HK1112612B - 3-(2-(dimethylamino)methyl(cyclohex-1-yl))phenol maleate and its crystalline forms - Google Patents

Description

The present invention relates to salts of maleic acid and 3-[2-dimethylamino]methyl- (cyclohex-1-yl) phenol according to formula I, stable crystalline forms of the salt and methods for their production, a pharmaceutical composition and the use of the salt as a pharmaceutical active substance in a composition.

EP-A1-0 753 506 does not contain any indication in which stoichiometry 3-[2-dimethylamino) methyl ((cyclohex-1-yl) phenolics with analgesic effects can be obtained. The text mentions that salts can also be obtained from the free bases, but maleic acid is not considered as a possible anion. The examples provide only hydrochlorides, i.e. a salt with a monovalent anion. EP-A9-0 753 506 does not contain any indication in which stoichiometry 3-[2-dimethylamino) overcyclohex-1-yl] phenolics with bivalent anion compounds can be obtained, for example, hemi-methacrylate or 1:1-methacrylate.

It was also found that 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) phenol with maleic acid forms a maleate as a crystalline solid, preferably in a 1:1 ratio of maleic acid anion and 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-pbenol. It was also found that the maleate is not hygroscopic, is air stable and does not form hydrates or solvates. It was also found that 3-[2-dimethylamino) methyl-cyclohex-1-yl]-phenol has only a few valuable properties, namely two crystalline compounds, at lower and higher temperatures, which make it particularly stable in water. For example, 3-dimethylamino-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-meth

A first subject matter of the invention is salts of maleic acid with 3-[2-dimethylamino) methyl-[cyclohex-1-yl]-phenol of formula I

The compounds of the invention, such as those of formula I, contain one chiral C-atom each at the 1st and 2nd positions of the cyclohexane ring. The compounds of the invention, such as those of formula I, include all stereoisomers and mixtures of stereoisomers. The structure of the (1R,2R) enantiomer of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol is as follows:

The compounds of formula I can be obtained from the free base and incorporated with maleic acid or maleic anhydride in the presence of water, analogous to the processes generally described for the production of salts in EP-A1-0 753 506. For example, the free base 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]phenol can be isolated from the hydrochloride described in Examples 9 and 10 of EP-A1-0 753 506. To do this, the hydrochloride is dissolved in an organic solvent mixed with an aqueous inorganic base, for example alkali base bases or alkali base hydrocarbonates (such as LiOH, NaOH, KHH, HHCO3 and NaCO3), and the organic phase is separated. The base can be either evaporated in the usual way and used directly after the solvent is dissolved or by evaporation to form a salt.

Surprisingly, salt formation was found to result in only one crystalline form when temperature is controlled and no temperatures above 100 °C are used.

The invention also relates to a method for the production of 3-[2-dimethylamino) methyl-[cyclohex-1-yl]-phenol-maleate of formula I, consisting of the combination of 3-[2-dimethylamino) methyl-[cyclohex-1-yl]-phenol and maleic acid, preferably with at least one of the components in a dissolved or suspended form.

The invention also relates to a process for the production of 3-[2-dimethylamino]methyl-[cyclohex-1-yl]phenol-malate of formula I, including the steps (a) Dissolve or suspend 3-[2-dimethylamino]methyl- (cyclohex-1-yl) phenol in a solvent; (b) Mix the solution or suspension with maleic acid or a maleic acid solution; and (c) Isolate the compound of formula I. preferably at no stage of the process where the temperature exceeds 100 °C and where steps (a) and (b) may be reversed.

The temperature should preferably not exceed 80 °C, preferably not exceed 70 °C and preferably not exceed 60 °C. The temperature at which the solution is obtained in step (a) is generally higher than at which the mixture is obtained in step (b).

The free base and maleic acid can be used in a molar ratio of 1:1 or the maleic acid can be used in excess, for example in a molar ratio of up to 1.3, preferably up to 1.1.

The amount of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol in the solution may be, for example, 5 to 70% by weight, preferably 10 to 60%, preferably 10 to 50% by weight, and preferably 15 to 40% by weight, depending on the solution.

In the processes described herein for the production of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol rnaleate, maleic acid may also be used in its anhydride form. Compatible inert solvents for 3-[2-dimethylamino]methyl- ((cyclohex-1-yl) ]-phenol and maleic acid and maleic acid anhydride are, for example, aliphatic, cycloaliphatic and aromatic hydrocarbons (hexane, heptane, petroleum ether, cyclohexane, methylcyclohexane, benzene, toluol, xylol), aliphatic aqueous solvents (methyl chloride, chloroform, di- and di-chloroethane), nitrile (at least diethyl nitrile, propyl acyl sulfone, benzene tetraphosphate), ether (diethyl tetraphosphate, diethyl tetraphosphate, t-methyl tetraphosphate, butyl methyl methacrylate, butyl methacrylate, butyl methacrylate, butyl methacrylate, butyl methacrylate, butyl methacrylate, butyl methacrylate, butyl methacrylate, butyl methacrylate, butyl methacrylate, butyl methacrylate, butyl methacrylate, butyl methacrylate, butyl methacrylate, butyl methacrylate, butyl methacrylate, butyl methacrylate, and methacrylate, butyl methacrylate, and methacrylate, butyl methacrylate, and methacrylate, and methacrylate, butyl methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and methacrylate, and

Mixing in the process step (b) may be by slow or rapid addition of one solution to another solution. One or both solutions may be heated. Mixing may also be done in such a way that one or both solutions are at room temperature or cooled, for example to -20 °C and preferably to -10 to +10 °C, except preferably -5 to +5 °C. After mixing, it may be heated and cooled and may be stirred for a period of time.

The crystalline residue can then be dried, for example by heating, vacuum drying or heating in vacuum, or by means of a heated and inert gas stream (air, nitrogen, noble gases) if necessary. The compounds of formula I are obtained in high yields and high purity. A further subject matter of the present invention is a salt of maleic acid and 3-[2-dimethylamino]methyl-[cyclohex-1-yl]phenol of formula I obtained by one of the processes described above.

The compounds of formula I and the method of manufacture of the invention offer considerable and sometimes unexpected advantages over corresponding hydrochlorides. Since no hydrates and solvates can be characterized, the choice of solvents is wide and uncritical. The stability in air and against moisture allows for open handling without special protective measures. The spontaneous formation of salt and crystalline precipitation and their good filterability allow industrial-scale processes.

The compounds of formula I are obtained in the present invention as a polymorphic solid, hereinafter referred to as form A. Amorphous forms of the compounds of formula I are easily obtained, for example, by freeze-drying or rapid cooling of solutions. Amorphous compounds of formula I are not very stable and tend to crystallize in the presence of moisture.

It has been found that the compounds of formula I form polymorphic forms as crystalline solids, which can be specifically prepared from 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) -phenol-maleate) and are particularly suitable as active substances for the formulation of pharmaceutical formulations due to their stability. It is known (see, for example, Z. Jane Li et al. in J. 88m. Sci., Vol. (((3), pp. 337 to 346 (1999)) that enantiomers give identical X-ray diffractograms and Raman spectra, thus forming identical polymorphic forms.

Another subject matter of the invention is a crystalline form of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-maleate of formula I, which has a characteristic X-ray diffraction pattern in the range 2° to 35° 20 with distinct characteristic lines, expressed in d-values (Å): 9.4 (vs), 6.8 (m), 5.56 (s), 5.30 (s), 5.22 (s), 4.71 (s), 4.66 (s), 4.24 (m), 4.12 (m), 4.03 (m), 3.98 (s) 3.76 (m), 3.27 (m); hereinafter referred to as form A.

Before and after the abbreviations in brackets mean: (vs) = very high intensity, (s) = high intensity, (m) = medium intensity, (w) = low intensity, and (vw) = very low intensity.

Another subject of the invention is a crystalline form A of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-maleate of formula I, which has a characteristic X-ray diffraction pattern with the following pronounced reflexes.

9,38	100
9,94	5
10,35	8
12,76	6
13,07	20
13,49	7
15,94	43
16,72	52
16,98	40
17,54	15
18,86	61
19,04	48
19,28	8
20,01	5
20,57	6
20,96	24
21,57	23
22,03	20
22,33	30
23,69	15
24,84	8
25,01	9
25,71	11
26,35	7
26,75	13
27,24	16
27,66	9
27,95	6
28,40	5
28,68	9
29,87	6
30,76	8
31,37	4
31,67	4
31,99	6
32,53	4
32,80	5
33,55	7
35,20	5
36,93	5
37,58	5
44, 54	6
45,70	4

The above table shows the peak layers (in 2 theta) and the relative intensities of the peaks, the most intense peak being standardized to a relative intensity of 100.

The application continues to be for a crystalline form A of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol maleate of formula I (polymorph A) characterised by a powder diffractogram comprising one or more of the following reflections: 9.38 (100), 9.94 (5) and 10.35 (8) (each ± 0,5 in 2 theta, relative intensity in brackets). Preferably, the powder diagram may also have one or more of the following reflections: 12.76 (6), 15.94 (43), 17.54 (15), 19.28 (8), 28.68 (9) and 31.99 (6) (each ± 0,2 in 2 theta, relative intensity in brackets).

Another subject of the invention is a crystalline form A of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-maleate of formula I, which has a characteristic Raman spectrum with characteristic lines, expressed in wavelengths (cm-1): Other

Position (cm-1)	Intensität
3060	m
3040	m
3021	m
2986	m
2966	s
2933	s
2920	s
2895	m
2879	m
2856	s
2812	w
1690	m
1616	m
1601	m
1569	vw
1467	m
1443	m
1412	w
1389	m
1361	w
1351	m
1332	w
1322	w
1306	w
1295	w
1289	w
1273	m
1247	m
1227	w
1211	m
1177	w
1167	w
1122	vw
1106	w
1081	w
1076	w
1055	m
1047	m
1025	w
999	vs
971	vw
957	m
929	w
901	w
855	m
843	m
817	w
796	w
754	m
707	vw
676	vw
635	m
614	w
572	vw
536	m
514	vw
486	vw
468	vw
454	w
425	vw
400	w
359	w
345	w
328	m
292	m
272	m
247	s
188	w
118	vs
105	vs
81	vs

Another subject of the invention is a crystalline form A of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-maleate of formula I, comprising one or more of the following characteristic bands in the Raman spectrum, each expressed in wavelengths (cm-1): 118 (vs), 188 (w), 400 (w), 676 (w), 2812 (w), 2879 (m),

preferably one or more of the following bands: The Commission shall be assisted by the Member States in the implementation of the provisions of this Regulation.

Another subject of the invention is a crystalline form A of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-maleate of formula I, which has an X-ray diffraction image as shown in Figure 1.

Another subject of the invention is a crystalline form A of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-maleate of formula I, which has a gamma spectrum as shown in Figure 2.

The crystalline form A is the most thermodynamically stable form at low temperatures up to, for example, about 100 °C and additionally has excellent chemical and physical stability. Polymorph A is insensitive to the influence of humidity even at high relative humidities up to 90% and stable even over a long period of time. No water uptake, no formation of hydrates and no transformation into other crystalline forms is observed under normal conditions. Polymorph A also shows no phase transformations in air and in the presence of moisture.Polymorph A is also non-hygroscopic and absorbs only small amounts of surface water. Polymorph A also does not form solvates under these conditions and no transformation is observed in contact with solvents. Solubility in polar solvents is very good. The melting point is about 167 °C and the melting point is about 135 J/g. Polymorph A can be produced as a solid powder with desired medium particle sizes, usually in the range of about 1 μm to 500 μm.

The compound of formula I forms another crystalline form B, which is thermodynamically stable at higher temperatures and is also stable under normal conditions of air and excluding humidity.

A further subject matter of the invention is a crystalline form of 3-[2-dimethylamino) methyl- (cyclohex-1-yl) phenol-maleate of formula I, which has a characteristic X-ray diffraction pattern in the range 2° to 35° 2θ with distinct characteristic lines, expressed in d-values (Å): 10.6 (m), 7.5 (m), 7.3 (m), 6.1 (s), 5.29 (s) 4.88 (m), 4.72 (m), 4.47 (vs), 4.43 (m), 4.26 (m), 4.24 (m), 3.99 (s), 3.71 (m), 3.52 8m), 3.30 (s); hereinafter referred to as Form B.

Another subject of the invention is a crystalline form B of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-maleate of formula I, which has a characteristic X-ray diffraction pattern with the following pronounced reflexes. Other

8,36	18
11,85	20
12,19	20
13,41	12
14,50	49
14,83	11
16,77	58
18,16	17
18,78	28
19,84	100
20,00	17
20,84	19
20,97	16
21,19	12
22,27	33
22,64	7
22,85	11
23,95	18
24,53	7
24,85	8
25,26	16
25,97	8
26,66	12
27,00	29
27,18	13
27,48	8
28,21	4
29,10	6
29,41	9
29,90	8
30,49	10
31,32	6
33,14	6
33,88	5
34,32	4
34,99	10
36,32	3
36,88	4
37,86	4
38,35	10
42,11	5
42,78	3
43,05	3
43,62	6
44,35	4
46,83	6
47,80	3
48,35	3

The above table shows the peak layers (in 2 theta) and the relative intensities of the peaks, the most intense peak being standardized to a relative intensity of 100.

Another subject matter of the invention is polymorph B of 3-[2-dimethylamino) methyl- (cyclohex-1-yl) ]phenol-maleate of formula I, characterized by a powder diffractogram comprising one or more of the following reflections: 8.36 (18), 14.5 (49) and 14.83 (11) (each ± 0.5 in 2 theta, relative intensity in brackets); preferably, the powder diagram may additionally have one or more of the following reflections: 11.85 (20), 12.19 (20), 18.16 (17), 22.85 (11), 29.1 (6) and 29.41 (6) (each ± 0.2 in 2 theta, relative intensity in brackets).

Another subject of the invention is a crystalline form B of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-maleate of formula I, which has a characteristic Raman spectrum with characteristic lines, expressed in wavelengths (cm-1):

Position (cm-1)	Intensität
3045	vs
3028	m
2974	s
2953	s
2928	vs
2896	s
2856	s
2829	m
1703	s
1621	m
1612	m
1583	m
1480	vw
1459	m
1446	m
1401	vw
1385	m
1360	s
1227	vw
1324	w
1313	m
1309	m
1295	m
1282	m
1253	w
1220	w
1211	m
1197	m
1178	w
1162	m
1124	w
1104	w
1081	w
1076	w
1052	m
1010	w
999	vs
971	vw
956	w
933	w
890	w
875	m
858	m
841	s
816	m
794	m
750	m
708	vw
628	w
620	w
605	vw
578	w
573	w
538	m
507	vw
472	w
455	w
449	w
418	w
372	w
340	m
307	w
272	m
246	s
229	m
101	vs
83	vs

Another subject of the invention is a crystalline form B of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-maleate of formula I comprising one or more of the following characteristic bands in the Raman spectrum, each expressed in wavelengths (cm-1): 229 (m), 875 (m) and 2829 (m),

preferably one or more of the following bands: The Commission shall adopt implementing acts laying down the rules for the application of this Regulation in respect of the following categories of products:

The subject of the invention is also a crystalline form B of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-maleate of formula I, which has an X-ray diffraction image as shown in Figure 3.

The subject matter of the invention is further a crystalline form B of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-maleate of formula I, which has a gamma spectrum as shown in Figure 4.

The polymorphic form B can be transformed into the crystalline form A. The forms A and B form an enantiotropic system with a transition point or range of about 100 to 120 °C. The invention is therefore also intended for mixtures of the crystalline forms A and B in arbitrary quantity ratios.

The crystalline form B is the most thermodynamically stable form at higher temperatures, for example at about 100 °C or more. Polymorph B additionally has excellent chemical stability at elevated temperatures even in the presence of humidity. The physical stability is lower, because at elevated pressure, and even higher temperatures with or without moisture, a conversion to polymorph A occurs.

The polymorphic forms can be produced from the salt 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-maleate by known crystallization methods, for example by stirring suspensions (setting phase equilibrium), precipitation, recrystallization, or evaporation of solvents. Diluted, saturated, or supersaturated solutions may be used, with or without injection with a crystal nucleometer. The temperatures for solution formation can be up to 100 °C. Crystallization can be initiated by cooling to about -100 °C to 30 °C, and preferably -30 °C to 20 °C, with continuous or amorphous precipitation.

The invention also relates to a method for the production of the crystalline form A of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-maleate, characterized by the following: (a) a solid, amorphous powder form of 3-[2-dimethylamino]methyl- (cyclohex-1-yl) phenol-malate treated with an inert gas containing water vapour; or (b) a suspension of the amorphous form of 3-[2-dimethylamino) methyl- (cyclohex-1-yl) phenol-malate produced in a solvent as a carrier and stirred until the complete crystalline form A is formed; or (c) 3-[2-dimethylamino) methyl- (cyclohex-1-yl) phenol atoms in a solvent and subsequently precipitated; or preferably containing at least one of these components in a dissolved or suspended form and the resulting product is isolated, provided that the temperature does not exceed 100 °C.

The temperature in the process steps a) and b) is preferably not more than 40 °C and the process is carried out at room temperature. Inert gases are for example air, nitrogen and noble gases, where air is particularly preferable for economic reasons. The relative humidity of the gases can be, for example, 40 to 90% and preferably 60 to 90%. The treatment time in process step a) depends mainly on the particle size and relative humidity and can be, for example, 5 to 100 hours.

In step (a), polymorph B can also be formed alongside form A if the relative humidity is too low and/or the treatment time is too short.

The treatment time in step (b) may be between 5 and 100 hours. After isolation, the solvent or solvent mixture used can be removed in the usual way by known drying methods.

In step (c) the crystalline form A, B or the amorphous form of 3-[2-dimethylamino) methyl- (cyclohex-1-yl) phenol-malate can be used to make solutions. The concentration of 3-[2-dimethylamino) methyl- (cyclohex-1-yl) phenol-malate in the solution depends on the temperature and the solvent chosen. The amount dissolved can be, for example, from 0.5 to 50, preferably 0.5 to 30, preferably 0.5 to 20, and particularly preferably 1 to 15%, by weight, depending on the solvent. The temperature of the solution can be up to 100 °C and preferably up to 60 °C. The solution can also be prepared at room temperature if one uses a high solvent, for example waterThe precipitation may be by cooling, partial or complete removal of the solvent, addition of a precipitator (non-solvent, e.g. heptane or methyl butyl ether) or a combination of these measures. Cooling may involve slow cooling or even cooling to temperatures of -20 °C and preferably 0 °C. The solvent may be heated, in gas stream, applied to a vacuum or a combination of these measures. Heating to remove the solvent means in the process step c) a temperature of not more than 70 °C and not more than 50 °C.

In step (d), the temperature should preferably not exceed 80 °C, preferably not exceed 70 °C and preferably not exceed 60 °C. The temperature of dissolving or suspending a component is generally higher than that of mixing.

A further subject matter of the present invention is a salt of formula I of maleic acid and 3-[2-dimethylamino]methyl-[cyclohex-1-yl]-phenol in the crystalline form A (polymorph A) obtained by one of the processes described above.

While the production of polymorphic form A is relatively uncritical, the polymorphic form B can only be obtained by a special process.

The invention is therefore also intended to produce the crystalline form B of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-maleate, characterised by dissolving 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-maleate in a mixture of tetrahydrofuran and water in a volume ratio of 0.8:1,2 to 1.2:0.8 and then completely removing the solvent mixture at a temperature of at least 80 °C. Deep evaporation in the open air is also possible, for example at room temperature in an open vessel (contact with humidity).

Tetrahydrofuran (THF) and water are preferably in a 1:1 volume ratio. Before removing the solvent mixture, the solution may be stirred for a specified period of time, for example up to 24 hours at elevated temperature (about 80 to 100 °C). Additionally, a gas stream and/or vacuum may be used to remove the solvent mixture. Heating to remove solvent means a temperature of at least 80 and preferably up to about 120 °C and preferably 90 to 100 °C. The solvent is particularly destilated at the evaporative rotation table.

It was also found that adjustment of phase equilibrium by stirring suspensions at a temperature of at least 120 °C leads to the formation of the crystalline form B.

A further subject matter of the present invention is a salt of formula I of maleic acid and 3-[2-dimethylamino]methyl-[cyclohex-1-yl]-phenol in the crystalline form B (polymorph B) obtained by one of the processes described above.

3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-maleate is therefore an excellent active substance for pharmaceutical formulations and particularly for analgesic medicinal products because of its favourable overall profile. Accordingly, the use of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-maleate of formula I as an active substance in medicinal products, preferably as an active substance in painkillers, is also an object of the invention. Here, as throughout the application, diasteres or mixtures of enantiomeric diasteres with a transconfiguration of the phenyl ring and the dimethylamylamine group (1,2R and 1,2R respectively) are used, with the absolute configuration of the dimethylamine enzyme (1,2R and 1,2R respectively) being particularly preferred. Another subject matter of the invention is a pharmaceutical composition containing an effective amount of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-malate of formula I and a pharmaceutical carrier or a pharmaceutical diluent.

The compound of formula I may be present in the form of crystalline form A, crystalline form B or a mixture of forms A and B. Preferably, the crystalline form A is included.

The amount of compounds in Formula I depends essentially on the formulation and the dosage desired during the period of administration. The amount of the salts of the invention to be administered to the patient may vary, depending, for example, on the weight or age of the patient and the type of application, the indication and the severity of the disease. Usually, at least one such compound is administered at a rate of 0.005 to 5000 mg/kg, preferably 0.05 to 500 mg/kg of the patient's body weight.

Oral formulations may be solid formulations, such as tablets, capsules, pills and capsules. Oral formulations may also be liquid formulations, such as solutions, suspensions, syrups or elexirs. Liquid and solid formulations also include incorporation of the compounds of Formula I into solid or liquid foods.

The compounds of formula I and the crystalline forms may be used directly as powder (micronised particles), granules, suspensions or solutions, or they may be mixed with other pharmaceutically acceptable ingredients and components and then pulverised to fill the powders into hard or soft gelatine capsules, to press into tablets, pills or lozenges, or to suspend or dissolve the powders in a carrier to produce suspensions, syrups or elixirs.

Pharmaceutically acceptable ingredients and components for the different types of formulation are known in themselves, for example, binders such as synthetic or natural polymers, pharmaceutical agents, lubricants, surfactants, sweeteners and flavourings, coatings, preservatives, colours, thickeners, excipients, antimicrobials and carriers for the different types of formulation.

Examples of binders are rubber arabic, rubber dragant, acacia rubber and biodegradable polymers such as homo- or copolyester of dicarboxylic acids, alkylendiols, polyalkyleneglycols and/or aliphatic hydroxycarbons; homo- or copolyamide of dicarboxylic acids, alkylendiamines and/or aliphatic aminocarbons; corresponding polyester polyamide copolymers, polyanhydrides, polyorthoester, polyphosphates and polycarbonates. The biodegradable polymers may be linear, cross-linked or interlinked. Specific examples are polyglycolytic acid, polyvinyl polyvinyl and poly-d1/milk glycolylic acid. Other examples of polymers which are soluble in water are polymers such as amyl or polyethylene, amyl or polypropylene, amyl or polyethylene, amyl or polypropylene, and their mixtures (e.g., polyethylene, polypropylene, polypropylene, and polypropylene, and their esters).

Examples of medicinal products are phosphates such as dicalcium phosphate.

Examples of lubricants are natural or synthetic oils, fats, waxes or fatty acid salts such as magnesium stearate.

Examples of surfactants include lecithin, phospholipids, octyl sulphate, decyl sulphate, dodecyl sulphate, tetradecyl sulphate, hexadecyl sulphate and octadecyl sulphate, sodium oleate or sodium caprate, 1-acylaminoethan-2-sulphonic acids such as 1-octanoylaminoethan-2-sulphonic acid, 1-deylaminoethan-2-sulphonic acid, 1-d-lactaminoethan-2-sulphonic acid, 1-tetraethylaminoethan-2-sulphonic acid, 1-hexanodetoyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl

Examples of sweeteners are sucrose, fructose, lactose or aspartame.

Examples of flavourings are peppermint, wintergreen oil or fruit flavourings such as cherry or orange flavourings.

Examples of coatings are gelatine, wax, shellac, sugar or biodegradable polymers.

Examples of preservatives are methyl or propyl paraben, sorbic acid, chlorbutanol and phenol.

Examples of aids are fragrances.

Examples of thickeners are synthetic polymers, fatty acids, fatty acid salts, fatty acid esters and fatty alcohols.

Examples of liquid media are water, alcohols (ethanol, glycerol, propylene glycol, liquid polyethylene glycols, polytriazine and oils) and solid media are talc, clay, microcrystalline cellulose, silicon dioxide, aluminum oxide and similar solids.

The composition of the invention may also contain isotonic agents such as sugars, physiological buffers and sodium chloride.

The composition of the invention may also be formulated as a breathing tablet or breathing powder which decomposes in an aqueous environment to form a drinking solution or suspension.

A syrup or elixir may contain the compound of formula I, a sugar such as sucrose or fructose as a sweetener, a preservative (such as methylparaben), a colouring agent and a flavouring agent (such as flavourings).

The composition of the invention may also be a delayed and controlled release formulation in contact with gastrointestinal body fluids to achieve a substantially constant and effective level of the active substance in blood plasma. For this purpose, the compounds of formula I may be embedded in a polymer matrix of a biodegradable polymer, a water-soluble polymer or both, where appropriate with an appropriate surfactant. Embedding may in this context involve the incorporation of microparticles into the polymer matrix.

The compounds of formula I may also be used in combination with at least one other pharmaceutical active substance for combination therapy, in which case at least one other active substance may be dispersed or dissolved in addition to the composition of the invention.

The invention also relates to the use of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol maleate of formula I to produce a pharmaceutical composition, particularly for the treatment of pain conditions.

The invention also relates to a procedure for the treatment of pain conditions by administering to a patient suffering from pain an effective amount of 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol-maleate of formula I.

The product (s) of the invention is preferably intended for the prophylaxis and/or treatment of pain, preferably from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain; migraine; depression; neurodegenerative diseases, preferably from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease and multiple sclerosis; cognitive disorders, preferably cognitive impairment, particularly preferably attention deficit disorder (ADD or ADD), pancreatitis; epilepsy; epilepsy; narcotic drugs; hallucinogens; nicotinamide dihydrotestosterols (especially nicotinamide dihydrotestosterols); nicotinamide dihydrotestosterols (especially nicotinamide dihydrotestols); nicotinamide dihydrotestols (especially nicotinamide dihydrotestols) for the prevention of and treatment of cardiovascular disease, alcohol and/or drug abuse; and/or drug abuse; for the treatment of patients with severe and severe impairment; for the treatment of alcohol and/drugs; for the treatment of obesity and/or drug dependence; for the treatment of alcohol and/ or other drugs; for the development of the immune system; for the prevention of narcotic drugs and/anti-alcotic drugs; for the treatment of alcohol and/anti-alcoagensing and/anti-alcoagensing and/anti-alcoagensing; for the treatment of narcotic drugs; for the treatment of narcotic drugs and/anti-alcotic drugs; for the treatment of narcotic drugs; for the treatment of narcotic drugs and/anti-alcotic drugs; for the treatment of narcotic drugs; for the treatment of narcotic drugs; for the treatment of narcotic drugs and/anti-alcotic drugs; for the treatment of narcotic drugs; for the treatment of narcotic drugs; for the treatment of narcotic drugs; for the treatment of narcotic drugs; for the treatment of narcotic drugs; for the treatment of narcotic drugs; for the treatment of narcotic drugs; the treatment of nar

In particular, the medicinal product (the pharmaceutical composition) of the invention is preferably suitable for the prophylaxis and/or treatment of pain, preferably acute pain, chronic pain, neuropathic pain or visceral pain; depression; epilepsy; Parkinson's disease; alcohol and/or drug abuse (in particular nicotine and/or cocaine) and/or drug abuse; alcohol and/or drug (in particular nicotine and/or cocaine) and/or drug dependence; preferably for the prophylaxis and/or reduction of withdrawal symptoms in alcohol and/or drug (in particular nicotine and/or cocaine/cocaine) and drug dependence; and for the development of opioid or drug tolerance, in particular.

The product of the invention is particularly suitable for the prophylaxis and/or treatment of pain, preferably acute pain, chronic pain, neuropathic pain or visceral pain.

It is particularly desirable to use at least one salt of the invention, preferably in the form of one of its pure stereoisomers, in particular its enantiomers or diastereomers, its racemate or in the form of a mixture of stereoisomers, in particular its enantiomers and/or diastereomers, in any mixing ratio, and one or more pharmaceutically compatible excipients, if any, to manufacture a medicinal product for the prophylaxis and/or treatment of pain, preferably selected from the group consisting of acute pain, in particular chronic pain, neuropathic pain and buffered pain, of migraine, depression, drug-induced neurodegenerative diseases, preferably selected from the group of existing antibodies, in particular anti-depressants, especially anti-morbid drugs, especially anti-depressants, especially anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotics, anti-psychotic, anti-psychotic, anti-psychotic, anti-psychotic, anti-psychotic, anti-psychotic, anti-psychotic, anti-psychotic

The medicinal product may be supplied in liquid, semi-solid or solid form, such as solutions for injection, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, patches, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticle form, such as pellets or granules, whether or not sold in tablets, bottled in capsules or suspended in a liquid, and may be administered as such.

In addition to at least one salt of the invention, where appropriate in the form of its pure stereoisomers, in particular enantiomers or diastereomers, its racemate or in the form of mixtures of the stereoisomers, in particular enantiomers or diastereomers, in any mixing ratio, the medicinal product of the invention (the pharmaceutical composition of the invention) usually contains other physiologically compatible pharmaceutical excipients which may be selected as excipients from the group consisting of carriers, fillers, solvents, lubricants, surfactants, dyes, preservatives, sprays, emulsifiers, emulsifiers, emulsifiers and emulsifiers.

The choice of physiologically compatible excipients and the amounts of excipients to be used depends on whether the medicinal product (the pharmaceutical composition) is to be administered orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or topically, for example for infections of the skin, mucous membranes and eyes.

Suitable percutaneous application preparations are also deposition preparations in solution or in a patch, where appropriate with the addition of skin penetration agents.

Oral or percutaneous preparations may release the salts of the present invention with delay.

Err1:Expecting ',' delimiter: line 1 column 236 (char 235)

The amount of the salts of the present invention to be administered to the patient may vary, depending, for example, on the weight or age of the patient, the type of application, the indication and the severity of the disease.

The following examples explain the invention in more detail, but are not limited to it.

Examples:

For all DSC measurements (unless otherwise specified), the heating rates are 10°C/minute; the temperatures indicated are peak maxima.

A) Manufacture of (+) - 1R,2R-3-[2-dimethylamino]methyl- (cyclohex-1-yl) phenol-maleate Example A1: Manufacture as crystalline form A

The mixture is heated to 50 °C under stirring and then cooled to 135 °C. The mixture is then filtered through a glass filter, washed off with 4 ml of ethyl acetate and dried during the retention period by airing for 5 minutes. The crystal content of the Acyclohexane is approximately 0.70 mg (85% FIG.D.S.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.A.R.R.A.A.R.A.R.A.R.A.A.R.A.R.A.R.A.R.A.R.A.R.A.R.A.A.R.A.R.R.A.A.R.A.R.A.R.A.A.R.A.R.A.R.A.R

When using twice the amount of (+) - ((1 R,2R) -3-[2- ((Dimethylamino) methyl ((cyclohex-1-yl)) phenol, only the 1:1 maleate is also formed.

Example A2: Manufacture as crystalline form A

6.22 g (53.5 mmol) maleic acid is dissolved in 130 ml of acetic acid ethyl ester in a glass flask and then stirred to a solution of 12.48 g (53.5 mmol) (+) -(1 R,2R) -[2-(dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol, at 50 °C. After adding 20 to 25 ml, a white precipitate forms. After adding the entire solution, the fine, white solid is filtered from the warm solution and washed with a little cold acetic acid ethyl ester. The residue is purified by means of air filtration. 18,38 g (98.3% of the acid (+1 °C) - (dimethylamino) - (R27) - (R27) - (R27) - (dimethylamino) -methyl) is obtained as a solid at 17 °C. The weight loss is only 3.8 mg (ethyl acetate). The X-ray diffraction corresponds to the form A; the DSC peaks are almost unchanged at 165.8 and 176.7.

Example A3: Manufacture as crystalline form B

The suspension is stirred at 70 °C for one hour and then cooled to room temperature. The suspension is then cooled to 4 °C in the refrigerator and the settling point is drained. The solid state is heated once with 4 ml of maleic acid and obtained by means of an X-ray. The solid form of manethyl phthalate (R-methyl phthalate) is obtained by means of a crystalline solution of 17 °C (97.7 °C) at 17 °C.

Example A4: Manufacture as crystalline form A

In another glass flask, 17.96 g (+) - (((1 R,2R) -3-[2- ((Dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol are also dissolved at room temperature in 108 ml of acetic acid ethyl ether and slowly dripped to the solution of maleic acid within 30 minutes. After adding about half of the medium, a white, voluminous fine crystalline solid is formed. The suspension is stirred for another 3 hours at 55 °C after full addition.

Example A5: Manufacture as crystalline form A

In another glass flask, 20 ml of acetic acid ethyl ester are heated to 45 °C and then stirred to make both solutions drip at the same time. A strong mist spontaneously forms. After the addition, the suspension is stirred for another 3 hours at 50 °C. The suspension is then allowed to cool by itself at room temperature. The low-drying is filtered with 10 ml of acetic acid and washed through the air for two minutes. The crystal form of D-methyl ether is obtained by X-ray analysis at 16 °C (57.03 °C) and the crystal form of D-methyl ether is obtained by X-ray analysis.

The test chemical is used to determine the concentration of the active substance in the test chemical. (a) Manufacture

24,64 g (+) - 1R,2R) - 3-[2-dimethylamino) methyl- ((cyclohex-1-yl) ]-phenol (purity 76.8% by HPLC analysis) are dissolved in 500 ml acetic acid ethyl ester in a 1I tri-half flask. Heat to 55 °C and stir at once to give 9.44 g maleic acid. Stir at this temperature for 4 hours and then for 2 hours at 20 °C. Afterwards, the precipitate is filtered, washed once with 20 ml acetic acid ethyl ester and then drained with medium-dry air.

(b) Cleaning by stirring

The resulting raw product is weighed in glass flasks, added to solvent and shaken in a thermometer at 50 °C for 4 hours. The solutions are then cooled overnight to 23 °C and then filtered. The yield and purity (HPLC) of the residue are determined. Further information is given in Table 1. The following abbreviations are used: EtAc is ethyl acetate, EtOH is ethanol, PrOH is i-propanol, AcNi is acetyl, Tol is toluene, Hex is n-hexane, DiEt is diethyl, BuMe is t-butyl methyl tetraethyl, THMe is methanol, Me is methyl ketone, AcF is methylated. Other

Menge Maleat (mg)	Lösungsmittel 1 (ml)	Lösungsmittel 2 (ml)	Ausbeute (%)	Reinheit (%)
56,3	EtAc (1,0)	--	97,2	84,6
55,9	PrOH (1,0)	--	73,0	96,7
56,2	Hex (1,0)	--	96,3	84,0
55,8	AcNi (1,0)	--	71,5	93,6
56,4	Tol (1,0)	--	97,2	84,0
62,6	DiEt (1,0)	--	97,0	84,6
53,5	BuMe (1,0)	--	97,4	84,2
55,2	Ace (1,0)	--	58,2	97,9
55,1	MeEt (1,0)	--	75,9	92,1
58,8	THF (1,0)	--	80,1	89,5
55,2	Ace (0,98)	EtOH (0,02)	52,0	97,9
60,4	Ace (0,96)	EtOH (0,04)	50,5	97,0
55,5	Ace (0,94)	EtOH (0,06)	37,1	98,2
58,2	Ace (0,92)	EtOH (0,08)	42,4	98,3
57,3	Ace (0,90)	EtOH (0,10)	39,6	98,2
517,1	PrOH( 10,0)	--	79,7	88,9
516,5	PrOH( 10,0)	--	79,4	87,5
511,2	PrOH(10,0)	--	80,7	89,0
516,4	Ace (10,0)	--	62,0	98,1
515,2	Ace (10,0)	--	64,8	96,4
511,6	Ace (10,0)	--	68,7	94,8
506,9	THF (10,0)	--	82,9	87,9
511,2	THF (10,0)	--	81,9	87,8
507,2	THF (10,0)	--	83,8	88,5
518,3	Ace (9,70)	EtOH (0,3)	48,3	98,6
514,3	Ace (9,70)	EtOH (0,3)	50,9	97,8
509,8	Ace (9,70)	EtOH (0,3)	50,2	98,7

The product can be obtained in good to excellent purity by purifying the raw product by stirring.

(b) Manufacture of amorphous (+) - 1 R,2R) - 3 - 2 Dimethylamino-methyl-cyclohex-1-yl-phenol-maleate Example B1: Freeze-drying

81.5 mg of the maleate produced in the A1 sample is dissolved in 3 ml of water and then cooled to -75 °C. Then, at this temperature and pressure of 0.011 mbar, it is freeze-dried for 23 hours. A solid, white residue is obtained, which tends to crystallize rapidly in the presence of moisture, essentially forming the crystalline form A. By means of Differential Scanning Calorimetry (DSC, heating rate 10 °C/minute), a glass conversion temperature of close to 30 °C is determined. An exothermic peak at 85 °C is attributed to a crystallization.

If 20 mg of the amorphous form is stored at room temperature and 20% and 90% humidity respectively for 24 hours, a mixture of crystalline forms A and B or only crystalline form A is obtained.

C) Production of the crystalline form A

The crystal shape is determined by comparison of the Raman spectra, unless otherwise specified.

Example C1: Felling with non-solvents

(a) Fishing with n-heptane 80 mg of the maleate produced in accordance with sample A1 is dissolved in 8 ml of acetone at room temperature. After that, 7.5 ml of n-heptane is stirred. A white precipitate is formed, which is filtered and dried in a stream of air at room temperature. 50 mg of white powder corresponding to the crystalline form A is obtained. 80 mg of the maleate produced in accordance with sample A1 is dissolved in 17 ml of tetrahydrofuran (THF) at room temperature. After that, 9 ml of n-heptane is stirred. A white precipitate is formed, which is filtered and dried in a stream of air at room temperature. 52 mg of white powder corresponding to the crystalline form A.c) precipitation with teriary butyl methyl ether (TBME) 80 mg of the maleate produced in accordance with the A1 method are dissolved in 21 ml THF at room temperature, and then stirred with 7.5 ml TBME. A white precipitate is formed, which is filtered and dried in a stream of air at room temperature, to obtain 48 mg of white powder corresponding to the crystalline form A.

Example C2: Phase balances with suspensions

(a) Suspension in acetone To 80 mg of maleate produced in accordance with example B1, add 0.5 ml of acetone and stir for 24 hours at room temperature. Add 0.5 ml of 1,4-dioxane to 80 mg of the maleate produced in accordance with example B1 and stir for 24 hours at room temperature. 80 mg of malate produced in accordance with example B1 shall be 0,5 ml of ethyl acetate is added and stirred for 24 hours at room temperature, then filtered and dried in a stream of air at room temperature to obtain 50 mg of the crystalline form A as a white powder. Add 0.1 ml and then twice to every 0.2 ml of water and stir for 24 hours at room temperature. Then filter and dry in a stream of air at room temperature. 49 mg of the crystalline form A is obtained as a white powder. Add 0,5 ml of isopropanol to 80 mg of the maleate produced in accordance with example B1 and stir for 24 hours at room temperature.The solution is then filtered and dried in a stream of air at room temperature. 54 mg of the crystalline form A is obtained as a white powder. f) Suspension in tetrahydrofuran Add 0.5 ml of THF to 80 mg of the maleate produced according to example B1. A solid aggregate is formed and crushed with a spatula. The resulting suspension is then stirred for 24 hours at room temperature.

The following table shows the results of the analysis:

(a) Crystallisation from methanol/methylene chloride 100 mg of the maleate produced in accordance with sample A1 is dissolved in 1 ml of methanol. After adding 14 ml of methylene chloride, a clear solution is obtained and left to stand at 5 °C for 5 days. The volume is then reduced to a quarter and left to stand at 5 °C again for a week. The solvent is then completely evaporated at room temperature. 98 mg of the crystalline form A is obtained in the form of a white powder. 60 mg of the maleate produced in accordance with example A1 is dissolved in 10 ml of toluene/acetone (1:1 v/v) at 60 °C and then cooled to room temperature.The solution is then left at 5 °C for 4 days, after which the large crystals are filtered and dried to obtain 28 mg of the crystalline form A in the form of white crystals. 51 mg of maleate produced in accordance with the A1 method is dissolved in 31 ml of ethyl acetate at 65 °C. It is then cooled to room temperature and needle-shaped crystals are formed within 2 hours. It is left for another 5 days at 5 °C, filtered and dried. 33 mg of the crystalline form A is obtained in the form of white needle-shaped crystals. Dissolve 100 mg of the maleate produced in accordance with example A1 in 7 ml THF at 65 °C and then cool to room temperature.The solution is then left at 5 °C for 4 days, after which the large crystals are filtered and dried to obtain 28 mg of the crystalline form A in the form of white large crystals. In a stirrer, 2,31 g of the malate salt obtained from sample A6a is suspended in 30 ml of isopropanol and heated to 80 °C within 20 minutes to form a clear solution at a turning rate of about 600 rpm, increasing the turning rate to 800 rpm and stirring at this temperature for 30 minutes, increasing the turning rate to 1000 rpm towards the end.The white solid is filtered and dried in the air (2,132 g, 92.3%). Only lines of the crystalline form A are measured using an X-ray powder diffractogram. The thermoanalysis (DSC) shows endothermic signals at 165.8 °C and 177.2 °C. The thermogravimetric analysis does not show significant weight loss, so that no solvated form can be present.Purity is 99.5% determined by HPLC. In a stirring flask, 2,32 g of the malate salt obtained from sample A6a is suspended in 30 ml of isopropanol and heated to 80 °C within 15 minutes at a turning rate of about 600 rpm (rotations per minute) to form a clear solution. The turning rate is increased to 800 rpm and stirred at this temperature for 20 minutes, with the turning rate being increased to 1000 rpm towards the end. Then, within 10 minutes, the temperature is reduced to 65 °C and stirred for 10 minutes at this temperature.The white solid is filtered and dried in air (2,132 g, 92.3%). According to the X-ray powder diffractogram, only lines of the crystalline form A are measured. The thermoanalysis (DSC) shows endothermic signals at 163.4 °C and 174.4 °C. The thermogravimetric analysis does not observe any significant weight loss, so that no solvated form can be present.

Example C4: Crystallisation by evaporation of solvent

(a) Solvent Acetone / THF 10 mg of maleate produced in accordance with example A1 is dissolved in 15 ml acetone/THF (1:1, v/v) and the solvent mixture is slowly evaporated at room temperature in the nitrogen stream until dry. 10 mg of maleate produced in accordance with sample A1 is dissolved in 15 ml of acetone/ethyl acetate (1:1, v/v) and the solvent mixture is slowly evaporated at room temperature in the nitrogen stream until dry. 10 mg of the maleate produced in accordance with example A1 is added to 15 ml of methylene chloride (1:1,v/v) dissolve and evaporate the solvent mixture slowly at room temperature in open air at room temperature to dry. 200 mg of the maleate produced in accordance with sample A1 is dissolved in 4 ml of water/THF (1:1, v/v) and the solution is filtered through a 0.22 μm filter. The solution is placed on a petri dish and the solvent mixture is slowly evaporated to dry under ambient conditions at room temperature in open air at room temperature. 188 mg of the crystalline form A is obtained in the form of needle-shaped crystals. 200 mg of the maleate produced in accordance with example A1 is dissolved in 4 ml of water/THF (1:1,The solution is placed on a petri dish, injected with crystals of polymorph B and the solvent mixture is slowly evaporated to dry at room temperature in open air at room temperature. After a day, needle-shaped crystals are formed. 160 mg of crystalline form A is obtained in the form of needle-shaped crystals. 200 mg of the maleate produced in accordance with example A1 is dissolved in 4 ml of water/THF (1:1, v/v) and filtered through a 0,22 μm filter.After one day, needle-shaped crystals are formed, giving 182 mg of crystalline form A in the form of needle-shaped crystals. 11 mg of the maleate produced in accordance with sample A1 is dissolved in 15 ml of 1,4-dioxane. The solution is placed in an open vial and the solvent is evaporated to dry under ambient conditions at room temperature for 4 days. 9 mg of the crystalline form A is obtained in the form of a white powder. Dissolve 10 mg of the maleate prepared in accordance with example A1 in 15 ml of THF, place the solution in a petri dish and slowly evaporate the solvent mixture to dry in open air at room temperature under ambient conditions at room temperature within 2 days.9 mg of crystalline form A is obtained as a white powder.i) Solvent THF / water 150 mg of the maleate produced in accordance with example A1 is dissolved in 3 ml THF/water (1:1, v/v). The solvent is then evaporated at 60 °C at the rotary evaporator to obtain 135 mg of the crystalline form A in the form of a white powder. 150 mg of the maleate produced in accordance with example A1 is dissolved in 3 ml of THF/water (1:1, v/v).22 μm filter. The solution is placed on a Petri dish and the solvent mixture is evaporated at room temperature under a stream of nitrogen until dry. 50 mg of the maleate produced in the A1 sample is dissolved in 40 ml of THF at 60 °C. It is then cooled with dry ice and left at -20 °C, forming a cloudiness. After 3 days, a white precipitate is formed, which is filtered and dried. 21 mg of the crystalline form A is obtained in the form of a white powder.

Example C5: Conversion of crystalline form B to form A

(a) Phase equilibrium with suspension in ethyl acetate 30 mg of the crystalline form B obtained in the sample D1 are suspended in 2 ml of ethyl acetate and stirred for 18 hours at 23 °C. The residue is then filtered and dried to obtain 15 mg of the crystalline form A in the form of a white powder. 30 mg of the crystalline form B obtained in the sample D1 are suspended in 2 ml of toluene and stirred for 18 hours at 23 °C. The residue is then filtered and dried to obtain 22 mg of crystalline form A in the form of a white powder.

D) Production of the crystalline form B Example D1:

250 mg of the maleate produced in accordance with example A1 is dissolved in 5 ml THF/water (1:1, v/v). The solvent mixture is then evaporated at 90 °C on the rotary evaporator. 208 mg of the crystalline form B is obtained in the form of a white powder. The melting point is about 178 °C and the melting point is about 125 J/g, measured with DSC at a heating rate of 10 °C/min. The X-ray diffraction image is shown in Figure 3 and the Raman spectrum is shown in Figure 4.

Example D2:

The solution is prepared in the same way as in example D1 but left for 22 hours before evaporation.

Example D3:

100 mg of the maleate produced in accordance with example A1 is dissolved in 2 ml of THF/water (1:1, v/v). The solution is then left to stand at room temperature for 3.5 hours. The solvent mixture is then evaporated at 90 °C in the rotary evaporator. 84 mg of the crystalline form B is obtained in the form of a white powder.

Example D4:

Two 250 mg of maleate prepared according to example A1 are dissolved in 5 ml THF/water (1:1, v/v) each. One solution is filtered through a 0.22 μm filter and the second solution through a 0.45 μm filter. The solutions are given to each a petri dish and the solvent mixture is slowly evaporated at room temperature in open air at room temperature under ambient conditions. After one day the formation of spherical crystals is observed. After 3 days the solvent mixture is evaporated and the residues consist of the crystalline form B in the form of spherical crystals.

(e) Stability studies Example E1: Storage of the amorphous form at high humidity

The amorphous form of example B1 is stored at room temperature and 75% relative humidity and samples are examined by Raman spectroscopy after 2 days, 1, 2, 3, 4 and 8 weeks.

Example E2: Storage of crystalline form A in high humidity

The maleate produced in accordance with example A1 is stored at room temperature and 75% relative humidity and samples are examined by Raman spectroscopy after 3 days, 1, 2, 3, 4, 8 and 10 weeks, and the samples remain practically unchanged after 10 weeks.

Example E3: Storage of crystalline form B in high humidity

The crystalline form B obtained in the sample D1 is stored at room temperature and 75% relative humidity and samples are examined by Raman spectroscopy after 3 days, 1, 2, 3, 4 and 8 weeks, and remain virtually unchanged after 8 weeks.

Example E4: Stability under painting conditions

(a) Crystalline form A during the evaporation The maleate produced in the sample A1 is boiled in a mortar dish with a plunger for 5 minutes, after which the crystalline form A remains unchanged. The crystalline form B in example D1 is heated in a mortar bowl with a clamp for 5 minutes, after which a mixture of crystalline forms A and B is formed. The maleate produced in accordance with example A1 is filled in an agate ball mill (Retsch MM200 mixer with 5 mm agate ball) and ground at 20 Hz and room temperature for 180 minutes. The crystalline form B as shown in example D1 is treated as shown in example E4c) and after 180 minutes a mixture of crystalline forms A and B is obtained.

Example E5: Stability under pressure

(a) Crystalline form A in the form of tablets The maleate produced in accordance with example A1 is filled in a tablet press and pressed under vacuum to form a tablet at a pressure of 100 MPa for 60 minutes, after which the crystalline form A remains unchanged. The crystalline form B as shown in example D1 is treated as shown in example E5a) and after 60 minutes a mixture of crystalline forms A and B is obtained.

Example E6: Water intake

The water absorption is measured by means of Dynamic Vapor Sorption (DVS) with the DVS-1 apparatus of Surface Measurement Systems Ltd. The sample is placed in a platinum cone on top of a microwave. The sample is first balanced at 50% relative humidity and then subjected to a pre-defined measurement programme. The temperature is 25 °C. The change in the sample's weight is determined. (a) Amorphous form The amorphous form has a marked water uptake of about 2.2% by weight up to about 33% relative humidity. At higher humidity the weight falls off again, which is caused by crystallization. The crystalline form A has a water uptake of only about 0.2% by weight. At the end of the measurement cycle, the essentially unchanged crystalline form A is present. The water absorption of the crystalline form B is only about 0.2% by weight, but at the end of the measurement cycle there is a mixture of the crystalline forms A and B.

Example E7: Stability at elevated temperature

The crystalline forms are stored in open and closed vessels and after a given time possible changes are measured chromatographically (HPLC) as a stability parameter. The crystalline form A is shown to be very stable in terms of chemical stability and crystal form. The crystalline form B is shown to be very stable in terms of chemical stability. The results are given in Table 2 below.

Polymorp h	Bedingungen	Zeit	HPLC
A	40 °C/75% r.L.	1 Woche	100,2%	A
A	60 °C/75% r.L.	4 Wochen	100,3%	A
A	60 °C (geschlossen)	1 Woche	100,2%	A
A	60 °C (geschlossen)	4 Wochen	100,5%	A
A	-18 °C (Referenz)	4 Wochen	100%	A
B	40 °C/75% r.L.	1 Woche	100.3%	A und B
B	60 °C/75% r.L.	4 Wochen	101,1%	A und B
B	60 °C (geschlossen)	1 Woche	100,6%	A und B
B	60 °C (geschlossen)	4 Wochen	100,9%	A und B
B	-18 °C (Referenz)	4 Wochen	100%	A und B

Example E8: Water uptake of maleate and hydrochloride (comparison)

The water absorption is measured by means of Dynamic Vapor Sorption (DVS) with the DVS-1 apparatus of Surface Measurement Systems Ltd. The sample is placed in a platinum cone on top of a microwave. The sample is then first balanced at 50% relative humidity and then subjected to a pre-defined measurement programme. The temperature is 25 °C. The change in the sample's weight is determined after a gradual increase in the relative humidity of 10% to 90% each. a) (+) - ((1 R.2R) -3-[2- ((Dimethylamino) methyl- ((cyclohex-1-yl) 1-phenol maleate (form A) A very low water uptake of 0,06% is found. The absorbed moisture is completely reabsorbed at about 10% relative humidity.b) (+) - ((1R,2R) -3-[2- ((Dimethylamino) methyl- ((cyclohex-1-yl)) -phenol hydrochloride (form D) A further increase to 90% of the relative humidity results in a total water uptake of about 5% by weight. Desorption by gradual reduction of the relative humidity by 10% releases more water than was absorbed before, i.e. a total of 8.5%.

E9: Wetting and drying of maleate and hydrochloride (comparison) Maleate and hydrochloride as shown in example E8 are first stored at 25 °C and 75% and 95% relative humidity for 7 days and then dried in the dryer at 50 °C under vacuum for 7 days. Before the storage begins, X-ray diffraction images (XRD), DSC to determine transition points (Tp), dry weight (TG) and Karl Fischer content (WG) are determined and the same values after wetting and drying. The X-ray diffraction images show no change in the crystalline forms A and D after wetting and drying. The output values for hydrochloride are 116.27 °C Tp, 0.3%.TgG for dry weight (TG) and the output values for water (WG) are 8.00%.TgG for relative humidity and air are 0.4%, and the output values are 0.4%, 0.4%, and 0.4%.TgG for relative humidity and air are 0.4%. Other

Salz	Tp (°C)	TG (%)	WG (%)	Tp (°C)	TG (%)	WG (%)
Maleat	165.41	--	0,20	165,33	-	0,20
Hydrochlori d	116,22	5,92	8,50	113,83	6,12	6,00

Salz	Tp (°C)	TG (%)	WG (%)	Tp (°C)	TG	WG (%)
Maleat	165.92 177,82	--	0,20	165,47 177,55	--	0,50
Hydrochlori d	116,52	7,84	8,50	114,47	6,74	6,60

The following shall be considered:

Differential scanning calorimetry (DSC): device name Perkin Elmer DSC 7 or Perkin Elmer Pyris 1. Variable measurements (heating rate) in gold or aluminium bricks.

The following information shall be provided for the purpose of the assessment:

PXRD is performed with a Philips 1710 powder X-ray diffractometer using CuKα radiation. D-distances are calculated from the 2θ values, using the wavelength of 1.54060 Å as the basis. It is generally accepted that the 2θ values have an error rate of ±0.1-0.2°. The experimental error in the d-distance values is therefore dependent on the location of the line (the peak).

Raman spectroscopy , please .

FT-Raman spectra are obtained with a Bruker RFS 100 FT-Raman system, which is operated with a Nd:YAG laser (wavelength 1064 nm) and a germanium detector cooled with liquid nitrogen.

Description of the figures

Figure 1 shows the X-ray diffraction of the polymorphic form. Figure 2 shows the Raman spectrum of the polymorphic form. Figure 3 shows the X-ray diffraction of the polymorphic form.

Claims (24)

1. Salts of maleic acid and 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol of the formula I
2. Salts according to claim 1, characterised in that the compound of the formula I is present as a diastereomer or a mixture of enantiomeric diastereomers with transconfiguration of the phenyl ring and of the dimethylaminomethyl group (1 R,2R or 1 S,2S configuration).
3. Salts according to claim 1 or 2, the compound being present as an enantiomer with the absolute configuration (1 R,2R).
4. A method for the production of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate of the formula I according to claim 1-3 comprising the combination of the components 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol and maleic acid.
5. A method according to claim 4 for the production of 3-[2-(dimethylamino)-methyl-(cyclohex-1-yl)]-phenol maleate of the formula I according to claim 1, comprising the steps

   a) dissolving 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol in a solvent,

   b) mixing the solution with maleic acid or a solution of maleic acid, and

   c) isolating the compound of the formula I.
6. A salt according to claim 1-3, the salt being present as crystalline form A, which comprises a characteristic X-ray diffraction pattern in the range from 2° to 35° 2θ with pronounced characteristic lines, expressed in d values (Å): 9.4 (vs), 6.8 (m), 5.56 (s), 5.30 (s), 5.22 (s), 4.71 (s), 4.66 (s), 4.24 (m), 4.12 (m), 4.03 (m), 3.98 (s) 3.76 (m), 3.27 (m).
7. A salt according to claim 1-3, the salt being present as crystalline form A, characterised by a powder diffractogram comprising one or more of the following reflections: 9.38, 9.94 and 10.35 (in each case ± 0.5 in 2 theta).
8. A salt according to claim 7, the salt being present as crystalline form A, characterised in that the powder diagram additionally comprises one or more of the following reflections: 12.76, 15.94, 17.54, 19.28, 28.68 and 31.99 (in each case ± 0.2 in 2 theta).
9. A salt according to claim 1-3, the salt being present as crystalline form A, characterised by a Raman spectrum comprising one or more of the following bands, in each case expressed in wavenumbers (cm-1): 118 (vs), 188 (w), 400 (w), 676 (w), 2812 (w), 2879 (m).
10. A salt according to claim 9, characterised by one or more of the following bands: 118 (vs), 188 (w), 292 (m), 328 (m), 359 (w), 400 (w), 486 (vw), 676 (w), 901 (w), 1025 (w), 1273 (m), 1351 (m), 1412 (w), 1569 (vw), 1601 (m), 1690 (m), 2812 (w), 2879 (m), 2986 (m), 3060 (m).
11. A salt, the salt being present as crystalline form A, according to one or more of claims 6-10, characterised in that 3-[2-(dimethytamino)methyl-(cyclohex-1-yl)]-phenol maleate is present in the configuration (1 R,2R).
12. A salt according to claim 1-3, the salt being present as crystalline form B, which comprises a characteristic X-ray diffraction pattern in the range from 2° to 35° 2θ with pronounced characteristic lines, expressed in d values (Å): 10.6 (m), 7.5 (m), 7.3 (m), 6.1 (s), 5.29 (s) 4.88 (m), 4.72 (m), 4.47 (vs), 4.43 (m), 4.26 (m), 4.24 (m), 3.99 (s), 3.71 (m), 3.52 (m), 3.30 (s).
13. A salt according to claim 1-3, the salt being present as crystalline form B, characterised by a powder diffractogram comprising one or more of the following reflections: 8.36, 14.5 and 14.83 (in each case ± 0.5 in 2 theta).
14. A salt according to claim 13, the salt being present as crystalline form B, characterised in that the powder diagram additionally comprises one or more of the following reflections: 11.85, 12.19, 18.16, 22.85, 29.1 and 29.41 (in each case ± 0.2 in 2 theta).
15. A salt according to claim 1-3, the salt being present as crystalline form B, characterised by a Raman spectrum comprising one or more of the following bands, in each case expressed in wavenumbers (cm-1): 229 (m), 875 (m) and 2829 (m).
16. A salt, the salt being present as crystalline form B, according to claim 15, characterised by one or more of the following bands: 229 (m), 307 (w), 372 (w), 605 (vw), 875 (m), 890 (w), 1010 (w), 1197 (m), 1401 (vw), 1480 (vw), 1583 (m), 1703 (s), 2829 (m), 2953 (s).
17. A method for the production of the crystalline form B of 3-[2-(dimethylamino)-methyl-(cyclohex-1-yl)]-phenol maleate, characterised in that 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate is dissolved in a mixture of tetrahydrofuran and water in the volume ratio of 0.8:1.2 to 1.2:0.8, and then the solvent mixture is removed completely (a) at a temperature of at least 80°C, or (b) at room temperature in an open vessel in an open atmosphere in contact with atmospheric humidity, or (c) a suspension of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate is stirred in a solvent as carrier at a temperature of at least 120°C until formation of the crystalline form B is complete.
18. A salt, the salt being present as crystalline form B, obtainable by a method according to claim 17.
19. A salt, the salt being present as crystalline form B, according to one or more of claims 12-16 and 18, characterised in that 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate is present in the configuration (1R,2R).
20. A pharmaceutical composition containing an active quantity of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate of the formula I according to claim 1-19 and a pharmaceutical excipient or a pharmaceutical diluent.
21. A composition according to claim 20, in which the compound of the formula I is present as crystalline form A, crystalline form B or in a mixture of forms A and B.
22. A composition according to claim 21, in which the compound of the formula I is contained as crystalline form A.
23. Use of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate of the formula I according to claim 1-22 to produce a pharmaceutical composition for treating pain.
24. 3-[2-(Dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate of the formula I according to claim 1-22 for treating pain.