage form, this could lead, for example, to a change in the solubility of the active substance, which leads to a change in the release behaviour and thus also a change in bioavailability. This results in an insufficient storage stability of the drug.

A further subject of the present invention is also the crystalline modification C of (1R,2R) 3- ((3-dimethylamino-1-ethyl-2-methyl-propyl) phenol.

The crystalline modification C of (1R,2R)-3- ((3-Dimethylamino-1-ethyl-2-methyl-propyl) phenol according to the invention comprises at least one X-ray diffraction reflex selected from the group consisting of 10,93±0,20 (2Θ), 12,41±0,20 (2Θ) and 26,22±0,20 (2Θ).

Preferably, the crystalline modification C according to the invention may additionally include at least one X-ray diffraction reflector selected from the group consisting of 8,10±0,20 (2Θ), 11,83±0,20 (2Θ), 26,54±0,20 (2Θ) and 26,72±0,20 (2Θ).

The crystalline modification C according to the invention may also be characterised by the addition of at least one X-ray diffraction reflector selected from the group consisting of 10,93±0,20 (2Θ), 12,41±0,20 (2Θ) and 26,22±0,20 (2Θ) and, if applicable, one or more X-ray diffraction reflectors selected from the group consisting of 8,10±0,20 (2Θ), 11,83±0,20 (2Θ), 26,54±0,20 (2Θ) and 26,72±0,20 (2Θ) in addition to at least one X-ray diffraction reflector selected from the group consisting of 13,71±0,20 (2Θ) and 26,22±0,20 (2Θ) and, if applicable, one or more X-ray diffraction reflectors selected from the group consisting of 8,10±0,20 (2Θ), 11,83±0,20 (2Θ), 11,83±0,20 (2Θ), 11,83±0,20 (2Θ), 12,84±0,20 (2Θ), 22,84±0,20 (2Θ), 22,84±0,220, (2Θ), 22,04±0,220, (2Θ), 22,04±0,220, (2Θ), 22,04±0,220, (2Θ), (2TT0,220, (2TT0,220, (2TT2,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,220,22,220,220,220,22,22,220,22,22,22,22,22,22,22,22,2

Figure 5 shows an X-ray powder diffractogram of the form C.

The crystalline modification C according to the invention is preferably endothermic in DSC studies at a peak temperature of 75-84 °C, preferably 76-83 °C, and even more preferably at 77-82 °C and in particular 78-81 °C, and/or endothermic at a peak temperature of 87-93 °C, preferably 88-92 °C, and even more preferably 89-91 °C.

The invention also relates to a process for the manufacture of the modification C described above, comprising the steps (a) Shake a suspension containing the crystalline modification A and/or the crystalline modification B of (1R,2R) 3- ((3-Dimethylamino-1-ethyl-2-methylpropyl) phenol, and (b) Vaporise the suspension medium in the air stream.

The suspension media are preferably alcohols, especially methanol, and aromatic hydrocarbons, especially toluene.

Preferably, the suspension in step (a) is shaken at a temperature above room temperature (20-25°C), e.g. in the range > 25 to 35 °C, preferably 30±3°C, preferably 30±2°C and preferably 30±1°C. The shaking time is preferably 1 to 6 hours, preferably 2 to 5 hours, and preferably 3-4 hours.

The suspension medium is then evaporated in the air stream, after cooling to room temperature, and the resulting residue is stored at room temperature, if necessary. Further processing, if necessary, may also be carried out by usual methods known to the professional, such as filtration, washing and/or drying.

A further subject matter of the invention concerns a crystalline modification C of (1R,2R)-3- ((3-dimethylamino-1-ethyl-2-methyl-propyl) phenol which is obtained by the process described above.

If applicable, the modifications A, B and C of the invention may also form co-crystals and solvates, each of which is covered by the invention.

The present invention also concerns a pharmaceutical composition containing the active substance (1R,2R) 3-dimethylamino-1-ethyl-2-methyl-propyl) phenol in crystalline form and at least one pharmaceutically compatible carrier.

Preferably, the pharmaceutical composition of the invention may contain a polymorph selected from the group consisting of modification A, modification B and modification C.

In particular, the pharmaceutical composition of the invention may contain modification A.

Also particularly preferred, the pharmaceutical composition of the invention may contain modification B.

A further subject matter of the present invention is a pharmaceutical form containing a pharmaceutical composition in accordance with the invention as described above.

The present invention also relates to a crystalline modification of (1R,2R)-3- ((3-dimethylamino-1-ethyl-2-methyl-propyl) phenol, in particular a crystalline modification A, B or C as described above as a medicinal product. Another subject matter of the invention concerns the use of at least one crystalline modification of (1R,2R)-3- ((3-dimethylamino-1-ethyl-2-methyl-propyl) phenol, in particular one crystalline modification of A, B or C, in the manufacture of a drug for the treatment of pain, in particular acute pain and chronic pain.

In addition to at least one crystalline form A, B or C of the invention or a mixture of at least two of these forms, the medicinal product of the invention may normally contain other pharmaceutically compatible additives or excipients such as carrier materials, fillers, solvents, diluents, dyes and/or binders. The choice of excipients and the amounts to be used depend on whether the product is to be administered orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally or topically, for example to treat infections of the skin, mucous membranes and eyes. For oral application, preparations in the form of tablets, drops, capsules, granules, drops, juices and syrups, for parenteral, topical and inhalation applications, solutions, suspensions, easily reconstitutable dry preparations and sprays are preferably suitable. The invention is based on crystalline forms in gel-based or in a tablet form, where appropriate with a percutaneous additive, which can be used to release crystalline forms or, if necessary, in powder form, which can be applied percutaneously.

The amount of active substance to be administered to the patient may vary, depending, for example, on the weight of the patient, the type of application, the indication and the severity of the disease. Figure 1 shows an XRPD spectrum of crystalline modification A.Figure 2 shows a RAMAN spectrum of crystalline modification A.Figure 3 shows an XRPD spectrum of crystalline modification B.Figure 4 shows a RAMAN spectrum of crystalline modification B.Figure 5 shows an XRPD spectrum of crystalline modification C.

The following illustrations of the invention are provided, which are merely illustrative and do not restrict the general idea of the invention.

Examples: Abbreviations

RTR room temperature, preferably 20-25°CTBMET-butylmethyl etherEtOHEthanolMEK2-butaneonTHFTetrahydrofurane2PrOH2-propanolEtOAcethylacetateMeCNAcetonitrileDMSODimethyl sulfoxideDMFdimethylformamideIRIRInfrared MinutesMinuteSeconds

Unless otherwise stated, solvent mixtures always refer to volume/volume.

A) Synthesis of modification A A1)

16,689 g (1R,2R) 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl) phenol hydrochloride (available as an analogue to the prescription in EP A 0 693 475) were dissolved in a 250 ml trihaline flask in 81 ml of distilled water and added at room temperature with 32 weight% sodium salts until a pH of 11 was reached (approximately 7 ml). After adding less ml, a white, tough substance was released which was dissolved in approximately 16 ml of vinegar ester. After completion of the addition, a white suspension was obtained and subsequently agitated for 1 hour. The pH was reduced to 10 and another 0.5 ml was added. The base was then compressed with a total of 288 ml of sodium salts. The extracted base was then combined with 32 ml of magnesium sulphate in water to create a vacuum and then dried.

The oil was then crushed in the mortar to produce an almost white crystalline solid of modification A, characterized by 1H-NMR, DSC, TG-FTIR, XRPD, Raman and HPLC.

A portion of the resulting crystalline solid was decrystallized as follows: 30 mg of modification A were weighed in a 20 ml container, mixed with 6 ml of 2-propanol and shaken at 30 °C and 400 revolutions per minute for 4 hours.

A2)

The solution was then removed in a vacuum at the rotary evaporator, leaving a colourless oil. To this oil, approximately 1 mg of Form A vaccination crystals were added and the sample was stored at room temperature for 2 days. A crystalline solid of Form A was obtained.

B) Synthesis of modification B B1)

From 3300 g (2R,3R) [3- ((3-Methoxyphenyl) 2-methyl-pentyl]dimethylamine, hydrobromide (available as an analogue to the prescription according to EP A 0 693 475) in methylcyclohexane, 3192 g (2R,3R) [3- ((3-Methoxyphenyl) 2-methyl-pentyl]dimethylamine in the free base was obtained first with a sodium salt solution of 45% by weight (acidity ratio = 4,11 mol/kg).

Methylcyclohexane was treated with 18.9 kg of methanesulfonic acid and 2458 g of D,L methionine, and then 3192 g (2R,3R) [3- ((3-Methoxyphenyl) 2-methyl-pentyl] dimethylamine was added and stirred at 82 °C for 18 hours. Then it was diluted with 10.3 L of water at not more than 80 °C and 9 L of methylcyclohexane was added. At not more than 42 °C, 17.3 L of ammonia was added until the pH was 8.8. At 45 °C, phase separation was performed and the organic phase was obtained at 40 °C with 3.2 g (1,2 R) 3-Resacyl-3-dimethylamino-1-methyl-2-propyl) anodic acid and then 1 hour at 36 °C. Finally, the methyl methyl methyl was stirred at not more than 5 °C and then in water at 12 °C (1,2 °C) and then in water at 26 °C (1,2 °C) and then in water at 12 °C (1,2 °C) with 5-3,2 °C (1,2 °C) dimethyl-methyl-methyl-propyl-methyl-methyl-methyl.

The resulting modification B compound is denoted by 1 in subsequent tests.

C) Synthesis of modification C C1)

48.6 mg of modification B were suspended in 10 mL of methanol and shaken with a Vortex at 30 °C and 400 rpm for 4 hours.

After 24 hours the residue was present as a mixture of oil and solid, and after further storage (72 hours, sealed, room temperature) a white solid was obtained.

C2)

30.23 mg of modification A were suspended in 6 ml toluene and shaken with a Vortex machine at 30 °C and 400 revolutions per minute for 4 hours. After cooling to RT, the solvent was evaporated at 23 °C in the air stream.

The peak temperatures found in DSC studies for the products obtained according to C1) and C2) were in the range of 78-82 °C and 87-90 °C respectively, and thus in the range of the peak temperatures found for modifications A and B. The products could therefore be a mixture of forms A and B. However, the powder diffractogram shows X-ray diffraction reflections which cannot be from a mixture of modifications A and B.

The following tests are performed: Example 1:

Amorphous (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl) phenol was obtained by rapid evaporation of a solution of the compound in the rotary evaporator. The oily residues were stored at RT or 5 °C. All samples crystallized within 24 hours. RT contained modification A or mixtures of modification A and modification B. At lower temperatures (5 °C) modification B was obtained. 1.1) 109.1 mg 1 were dissolved in 2 ml of TBME. The solvent was removed at the rotary evaporator. A colourless oil was obtained. The residue was stored overnight in RT. A mixture of modifications A and B was obtained.1.2) 100 mg 1 was dissolved in 2 ml of EtOH.The solvent was removed at the rotary evaporator. A colourless oil was obtained. The residue was stored overnight at RT. Modification A was obtained.1.3) 105.6 mg 1 were dissolved in 2 ml EtOAc. The solvent was removed at the rotary evaporator. A colourless oil was obtained. The residue was stored overnight at RT. A mixture of modifications A and B.1.4) 100.9 mg 1 were dissolved in 2 ml acetone. The residue was removed at the rotary evaporator. A colourless oil was obtained. The residue was stored overnight at 5°C. Modification B.1.5) 100.0 mg 1 were dissolved in 2 ml MEK.The solvent was removed at the rotary evaporator. A colourless oil was obtained. The residue was stored overnight at 5°C. Modification B.1.6 was obtained. 99.5 mg 1 were dissolved in 2 ml THF. The solvent was removed at the rotary evaporator. A colourless oil was obtained. The residue was stored overnight at 5°C. Modification B was obtained.

Example 2:

Amorphous (1R,2R) 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl) phenol was obtained by rapid evaporation of a solution of the compound in the rotary evaporator or in the nitrogen stream. The oily residues were suspended in various solvents and the resulting mixtures were stirred at RT or 5 °C. No formation of solvates was observed in the selected solvents. 2.1) 96.9 mg 1 were dissolved in 1 ml THF. The solution was filtered and then removed from the solvent at RT under a strong nitrogen stream. 500 μl TBME were added to the resulting residue. The mixture was stirred at RT for 2 weeks. All solids were dissolved.2.2) 104.2 mg 1 were dissolved in 1 ml THF.The solution was filtered and then the solvent was removed at RT under a strong nitrogen current. 500 μl TBME were added to the resulting residue. The mixture was stirred at RT for 2 weeks. All solids were dissolved.2.3) 99.9 mg 1 was dissolved in 1 ml THF. The solution was filtered and then the solvent was removed at RT under a strong nitrogen current. 500 μl H2O were added to the resulting residue. The mixture was stirred at RT for 1 week. The resulting crystalline residue was filtered. A modification was obtained.2.4) 95.3 B 1 mg were dissolved in 1 ml THF.The solution was filtered and then the solvent was removed at RT under a strong nitrogen stream. 500 μl IPE was added to the resulting residue. The mixture was stirred at RT for 2 weeks. All solids were dissolved.2.5) 101.7 mg 1 was dissolved in 1 ml THF. The solution was filtered and then the solvent was removed at RT under a strong nitrogen stream. 500 μl H2O/EtOH (1:1) was added to the resulting residue. The mixture was stirred at RT for 1 week. The resulting crystalline residue was filtered.The solution was filtered and then the solvent was removed at RT under heavy nitrogen flow. 500 μl acetone/EtOH (1:1) were added to the resulting residue. The mixture was stirred at RT for 2 weeks. Two liquid phases were formed.2.7) 96.9 mg 1 was dissolved in 1 ml THF. The solution was filtered and then the solvent was removed at RT under heavy nitrogen flow. 500 μl TBME were added to the resulting residue. The mixture was stirred at 5°C for 2 weeks. All solids were dissolved.2.8) 109.0 mg 1 was dissolved in 1 ml THF.The solution was filtered and then the solvent was removed at RT under a strong nitrogen current. 500 μl heptane/TBME (1:1) were added to the resulting residue. The mixture was stirred at 5°C for 1 week. The resulting crystalline residue was filtered. Modification B.2.9) was obtained. 98.5 mg 1 were dissolved in 1 ml THF. The solution was filtered and then the solvent was removed at RT under a strong nitrogen current. 500 μl H2O were added to the resulting residue. The mixture was stirred at 5°C for 1 week. The resulting crystalline residue was defrosted.A mixture of modifications A and B was obtained.2.10) 100,7 mg 1 was dissolved in 1 ml THF. The solution was filtered and then the solvent was removed at RT under high nitrogen flow. 500 μl IPE was added to the resulting residue. The mixture was stirred at 5°C for 2 weeks. All solids were dissolved.2.11) 96,7 mg 1 was dissolved in 1 ml THF. The solution was filtered and then the solid solvent was removed at low nitrogen flow. 500 μl EtOH/H2O (1:1) was added to the resulting residue. The mixture was stirred at 5°C for 1 week.The resulting crystalline residue was filtered. Modification B was obtained.2.12) 105.1 mg 1 were dissolved in 1 ml THF. The solution was filtered and then removed from the solvent at RT under a strong nitrogen stream. 500 μl acetone/H2O (1:1) were added to the resulting residue. The mixture was stirred at 5°C for 1 week. The resulting crystalline residue was filtered. Modification B was obtained.

Example 3:

Crystallisation trials have been carried out by steam diffusion using saturated hydrocarbons and ether as precipitators, and only in one case a crystalline precipitation, the modification B, has been obtained. The solution was stored in a saturated n-hexane atmosphere at RT for 8 weeks. No precipitation was obtained.3.2) 200 mg 1 was dissolved in 2 ml EtOAc. The solution was stored in a saturated n-hexane atmosphere at RT for 8 weeks. No precipitation was obtained.3.3) 200 mg 1 was dissolved in 2 ml toluene.The solution was stored in a saturated n-hexane atmosphere at RT for 8 weeks. No precipitation was obtained.3.4) 200 mg 1 were dissolved in 2 ml THF. The solution was stored in a saturated n-hexane atmosphere at RT for 8 weeks. The crystalline precipitation formed was filtered. Modification B was obtained.3.5) 200 mg 1 were dissolved in 2 ml 2PrOH. The solution was stored in a saturated IPE atmosphere at RT for 8 weeks. No precipitation was obtained.3.6) 200 mg 1 were dissolved in 2 ml EtOAc. The solution was stored in a saturated IPE atmosphere at RT for 8 weeks.No precipitation was obtained.3.7) 200 mg 1 were dissolved in 2 ml of toluene. The solution was stored in a saturated IPE atmosphere at RT for 8 weeks. No precipitation was obtained.3.8) 200 mg 1 were dissolved in 2 ml of THF. The solution was stored in a saturated IPE atmosphere at RT for 8 weeks. No precipitation was obtained.3.9) 200 mg 1 were dissolved in 2 ml of 2-PrOH. The solution was stored in a saturated TBME atmosphere at RT for 8 weeks. No precipitation was obtained.3.10) 200 mg 1 were dissolved in 2 ml of AcO Etc.The solution was stored in a saturated TBME atmosphere at RT for 8 weeks. No precipitation was obtained.3.11) 200 mg 1 were dissolved in 2 ml of toluene. The solution was stored in a saturated TBME atmosphere at RT for 8 weeks. No precipitation was obtained.3.12) 200 mg 1 were dissolved in 2 ml of THF. The solution was stored in a saturated TBME atmosphere at RT for 8 weeks. No precipitation was obtained.3.13) 200 mg 1 were dissolved in 1 ml of EtOAc. The solution was stored in a saturated cyclohexane atmosphere at RT for 1 week.No precipitation was obtained. The sample was stored at 5°C for two weeks. No precipitation was obtained.3.14) 200 mg 1 were dissolved in 3 ml of MeCN. The solution was stored in a saturated cyclohexane atmosphere at RT for 1 week. No precipitation was obtained. The sample was stored at 5°C for two weeks. No precipitation was obtained.3.15) 200 mg 1 were dissolved in 1 ml of DMSO. The solution was stored in a saturated cyclohexane atmosphere at RT for 3 weeks. No precipitation was obtained.The solution was stored in a saturated pentane atmosphere at RT for 1 week. No precipitation was obtained. The sample was stored at 5°C for 2 weeks. No precipitation was obtained.3.17) 200 mg 1 was dissolved in 3 ml MeCN. The solution was stored in a saturated pentane atmosphere at RT for 1 week. No precipitation was obtained. The sample was stored at 5°C for 2 weeks. No precipitation was obtained.3.18) 200 mg 1 was dissolved in 1 ml DMSO.The solution was stored in a saturated pentane atmosphere at RT for 3 weeks without precipitation.

Example 4:

The sample was stored at 5 °C for 10 days. No change was observed.4.2) 100 mg 1 was dissolved in 0.5 ml 1,4-dioxane. 2 ml H2O was added gradually until the solution was dissolved and a sticky resin was produced. The sample was stored overnight at 5 °C. After scratching with a spatula, the resin crystallized and the crystalline solid was filtered. Modification B was obtained.4.3) 100 mg 1 was dissolved in 0.5 ml EtOAc.The sample was stored at 5°C for 6 days and the resulting solid was filtered. A crystalline powder was obtained.4.4) 100 mg 1 was dissolved in 1 ml of dioxane. 3 ml of heptane was added gradually until the solution was cloudy. The sample was stored at 5 °C for 1 week. No change was observed.4.5) 100 mg 1 ml was dissolved in 1 ml of dioxane.No change was observed.4.6) 100 mg 1 was dissolved in 1 ml EtOAc. 1 ml pentane was added gradually until the solution became cloudy. The sample was stored at 5 °C for 1 week. No change was observed.4.7) 100 mg 1 was dissolved in 2.5 ml MeOH. 3 ml H2O was added gradually until the solution became cloudy and a colourless solid was produced. The sample was stored in RT for 1 week and the resulting solid was filtered. A crystalline powder of modification A was obtained.4.8) 100 mg 1 was dissolved in 500 μl 2PrOH.The resulting solid was filtered. A crystalline powder of modification B was obtained.4.9) 100 mg 1 was dissolved in 500 μl EtOH.The resulting solid was filtered. A crystalline powder of modification B was obtained.4.11) 100 mg 1 was dissolved in 1 ml DMSO. 1 ml H2O was added gradually and the mixture was stirred at RT for 5 days. The resulting solid was filtered. A crystalline powder of modification B was obtained.4.12) 100 mg 1 was dissolved in 500 μl EtOAc. 2 ml pentane was added gradually and the mixture was stirred at RT for several hours. It formed a sticky solid. The sample was stored at 5°C for 3 weeks and the resulting solid was filtered.4.13) 100 mg 1 were dissolved in 500 μl EtOAc. 2 ml n-hexane were added gradually and the mixture was stirred for a few hours at RT. A sticky solid formed. The sample was stored at 5°C for 2 weeks and the resulting solid was filtered. A crystalline powder of modification B was obtained.A crystalline powder of modification B was obtained.4.15) 100 mg 1 were dissolved in 500 μl EtOAc. 2 ml of cyclohexane were added gradually and the mixture was stirred at RT for several hours. A sticky solid was formed. The sample was stored at 5°C for 2 weeks and the resulting solid was filtered. A crystalline powder was obtained.

Example 5:

5.1) The solution obtained in example 2.1 was stored in an open container at RT to evaporate the solvent. After 1 week a crystalline solid of modification A was obtained.5.2) The solution obtained in example 2.2 was stored at RT in an open container to evaporate the solvent. After 1 week a crystalline solid of modification A was obtained.5.3) The solution obtained in example 2.4 was stored at RT in an open container to evaporate the solvent. After 1 week a crystalline solid of modification A was obtained.5.4) The solution obtained in example 2.6 was stored at RT in an open container,After 1 week, a crystalline solid of modification A was obtained.5.5) The solution obtained in Example 2.7 was stored in an open vessel at RT to evaporate the solvent. After 2 days, a crystalline solid of modification B was obtained.5.6) The solution obtained in Example 2.10) was stored at RT in an open vessel to evaporate the solvent. After 2 days, a crystalline solid of modification B was obtained.5.7) The solution obtained in Example 4.1 was stored at RT in an open vessel to evaporate the solvent. After 2 days, a crystalline solid of modification A was obtained.5.8) The solution obtained in Example 4.4 was stored in an open container at RT to evaporate the solvent. After 6 days a crystalline solid of modification A was obtained.5.9) The solution obtained in Example 4.5 was stored at RT in an open container to evaporate the solvent. After 6 days a crystalline solid of modification B was obtained.5.10) The solution obtained in Example 4.6 was stored at RT in an open container to evaporate the solvent. After 6 days a crystalline solid of modification B was obtained.

Example 6:

The crystalline modification B of (1R,2R) 3- ((3-dimethylamino-1-ethyl-2-methylpropyl) phenol showed no change when slurrying in various solvents. The mixture was stirred at RT for 2 days and the resulting solid was filtered. A crystalline powder of modification B was obtained.The mixture was stirred at RT for 2 days and the resulting solid was filtered. A crystalline powder of modification B was obtained.6.4) 100 mg 1 were suspended in 500 μl IPE. The mixture was stirred at RT for 2 days and the resulting solid was filtered. A crystalline powder of modification B was obtained.6.5) 100 mg 1 were suspended in 500 μl H2O/EtOH (1:1) were obtained. The mixture was stirred at RT for 2 days and the resulting solid was filtered. A crystalline powder of modification B was obtained.

Example 7:

An attempt has been made to produce the amorphous modification of (1R,2R) 3- ((3-Dimethylamino-1-ethyl-2-methyl-propyl) phenol by evaporation, lyophilisation or melting. The solution was removed by a freeze dryer (-85°C, 0.5 mbar). A colourless residue was left which spontaneously crystallized before it was possible to perform a PXRD analysis. A modification was obtained with traces of modification A.7.4) The 150 mg were melted at 88-91 °C. The modification was obtained by melting an amorphous ice crystal with a film of frozen ice.

Example 8:

The effect of mechanical stresses on the samples during grinding with a ball mill (Retsch MM200 type, agate vessel and agate ball 5 mm in diameter) and pressure during the preparation of a tablet was investigated. 8.1) One tablet of 100 mg 1 was produced on an IR tablet press (pressure 10 t, 30 min). Modification B was obtained.8.2) One tablet of 100 mg product of modification A was produced on an IR tablet press (pressure 10 t, 30 min) as described in example 5.8. Modification A was obtained.8.3) 16 mg of the crystalline modification B were ground in a ball mill (shake frequency: 30 sec-1 RT) as follows: 2 times 90 min, 1 times 60 min, 2 times 30 min interruption. Modification B was obtained.8.4) 15 mg of the crystalline form A were ground in a ball mill (shelf frequency: 30 sec-1, RT) as follows: 2 times 90 min, 1 time 60 min, 2 times 30 min interruption. Modification B was obtained.

Example 9:

9.2) 19.8 mg of Modification A and 20.5 mg of Modification B were suspended in 300 μl Aceton/H2O (8:2) The suspension was suspended in an Eppendorf Thermomixer at RT overnight The resulting solid was filtered and characterised by RT.The suspension was stirred at 5 °C for three days. The resulting solid was filtered and characterized by FT Raman. Modification B was obtained.9.4) 20.5 mg of Modification A and 20.9 mg of Modification B were suspended in 200 μl IPE. The suspension was stirred at 50 °C overnight. The resulting solid was filtered and characterized by FT Raman. Modification B was obtained.9.5) 15 mg of Modification A and 15 mg of Modification B were suspended in 1 ml Aceton/H2O (8:2) The suspension was stirred at 50 °C overnight. The resulting solid was filtered and characterized by FT Raman. Modification B was obtained.9.6) 20.5 mg modification A and 20.9 mg modification B were suspended in 200 μl IPE. The suspension was stirred at 50 °C overnight. All solids were dissolved. After cooling to RT, small amounts of a colourless solid were released. The solvent was removed under nitrogen flow. Modification B was obtained.

The Commission shall adopt implementing acts laying down the rules for the application of this Regulation. The following information shall be provided for the purpose of the test:

XRPD studies were performed with a STOE Stage P X-ray powder diffractometer in transmission geometry using germanium monocrystalline monochromatized CuKα1 radiation. D-distances are calculated from the 2θ values, using the wavelength of 1.54060 A. It is generally accepted that the 20 values have an error rate of ± 0.2 ° in 20.

Modification A

Table 1 shows the peak list of modification A. The uncertainty in the 20 values is ± 0,2 ° in 20. Other

Tabelle 1:

2Θ	rel. I	2Θ	rel. I	2Θ	rel. I	2Θ	rel. I	2Θ	rel. I
13,71	30	20,20	15	24,75	9	30,68	5	36,24	2
14,11	9	20,92	12	25,33	18	31,43	3	36,54	1
14,80	45	21,12	5	27,32	5	32,21	4	36,87	1
15,58	100	21,90	7	27,55	6	32,98	3	37,06	2
16,31	3	22,21	6	28,05	2	33,41	2	37,48	2
16,89	18	22,50	18	28,37	3	33,76	1	37,87	1
17,79	37	23,30	3	29,62	1	34,17	1	38,64	3
18,45	34	24,04	2	29,90	5	34,45	1	39,48	2
19,07	8	24,37	17	30,28	1	35,98	2

The indexing of the diffractogram of the shape A with the WinXPow Index (version 2.03) program of STOE & Cie GmbH yielded the following grid constants, which are in good agreement with those obtained in the context of a single crystal structure determination: The test chemical is a chemical that is used to determine the concentration of a substance in a solution.

Modification B

Table 2 shows the peak list of modification B. The uncertainty in the 20 values is ± 0,2 ° in 2Θ, rel. I indicates the relative intensity of the respective peak. Other

Tabelle 2:

2Θ	rel. I	2Θ	rel. I	2Θ	rel. I	2Θ	rel. I	2Θ	rel. I
14,11	47	20,80	30	25,36	8	31,54	1	37,12	2
14,44	35	22,00	10	27,58	9	32,11	3	37,32	2
16,08	100	22,49	17	27,79	5	32,45	1	37,75	1
17,17	42	22,85	4	29,06	19	32,76	3	38,13	1
17,43	33	23,40	26	29,89	10	33,61	2	38,72	2
18,67	5	24,15	12	30,11	5	33,94	1	39,63	3
18,81	37	24,51	31	30,31	2	35,49	2	40,01	1
19,50	1	24,88	4	31,00	6	35,95	3
20,24	15	25,24	5	31,17	4	36,54	4

The indexing of the diffractogram of the B-form with the WinXPow Index (version 2.03) program of STOE & Cie GmbH yielded the following grid constants, which are in good agreement with those obtained by determining the single crystal structure: The test chemical is a chemical that is used to determine the concentration of a substance in a solution.

The following amendments shall be made:

Table 3 shows the peak list of modification C. The uncertainty in the 2Θ values is ± 0,2 ° in 2Θ, rel. I indicates the relative intensity of the respective peak. Other

Tabelle 3:

2Θ	rel. I	2Θ	rel. I	2Θ	rel. I	2Θ	rel. I	2Θ	rel. I	2Θ	rel. I
8,10	4	16,10	53	20,23	32	24,39	15	28,48	4	33,66	4
10,93	8	16,43	100	20,71	9	24,92	39	29,64	1	35,52	3
11,83	4	16,91	16	20,94	12	25,35	14	29,94	7	36,05	4
12,41	9	17,32	5	21,17	39	26,22	17	30,54	7	36,64	3
13,71	14	17,58	27	21,90	6	26,54	9	30,68	5	37,54	3
14,13	11	17,82	27	22,23	8	26,72	10	31,03	2	38,45	2
14,82	24	18,01	30	22,52	11	27,33	4	31,52	3	39,15	3
15,34	38	18,46	25	23,32	2	27,63	5	32,29	3	40,05	6
15,59	58	19,05	33	24,12	4	27,84	7	32,93	5

The data shall be collected and processed in accordance with the following procedures:

Differential Scanning Calorimetry (DSC): Device name Perkin Elmer DSC 7 or Perkin Elmer Pyris 1. Unless otherwise specified, the samples were weighed in a sealed gold plate. The measurement was made with a nitrogen stream in a temperature range of -50 °C to 250 °C at a heating rate of 10 °C/min. The temperatures reported in connection with DSC studies are the temperatures of the peak maxima (peak temperature TP). Other

DSC

Modifikation A

Modifikation B

Modifikation C

The following are the main components of the test:

The crystalline modifications A and B of (1R,2R) 3-dimethylamino-1-ethyl-2-methylpropyl) phenol were characterised each by Fourier transform (FT) RAMAN spectrometry. For this purpose, the FT-Raman spectra were recorded on a Bruker RFS100 RAMAN spectrometer (Nd-YAG 100 mW laser, excitation 1064 nm, Ge-detector, 64 scans, 25-3500 cm-1, resolution 2 cm-1).

The following information shall be provided in the report:

The crystalline modifications A and B of (1R,2R) 3- ((3-Dimethylamino-1-ethyl-2-methylpropyl) phenol were each characterised by means of Thermogravimetric Fourier Transform Infrared Spectroscopy (TG-FTIR). The corresponding spectra were obtained with a TG 209 thermo-microwave and a Bruker FT-IR Vector 22 spectrometer (aluminium brick (open or micro-opened), nitrogen atmosphere, heating rate 10 °C/min, 25-250 °C)

The TG-FTIR studies showed that both modifications decompose above 160 °C.

The data are collected by the Member States.

The crystalline modifications A and B of (1R,2R) 3- ((3-dimethylamino-1-ethyl-2-methyl-propyl) phenol were characterised by dynamic vapor absorption (DVS) and were studied in dynamic mode (5% relative humidity/hour).

The DVS cycles are reversible, and at 25 °C mass changes of 0.8% for modification A and 0.3% for modification B were found, both modifications being only slightly hygroscopic.

Analytical methods - Rate of resolution

Two different tests were performed to investigate the rate of dissolution of modifications A and B in water.

In the first determination, a suspension of modification A or B was stirred in water without taking into account the particle size distribution.

In the second determination, a fresh sample of modification A was produced and tablets were produced for both modifications A and B. The respective form was not affected by the tabletisation, but both samples showed a resolution rate of 0.003 mg/ min cm2.

Claims

The chemical composition of the product is determined by the following equation:
Crystalline modification of (1R,2R) 3- ((3-Dimethylamino-1-ethyl-2-methylpropyl) phenol (modification A) as described in claim 1 including an X-ray diffraction reflex at 15,58±0,20 (2Θ).
Crystalline modification A as described in claim 2, characterised by addition of at least one X-ray diffraction reflector selected from the group consisting of 28,37 ± 0,20 (2Θ) and 34,45 ± 0,20 (2Θ).
Crystalline modification A as described in claim 2 or 3, characterised by an additional X-ray diffraction reflection selected from the group consisting of 13,71±0,20 (2Θ), 14,80±0,20 (2Θ), 16,89±0,20 (2Θ), 17,79±0,20 (2Θ), 18,45±0,20 (2Θ), 20,20±0,20 (2Θ), 20,92±0,20 (2Θ), 22,50±0,20 (2Θ), 24,37±0,20 (2Θ) and 25,33±0,20 (2Θ).
Crystalline modification A according to one of the following claims 2-4, characterised by an additional X-ray diffraction reflection selected from the group consisting of 14,11±0,20 (2Θ), 19,07±0,20 (2Θ), 21,12±0,20 (2Θ), 21,90±0,20 (2Θ), 22,21±0,20 (2Θ), 24,75±0,20 (2Θ), 27,32±0,20 (2Θ), 27,55±0,20 (2Θ), 29,90±0,20 (2Θ) and 30,68±0,20 (2Θ).
Crystalline modification A according to one of the following claims 2-5, characterised by not containing at least one X-ray diffraction reflector selected from the group consisting of 8,10±0,20 (2Θ), 10,93±0,20 (2Θ), 11,83±0,20 (2Θ), 12,41 ±0,20 (2Θ), 26,22±0,20 (2Θ), 26,54±0,20 (2Θ) and 26,72±0,20 (2Θ).
Crystalline modification A according to one of claims 2 to 6, characterised by an endothermic temperature in the DSC in the range of 75 to 84 °C.
Method for producing crystalline modification A according to one of claims 2-7 including the steps Other
(a) a solution of (1R,2R) 3-dimethylamino-1-ethyl-2-methylpropyl) phenol and

(b) Storage of the residue obtained in accordance with step (a) at a temperature > 5 °C.
Crystalline modification A of (1R,2R) 3- ((3-Dimethylamino-1-ethyl-2-methylpropyl) phenol obtained by a process as described in claim 8.
Crystalline modification (1R,2R) 3- ((3-Dimethylamino-1-ethyl-2-methyl-propyl) phenol (modification B) as specified in claim 1 including an X-ray diffraction reflex of 29,06 ± 0,20 (2Θ).
Crystalline modification B as described in claim 10 characterised by addition of at least one X-ray diffraction reflector selected from the group consisting of 19,50±0,20 (2Θ), 35,49±0,20 (2Θ) and 40,01±0,20 (2Θ).
Crystalline modification B as defined in claim 10 or 11, characterised by an additional X-ray diffraction reflection selected from the group consisting of 14,11±0,20 (2Θ), 14,44±0,20 (2Θ), 16,08±0,20 (2Θ), 17,17±0,20 (2Θ), 17,43±0,20 (2Θ), 18,81 ±0,20 (2Θ), 20,24±0,20 (2Θ), 20,80±0,20 (2Θ), 22,00 ±0,20 (2Θ), 22,49±0,20 (2Θ), 23,40±0,20 (2Θ), 24,15±0,20 (2Θ), 24,51±0,20 (2Θ) and 29,89±0,20 (2Θ).
Crystalline modification B according to one of claims 10 to 12, characterised by the addition of at least one X-ray diffraction reflector selected from the group consisting of 18,67±0,20 (2Θ), 25,24±0,20 (2Θ), 25,36±0,20 (2Θ), 27,58±0,20 (2Θ), 27,79±0,20 (2Θ), 30,11±0,20 (2Θ) and 31,00±0,20 (2Θ).
Crystalline modification B according to one of claims 10-13 characterised by not containing at least one X-ray diffraction reflector selected from the group consisting of 8,10±0,20 (2Θ), 10,93±0,20 (2Θ), 11,83±0,20 (2Θ), 12,41±0,20 (2Θ), 26,22±0,20 (2Θ), 26,54±0,20 (2Θ) and 26,72±0,20 (2Θ).
Crystalline modification B according to one of claims 10-14 characterised by an endothermic temperature in the DSC in the range 87-93°C.
Method for producing crystalline modification B according to one of claims 10-15 including the steps Other
(a) a solution of (1R,2R) 3-dimethylamino-1-ethyl-2-methylpropyl) phenol and

(b1) store the residue obtained in accordance with step (a) at a temperature ≤ 5 °C; or

(b2) Suspend the residue obtained in accordance with step (a) and stir the suspension.
Method for producing crystalline modification B according to one of claims 10-15 including step
(a) Precipitation of (1R,2R) 3-dimethylamino-1-ethyl-2-methylpropyl) phenol from solution.
Crystalline modification B of (1R,2R) 3- ((3-Dimethylamino-1-ethyl-2-methylpropyl) phenol obtained by a process as described in claim 16 or 17.
Crystalline modification C of (1R,2R) 3- ((3-Dimethylamino-1-ethyl-2-methylpropyl) phenol containing at least one X-ray diffraction reflex selected from the group consisting of 10,93±0,20 (2Θ), 12,41±0,20 (2Θ) and 26,22±0,20 (2Θ).
Crystalline modification C as defined in claim 19, characterised by addition of at least one X-ray diffraction reflector selected from the group consisting of 8,10±0,20 (2Θ), 11,83±0,20 (2Θ), 26,54±0,20 (2Θ) and 26,72±0,20 (2Θ).
Crystalline modification C as defined in claim 19 or 20, characterised by an additional X-ray diffraction reflection selected from the group consisting of 13,71±0,20 (2Θ), 14,13±0,20 (2Θ), 14,82±0,20 (2Θ), 15,34±0,20 (2Θ), 15,59±0,20 (2Θ), 16,10±0,20 (2Θ), 16,43±0,20 (2Θ), 16,91±0,20 (2Θ), 17,32±0,20 (2Θ), 17,58±0,20 (2Θ), 17,82±0,20 (2Θ), 18,01±0,20 (2Θ), 18,46±0,20 (2Θ), 19,05±0,20 (2Θ), 20,82±0,20 (2Θ), 20,23±0,20 (2Θ), 20,71±0,20 (2Θ), 20,94±0,20 (2Θ), 21,59±0,20 (2Θ), 21,64±0,20 (2Θ), 31,90±0,20±±2,20±2,2±2,2±2,2±2,2±2,2±2,2±2,2±2,2±2,2±2,2±2,2±2,2±2,2±2,2±2,2±2,2±2,2±2,2±2,2±2,2±2,2±2,2±2,2±2,22,2±3,22,22,22,22,22,22,22,22,23,23,23,23,23,23,23,23,24,24,24,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,25,2
Crystalline modification C according to one of claims 19-21, characterised by having an endothermic peak temperature of 75-84°C and/or an endothermic peak temperature of 87-93°C in DSC studies.
Method for producing crystalline modification C according to one of claims 19-22 including the steps Other
(a) Shake a suspension containing the crystalline modification A and/or the crystalline modification B of (1R,2R) 3-dimethylamino-1-ethyl-2-methylpropyl) phenol, and

(b) Evaporation of the suspension medium in the air stream.
Crystalline modification C of (1R,2R) 3- ((3-Dimethylamino-1-ethyl-2-methylpropyl) phenol obtained by a process as claimed by 23.
Pharmaceutical composition comprising a crystalline modification of (1R,2R) 3- ((3-Dimethylamino-1-ethyl-2-methylpropyl) phenol according to one or more of claims 1-7, 9-15, 18-22 and 24 and a pharmaceutically compatible carrier.
Pharmaceutical formulation comprising a pharmaceutical composition as claimed 25.
Crystalline modification of (1R,2R) 3- ((3-Dimethylamino-1-ethyl-2-methylpropyl) phenol according to one or more of claims 1-7, 9-15, 18-22 and 24 as a medicinal product.
Use of a crystalline modification of (1R,2R) 3- ((3-Dimethylamino-1-ethyl-2-methylpropyl) phenol according to one or more of claims 1-7, 9-15, 18-22 and 24 to produce a medicinal product for the control of pain.