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

Abstract

A novel crystalline form of a (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride compound, methods of producing the compound, and related methods of use including treatment methods and pharmaceutical compositions containing the compound.

Description

FIELD OF THE INVENTION

This invention relates to solid crystalline forms of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride compounds, methods of producing these compounds, and related treatments, including use as analgesics as well as pharmaceutical compositions containing these compounds.

BACKGROUND OF THE INVENTION

The treatment of pain conditions is of great importance in medicine. There is currently a world-wide need for additional pain therapy. The pressing requirement for a target-oriented treatment of pain conditions which is right for the patient, which is to be understood as the successful and satisfactory treatment of pain for the patients, is documented in the large number of scientific works which have recently and over the years appeared in the field of applied analgesics or on basic research on nociception.

BRIEF SUMMARY OF THE INVENTION

One object of the present invention is to provide new solid forms of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride useful in the treatment or inhibition of pain.

U.S. Pat. Nos. 6,248,737 and 6,344,558 as well as European Patent EP 693 475 B1 disclose the substance and the synthesis of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride in example 25. As proven by X-ray diffraction the 1R,2R configuration as shown in the drawing of the structure in example 25 is correct although the configuration is reported as (−)-(1R,2S) in U.S. Pat. No. 6,248,737 and (−)-(1S,2S) in U.S. Pat. No. 6,344,558 as well as in EP 693 475 B1.

It has now been surprisingly found that (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride can be produced in a reproducible manner in two different crystalline forms. The present invention provides a new form (Form A) of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride which is different from the form already known (Form B) obtained by the procedure described in example 25 of U.S. Pat. No. 6,248,737 and U.S. Pat. No. 6,344,558 as well as EP 693 475 B1. This new Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride is very stable at ambient conditions and therefore useful for producing a pharmaceutical composition.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-ray diffraction pattern;

FIG. 2 shows an infrared spectrum;

FIG. 3 shows a RAMAN spectrum;

FIG. 4 shows an X-ray diffraction pattern;

FIG. 5 shows an infrared spectrum;

FIG. 6 shows a RAMAN spectrum;

FIG. 7 shows an X-ray diffraction pattern;

FIG. 8 shows an X-ray diffraction pattern

SUMMARY OF THE INVENTION

The new crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride can be identified by X-ray powder diffraction. The X-ray diffraction (“XRPD”) pattern is shown in FIG. 1 with the peak listing shown as Table 1.

The most important X-ray lines (2-theta values) in terms of intensity characterizing Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride showing one or a combination of the following in a powder diffraction measurement when measured using Cu K_α radiation at ambient temperature are 14.5±0.2, 18.2±0.2, 20.4±0.2, 21.7±0.2 and 25.5±0.2.

To discriminate crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride from Form B it is more advantageous to look at the unique peaks in the X-ray diffraction diagram, i.e. e.g. the lines with sufficient intensity at 2-theta values, where Form B does not show lines with significant intensity. Such characteristic X-ray lines (2-theta values) for Form A in a powder diffraction pattern when measured using CuK_α radiation at ambient temperature are: 15.1±0.2, 16.0±0.2, 18.9±0.2, 20.4±0.2, 22.5±0.2, 27.3±0.2, 29.3±0.2 and 30.4±0.2.

Another method to identify crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride is IR-spectroscopy. The IR-Spectrum of Form A is shown as FIG. 2 with the peak listing shown in comparison to Form B as Table 2.

In the IR-spectrum it is characteristic for crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride to show a combination of the following IR bands: 3180±4 cm⁻¹, 2970±4 cm⁻¹, 2695±4 cm⁻¹, 2115±4 cm⁻¹, 1698±4 cm⁻¹, 1462±4 cm⁻¹, 1032±4 cm⁻¹, and/or 972±4 cm⁻¹.

RAMAN technique can also be used to identify of the crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride. Especially the range between 800 cm⁻¹ and 200 cm⁻¹, which is shown in FIG. 3, is advantageously used also by way of RAMAN microscopy.

Crystal structure analysis of Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride showed monoclinic crystals with the following parameters of the elemental cell (length of side and angle):

a: 7.11 Å

b: 11.62 Å

c: 17.43 Å

β: 95.0°.

The elemental cell of the crystal of crystalline Form A has a volume of 1434±5 ų and a calculated density of 1.20±0.01 g/cm³.

The invention further relates to processes for the preparation of crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride.

The process starts from crystalline Form B of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride prepared according to U.S. Pat. Nos. 6,248,737 or 6,344,558 or European Patent EP 693 475 B1 incorporated herein by reference.

In one embodiment of the process (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A is produced by dissolving the (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form B in acetone, acetonitrile or isopropanol, optionally followed by filtering, leaving the solution to crystallize and isolating the crystals of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A preferably by filtering again.

If acetone or acetonitrile is used it is preferred that during this process the temperature is kept below +40° C., more preferably below +25° C., especially after filtering. It is further preferred that in this process between 5 mg and 1 mg, more preferably between 2.5 mg and 1.4 mg, especially between 2.0 mg and 1.4 mg (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride is dissolved per ml solvent.

The use of isopropanol is preferred, if seed crystals of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A are available. The isopropanol used preferably contains about 0.5% per volume of water. The dissolution of the (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form B in isopropanol is performed at temperatures above room temperature, preferably above 65° C. but not exceeding 80° C. After complete dissolution the heat is turned of and the seed crystals are added during a first cooling phase. Thereafter the resulting mixture is cooled down to ≦15° C., preferably ≦10° C. and especially ≦5° C.

Optionally it is possible to reduce the solvent by evaporation, preferably in an evaporator under reduced pressure. Preferably the remaining volume of the solution after evaporation should not be less than 20% of the volume at the beginning of the process. Optionally it is also possible to add active carbon to the solution originally prepared.

In a preferred embodiment of the invention the (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A obtained by the process described above is redesolved in acetone acetonitrile or isopropanol, preferably in the solvent already used in the first step, optionally is filtered to remove any insoluble residue and, optionally after reducing the amount of solvent by evaporation, is left to crystallize.

It is preferred that in the last crystallization step the temperature is maintained at ≦15° C., more preferably ≦10° C. and especially ≦5° C.

In a further embodiment of the process according to the invention (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A is produced in the solid state by cooling (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form B between 24 h and 168 h to a temperature between −4° C. and −80° C. It is preferred that in this process the cooling temperature is between −10° C. and −60° C., preferably between −15° C. and −50° C., especially between −25° C. and −40° C. and the cooling is carried out for a time between 24h and 120 h, preferably between 24 h and 72 h, especially between 24 h and 48 h.

This invention further relates to a new Crystalline Form A of (−)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride obtainable by dissolving (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form B in acetonitrile together with active carbon, heating the solution to the boiling point, removing the active carbon by filtering, stirring the solution at a temperature below 40° C., removing insoluble residue by filtering and removing part of the solvent leaving (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form A to crystallize, redissolving the crystals so obtained in acetonitrile, removing insoluble residue by filtering and removing part of the solvent leaving (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form A to crystallize.

Crystalline Form A according to the invention has the same pharmacological activity as Form B but is more stable under ambient conditions. It can be advantageously used as active ingredient in pharmaceutical compositions.

Therefore the invention further relates to a pharmaceutical composition containing as active ingredient (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A according to the invention and at least one suitable additive and/or auxiliary substance.

Such pharmaceutical composition according to the invention contains, in addition to crystalline Form A (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride, one or more suitable additive and/or auxiliary substance such as for example carrier materials, fillers, solvents, diluents, coloring agents and/or binders, and may be administered as liquid medicament preparations in the form of injectable solutions, drops or juices, as semi-solid medicament preparations in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols. The choice of the auxiliary substances, etc., as well as the amounts thereof to be used depend on whether the medicament is to be administered orally, per orally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or topically, for example to the skin, the mucous membranes or the eyes. For oral application suitable preparations are in the form of tablets, sugar-coated pills, capsules, granules, droplets, juices and syrups, while for parenteral, topical and inhalative application suitable forms are solutions, suspensions, readily reconstitutable dry preparations, as well as sprays. Form A in a depot form, in dissolved form or in a plaster, optionally with the addition of agents promoting skin penetration, are suitable percutaneous application preparations. Preparation forms that can be administered orally or percutaneously can provide for the delayed release of crystalline Form A according to the invention. In principle further active constituents known to the person skilled in the art may be added to the medicaments according to the invention.

Preferred formulations for crystalline Form A (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride according to the invention are presented in the PCT-application WO 03/035054 incorporated herein by reference.

The amount of active constituent to be administered to the patient varies depending on the patient's weight, on the type of application, medical indication and severity of the condition. Normally 0.005 to 1000 mg/kg, preferably 0.05 to 5 mg/kg of crystalline Form A according to the invention are administered.

Preferably, the crystalline Form A according to the invention is used for the treatment of pain or the treatment of urinary incontinence. Accordingly the invention also relates to the use of crystalline Form A according to the invention for the treatment of pain or the treatment of urinary incontinence.

Additionally the invention relates to a method of treatment using a sufficient amount of crystalline Form A according to the invention for the treatment of a disease, especially pain or urinary incontinence.

Certain embodiments of the present invention may be further understood by reference to the following specific examples. These examples and the terminology used herein are for the purpose of describing particular embodiments only and are not intended to be limiting.

EXAMPLE 1

Master Recipe for Preparation of Form A

The master recipe is valid for a 50 ml scale.

Provide 1.9 g (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride prepared according to example 25 of European Patent EP 693 475 B1 in a 50 ml glass round bottom vessel with a 3-blade overhead stirrer with baffles.

Add 25 ml isopropanol and 0.5% (v/v) water

Stir at 800 rpm

Heat to 80° C.

Hold temperature while stirring for 10 minutes

Cool to 65° C.

Add 0.056 g seeds (Mean Sq. Wt. CL=58 μm², Median No Wt. CL=22 μm)

Cool to 0° C. over 1 h

Filter slurry through PTFE filter column (5 μm pore size)

Dry solid material under slight vacuum until constant weight (approx. 24 h)

Repeat the same procedure with the dry solid material obtained

EXAMPLE 2

Preparation of Form A (1)

(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was prepared according to example 25 of European Patent EP 693 475 B1. 32.2 mg of the thus synthesized (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was—by slight heating up to 40° C. and/or agitating on an orbital shaker for 30 min—dissolved in 20 ml acetone. Following that the solution was filtered through a nylon syringe filter having a mesh of 0.20 μm and the solution was left to crystallize by slow evaporation of the solvent. Crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was generated as proven by X-ray powder diffraction and by RAMAN microscopic analysis.

EXAMPLE 3

Preparation of Form A (2)

(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was prepared according to example 25 of European Patent EP 693 475 B1. 32.2 mg of the thus synthesized (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was—if necessary by agitating for e.g. 30 min—dissolved in 20 ml acetone. Following that the solution was filtered with a nylon syringe filter having a mesh of 0.20 μm and the solution was left to crystallize by slow evaporation of the solvent. In no step after and including the dissolving the temperature was allowed to rise above +25° C. Crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was generated as proven by X-ray powder diffraction experiment and by RAMAN microscopic analysis.

Example 4

Preparation of Form A (3)

(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was prepared according to example 25 of European Patent EP 693 475 B1. 350 mg of the thus synthesized (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride were dissolved in 50 ml acetonitrile in a 250 ml flask. The mixture was stirred for 1.5 h on a water bath heated to 37° C.±1° C. Any insoluble residue was removed by filtering. Of the clear solution 35 ml was removed on a rotation evaporator at 70-80 mbar and a temperature of the water bath of 30° C.±1° C. The precipitated solid compound was filtered by vacuum. Crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was generated as proven by X-ray powder diffraction and by RAMAN microscopic analysis.

Example 5

Preparation of Form A (4)

(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was prepared according to example 25 of European Patent EP 693 475 B1. The thus synthesized (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was stored for 72 h at −40° C. Crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was generated as proven by X-ray powder diffraction and by RAMAN microscopic analysis.

EXAMPLE 6

Preparation of Form A (5)

(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was prepared according to example 25 of European Patent EP 693 475 B1. 370 mg of the thus synthesized (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride were added to 40 ml acetonitrile and 100 mg active carbon in a 100 ml flask and heated to the boiling point. The active carbon was filtered off from the hot solution by means of a paper filter and the filtrate concentrated to a volume of approx. 10 ml in a rotation evaporator at 150±10 mbar and 50° C. The solution was slowly rotated for 30 minutes at room temperature. Following that the solution was allowed to stand for 30 minutes at room temperature and than for 1 hour at 4° C. The Crystals are filtered by vacuum through a glass filter (276 mg yield).

266 mg of these Crystals were dissolved at room temperature in 45 ml acetonitrile, insoluble residues were removed by filtration and the solution was rotated for 1.5 h at 35-40° C. at atmospheric pressure in a rotation evaporator. Than the solution was concentrated at 50° C. and 150±10 mbar to a volume of approx. 10 ml and then slowly rotated for 30 minutes at room temperature. Following that the flask was allowed to stand for 12 h at 4° C.

The precipitated solid is filtered by vacuum through a glass filter and dried in the air.

Yield:

151 mg (40.8% of the theory in relation to used educt), white microcrystalline solid form

EXAMPLE 7

Preparation of Form B (1)

(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was prepared according to example 25 of European Patent EP 693 475 B1. Crystalline Form B of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was generated as proven by X-ray powder diffraction and by RAMAN microscopic analysis.

EXAMPLE 8

Preparation of Form B (2)

(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride prepared according to one of the examples 1 to 5 was milled for at least 20 min. Then it was kept at 130° C. in an oven for 80 min. Crystalline Form B of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was generated as proven by X-ray powder diffraction and by RAMAN microscopic analysis.

EXAMPLE 9

Preparation Form B (3)

(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride prepared according to one of the examples 1 to 5 was cryogrinded for at least 15 min. Then it was kept at 125° C. in a TGA for 30 min. Crystalline Form B of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride was generated as proven by X-ray powder diffraction and by RAMAN microscopic analysis.

EXAMPLE 10

X-Ray Powder Diffraction Patterns of Forms A (1) and B (1)

Powder Data Collection was performed with a STOE Stadi P Transmission Powder Diffractometer equipped with a curved germanium monochromator and a linear position sensitive detector. The very carefully ground powders were prepared as flat samples. As source of the beam a copper X-ray tube with monochromatized Cu Kα₁ (λ=1.54051 Å) radiation generated at 50 kV and 30 mA was used. The 2θ area for the measurement was 5°-40°. The used step width was 0.02 degrees in 2 theta. The data were collected at a temperature of 23±1°.

The X-ray pattern for Form A is shown in FIG. 1, the X-ray pattern for Form B in FIG. 4.

The data are shown in Table 1.

TABLE 1
Peak and Relative Intensity Listing (°2θ,
peaks with I/I1 value of 10 and over)
Peak No.	A	I/I1	B	I/I1
1	9.07	10	14.58	100
2	10.11	9	14.94	9
3	14.51	100	15.42	19
4	15.08	24	15.76	27
5	15.39	11	16.05	8
6	15.69	22	16.77	14
7	15.96	24	18.01	60
8	16.62	13	19.60	39
9	17.00	20	20.18	27
10	18.24	63	20.98	19
11	18.88	28	21.43	14
12	20.00	23	21.99	65
13	20.39	47	23.71	4
14	21.66	47	24.73	43
15	22.54	41	25.10	14
16	24.27	28	25.71	21
17	25.03	13	26.29	10
18	25.47	43	26.81	5
19	25.84	20	27.76	20
20	26.04	27	28.19	39
21	26.94	13	29.20	12
22	27.29	29	29.86	13
23	27.63	28	30.28	5
24	28.33	20	30.58	6
25	28.72	12	31.15	22
26	29.09	12	32.41	6
27	29.29	21	32.91	5
28	29.76	11	33.17	6
29	30.37	23	34.34	6
30	30.74	11	35.88	9
31	31.70	14	36.29	7
32	34.37	11	39.08	9

EXAMPLE 11

IR Spectrum of Forms A and B

The mid IR spectra were acquired on a Nicolet model 860 Fourier transform IR spectrophotometer equipped with a globar source, Ge/KBr beamsplitter, and deterated triglycine sulfate (DTGS) detector. A Spectra-Tech, Inc. diffuse reflectance accessory was utilized for sampling. Each spectrum represents 256 co-added scans at a spectral resolution of 4 cm⁻¹. A background data set was then acquired with an alignment mirror in place. A single beam sample data set was then acquired. Subsequently, a Log 1/R (R=Reflectance) spectrum was acquired by rationing the two data sets against each other. The spectrophotometer was calibrated (wavelength) with polystyrene at the time of use.

The spectrum for Form A is shown in FIG. 2. The spectrum for Form B is shown in FIG. 5.

The data are shown in Table 2.

TABLE 2
IR Peak Listing
Form A	Form B
	Intensity (log		Intensity (log
Peak Pos. (cm−1)	1/R)	Peak Pos. (cm−1)	1/R)
3180.4	1.878	3170.2	2.196
2970	1.856	3013.1	1.791
1462.1	1.848	2962.5	2.098
2695.2	1.841	2933.4	1.945
1600.9	1.838	2682	2.116
1281.6	1.771	1940.5	1.242
1378.3	1.763	1870.7	1.246
1219.9	1.754	1801.7	1.201
1181.2	1.748	1749.5	1.236
1503.6	1.743	1598.1	2.138
1256.5	1.734	1503.2	1.755
712.6	1.725	1451.5	2.164
879.8	1.713	1417.2	1.89
684.7	1.692	1396.3	1.843
798.7	1.681	1377.1	1.864
1313.6	1.673	1353.2	1.726
1005.1	1.655	1313.2	1.661
731.2	1.63	1280.7	1.977
1090.9	1.626	1254.8	1.973
810.2	1.622	1217.6	2.015
971.5	1.588	1177.5	1.868
842.6	1.576	1154.6	1.597
831.7	1.574	1136.4	1.431
1111.5	1.55	1111.3	1.512
1049.8	1.534	1090.3	1.625
1136.5	1.498	1065.9	1.425
461.3	1.476	1049.9	1.52
1065.8	1.457	1004.6	1.813
495.1	1.438	958.7	1.855
542.1	1.408	946.6	1.735
595.8	1.384	912.5	1.292
527.9	1.327	877.8	1.951
912.4	1.304	842.7	1.657
1032.4	1.3	831.4	1.664
416.9	1.287	810.7	1.715
1698.3	1.282	795.2	1.892
1940.5	1.279	730.6	1.855
1870.6	1.277	711.7	2.04
1749.4	1.268	683.4	1.917
1801.6	1.208	595.6	1.439
2115.5	1.061	542.1	1.497
		527.7	1.425
		495.1	1.663
		464.4	1.622
		416.7	1.439

EXAMPLE 12

Single Crystal Structure Analysis of Form A

A colorless crystal of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride prepared according to one of the examples 2 to 6 having approximate dimensions of 0.6×0.60×0.50 mm was mounted on a glass fiber in random orientation. Preliminary examination and data collection were performed with Cu K_α radiation (1.54184 Å) on a Enraf-Nonius CAD4 computer controlled kappa axis diffractometer equipped with a graphite crystal, incident beam monochromator.

Cell constants and an orientation matrix for data collection were obtained from least-squares refinement using the setting angles of 25 reflections in the range 16°<θ<24°, measured by the computer controlled diagonal slit method of centering. The monoclinic cell parameters and calculated volume are:

a=7.110(3),b =11.615(4), c=17.425(6) Å, β=95.00(3), V=1433.5(10) ų. For Z=4 and formula weight of 257.79 the calculated density is 1.20 g·cm⁻³. The space group was determined to be P2₁ (No. 19).

The data were collected at a temperature of −103±5° C. using ω-θ scan technique. The scan rate varied from 4 to 20°/min (in ω). The variable scan rate allows rapid data collection for intense reflections where a fast scan rate is used and assures good counting statistics for weak reflections where a slow scan rate is used. Data were collected to a maximum of 2θ of 75.110. The scan range (in°) was determined as a function of θ to correct for the separation of the Kα doublet. The scan width was calculated as follows: θ scan width=0.8+0.140 tan θ

Moving-crystal moving-counter background counts were made by scanning an additional 25% above and below this range. Thus the ratio of peak counting time to background counting time was 2:1. The counter aperture was also adjusted as a function of θ. The horizontal aperture width ranged from 2.4 to 2.5 mm; the vertical aperture was set at 4.0 mm.

The data for Form A as collected in a commonly known “.cif”-document for complete reference of distances within the molecule are shown in Table 3.

TABLE 3
_audit_creation_method           SHELXL-97
_chemical_name_systematic
;
?
;
_chemical_name_common            ?
_chemical_melting_point          ?
_chemical_formula_moiety         ?
_chemical_formula_sum
‘C14 H24 Cl N O’
_chemical_formula_weight         257.79
loop—
_atom_type_symbol
_atom_type_description
_atom_type_scat_dispersion_real
_atom_type_scat_dispersion_imag
_atom_type_scat_source
‘Cl’  ‘Cl’  0.3639   0.7018
‘International Tables Vol C Tables 4.2.6.8 and 6.1.1.4’
‘O’  ‘O’  0.0492   0.0322
‘International Tables Vol C Tables 4.2.6.8 and 6.1.1.4’
‘N’  ‘N’  0.0311   0.0180
‘International Tables Vol C Tables 4.2.6.8 and 6.1.1.4’
‘C’  ‘C’  0.0181   0.0091
‘International Tables Vol C Tables 4.2.6.8 and 6.1.1.4’
‘H’  ‘H’  0.0000   0.0000
‘International Tables Vol C Tables 4.2.6.8 and 6.1.1.4’
_symmetry_cell_setting           ?
_symmetry_space_group_name_H-M   ?
loop—
_symmetry_equiv_pos_as_xyz
‘x, y, z’
‘−x, y+1/2, −z’
_cell_length_a                   7.110(3)
_cell_length_b                   11.615(4)
_cell_length_c                   17.425(6)
_cell_angle_alpha                90.00
_cell_angle_beta                 95.00(3)
_cell_angle_gamma                90.00
_cell_volume                     1433.5(10)
_cell_formula_units_Z            4
_cell_measurement_temperature    170(2)
_cell_measurement_reflns_used    ?
_cell_measurement_theta_min      ?
_cell_measurement_theta_max      ?
_exptl_crystal_description       ?
_exptl_crystal_colour            ?
_exptl_crystal_size_max          ?
_exptl_crystal_size_mid          ?
_exptl_crystal_size_min          ?
_exptl_crystal_density_meas      ?
_exptl_crystal_density_diffrn    1.195
_exptl_crystal_density_method    ‘not measured’
_exptl_crystal_F_000             560
_exptl_absorpt_coefficient_mu    2.230
_exptl_absorpt_correction_type   ?
_exptl_absorpt_correction_T_min  ?
_exptl_absorpt_correction_T_max  ?
_exptl_absorpt_process_details   ?
_exptl_special_details
;
?
;
_diffrn_ambient_temperature      170(2)
_diffrn_radiation_wavelength     1.54184
_diffrn_radiation_type           CuK\a
_diffrn_radiation_source         ‘fine-focus sealed tube’
_diffrn_radiation_monochromator  graphite
_diffrn_measurement_device_type  ?
_diffrn_measurement_method       ?
_diffrn_detector_area_resol_mean ?
_diffrn_standards_number         ?
_diffrn_standards_interval_count ?
_diffrn_standards_interval_time  ?
_diffrn_standards_decay_%        ?
_diffrn_reflns_number            4531
_diffrn_reflns_av_R_equivalents  0.0000
_diffrn_reflns_av_sigmaI/netI    0.0951
_diffrn_reflns_limit_h_min       0
_diffrn_reflns_limit_h_max       8
_diffrn_reflns_limit_k_min       −14
_diffrn_reflns_limit_k_max       14
_diffrn_reflns_limit_l_min       −21
_diffrn_reflns_limit_l_max       21
_diffrn_reflns_theta_min         4.58
_diffrn_reflns_theta_max         75.11
_reflns_number_total             4531
_reflns_number_gt                4051
_reflns_threshold_expression     >2sigma(I)
_computing_data_collection       ?
_computing_cell_refinement       ?
_computing_data_reduction        ?
_computing_structure_solution    ‘SHELXS-86 (Sheldrick, 1990)’
_computing_structure_refinement  ‘SHELXL-97 (Sheldrick, 1997)’
_computing_molecular_graphics    ?
_computing_publication_material  ?
_refine_special_details
;
Refinement of F{circumflex over ( )}2{circumflex over ( )} against ALL reflections. The weighted R-factor wR and
goodness of fit S are based on F{circumflex over ( )}2{circumflex over ( )}, conventional R-factors R are based
on F, with F set to zero for negative F{circumflex over ( )}2{circumflex over ( )}. The threshold expression of
F{circumflex over ( )}2{circumflex over ( )} > 2sigma(F{circumflex over ( )}2{circumflex over ( )}) is used only for calculating R-factors(gt) etc. and is
not relevant to the choice of reflections for refinement. R-factors based
on F{circumflex over ( )}2{circumflex over ( )} are statistically about twice as large as those based on F, and R-
factors based on ALL data will be even larger.
;
_refine_ls_structure_factor_coef Fsqd
_refine_ls_matrix_type           full
_refine_ls_weighting_scheme      calc
_refine_ls_weighting_details
‘calc w=1/[\s{circumflex over ( )}2{circumflex over ( )}(Fo{circumflex over ( )}2{circumflex over ( )})+(0.1109P){circumflex over ( )}2{circumflex over ( )}+0.1653P] where P=(Fo{circumflex over ( )}2{circumflex over ( )}+2Fc{circumflex over ( )}2{circumflex over ( )})/3’
_atom_sites_solution_primary     direct
_atom_sites_solution_secondary   difmap
_atom_sites_solution_hydrogens   geom
_refine_ls_hydrogen_treatment    mixed
_refine_ls_extinction_method     none
_refine_ls_extinction_coef       ?
_refine_ls_abs_structure_details
‘Flack H D (1983), Acta Cryst. A39, 876-881’
_refine_ls_abs_structure_Flack   0.027(19)
_refine_ls_number_reflns         4531
_refine_ls_number_parameters     323
_refine_ls_number_restraints     1
_refine_ls_R_factor_all          0.0643
_refine_ls_R_factor_gt           0.0588
_refine_ls_wR_factor_ref         0.1673
_refine_ls_wR_factor_gt          0.1629
_refine_ls_goodness_of_fit_ref   1.035
_refine_ls_restrained_S_all      1.035
_refine_ls_shift/su_max          0.003
_refine_ls_shift/su_mean         0.000
loop—
_atom_site_label
_atom_site_type_symbol
_atom_site_fract_x
_atom_site_fract_y
_atom_site_fract_z
_atom_site_U_iso_or_equiv
_atom_site_adp_type
_atom_site_occupancy
_atom_site_symetry_multiplicity
_atom_site_calc_flag
_atom_site_refinement_flags
_atom_site_disorder_assembly
_atom_site_disorder_group
Cl1 Cl 0.21479(13) 0.35406(8) 0.98781(6) 0.0288(2) Uani 1 1 d . . .
Cl2 Cl 0.72788(13) 0.25508(8) 0.50890(6) 0.0280(2) Uani 1 1 d . . .
O1 O −0.0588(5) 0.5289(3) 0.90769(18) 0.0362(7) Uani 1 1 d . . .
H1 H −0.038(15) 0.457(10) 0.918(5) 0.11(3) Uiso 1 1 d . . .
N1 N 0.0822(4) 0.3979(3) 0.49638(17) 0.0220(6) Uani 1 1 d . . .
H1A H −0.0096 0.3523 0.5133 0.026 Uiso 1 1 calc R . .
O2 O 0.4799(4) 0.0769(3) 0.57952(16) 0.0364(7) Uani 1 1 d . . .
H2 H 0.531(14) 0.131(9) 0.551(5) 0.10(3) Uiso 1 1 d . . .
N2 N 0.5722(5) 0.2083(3) 1.0053(2) 0.0269(7) Uani 1 1 d . . .
H2A H 0.4770 0.2536 0.9841 0.032 Uiso 1 1 calc R . .
C1 C 0.2263(6) 0.3215(4) 0.4667(2) 0.0331(10) Uani 1 1 d . . .
H1A H 0.1737 0.2848 0.4189 0.043 Uiso 1 1 calc R . .
H1B H 0.2630 0.2622 0.5051 0.043 Uiso 1 1 calc R . .
H1C H 0.3374 0.3671 0.4564 0.043 Uiso 1 1 calc R . .
C2 C −0.0085(6) 0.4736(4) 0.4336(2) 0.0313(9) Uani 1 1 d . . .
H2A H 0.0838 0.5299 0.4182 0.041 Uiso 1 1 calc R . .
H2B H −0.1162 0.5141 0.4525 0.041 Uiso 1 1 calc R . .
H2C H −0.0523 0.4261 0.3891 0.041 Uiso 1 1 calc R . .
C3 C 0.1580(5) 0.4713(3) 0.5628(2) 0.0224(7) Uani 1 1 d . . .
H3A H 0.0525 0.5130 0.5827 0.029 Uiso 1 1 calc R . .
H3B H 0.2438 0.5287 0.5439 0.029 Uiso 1 1 calc R . .
C4 C 0.2627(5) 0.4056(3) 0.6291(2) 0.0207(7) Uani 1 1 d . . .
H4 H 0.3700 0.3668 0.6086 0.027 Uiso 1 1 calc R . .
C5 C 0.1401(6) 0.3130(4) 0.6613(2) 0.0290(8) Uani 1 1 d . . .
H5A H 0.2110 0.2747 0.7048 0.038 Uiso 1 1 calc R . .
H5B H 0.1040 0.2563 0.6210 0.038 Uiso 1 1 calc R . .
H5C H 0.0262 0.3484 0.6788 0.038 Uiso 1 1 calc R . .
C6 C 0.3437(5) 0.4902(3) 0.6925(2) 0.0218(7) Uani 1 1 d . . .
H6 H 0.4100 0.4422 0.7324 0.028 Uiso 1 1 calc R . .
C7 C 0.4927(5) 0.5729(4) 0.6656(2) 0.0272(8) Uani 1 1 d . . .
H7A H 0.4328 0.6227 0.6252 0.035 Uiso 1 1 calc R . .
H7B H 0.5381 0.6223 0.7090 0.035 Uiso 1 1 calc R . .
C8 C 0.6603(6) 0.5138(4) 0.6351(3) 0.0378(10) Uani 1 1 d . . .
H8A H 0.7580 0.5710 0.6270 0.049 Uiso 1 1 calc R . .
H8B H 0.6204 0.4761 0.5860 0.049 Uiso 1 1 calc R . .
H8C H 0.7111 0.4561 0.6723 0.049 Uiso 1 1 calc R . .
C9 C 0.1930(5) 0.5552(3) 0.7326(2) 0.0213(7) Uani 1 1 d . . .
C10 C 0.1188(6) 0.6603(3) 0.7050(2) 0.0249(8) Uani 1 1 d . . .
H10 H 0.1604 0.6936 0.6577 0.032 Uiso 1 1 calc R . .
C11 C −0.0137(6) 0.7175(3) 0.7448(2) 0.0281(8) Uani 1 1 d . . .
H11 H −0.0656 0.7908 0.7248 0.036 Uiso 1 1 calc R . .
C12 C −0.0739(6) 0.6733(4) 0.8117(2) 0.0278(8) Uani 1 1 d . . .
H12 H −0.1670 0.7153 0.8392 0.036 Uiso 1 1 calc R . .
C13 C −0.0019(6) 0.5686(4) 0.8404(2) 0.0265(8) Uani 1 1 d . . .
C14 C 0.1313(5) 0.5102(3) 0.8001(2) 0.0234(8) Uani 1 1 d . . .
H14 H 0.1819 0.4364 0.8198 0.030 Uiso 1 1 calc R . .
C20 C 0.7093(7) 0.2841(5) 1.0502(3) 0.0414(11) Uani 1 1 d . . .
H20A H 0.6484 0.3193 1.0927 0.054 Uiso 1 1 calc R . .
H20B H 0.7521 0.3445 1.0166 0.054 Uiso 1 1 calc R . .
H20C H 0.8179 0.2384 1.0710 0.054 Uiso 1 1 calc R . .
C21 C 0.4877(7) 0.1235(5) 1.0570(3) 0.0410(11) Uani 1 1 d . . .
H21A H 0.4403 0.1642 1.1006 0.053 Uiso 1 1 calc R . .
H21B H 0.5842 0.0677 1.0760 0.053 Uiso 1 1 calc R . .
H21C H 0.3833 0.0830 1.0281 0.053 Uiso 1 1 calc R . .
C22 C 0.6542(6) 0.1458(3) 0.9408(2) 0.0248(8) Uani 1 1 d . . .
H22A H 0.5532 0.1026 0.9118 0.032 Uiso 1 1 calc R . .
H22B H 0.7472 0.0900 0.9629 0.032 Uiso 1 1 calc R . .
C23 C 0.7484(5) 0.2230(3) 0.8856(2) 0.0221(7) Uani 1 1 d . . .
H23 H 0.8433 0.2688 0.9162 0.029 Uiso 1 1 calc R . .
C24 C 0.6086(6) 0.3070(4) 0.8447(2) 0.0290(8) Uani 1 1 d . . .
H24A H 0.5114 0.2639 0.8133 0.038 Uiso 1 1 calc R . .
H24B H 0.6755 0.3580 0.8115 0.038 Uiso 1 1 calc R . .
H24C H 0.5491 0.3530 0.8830 0.038 Uiso 1 1 calc R . .
C25 C 0.8541(5) 0.1512(3) 0.8274(2) 0.0201(7) Uani 1 1 d . . .
H25 H 0.9081 0.2070 0.7933 0.026 Uiso 1 1 calc R . .
C26 C 1.0222(6) 0.0857(4) 0.8681(2) 0.0283(8) Uani 1 1 d . . .
H26A H 1.0938 0.1379 0.9040 0.037 Uiso 1 1 calc R . .
H26B H 0.9748 0.0224 0.8982 0.037 Uiso 1 1 calc R . .
C27 C 1.1528(6) 0.0374(4) 0.8118(3) 0.0356(10) Uani 1 1 d . . .
H27A H 1.0856 −0.0210 0.7794 0.046 Uiso 1 1 calc R . .
H27B H 1.2632 0.0024 0.8403 0.046 Uiso 1 1 calc R . .
H27C H 1.1941 0.0997 0.7792 0.046 Uiso 1 1 calc R . .
C28 C 0.7250(5) 0.0740(3) 0.7756(2) 0.0220(7) Uani 1 1 d . . .
C29 C 0.6682(5) −0.0349(3) 0.7991(2) 0.0238(8) Uani 1 1 d . . .
H29 H 0.7118 −0.0637 0.8505 0.031 Uiso 1 1 calc R . .
C30 C 0.5507(5) −0.1019(3) 0.7501(2) 0.0263(8) Uani 1 1 d . . .
H30 H 0.5114 −0.1776 0.7677 0.034 Uiso 1 1 calc R . .
C31 C 0.4871(6) −0.0654(3) 0.6769(2) 0.0260(8) Uani 1 1 d . . .
H31 H 0.4048 −0.1144 0.6428 0.034 Uiso 1 1 calc R . .
C32 C 0.5427(6) 0.0430(4) 0.6529(2) 0.0258(8) Uani 1 1 d . . .
C33 C 0.6604(5) 0.1116(4) 0.7018(2) 0.0240(8) Uani 1 1 d . . .
H33 H 0.6986 0.1876 0.6842 0.031 Uiso 1 1 calc R . .
loop—
_atom_site_aniso_label
_atom_site_aniso_U_11
_atom_site_aniso_U_22
_atom_site_aniso_U_33
_atom_site_aniso_U_23
_atom_site_aniso_U_13
_atom_site_aniso_U_12
Cl1 0.0230(5) 0.0271(5) 0.0358(5) −0.0027(4) −0.0009(3) 0.0042(3)
Cl2 0.0231(4) 0.0250(4) 0.0353(5) −0.0018(4) −0.0017(3) −0.0047(3)
O1 0.0351(18) 0.0412(18) 0.0333(16) 0.0069(14) 0.0084(13) 0.0127(14)
N1 0.0190(15) 0.0277(16) 0.0181(14) 0.0011(12) −0.0043(11) −0.0050(12)
O2 0.0330(17) 0.052(2) 0.0214(13) 0.0053(14) −0.0109(11) −0.0124(15)
N2 0.0224(17) 0.0311(17) 0.0272(16) 0.0015(14) 0.0018(13) 0.0078(14)
C1 0.029(2) 0.044(2) 0.0261(19) −0.0056(18) 0.0013(16) 0.0060(18)
C2 0.025(2) 0.041(2) 0.0259(18) 0.0107(17) −0.0083(15) −0.0045(17)
C3 0.0200(18) 0.0203(17) 0.0259(17) 0.0015(14) −0.0042(14) −0.0042(13)
C4 0.0188(18) 0.0229(17) 0.0198(16) −0.0007(14) −0.0019(13) 0.0026(14)
C5 0.033(2) 0.0253(19) 0.0280(19) 0.0018(15) −0.0032(16) −0.0035(16)
C6 0.0174(18) 0.0263(18) 0.0203(16) −0.0021(14) −0.0064(13) 0.0059(14)
C7 0.0176(19) 0.030(2) 0.032(2) −0.0103(17) −0.0063(14) 0.0003(15)
C8 0.020(2) 0.040(2) 0.054(3) −0.011(2) 0.0051(18) −0.0026(18)
C9 0.0175(18) 0.0256(18) 0.0194(16) −0.0055(14) −0.0067(13) 0.0009(14)
C10 0.0233(19) 0.0245(18) 0.0257(18) 0.0002(15) −0.0039(14) 0.0005(14)
C11 0.023(2) 0.0279(19) 0.032(2) 0.0003(16) −0.0088(15) 0.0054(15)
C12 0.0196(19) 0.031(2) 0.032(2) −0.0052(17) −0.0005(15) 0.0054(15)
C13 0.022(2) 0.033(2) 0.0236(17) 0.0001(16) −0.0024(14) 0.0030(16)
C14 0.0202(18) 0.0237(19) 0.0250(18) 0.0001(15) −0.0051(14) 0.0046(14)
C20 0.040(3) 0.051(3) 0.032(2) −0.012(2) −0.0028(19) −0.001(2)
C21 0.039(3) 0.049(3) 0.037(2) 0.010(2) 0.0164(19) 0.010(2)
C22 0.027(2) 0.0229(18) 0.0249(18) −0.0006(15) 0.0024(15) 0.0020(15)
C23 0.0209(18) 0.0224(17) 0.0221(17) −0.0019(14) −0.0027(13) 0.0025(13)
C24 0.032(2) 0.0271(19) 0.0274(19) 0.0020(16) −0.0009(16) 0.0077(16)
C25 0.0148(16) 0.0245(17) 0.0200(16) 0.0009(14) −0.0032(12) 0.0011(13)
C26 0.0207(19) 0.033(2) 0.0301(19) −0.0017(17) −0.0040(15) 0.0065(16)
C27 0.025(2) 0.039(2) 0.043(2) 0.001(2) 0.0045(17) 0.0067(18)
C28 0.0179(18) 0.0271(18) 0.0209(17) −0.0011(15) 0.0006(13) 0.0049(14)
C29 0.0215(19) 0.0248(18) 0.0251(17) −0.0013(15) 0.0014(14) 0.0032(14)
C30 0.024(2) 0.0218(18) 0.033(2) −0.0042(16) 0.0055(15) −0.0009(15)
C31 0.0188(19) 0.031(2) 0.0283(19) −0.0104(16) 0.0013(14) −0.0021(15)
C32 0.0212(19) 0.035(2) 0.0213(17) −0.0022(15) 0.0023(14) −0.0019(16)
C33 0.0173(18) 0.0299(19) 0.0246(18) 0.0005(15) 0.0014(13) −0.0043(14)
_geom_special_details
;
All esds (except the esd in the dihedral angle between two l.s. planes)
are estimated using the full covariance matrix. The cell esds are taken
into account individually in the estimation of esds in distances, angles
and torsion angles; correlations between esds in cell parameters are only
used when they are defined by crystal symmetry. An approximate
(isotropic)
treatment of cell esds is used for estimating esds involving l.s. planes.
;
loop—
_geom_bond_atom_site_label_1
_geom_bond_atom_site_label_2
_geom_bond_distance
_geom_bond_site_symmetry_2
_geom_bond_publ_flag
O1 C13 1.355(5) . ?
O1 H1 0.86(11) . ?
N1 C1 1.482(5) . ?
N1 C3 1.499(5) . ?
N1 C2 1.504(5) . ?
N1 H1A 0.9100 . ?
O2 C32 1.374(5) . ?
O2 H2 0.90(9) . ?
N2 C20 1.485(6) . ?
N2 C21 1.495(6) . ?
N2 C22 1.497(5) . ?
N2 H2A 0.9100 . ?
C1 H1A 0.9801 . ?
C1 H1B 0.9801 . ?
C1 H1C 0.9801 . ?
C2 H2A 0.9801 . ?
C2 H2B 0.9801 . ?
C2 H2C 0.9801 . ?
C3 C4 1.524(5) . ?
C3 H3A 0.9800 . ?
C3 H3B 0.9800 . ?
C4 C5 1.522(5) . ?
C4 C6 1.553(5) . ?
C4 H4 0.9800 . ?
C5 H5A 0.9801 . ?
C5 H5B 0.9801 . ?
C5 H5C 0.9801 . ?
C6 C9 1.528(5) . ?
C6 C7 1.533(6) . ?
C6 H6 0.9800 . ?
C7 C8 1.511(6) . ?
C7 H7A 0.9800 . ?
C7 H7B 0.9800 . ?
C8 H8A 0.9801 . ?
C8 H8B 0.9801 . ?
C8 H8C 0.9801 . ?
C9 C14 1.392(5) . ?
C9 C10 1.398(5) . ?
C10 C11 1.386(6) . ?
C10 H10 0.9800 . ?
C11 C12 1.376(6) . ?
C11 H11 0.9800 . ?
C12 C13 1.395(6) . ?
C12 H12 0.9800 . ?
C13 C14 1.402(5) . ?
C14 H14 0.9800 . ?
C20 H20A 0.9801 . ?
C20 H20B 0.9801 . ?
C20 H20C 0.9801 . ?
C21 H21A 0.9801 . ?
C21 H21B 0.9801 . ?
C21 H21C 0.9801 . ?
C22 C23 1.513(5) . ?
C22 H22A 0.9800 . ?
C22 H22B 0.9800 . ?
C23 C24 1.525(5) . ?
C23 C25 1.556(5) . ?
C23 H23 0.9800 . ?
C24 H24A 0.9801 . ?
C24 H24B 0.9801 . ?
C24 H24C 0.9801 . ?
C25 C28 1.523(5) . ?
C25 C26 1.537(5) . ?
C25 H25 0.9800 . ?
C26 C27 1.517(5) . ?
C26 H26A 0.9800 . ?
C26 H26B 0.9800 . ?
C27 H27A 0.9801 . ?
C27 H27B 0.9801 . ?
C27 H27C 0.9801 . ?
C28 C33 1.397(5) . ?
C28 C29 1.400(6) . ?
C29 C30 1.382(6) . ?
C29 H29 0.9800 . ?
C30 C31 1.381(6) . ?
C30 H30 0.9800 . ?
C31 C32 1.395(6) . ?
C31 H31 0.9800 . ?
C32 C33 1.392(6) . ?
C33 H33 0.9800 . ?
loop—
_geom_angle_atom_site_label_1
_geom_angle_atom_site_label_2
_geom_angle_atom_site_label_3
_geom_angle
_geom_angle_site_symmetry_1
_geom_angle_site_symmetry_3
_geom_angle_publ_flag
C13 O1 H1 116(6) . . ?
C1 N1 C3 113.4(3) . . ?
C1 N1 C2 111.2(3) . . ?
C3 N1 C2 109.4(3) . . ?
C1 N1 H1A 107.5 . . ?
C3 N1 H1A 107.5 . . ?
C2 N1 H1A 107.5 . . ?
C32 O2 H2 127(6) . . ?
C20 N2 C21 110.7(4) . . ?
C20 N2 C22 113.7(3) . . ?
C21 N2 C22 109.6(3) . . ?
C20 N2 H2A 107.5 . . ?
C21 N2 H2A 107.5 . . ?
C22 N2 H2A 107.5 . . ?
N1 C1 H1A 109.5 . . ?
N1 C1 H1B 109.5 . . ?
H1A C1 H1B 109.5 . . ?
N1 C1 H1C 109.5 . . ?
H1A C1 H1C 109.5 . . ?
H1B C1 H1C 109.5 . . ?
N1 C2 H2A 109.5 . . ?
N1 C2 H2B 109.5 . . ?
H2A C2 H2B 109.5 . . ?
N1 C2 H2C 109.5 . . ?
H2A C2 H2C 109.5 . . ?
H2B C2 H2C 109.5 . . ?
N1 C3 C4 114.8(3) . . ?
N1 C3 H3A 108.6 . . ?
C4 C3 H3A 108.6 . . ?
N1 C3 H3B 108.6 . . ?
C4 C3 H3B 108.6 . . ?
H3A C3 H3B 107.6 . . ?
C5 C4 C3 112.1(3) . . ?
C5 C4 C6 111.9(3) . . ?
C3 C4 C6 110.4(3) . . ?
C5 C4 H4 107.4 . . ?
C3 C4 H4 107.4 . . ?
C6 C4 H4 107.4 . . ?
C4 C5 H5A 109.5 . . ?
C4 C5 H5B 109.5 . . ?
H5A C5 H5B 109.5 . . ?
C4 C5 H5C 109.5 . . ?
H5A C5 H5C 109.5 . . ?
H5B C5 H5C 109.5 . . ?
C9 C6 C7 111.2(3) . . ?
C9 C6 C4 114.0(3) . . ?
C7 C6 C4 113.7(3) . . ?
C9 C6 H6 105.7 . . ?
C7 C6 H6 105.7 . . ?
C4 C6 H6 105.7 . . ?
C8 C7 C6 114.2(4) . . ?
C8 C7 H7A 108.7 . . ?
C6 C7 H7A 108.7 . . ?
C8 C7 H7B 108.7 . . ?
C6 C7 H7B 108.7 . . ?
H7A C7 H7B 107.6 . . ?
C7 C8 H8A 109.5 . . ?
C7 C8 H8B 109.5 . . ?
H8A C8 H8B 109.5 . . ?
C7 C8 H8C 109.5 . . ?
H8A C8 H8C 109.5 . . ?
H8B C8 H8C 109.5 . . ?
C14 C9 C10 118.7(3) . . ?
C14 C9 C6 119.0(3) . . ?
C10 C9 C6 122.2(3) . . ?
C11 C10 C9 119.9(4) . . ?
C11 C10 H10 120.0 . . ?
C9 C10 H10 120.0 . . ?
C12 C11 C10 121.3(4) . . ?
C12 C11 H11 119.3 . . ?
C10 C11 H11 119.3 . . ?
C11 C12 C13 119.8(4) . . ?
C11 C12 H12 120.1 . . ?
C13 C12 H12 120.1 . . ?
O1 C13 C12 118.6(4) . . ?
O1 C13 C14 122.3(4) . . ?
C12 C13 C14 119.0(4) . . ?
C9 C14 C13 121.2(3) . . ?
C9 C14 H14 119.4 . . ?
C13 C14 H14 119.4 . . ?
N2 C20 H20A 109.5 . . ?
N2 C20 H20B 109.5 . . ?
H20A C20 H20B 109.5 . . ?
N2 C20 H20C 109.5 . . ?
H20A C20 H20C 109.5 . . ?
H20B C20 H20C 109.5 . . ?
N2 C21 H21A 109.5 . . ?
N2 C21 H21B 109.5 . . ?
H21A C21 H21B 109.5 . . ?
N2 C21 H21C 109.5 . . ?
H21A C21 H21C 109.5 . . ?
H21B C21 H21C 109.5 . . ?
N2 C22 C23 114.4(3) . . ?
N2 C22 H22A 108.7 . . ?
C23 C22 H22A 108.7 . . ?
N2 C22 H22B 108.7 . . ?
C23 C22 H22B 108.7 . . ?
H22A C22 H22B 107.6 . . ?
C22 C23 C24 111.7(3) . . ?
C22 C23 C25 111.3(3) . . ?
C24 C23 C25 111.8(3) . . ?
C22 C23 H23 107.3 . . ?
C24 C23 H23 107.3 . . ?
C25 C23 H23 107.3 . . ?
C23 C24 H24A 109.5 . . ?
C23 C24 H24B 109.5 . . ?
H24A C24 H24B 109.5 . . ?
C23 C24 H24C 109.5 . . ?
H24A C24 H24C 109.5 . . ?
H24B C24 H24C 109.5 . . ?
C28 C25 C26 112.8(3) . . ?
C28 C25 C23 113.7(3) . . ?
C26 C25 C23 111.4(3) . . ?
C28 C25 H25 106.1 . . ?
C26 C25 H25 106.1 . . ?
C23 C25 H25 106.1 . . ?
C27 C26 C25 112.3(3) . . ?
C27 C26 H26A 109.1 . . ?
C25 C26 H26A 109.1 . . ?
C27 C26 H26B 109.1 . . ?
C25 C26 H26B 109.1 . . ?
H26A C26 H26B 107.9 . . ?
C26 C27 H27A 109.5 . . ?
C26 C27 H27B 109.5 . . ?
H27A C27 H27B 109.5 . . ?
C26 C27 H27C 109.5 . . ?
H27A C27 H27C 109.5 . . ?
H27B C27 H27C 109.5 . . ?
C33 C28 C29 118.2(4) . . ?
C33 C28 C25 119.6(3) . . ?
C29 C28 C25 122.2(3) . . ?
C30 C29 C28 120.1(4) . . ?
C30 C29 H29 120.0 . . ?
C28 C29 H29 120.0 . . ?
C31 C30 C29 122.0(4) . . ?
C31 C30 H30 119.0 . . ?
C29 C30 H30 119.0 . . ?
C30 C31 C32 118.4(4) . . ?
C30 C31 H31 120.8 . . ?
C32 C31 H31 120.8 . . ?
O2 C32 C31 117.4(4) . . ?
O2 C32 C33 122.3(4) . . ?
C31 C32 C33 120.3(4) . . ?
C28 C33 C32 121.1(4) . . ?
C28 C33 H33 119.5 . . ?
C32 C33 H33 119.5 . . ?
_diffrn_measured_fraction_theta_max 0.775
_diffrn_reflns_theta_full        75.11
_diffrn_measured_fraction_theta_full 0.775
_refine_diff_density_max   0.686
_refine_diff_density_min   −0.696
_refine_diff_density_rms   0.072

EXAMPLE 13

Single Crystal Structure Analysis of Form B

A colorless chunk of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride prepared according to one of the examples 7 to 9 having approximate dimensions of 0.44×0.40×0.35 mm was mounted on a glass fiber in random orientation. Preliminary examination and data collection were performed with Mo K_α radiation (λ=0.71073 Å) on a Nonius KappaCCD diffractometer.

Cell constants and an orientation matrix for data collection were obtained from least-squares refinement using the setting angles of 6172 reflections in the range 5<θ<27°. The orthorhombic cell parameters and calculated volume are: a=7.0882(3), b=11.8444(6), c=17.6708(11) Å, V=1483.6(2)ų. For and formula weight of 257.79 the calculated density is 1.15 g·cm⁻³. The refined mosaicity from DENZO/SCALEPACK was 0.680 (<1 mod, <2 poor) indicating moderate crystal quality. The space group was determined by the program ABSEN. From the systematic presence of:

• • h00 h=2n
  • 0k0 k=2n
  • 001 l=2n and from subsequent least-squares refinement, the space group was determined to be P2₁2₁2₁ (number 19).

The data were collected to a maximum 2θ value of 55.0°, at a temperature of 343±1 K. [0079] The data from examples 12 and 13 are compared in Table 3:

	TABLE 3
	Form A (monoklin)	Form B (orthorhombic)
Formula	C14H24ClNO	C14H24ClNO
M.W./g/mol	257,79	257,79
Space group	No. 4, P21	No. 19, P212121
Z (No. of Units)	4	4
a/Å	7,110(3)	7,0882(3)
b/Å	11,615(4)	11,8444(6)
c/Å	17,425(6)	17,6708(11)
α/°	90	90
β/°	95,00(3)	90
γ/°	90	90
Volume of elementary	1434	1484
cell/Å3
Density (calc.)/g/cm3	1.20	1.15

The data for Form B as collected in a commonly known “.cif”-document for complete reference of distances within the molecule are shown below Table 4:

TABLE 4
_audit_creation_method           SHELXL-97
_chemical_name_systematic
;
?
;
_chemical_name_common            ?
_chemical_melting_point          ?
_chemical_formula_moiety         ?
_chemical_formula_sum
‘C14 H2 H22 Cl N O’
_chemical_formula_weight         257.79
loop—
_atom_type_symbol
_atom_type_description
_atom_type_scat_dispersion_real
_atom_type_scat_dispersion_imag
_atom_type_scat_source
‘C’  ‘C’ 0.0033 0.0016
‘International Tables Vol C Tables 4.2.6.8 and 6.1.1.4’
‘Cl’  ‘Cl’  0.1484   0.1585
‘International Tables Vol C Tables 4.2.6.8 and 6.1.1.4’
‘O’  ‘O’  0.0106   0.0060
‘International Tables Vol C Tables 4.2.6.8 and 6.1.1.4’
‘N’  ‘N’  0.0061   0.0033
‘International Tables Vol C Tables 4.2.6.8 and 6.1.1.4’
‘H’  ‘H’  0.0000   0.0000
‘International Tables Vol C Tables 4.2.6.8 and 6.1.1.4’
‘H’  ‘H’  0.0000   0.0000
‘International Tables Vol C Tables 4.2.6.8 and 6.1.1.4’
_symmetry_cell_setting           ?
_symmetry_space_group_name_H-M   ?
loop—
_symmetry_equiv_pos_as_xyz
‘x, y, z’
‘−x+1/2, −y, z+1/2’
‘−x, y+1/2, −z+1/2’
‘x+1/2, −y+1/2, −z’
_cell_length_a                   7.0882(3)
_cell_length_b                   11.8444(6)
_cell_length_c                   17.6708(11)
_cell_angle_alpha                90.00
_cell_angle_beta                 90.00
_cell_angle_gamma                90.00
_cell_volume                     1483.56(13)
_cell_formula_units_Z            4
_cell_measurement_temperature    343 (2)
_cell_measurement_reflns_used    ?
_cell_measurement_theta_min      ?
_cell_measurement_theta_max      ?
_exptl_crystal_description       ?
_exptl_crystal_colour            ?
_exptl_crystal_size_max          ?
_exptl_crystal_size_mid          ?
_exptl_crystal_size_min          ?
_exptl_crystal_density_meas      ?
_exptl_crystal_density_diffrn    1.154
_exptl_crystal_density_method    ‘not measured’
_exptl_crystal_F_000             560
_exptl_absorpt_coefficient_mu    0.244
_exptl_absorpt_correction_type   ?
_exptl_absorpt_correction_T_min  ?
_exptl_absorpt_correction_T_max  ?
_exptl_absorpt_process_details   ?
_exptl_special_details
;
?
;
_diffrn_ambient_temperature      343 (2)
_diffrn_radiation_wavelength     0.71073
_diffrn_radiation_type           MoK\a
_diffrn_radiation_source         ‘fine-focus sealed tube’
_diffrn_radiation_monochromator  graphite
_diffrn_measurement_device_type  ?
_diffrn_measurement_method       ?
_diffrn_detector_area_resol_mean ?
_diffrn_standards_number         ?
_diffrn_standards_interval_count ?
_diffrn_standards_interval_time  ?
_diffrn_standards_decay_%        ?
_diffrn_reflns_number            3207
_diffrn_reflns_av_R_equivalents  0.0000
_diffrn_reflns_av_sigmaI/netI    0.0554
_diffrn_reflns_limit_h_min       −9
_diffrn_reflns_limit_h_max       9
_diffrn_reflns_limit_k_min       −15
_diffrn_reflns_limit_k_max       15
_diffrn_reflns_limit_l_min       −22
_diffrn_reflns_limit_l_max       22
_diffrn_reflns_theta_min         5.04
_diffrn_reflns_theta_max         27.49
_reflns_number_total             3207
_reflns_number_gt                2527
_reflns_threshold_expression     >2sigma(I)
_computing_data_collection       ?
_computing_cell_refinement       ?
_computing_data_reduction        ?
_computing_structure_solution    ‘SHELXS-97 (Sheldrick, 1990)’
_computing_structure_refinement  ‘SHELXL-97 (Sheldrick, 1997)’
_computing_molecular_graphics    ?
_computing_publication_material  ?
_refine_special_details
;
Refinement of F{circumflex over ( )}2{circumflex over ( )} against ALL reflections. The weighted R-factor wR and
goodness of fit S are based on F{circumflex over ( )}2{circumflex over ( )}, conventional R-factors R are based
on F, with F set to zero for negative F{circumflex over ( )}2{circumflex over ( )}. The threshold expression of
F{circumflex over ( )}2{circumflex over ( )} > 2sigma(F{circumflex over ( )}2{circumflex over ( )}) is used only for calculating R-factors(gt) etc. and is
not relevant to the choice of reflections for refinement. R-factors based
on F{circumflex over ( )}2{circumflex over ( )} are statistically about twice as large as those based on F, and R-
factors based on ALL data will be even larger.
;
_refine_ls_structure_factor_coef Fsqd
_refine_ls_matrix_type           full
_refine_ls_weighting_scheme      calc
_refine_ls_weighting_details
‘calc w=1/[\s{circumflex over ( )}2{circumflex over ( )}(Fo{circumflex over ( )}2{circumflex over ( )})+(0.0664P){circumflex over ( )}2{circumflex over ( )}+0.0700P] where P=(Fo{circumflex over ( )}2{circumflex over ( )}+2Fc{circumflex over ( )}2{circumflex over ( )})/3’
_atom_sites_solution_primary     direct
_atom_sites_solution_secondary   difmap
_atom_sites_solution_hydrogens   geom
_refine_ls_hydrogen_treatment    mixed
_refine_ls_extinction_method     SHELXL
_refine_ls_extinction_coef       0.033(7)
_refine_ls_extinction_expression
‘Fc{circumflex over ( )}*{circumflex over ( )}=kFc[1+0.001xFc{circumflex over ( )}2{circumflex over ( )}\1{circumflex over ( )}3{circumflex over ( )}/sin(2\q)]{circumflex over ( )}−1/4{circumflex over ( )}’
_refine_ls_abs_structure_details
‘Flack H D (1983), Acta Cryst. A39, 876-881’
_refine_ls_abs_structure_Flack   −0.03(8)
_refine_ls_number_reflns         3207
_refine_ls_number_parameters     167
_refine_ls_number_restraints     0
_refine_ls_R_factor_all          0.0598
_refine_ls_R_factor_gt           0.0440
_refine_ls_wR_factor_ref         0.1246
_refine_ls_wR_factor_gt          0.1137
_refine_ls_goodness_of_fit_ref   1.012
_refine_ls_restrained_S_all      1.012
_refine_ls_shift/su_max          0.001
_refine_ls_shift/su_mean         0.000
loop—
_atom_site_label
_atom_site_type_symbol
_atom_site_fract_x
_atom_site_fract_y
_atom_site_fract_z
_atom_site_U_iso_or_equiv
_atom_site_adp_type
_atom_site_occupancy
_atom_site_symetry_multiplicity
_atom_site_calc_flag
_atom_site_refinement_flags
_atom_site_disorder_assembly
_atom_site_disorder_group
Cl Cl 0.79778(8) −0.19590(5) 0.76458(4) 0.0741(2) Uani 1 1 d . . .
O33 O 0.4870(3) 0.0085(2) 0.34428(12) 0.0944(7) Uani 1 1 d . . .
H33 H 0.516(4) 0.066(2) 0.329(2) 0.080(10) Uiso 1 1 d . . .
N6 N 0.5522(3) 0.15710(17) 0.75449(11) 0.0635(5) Uani 1 1 d . . .
H6 H 0.471(3) 0.1983(17) 0.7365(13) 0.054(6) Uiso 1 1 d . . .
C1 C 1.1558(4) −0.0160(3) 0.5596(2) 0.0984(9) Uani 1 1 d . . .
H1A H 1.0962 −0.0753 0.5313 0.148 Uiso 1 1 calc R . .
H1B H 1.2620 −0.0460 0.5867 0.148 Uiso 1 1 calc R . .
H1C H 1.1980 0.0419 0.5256 0.148 Uiso 1 1 calc R . .
C2 C 1.0168(3) 0.0333(2) 0.61491(17) 0.0746(7) Uani 1 1 d . . .
H2A H 1.0815 0.0871 0.6472 0.090 Uiso 1 1 calc R . .
H2B H 0.9682 −0.0266 0.6469 0.090 Uiso 1 1 calc R . .
C3 C 0.8514(3) 0.09247(19) 0.57579(13) 0.0585(5) Uani 1 1 d . . .
H3 H 0.9079 0.1455 0.5398 0.070 Uiso 1 1 calc R . .
C4 C 0.7395(3) 0.16542(17) 0.63274(13) 0.0585(5) Uani 1 1 d . . .
H4 H 0.8312 0.2119 0.6602 0.070 Uiso 1 1 calc R . .
C5 C 0.6394(3) 0.09217(18) 0.69087(13) 0.0635(5) Uani 1 1 d . . .
H5A H 0.5415 0.0492 0.6655 0.076 Uiso 1 1 calc R . .
H5B H 0.7293 0.0388 0.7117 0.076 Uiso 1 1 calc R . .
C6 C 0.4611(5) 0.0782(3) 0.80888(19) 0.0960(9) Uani 1 1 d . . .
H6A H 0.3594 0.0393 0.7842 0.144 Uiso 1 1 calc R . .
H6B H 0.4128 0.1200 0.8512 0.144 Uiso 1 1 calc R . .
H6C H 0.5524 0.0243 0.8264 0.144 Uiso 1 1 calc R . .
C7 C 0.6834(5) 0.2342(3) 0.79430(17) 0.0952(9) Uani 1 1 d . . .
H7A H 0.7907 0.1923 0.8120 0.143 Uiso 1 1 calc R . .
H7B H 0.6200 0.2680 0.8366 0.143 Uiso 1 1 calc R . .
H7C H 0.7246 0.2922 0.7601 0.143 Uiso 1 1 calc R . .
C31 C 0.7273(3) 0.01306(18) 0.52863(12) 0.0569(5) Uani 1 1 d . . .
C32 C 0.6643(3) 0.04721(19) 0.45831(13) 0.0613(5) Uani 1 1 d . . .
H32 H 0.6984 0.1181 0.4403 0.074 Uiso 1 1 calc R . .
C33 C 0.5509(3) −0.0219(2) 0.41378(14) 0.0679(6) Uani 1 1 d . . .
C34 C 0.5050(3) −0.1291(2) 0.43950(16) 0.0735(7) Uani 1 1 d . . .
H34 H 0.4325 −0.1772 0.4097 0.088 Uiso 1 1 calc R . .
C35 C 0.5679(4) −0.1637(2) 0.50977(16) 0.0750(7) Uani 1 1 d . . .
H35 H 0.5352 −0.2351 0.5274 0.090 Uiso 1 1 calc R . .
C36 C 0.6782(3) −0.09456(19) 0.55416(14) 0.0658(6) Uani 1 1 d . . .
H36 H 0.7200 −0.1195 0.6012 0.079 Uiso 1 1 calc R . .
C41 C 0.6029(4) 0.2461(2) 0.59309(16) 0.0802(7) Uani 1 1 d . . .
H41A H 0.5030 0.2036 0.5700 0.120 Uiso 1 1 calc R . .
H41B H 0.6693 0.2879 0.5549 0.120 Uiso 1 1 calc R . .
H41C H 0.5506 0.2975 0.6295 0.120 Uiso 1 1 calc R . .
loop—
_atom_site_aniso_label
_atom_site_aniso_U_11
_atom_site_aniso_U_22
_atom_site_aniso_U_33
_atom_site_aniso_U_23
_atom_site_aniso_U_13
_atom_site_aniso_U_12
C1 0.0707(3) 0.0656(3) 0.0860(4) 0.0046(3) −0.0013(3) −0.0128(3)
O33 0.1018(14) 0.1073(16) 0.0741(13) 0.0123(12) −0.0167(10) −0.0428(12)
N6 0.0630(10) 0.0682(10) 0.0594(12) 0.0060(8) 0.0034(9) 0.0149(9)
C1 0.0675(14) 0.106(2) 0.122(3) −0.0124(19) 0.0145(15) 0.0174(15)
C2 0.0520(11) 0.0864(16) 0.0854(17) −0.0006(13) −0.0005(11) 0.0117(11)
C3 0.0520(10) 0.0639(11) 0.0597(12) 0.0054(9) 0.0044(9) −0.0018(9)
C4 0.0619(11) 0.0541(10) 0.0594(12) 0.0039(8) −0.0006(9) 0.0009(8)
C5 0.0679(12) 0.0575(11) 0.0650(13) 0.0048(10) 0.0092(11) 0.0092(10)
C6 0.1016(19) 0.100(2) 0.087(2) 0.0228(17) 0.0333(17) 0.0144(17)
C7 0.0951(18) 0.118(2) 0.0731(17) −0.0210(15) −0.0121(16) −0.0001(18)
C31 0.0529(9) 0.0585(11) 0.0592(12) 0.0021(9) 0.0123(9) 0.0037(9)
C32 0.0597(11) 0.0633(12) 0.0609(13) 0.0000(9) 0.0078(10) −0.0083(9)
C33 0.0645(11) 0.0813(15) 0.0578(13) −0.0030(11) 0.0069(10) −0.0135(12)
C34 0.0689(13) 0.0707(14) 0.0809(17) −0.0113(13) 0.0153(12) −0.0161(11)
C35 0.0866(15) 0.0585(12) 0.0799(17) 0.0007(11) 0.0238(14) −0.0033(12)
C36 0.0717(13) 0.0584(11) 0.0672(13) 0.0039(10) 0.0129(12) 0.0062(11)
C41 0.0963(17) 0.0707(14) 0.0734(16) 0.0141(12) 0.0053(14) 0.0239(13)
_geom_special_details
;
All esds (except the esd in the dihedral angle between two l.s. planes)
are estimated using the full covariance matrix. The cell esds are taken
into account individually in the estimation of esds in distances, angles
and torsion angles; correlations between esds in cell parameters are only
used when they are defined by crystal symmetry. An approximate
(isotropic)
treatment of cell esds is used for estimating esds involving l.s. planes.
;
loop—
_geom_bond_atom_site_label_1
_geom_bond_atom_site_label_2
_geom_bond_distance
_geom_bond_site_symmetry_2
_geom_bond_publ_flag
O33 H33 0.76(3) . ?
O33 C33 1.358(3) . ?
N6 H6 0.82(2) . ?
N6 C7 1.481(4) . ?
N6 C6 1.488(3) . ?
N6 C5 1.496(3) . ?
C1 C2 1.505(4) . ?
C2 C3 1.531(3) . ?
C3 C31 1.534(3) . ?
C3 C4 1.546(3) . ?
C4 C5 1.520(3) . ?
C4 C41 1.530(3) . ?
C31 C32 1.381(3) . ?
C31 C36 1.396(3) . ?
C32 C33 1.391(3) . ?
C33 C34 1.387(4) . ?
C34 C35 1.382(4) . ?
C35 C36 1.377(4) . ?
loop—
_geom_angle_atom_site_label_1
_geom_angle_atom_site_label_2
_geom_angle_atom_site_label_3
_geom_angle
_geom_angle_site_symmetry_1
_geom_angle_site_symmetry_3
_geom_angle_publ_flag
H33 O33 C33 118(3) . . ?
H6 N6 C7 104.9(15) . . ?
H6 N6 C6 108.8(16) . . ?
C7 N6 C6 110.7(2) . . ?
H6 N6 C5 107.8(16) . . ?
C7 N6 C5 114.5(2) . . ?
C6 N6 C5 110.0(2) . . ?
C1 C2 C3 112.7(3) . . ?
C2 C3 C31 113.8(2) . . ?
C2 C3 C4 110.8(2) . . ?
C31 C3 C4 113.71(16) . . ?
C5 C4 C41 111.75(18) . . ?
C5 C4 C3 111.13(17) . . ?
C41 C4 C3 112.08(19) . . ?
N6 C5 C4 114.03(18) . . ?
C32 C31 C36 118.5(2) . . ?
C32 C31 C3 119.66(19) . . ?
C36 C31 C3 121.8(2) . . ?
C31 C32 C33 121.6(2) . . ?
O33 C33 C34 117.5(2) . . ?
O33 C33 C32 123.2(2) . . ?
C34 C33 C32 119.3(2) . . ?
C35 C34 C33 119.3(2) . . ?
C36 C35 C34 121.2(2) . . ?
C35 C36 C31 120.0(2) . . ?
_diffrn_measured_fraction_theta_max 0.977
_diffrn_reflns_theta_full        27.49
_diffrn_measured_fraction_theta_full 0.977
_refine_diff_density_max   0.265
_refine_diff_density_min   −0.202
_refine_diff_density_rms   0.061

EXAMPLE 14

RAMAN Spectrum of Forms A and B

Form A and B were investigated using RAMAN spectroscopy. The RAMAN spectrometer used was a Bruker Raman FT 100. The RAMAN Microscope was a Renishaw 1000 System, 20× Obj. Long working distance, diode laser 785 nm. Raman spectroscopy was able to distinguish clearly between Forms A and B. Differences between the spectra of the two forms appear in the whole spectral range (3200-50 cm⁻¹), but the difference in the range between 800-200 cm-1 were most significant.

The results for Form A are shown in FIG. 3, the results for Form B in FIG. 6.

Furthermore the samples were investigated by RAMAN microscopy. The spectra of both forms were also distinguishable. Here, spectra were taken in the wavenumber range of 2000-100 cm⁻¹.

EXAMPLE 16

Variable Temperature X-ray Powder Diffraction Experiment

A variable temperature X-ray powder diffraction experiment was run thereby producing Form B from Form A. Form A converted to Form B from 40-50° C. during the experiment. The result is reversible with Form B changing over into Form A at lower temperature.

The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.

Claims

1. A crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu Kα radiation at 15.1±0.2, 16.0±0.2, 18.9±0.2, 20.4±0.2, 22.5±0.2, 27.3±0.2, 29.3±0.2 and 30.4±0.2.

2. The crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride according to claim 1 exhibiting at least X-ray lines (2-theta values) in a powder diffraction when measured using Cu Kα radiation at 14.5±0.2, 18.2±0.2, 20.4±0.2, 21.7±0.2 and 25.5±0.2.

3. The crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride according to claim 1 exhibiting an X-ray pattern (2-theta values) in a powder diffraction when measured using Cu Kα radiation essentially the sames as that provided in FIG. 1.

4. The crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride according to claim 1 wherein the crystal has a monoclinic form.

5. A process for producing a (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A comprising the steps of: dissolving a (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form B in acetone, acetonitrile or isopropanol to form a solution; leaving the solution to crystallize and isolating crystals of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A.

6. The process for producing a (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A according to claim 5 wherein during the process the temperature is kept below +40° C.

7. The process for producing a (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A according to claim 5 wherein during the process the temperature is kept below +25° C.

8. The process of claim 5 wherein said (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form B is dissolved in acetonitrile, and further comprising the steps of: stirring the solution; removing insoluble residue by filtering and evaporating the acetonitrile leaving (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form A to crystallize.

9. The process according to claim 5 wherein said (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form B is dissolved in isopropanol at temperatures above room temperature, and after complete dissolution no further heat is provided and further comprising: adding seed crystals of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A and then cooling the mixture down to ≦15° C.

10. The process of claim 9, wherein said (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form B is dissolved in isopropanol at a temperature above 65° C. but not exceeding 80° C.

11. The process of claim 9, wherein said mixture is cooled down to <10° C.

12. The process of claim 9, wherein said mixture is cooled down to <5° C.

13. The process according to claim 5 further comprising redissolving the (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A in a solvent selected from acetone, acetonitrile and isopropanol, then optionally filtering the solution to remove any insoluble residue and optionally reducing the amount of solvent by evaporation, then allowing the solution to crystallize.

14. The process of claim 13, wherein said solvent is the same as that used to form the (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of crystalline Form A before the step of redissovling.

15. The process of claim 13, wherein during the step of allowing the solution to crystallize, the temperature is maintained at ≦15° C.

16. The process of claim 13, wherein during the step of allowing the solution to crystallize, the temperature is maintained at <10° C.

17. The process of claim 13, wherein during the step of allowing the solution to crystallize, the temperature is maintained at ≦5° C.

18. A process for producing crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride comprising the step of cooling (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)- hydrochloride phenol of Form B for a time between 24 hours and 168 hours at a temperature of between −4° C. and −80° C.

19. The process of claim 18 wherein the cooling temperature is between −10° C. and −60° C.

20. The process of claim 18, wherein the cooling temperature is between −15° C. and −50° C.

21. The process of claim 18, wherein the cooling temperature is between −25° C. and −40° C.

22. The process of claim 18, wherein the cooling is carried out for a time between 24 hours and 120 hours.

23. The process of claim 18, wherein the cooling is carried out for a time between 24 hours and 72 hours.

24. The process of claim 18, wherein the cooling is carried out for a time between between 24 hours and 48 hours.

25. A crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride produced by the process of: dissolving (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form B in acetonitrile together with active carbon, heating the solution to the boiling point, removing the active carbon by filtering, stirring the solution at a temperature below 40° C., removing insoluble residue by filtering and removing part of the solvent, leaving (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form A to crystallize, redissolving the resulting crystals in acetonitrile, removing insoluble residue by filtering and removing part of the solvent, and leaving (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form A to crystallize.

26. A pharmaceutical composition comprising, as an active ingredient, a crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu Kα radiation at 15.1±0.2, 16.0±0.2, 18.9±0.2, 20.4±0.2, 22.5±0.2, 27.3±0.2, 29.3±0.2 and 30.4±0.2, and at least one suitable additive or auxiliary substance.

27. A pharmaceutical composition comprising, as an active ingredient, a crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride produced by the process of dissolving (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form B in acetonitrile together with active carbon, heating the solution to the boiling point, removing the active carbon by filtering, stirring the solution at a temperature below 40° C., removing insoluble residue by filtering and removing part of the solvent, leaving (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form A to crystallize, redissolving the resulting crystals in acetonitrile, removing insoluble residue by filtering and removing part of the solvent, and leaving (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride of Form A to crystallize, and at least one suitable additive or auxiliary substance.

28. A method of treating or inhibiting pain or urinary incontinence, said method comprising the step of administering a pharmaceutically effective amount of a crystalline Form A of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu Kα radiation at 15.1±0.2, 16.0±0.2, 18.9±0.2, 20.4±0.2, 22.5±0.2, 27.3±0.2, 29.3±0.2 and 30.4±0.2 to a subject in need thereof.