A crystalline salt of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol and hydrogen chloride, preferably in a 1:1 composition, including various crystalline forms of this salt, processes for preparing the various crystalline forms of this salt, pharmaceutical compositions containing the various crystalline forms of this salt, and the use of this salt as a pharmacologically active agent in a pharmaceutical composition to treat or inhibit pain or other disorders or disease states.

The present invention relates to a crystalline salt of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol and hydrogen chloride, preferably in a composition of 1:1, to various crystalline forms of this salt and also to processes for preparation thereof, to a pharmaceutical composition, and to the use of the salt as pharmaceutical active substance in a medicament.
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenols having analgesic activity are described in published European patent application no. EP 753,506. In the description it is mentioned that salts—such as hydrochlorides, for example—can also be prepared from the free bases of these compounds. But EP 753 506 contains no references to the fact that these hydrochlorides can be obtained in the form of a crystalline solid substance.
It has now surprisingly been found that 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol forms with hydrogen chloride an addition salt in the form of a crystalline solid substance, preferably in a composition in the ratio 1:1. It has furthermore been found that 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol HCl in the form of crystalline solids form polymorphous forms which can each be selectively prepared and which are particularly suitable, at least partly by reason of their stability, as active substance for formulating pharmaceutical compositions. For example, the crystalline form II is suitable, by reason of its kinetic stability, as active substance for formulating pharmaceutical compositions. Moreover, the crystalline form V is suitable, by reason of its stability in the presence of water, for example in the form of atmospheric moisture, as active substance for formulating pharmaceutical compositions. Furthermore it has been found that the hydrochloride salts are distinguished by very good solubility in water. A first subject of the invention is therefore constituted by crystalline salts of hydrogen chloride with 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol, whereby 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of the following formula (1) is preferred.

The compounds of the formula (1) contain a chiral C atom in the 1-position and 2-position of the cyclohexane ring. The compounds of the formula (1) encompass all the stereoisomers and mixtures of stereoisomers. Preferred are diastereomers or mixtures of enantiomeric diastereomers with trans configuration of the phenyl ring and of the dimethylaminomethyl group (1R,2R configuration and 1S,2S configuration, respectively), the enantiomer with the absolute configuration (1R,2R) being quite particularly preferred.
The structure of the (1R,2R) enantiomer of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol is reproduced below:

The invention also relates to a process for preparing 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of formula (1), the process comprising:    a) dissolving or suspending 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol in a solvent, or charging 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol in bulk,    b) mixing the solution, the solid substance or the suspension with a solution of hydrogen chloride, in particular hydrochloric acid, optionally cooling or heating and holding at a temperature between −80° C. and 150° C., preferably between −20° C. and 30° C., particularly preferably between −5° C. and 5° C., up until the complete formation of a solid substance, and    c) isolating the compound of the formula (1).
Alternatively, of course, 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol in solution, in the form of a suspension, or in bulk may also be introduced into a solution or gas containing hydrogen chloride.
The hydrochloric acid in step b) of the process stated above may, in particular, be present in the form of an aqueous solution or in the form of a solution in an organic solvent, preferably in a solvent selected from the group consisting of diethyl ether, tert.-butylmethyl ether and tetrahydrofuran.
The invention also relates to a process for preparing 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of formula (1), the process comprising:    a) dissolving 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol in a solvent, or charging 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol in bulk, and    b) introducing hydrogen-chloride gas into the solution or suspension, or passing hydrogen-chloride gas over the solid substance.
In the salification process according to the invention, the compounds of the formula (1) are also obtained in an amorphous form. Amorphous forms of the compounds of the formula (1) are obtainable, for example, simply by freeze drying or rapid cooling of solutions. Amorphous compounds of the formula (1) are not very stable, and in the presence of moisture tend to form hydrates. Likewise, amorphous forms of the compounds of the formula (1) in solvating solvents—such as, for example, acetone, ethanol, methanol, methyl ethyl ketone, isopropanol, n-propanol and n-octanol—are suitable for preparing the corresponding solvates. The amorphous form of the compounds of the formula (1) can likewise be used for selective preparation of crystalline forms.
It has been found that the compounds of the formula (1) in the form of crystalline solids form polymorphous forms which can be selectively prepared from 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride and which by reason of their stability are particularly suitable as active substance for formulating pharmaceutical compositions. The crystalline form II is preferably suitable, by reason of its kinetic stability, as active substance for formulating pharmaceutical compositions. Likewise the crystalline form V, by reason of its stability in the presence of water, for example in the form of atmospheric moisture, is preferably suitable as active substance for formulating pharmaceutical compositions.
It is known—inter alia, from Z. Jane Li et al. in J. Pharm. Sci., 1999, Vol. 88(3), pages 337 to 346—that enantiomers yield identical X-ray diffractograms and Raman spectra, and consequently form the same polymorphous forms. Polymorphous forms of all enantiomers are consequently encompassed within the scope of this invention.
The invention further relates to a crystalline form of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1), which exhibits a characteristic X-ray diffraction pattern within the range from 2° to 35° 2θ with pronounced characteristic signals (peaks), expressed in 2-theta values:
11.2 (w), 14.1 (m), 17.1 (w), 19.5 (w), 19.8 (vs), 20.5 (w), 21.5 (m),
24.1 (m), 26.1 (s), 26.8 (w), 31.3 (m);
designated hereinafter as form I.
The invention further relates to another crystalline form I of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol HCl of formula (1), which exhibits a characteristic X-ray diffraction pattern with the following pronounced reflections.
The measuring accuracy of the 2theta values lies within the range of ±0.2.
2ThetaIntensity (relative)9.09110.22111.222412.21413.03213.47314.124314.901516.69317.162418.051018.891419.532619.7810020.221220.482821.464322.241122.502122.711924.123426.097326.814327.682228.262528.511429.961431.284632.58833.03634.521535.442835.671536.38837.94838.59839.661840.131540.881441.722142.44943.154444.354745.701046.551147.13847.841548.691049.6814
In this application, the abbreviations in brackets signify:                (vs)=very strong intensity,        (s)=strong intensity,        (m)=medium intensity,        (w)=weak intensity, and        (vw)=very weak intensity.The abbreviation 'sh' in the tables of the Raman spectra signifies 'shoulder'.
The crystalline form I of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1) exhibits a characteristic Raman spectrum with characteristic bands, which is described by the following wave numbers (cm−1):
Wave number [cm−1]Intensity82S107VS177W251M284VW346W362VW423VW434VW479VW533W626VW634VW754VW762W787VW794VW823W838W861VW884VW936VW954VW972VW1001VS1056W1070W1080VW1102VW1122VW1154VW1162VW1184VW1208VW1227VW1274W1286W1293W1306W1316W1335VW1350VW1367VW1439W1449W1470W1584W1611W2633VW2662VW2714VW2805VW2856M2901M2922M2942M2957M2983W3008W3017W3025W3042W3051M3074VW3196VWIn the tables, wave numbers are stated with a precision of ±4 cm−1.
The invention further relates to a crystalline form I of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1), which possesses a characteristic X-ray diffraction pattern as represented in FIG. 1.
The invention also relates to a crystalline form I of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1), which is characterized by a Raman spectrum as represented in FIG. 2.
The crystalline form I is thermodynamically the most stable form at low temperatures up to approximately 40° C. The crystalline form I in the presence of atmospheric moisture with a relative air humidity >50% irreversibly forms hydrates of the crystalline form V. At a relative air humidity >95%, hydrates result having a proportion of water of crystallization, relative to the total weight of the hydrate, within the range from 8% to 10%. In order to avoid the formation of hydrates, the compounds of the crystalline form I can advantageously be stored in a low-moisture environment, for example in a vessel over phosphorus pentoxide or molecular sieve. Likewise, a storage of the crystalline form I under dry protective gas (for example, nitrogen) is advisable. The melting-point amounts to approximately 150° C.
Polymorph I can be prepared in the form of solid powder having desired mean particle sizes, which, as a rule, lie within the range from 1 μm to approximately 500 μm. The compound of the formula (1) forms a further crystalline form II which is thermodynamically stable at higher temperatures and which is likewise stable under normal conditions in air and with exclusion of atmospheric moisture. The crystalline form II is also capable of being handled in such a way that it can be employed for the preparation of pharmaceutical compositions.
The invention further includes a crystalline form of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1), which exhibits a characteristic X-ray diffraction pattern within the range from 2° to 35° 2θ with pronounced characteristic lines, expressed in 2theta values:
11.1 (m), 12.9 (w), 16.1 (m), 17.1 (w), 19.1 (s), 19.6 (w),
19.9 (m), 23.2 (w), 25.8 (w), 26.1 (s), 33.6 (w);
designated hereinafter as form II.
The invention also includes a crystalline form II of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol HCl of the formula (1), which exhibits a characteristic X-ray diffraction pattern with the following pronounced reflections.
2ThetaIntensity (relative)11.065611.551212.972713.701814.10615.03916.155517.072518.48419.1010019.562519.903621.131121.95922.21422.661523.262624.641524.95425.43725.822226.128226.71427.021927.66828.44628.72529.07329.65730.34631.44531.95632.421433.621533.99734.64735.21536.171037.39238.30338.96339.24439.621040.35241.26441.82342.38342.89544.16344.76445.351145.85446.18247.09348.453
A further subject of the invention is a crystalline form II of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1), which exhibits a characteristic Raman spectrum with characteristic bands, which is described by the following wave numbers (cm−1):
Wave number [cm−1]Intensity90S123VS171W230VW248M341W384VW457VW475VW505VW532W573VW624VW638W682VW706VW761W795W817VW844W857VW894VW936VW957VW971VW989VW997S1010VW1054W1075W1085VW1124VW1168VW1212VW1250VW1276W1294W1317VW1339VW1355VW1361W1391VW1414VW1441W1462W1529VW1586W1614W2477VW2519VW2665VW2734VW2768VW2814VW2850M2889M2920M2929S2938S2968M3019M3040W3067W3103VW3181VW3229VW3248VW
The invention also relates to a crystalline form II of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1), which possesses a characteristic X-ray diffraction pattern as represented in FIG. 3.
The invention also includes a crystalline form II of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1), which is characterized by a Raman spectrum as represented in FIG. 4.
The compounds of the crystalline form II are less hygroscopic than the compounds of the crystalline forms I, III and IV, and form hydrates of the crystalline form V only at a relative air humidity >70%. For instance, after 5 hours of storage of the crystalline form II at a relative air humidity of 60% no appreciable absorption of water can be established (proportion of water <0.15 wt. %). The crystalline form II is converted only slowly, by stir-mixing in ethyl acetate at a temperature between 20° C. and 30° C., preferably at a temperature of 23° C., into the form I which is thermodynamically more stable at this temperature, so that only after 32 days has the crystalline form II been completely converted into the crystalline form I. A small proportion of the crystalline form I can be detected after three days of stir-mixing. The conversion of the crystalline form II into the crystalline form I by stir-mixing takes place only slowly also in the presence of seed crystals of the crystalline form I. The low hygroscopicity and the kinetic stability make the crystalline form II a suitable active substance in pharmaceutical formulations.
The compounds of the crystalline form II possess good chemical stability. In the presence of atmospheric moisture with a relative air humidity >70° C. they form hydrates of the crystalline form V only slowly. At a relative air humidity >95%, hydrates result having a proportion of water of crystallization, relative to the total weight of the hydrate, within the range from 8% to 10%. In order to avoid the formation of hydrates, the compounds of the crystalline form II are advantageously stored in a low-moisture environment, for example in a vessel stored over phosphorus pentoxide or molecular sieve. Likewise, a storage of the crystalline form II under dry protective gas (for example, nitrogen) is advisable.
The melting-point lies within the range between 175° C. and 178° C., and the enthalpy of fusion amounts to approximately 93.3 J/g, determined by DSC at a heating-rate of 10° C./minute. Polymorph III can be prepared in the form of solid powder having desired mean particle sizes, which, as a rule, lie within the range from 1 μm to approximately 500 μm.
The compound of the formula (1) forms a further stable crystalline form III, which is thermodynamically stable at higher temperatures, preferably at a temperature between 70° C. and 155° C., particularly preferably at a temperature between 75° C. and 151° C., and which is likewise stable under normal conditions in air and with exclusion of atmospheric moisture.
The invention also relates to a crystalline form of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1), which exhibits a characteristic X-ray diffraction pattern within the range from 2° to 35° 2θ with pronounced characteristic lines, expressed in 2theta values:
6.9 (s), 13.9 (m), 16.3 (m), 17.7 (w), 20.9 (vs), 22.1 (w), 22.5 (w), 27.8 (w);
designated hereinafter as form III.
The invention also includes a crystalline form III of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol HCl of formula I, which exhibits a characteristic X-ray diffraction pattern with the following pronounced reflections:
2ThetaIntensity (relative)6.94718.85310.93511.41812.18413.884416.264216.67217.702418.341018.79919.18519.63620.07520.8810021.411021.60822.042122.532423.03623.59824.02424.73425.48226.04626.49927.54827.841628.85329.23729.99730.92231.23431.65632.04232.47532.84633.95334.47235.11535.83336.36237.07337.90438.67639.22339.81340.49341.24342.45343.67245.90247.19248.673
A further subject of the invention is a crystalline form III of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1), which exhibits a characteristic Raman spectrum with characteristic bands, which is described by the following wave numbers (cm−1):
Wave number [cm−1]Intensity75.65S94.93VS194.25VW244.39M286.33VW338.40W386.13VW443.99VW456.04VW481.59VW533.66W573.67VW624.30VW635.87VW702.88VW755.91W784.36VW793.52VW797.86VW819.07VW840.29W848.00W852.34W869.21VW897.66VW936.71VW958.89W974.31VW999.87VS1051.45W1071.70W1103.52VW1124.25VW1147.88VW1159.45VW1167.16W1213.44VW1232.25VW1249.60VW1264.55VW1277.08VW1293.48W1307.94W1311.80W1335.42VW1367.24VW1399.06VW1431.84VW1444.86W1466.07W1479.09W1529.71VW1587.08W1605.40W1653.62VW1661.33VW1704.24VW2675.22W2700.29VW2707.04VW2722.95VW2812.14W2852.16S2858.91S2891.21M2912.91M2924.48M2939.42S2949.55M2960.63M3019.45M3048.86M3071.04W3174.69VW3204.10VW3236.41VW
A further subject of the invention is a crystalline form III of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1), which exhibits a characteristic X-ray diffraction pattern as shown in FIG. 5.
The invention further relates to a crystalline form III of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of formula (1), which is characterized by a Raman spectrum as shown in FIG. 6.
The crystalline form III in the presence of atmospheric moisture with a relative air humidity >50% irreversibly forms hydrates of the crystalline form V. At a relative air humidity >95%, hydrates result having a proportion of water of crystallization, relative to the total weight of the hydrate, within the range from 8% to 10%. In order to avoid the formation of hydrates, the compounds of the crystalline form III can advantageously be stored in a low-moisture environment, for example in a vessel over phosphorus pentoxide or a molecular sieve. Likewise, it is advisable to store the crystalline form III under dry protective gas (for example, nitrogen).
The melting-point lies within the range between 155° C. and 158° C., and the enthalpy of fusion amounts to approximately 87 J/g, determined by DSC at a heating-rate of 10° C./minute. Polymorph III can be prepared in the form of solid powder having desired mean particle sizes, which, as a rule, lie within the range from 1 μm to approximately 500 μm.
The compound of the formula (1) forms a further stable crystalline form IV which is thermodynamically stable at higher temperatures, preferably at a temperature between 70° C. and 155° C., particularly preferably at a temperature between 75° C. and 130° C., still more preferably at a temperature between 75° C. and 122° C., and which is also stable under normal conditions in air and with exclusion of atmospheric moisture.
The invention also relates to a crystalline form of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of formula (1), which exhibits a characteristic X-ray diffraction pattern within the range from 20 to 35° 2θ with the following pronounced characteristic lines, expressed in 2theta values:
12.0 (m), 13.0 (m), 17.3 (m), 17.7 (m), 19.2 (s), 19.7 (m), 20.2 (m),
21.3 (m), 23.4 (m), 24.2 (m), 24.6 (m), 43.1 (vs), 44.2 (vs);
designated hereinafter as form IV.
The invention also relates to a crystalline form IV of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol HCl of the formula (1), which exhibits a characteristic X-ray diffraction pattern with the following pronounced reflections:
2ThetaIntensity (relative)10.73612.044212.383213.025913.78614.71614.96515.622115.91816.651217.284217.734718.782319.228619.673920.165120.591721.304722.077823.404324.254724.564125.041425.441925.723127.222227.823528.531429.132429.623129.992130.581231.332131.571831.911632.451832.851333.331033.751534.482534.921835.461636.441237.361838.151838.582039.671440.561741.051541.631441.851442.571543.149643.256044.2410045.992346.811649.0622
The invention also includes a crystalline form IV of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1), which exhibits a characteristic Raman spectrum with characteristic bands described by the following wave numbers (cm−1):
Wave number [cm−1]Intensity85S115S123S190VW243M337W386VW448VW476VW502VW534W574VW625W637VW709VW724VW748W761W794VW819VW833W844W858VW891VW913VW936VW957VW970VW988VW999VS1052W1071VW1083VW1104VW1123VW1160W1211VW1251VW1278W1293W1321W1337VW1366W1401VW1444W1463W1476VW1585W1614W2665VW2684VW2697VW2701VW2817W2853M2897M2914M2925M2938S2964M3017W3028W3043M3074VW3083VW
The invention also relates to a crystalline form IV of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1), which exhibits a characteristic X-ray diffraction pattern as shown in FIG. 7.
The invention additionally includes a crystalline form IV of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of formula (1), which is characterized by a Raman spectrum as shown in FIG. 8.
In the presence of atmospheric moisture at a relative air humidity >50%, the crystalline form IV irreversibly forms hydrates of the crystalline form V. At a relative air humidity >95%, hydrates result having a proportion of water of crystallization, relative to the total weight of the hydrate, within the range from 8% to 10%. In order to avoid the formation of hydrates, the compounds of the crystalline form IV can advantageously be stored in a low-moisture environment, for example in a vessel over phosphorus pentoxide or over a molecular sieve. Likewise, it is advisable to store the crystalline form IV under dry protective gas (for example, nitrogen).
The melting-point lies within the range between 166° C. and 172° C., and the enthalpy of fusion amounts to approximately 78 J/g, determined by DSC at a heating-rate of 10° C./minute. Polymorph IV can be prepared in the form of solid powder having desired mean particle sizes, which, as a rule, lie within the range from 1 μm to approximately 500 μm.
The compound of the formula (1) furthermore forms stable hydrates of the crystalline form V, which are stable in air under normal conditions.
The hydrates of the crystalline form V preferably exhibit a content of water of crystallization within the range from 1% to 10%, particularly preferably within the range from 5% to 9%, quite particularly preferably within the range from 6% to 8.5%, still more preferably within the range from 7% to 8%, relative to the weight of the hydrate.
The invention also relates to a crystalline form of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1), which exhibits a characteristic X-ray diffraction pattern within the range from 20 to 35° 2θ with pronounced characteristic lines, expressed in 2theta values:
11.4 (m), 12.1 (m), 16.7 (w), 19.2 (m), 19.4 (w), 20.1 (m), 21.1 (m),
22.4 (vs), 24.0 (m), 31.3 (w);
designated in the following as form V.
The invention further relates to a crystalline form V of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol HCl of formula (1), which exhibits a characteristic X-ray diffraction pattern with the following pronounced reflections.
2ThetaIntensity (relative)9.06611.476012.153613.43914.321114.89616.721717.42418.12518.82619.234619.443120.075020.68821.095021.88822.4210023.00523.53624.044624.373324.542624.582725.05725.892926.52726.99627.321227.911328.651030.111330.931731.292032.431732.961133.74534.11634.46734.84935.89736.31636.88737.381237.71838.06538.99740.01740.72541.70442.35542.94843.86544.15544.70445.07645.65646.24547.31648.23449.124
The invention also includes a crystalline form V of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of formula (1), which exhibits a characteristic Raman spectrum with characteristic bands described by the following wave numbers (cm−1):
Wave number [cm−1]Intensity96.38VS252.59W270.91W337.44W371.67VW448.81VW469.06VW507.14VW535.11W572.23VW624.30VW704.81VW751.58W794.48VW817.14VW837.39W857.16VW886.09VW915.01VW935.26VW952.62VW999.38S1053.38W1100.15VW1120.40VW1159.45VW1211.03VW1251.05VW1271.78VW1294.44W1308.42VW1336.87VW1355.19VW1368.69W1405.81VW1440.52W1459.81W1502.71VW1600.58W2667.03VW2702.70VW2728.74VW2811.66VW2855.05M2895.55M2934.60M2966.42M3032.47W
The invention also relates to a crystalline form V of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1), which exhibits a characteristic X-ray diffraction pattern as shown in FIG. 9.
The invention additionally relates to a crystalline form V of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1), which is characterized by a Raman spectrum as represented in FIG. 10.
The crystalline form V is stable at ambient temperature in air and is therefore particularly suitable as an active substance in pharmaceutical formulations.
The crystalline form V can be dehydrated only with difficulty. The use of vacuum and/or of hygroscopic reagents—such as phosphorus pentoxide, for example—results only in an incomplete release of water from the crystalline form V. In the presence of water—which may be present, for example, in the form of water vapor or atmospheric moisture—the partially dehydrated compound of the crystalline form V quickly absorbs said water again. The compounds of the crystalline form V do not change under elevated pressure—for example, at a pressure of 8000 bar for a period of 60 minutes—or in the course of grinding, and no conversion into the crystalline forms I, II, III or IV is observed under the influence of elevated pressure.
The melting-point of the compounds of the crystalline form V lies within the temperature range from 105° C. to 115° C., and the enthalpy of fusion determined by DSC at a heating-rate of 10° C./minute amounts to approximately 77 J/g.
The compound of the formula (1) forms stable solvates in solvating solvents such as, for example, ethanol, methanol, methyl ethyl ketone, isopropanol, n-propanol, n-octanol and acetone. The solvates are isomorphous to one another and likewise to the hydrate having the crystalline form V. The solvent cannot be removed, or cannot be completely removed, by vacuum.
The replacement of ethanol in an appropriate solvate of compounds of the formula (1) is possible by storage at elevated air humidity, for example by storage in the presence of a supersaturated aqueous solution of magnesium nitrate or in the presence of a supersaturated aqueous solution of sodium chloride for a period of at least two months, preferably for a period of at least four months.
The polymorphous forms I, II, III, IV and V can each be converted into other crystalline forms. For example, the polymorphous forms II, III and IV can be converted into the polymorphous form I; the polymorphous forms III and IV can be converted into the polymorphous form II; the polymorphous forms III can be converted into the polymorphous form IV, and the polymorphous forms I and II can be converted into the polymorphous forms III or IV. A further subject of the invention is therefore also constituted by mixtures of the crystalline forms I, II, III, IV and V in, as such, arbitrary mixing ratios.
The crystal lattices of forms I, II, III, IV and V are clearly different from one another, so that the Raman spectra and X-ray diffraction patterns exhibit great differences. For instance, form I exhibits a peak with strong intensity within the range of 19°2θ, form III exhibits peaks with strong intensity within the ranges of 7°, 14° and 21° 2θ, and form V exhibits peaks with strong intensity within the ranges of 12° and 22° 2θ.
The polymorphous forms I, II, III and IV can be prepared by crystallization procedures known as such from the salt 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, for example by stirring of suspensions (adjustment of phase equilibria), precipitation, recrystallization, evaporation of solvents or crystallization from the melt. Diluted, saturated or supersaturated solutions may be used, with or without seeding with a crystal nucleator. The temperatures for forming solutions may amount to up to 100° C. The crystallization can be initiated by cooling to approximately −100° C. to 30° C., and preferably −30° C. to 20° C., whereby cooling may take place continuously or in stepwise manner. For the purpose of preparing solutions or suspensions, use may be made of amorphous or crystalline starting materials, in order to achieve high concentrations in solutions and to obtain other crystalline forms.
The invention therefore also relates to a process for preparing the crystalline form I of 3-[2 (dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, wherein:    a) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in the crystalline form III and 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in the crystalline form IV or 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)phenol hydrochloride in the crystalline form V are stirred in a solvent, preferably in a quantitative ratio between 1:100 and 100:1, particularly preferably in a quantitative ratio between 1:10 and 10:1, quite particularly preferably in a quantitative ratio between 1:5 and 5:1, up until the complete formation of the crystalline form I, or    b) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in the crystalline form II and 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in the crystalline form I are stirred in a solvent, preferably in a quantitative ratio between 100:1 and 8:1, particularly preferably in a quantitative ratio between 11:1 and 9:1, up until the complete formation of the crystalline form I,whereby the temperature in processes a) and b) is at most 40° C., preferably at most 30° C., particularly preferably at most 25° C.
Processes a) and b) can be carried out in the presence of air or in the presence of inert gases such as, for example, nitrogen and noble gases. It is preferred to work in an air environment for economic reasons. The relative humidity of the gases preferably is <50%, particularly preferably <20%, especially preferably <5%.
The duration of processes a) and b) depends substantially on the size of the crystals and on the concentration of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, and may preferably amount to from 1 hour to 250 hours, particularly preferably 3 hours to 72 hours, and especially preferably 5 hours to 25 hours. The concentration of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride preferably amounts to 0.5% to 50%, particularly preferably 2% to 30%, quite particularly preferably 5% to 20%, still more preferably 5% to 8%, in each instance relative to the weight of the solvent.
After isolation, the crystalline residue can be dried in conventional manner, whereby temperatures above 40° C. are advantageously avoided.
Processes a) and b) are preferably carried out in non-solvating solvents. Particularly preferred are solvents selected from the group consisting of aliphatic, cycloaliphatic and aromatic hydrocarbons (hexane, heptane, petroleum ether, cyclohexane, methyl cyclohexane, benzene, toluene, xylene), aliphatic halogenated hydrocarbons (dichloromethane, chloroform, dichloroethane and tetrachloroethane), nitriles (acetonitrile, propionitrile, benzonitrile), ethers (diethyl ether, dibutyl ether, tert.-butylmethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxan), long-chain alcohols (butanol, tert.-butanol, pentanol, octanol, decanol) and carboxylic-acid esters and lactones propyl acetate, ethyl acetate or methyl acetate, valerolactone). The solvent ethyl acetate is especially preferred.
The solvents can be used individually or in a mixture of at least two solvents. It is preferred to use physiologically harmless solvents that are known to persons skilled in the art. After isolation, the solvent or solvent mixture that has been used can be removed in conventional manner by known drying processes.
The invention also relates to a crystalline form I of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1), obtainable by one of the processes described above.
The invention additionally includes a process for preparing the crystalline form II of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, wherein    a) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in the crystalline form IV or a mixture of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in the crystalline form III and 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride in the crystalline form V is heat-treated at a temperature between 150° C. and 160° C., preferably at a temperature between 154° C. and 158° C., up until the complete formation of the crystalline form II, or    b) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in the crystalline form II and 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in the crystalline form III or 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride in the crystalline form IV is stirred in a solvent, preferably in a quantitative ratio between 1:100 and 1:8, particularly preferably in a quantitative ratio between 1:11 and 1:9, up until the complete formation of the crystalline form II, or    c) a suspension of the amorphous form of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a solvent, preferably a solvent that does not form solvates, as a carrier is stirred at a temperature between 30° C. and 50° C., preferably at a temperature between 35° C. and 45° C., particularly preferably at a temperature of 40° C., until the complete formation of the crystalline form II occurs; or    d) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in the crystalline form III and 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in the crystalline form IV are stirred in a solvent, preferably in a quantitative ratio between 1:100 and 100:1, particularly preferably in a quantitative ratio between 1:10 and 10:1, especially preferably in a quantitative ratio between 1:5 and 5:1, until the complete formation of the crystalline form II occurs;whereby the temperature in processes b) and d) is at most 60° C., preferably at most 40° C., particularly preferably at most 30° C., especially preferably at most 25° C.
Processes b), c) and d) can be carried out in the presence of air or in the presence of inert gases such as, for example, nitrogen and noble gases. It is preferred to work in an air environment for economic reasons. The relative humidity of the gases preferably is <50%, particularly preferably <20%, especially preferably <5%.
The duration of processes b) and d) depends substantially on the size of the crystals and on the concentration of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, and may preferably amount to from 1 hour to 250 hours, particularly preferably 3 hours to 72 hours, especially preferably 5 hours to 25 hours. The duration of process c) preferably amounts to at least 300 hours, particularly preferably at least 350 hours, especially preferably at least 400 hours. The concentration of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydro-chloride in processes b), c) and d) preferably is 0.5% to 50%, particularly preferably 2% to 30%, quite particularly preferably 5% to 20%, still more preferably 5% to 8%, in each instance relative to the weight of the solvent.
Processes b), c) and d) are preferably carried out in non-solvating solvents. Particularly preferred are solvents selected from the group consisting of aliphatic, cycloaliphatic and aromatic hydrocarbons (hexane, heptane, petroleum ether, cyclohexane, methyl cyclohexane, benzene, toluene, xylene), aliphatic halogenated hydrocarbons (dichloromethane, chloroform, dichloroethane and tetrachloroethane), nitriles (acetonitrile, propionitrile, benzonitrile), ethers (diethyl ether, dibutyl ether, tert.-butyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxan), long-chain alcohols (butanol, tert.-butanol, pentanol, octanol, decanol) and carboxylic-acid esters and lactones (propyl acetate, ethyl acetate or methyl acetate, valerolactone). The solvent ethyl acetate is especially preferred.
The solvents can be used individually or in a mixture of at least two solvents. It is advantageous to use physiologically harmless solvents that are known to persons skilled in the art. After isolation, the solvent and/or solvent mixture that has been used can be removed in conventional manner by known drying processes.
The invention also relates to a crystalline form II of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of formula (1), obtainable by one of the processes described above.
The invention likewise relates to a process for preparing the crystalline form III of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, wherein    a) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in the form of an ethanol solvate or acetone solvate is dissolved in a solvent and stirred and subsequently precipitated, or    b) a suspension of the amorphous form of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a solvent, preferably in a solvent that does not form solvates, as a carrier, is stirred at a temperature between 30° C. and 80° C., preferably at a temperature between 35° C. and 50° C., particularly preferably at a temperature of 40° C., until complete formation of the crystalline form III occurs.
In process step a) the crystalline forms I, II, IV, the amorphous form of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride or corresponding mixtures can be used for preparing solutions. The concentration of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in the solution depends on the chosen temperature and on the solvent. The dissolved quantity may preferably amount to from 0.5% to 50%, particularly preferably from 2% to 30%, quite particularly preferably 3% to 25%, and still more preferably 5% to 20%, relative to the solvent. The dissolution temperature may be up to 70° C. and preferably up to 60° C. Ethyl acetate is preferably used as solvent for preparing solutions.
Precipitation can be effected by cooling, partial or complete removal of the solvent, addition of a solvent in which 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride exhibits only a low solubility—such as, for example, heptane, tert.-butylmethyl ether or ethyl acetate and corresponding mixtures—or by a combination of these measures. 'Cooling' may signify slow cooling or chilling to temperatures down to −20° C. and preferably to 0° C. The solvent can be removed by heating, in a stream of gas, applying a vacuum, or a combination of these measures. In process stage a), heating for the purpose of removing solvent implies a temperature of at most 40° C., and preferably of at most 3O° C.
Process b) can be carried out in the presence of air or in the presence of inert gases such as, for example, nitrogen and noble gases. It is preferred to work in an air environment for economic reasons. The relative humidity of the gases preferably is <50%, particularly preferably <40%, especially preferably <20%.
The duration of process b) depends substantially on the size of the crystals and on the concentration of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, and may preferably amount to from 1 hour to 350 hours, particularly preferably 10 hours to 300 hours, especially preferably 20 hours to 300 hours. The concentration of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]-phenol hydrochloride in process b) preferably amounts to 0.5% to 50%, particularly preferably 2% to 30%, quite particularly preferably 5% to 20%, still more preferably 5% to 15%, in each instance relative to the weight of the solvent. After isolation, the crystalline residue can be dried in conventional manner, whereby temperatures above 40° C. are advantageously avoided.
Process b) is preferably carried out in non-solvating solvents. Particularly preferred are solvents selected from the group consisting of aliphatic, cycloaliphatic and aromatic hydrocarbons (hexane, heptane, petroleum ether, cyclohexane, methyl cyclohexane, benzene, toluene, xylene), aliphatic halogenated hydrocarbons (dichloromethane, chloroform, dichloroethane and tetrachloroethane), nitriles (acetonitrile, propionitrile, benzonitrile), ethers (diethyl ether, dibutyl ether, tert.-butylmethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxan), long-chain alcohols (butanol, tert.-butanol, pentanol, octanol, decanol) and carboxylic-acid esters and lactones (propyl acetate, ethyl acetate or methyl acetate, valerolactone). The solvents heptane, tert.-butylmethyl ether and ethyl acetate are especially preferred.
The invention also relates to a crystalline form III of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1), obtainable by one of the processes described above.
The invention likewise relates to a process for preparing the crystalline form IV of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, wherein    a) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in the crystalline form III is heat-treated at a temperature between 150° C. and 160° C., preferably at a temperature between 154° C. and 158° C., until complete formation of the crystalline form IV occurs, or    b) a suspension of the amorphous form of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a solvent, preferably in a solvent that does not form solvates, as a carrier, is stirred at a temperature between 40° C. and 120° C., preferably at a temperature between 40° C. and 100° C., particularly preferably at a temperature between 40° C. and 80° C., until complete formation of the crystalline form IV occurs; or    c) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in the crystalline form IV and 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in the crystalline form III are stirred in a solvent, preferably in a quantitative ratio between 1:100 and 1:8, particularly preferably in a quantitative ratio between 1:11 and 1:9, until complete formation of the crystalline form IV occurs;whereby the temperature in process c) is at most 40° C., preferably at most 30° C., particularly preferably at most 25° C.
Processes b) and c) can be carried out in the presence of air or in the presence of inert gases such as, for example, nitrogen and noble gases. It is preferred to work in an air environment for economic reasons. The relative humidity of the gases preferably is <50%, particularly preferably <40%, especially preferably <20%.
The duration of processes b) and c) depends substantially on the size of the crystals and on the concentration of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, and may preferably amount to from 1 hour to 250 hours, particularly preferably 10 hours to 200 hours, especially preferably 30 hours to 150 hours. The concentration of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]-phenol hydrochloride preferably amounts to 0.5% to 50%, particularly preferably 0.5% to 20%, quite particularly preferably 0.5% to 10%, still more preferably 1% to 8%, in each instance relative to the weight of the solvent. After isolation, the crystalline residue can be dried in conventional manner, whereby temperatures above 40° C. are advantageously avoided.
Processes b) and c) are preferably implemented in non-solvating solvents. Particularly preferred are solvents selected from the group consisting of aliphatic, cycloaliphatic and aromatic hydrocarbons (hexane, heptane, petroleum ether, cyclohexane, methyl cyclohexane, benzene, toluene, xylene), aliphatic halogenated hydrocarbons (dichloromethane, chloroform, dichloroethane and tetrachloroethane), nitriles (acetonitrile, propionitrile, benzonitrile), ethers (diethyl ether, dibutyl ether, tert.-butylmethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxan), long-chain alcohols (butanol, tert.-butanol, pentanol, octanol, decanol) and carboxylic-acid esters and lactones (propyl acetate, ethyl acetate or methyl acetate, valerolactone). The solvent tert.-butylmethyl ether is especially preferred.
The solvents can be used individually or in a mixture of at least two solvents. It is advantageous to use physiologically harmless solvents that are known to persons skilled in the art. After isolation, the solvent and/or solvent mixture that has been used can be removed in conventional manner by known drying processes.
The invention further relates to a crystalline form IV of 3-[2-(dimethyl-amino)methyl(cyclohex-1-yl)]phenol hydrochloride of formula (1), obtainable by one of the processes described above.
The invention likewise includes a process for preparing the crystalline form V of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, wherein    a) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in the crystalline form I, II, III or IV is left to stand in air or is treated with water vapor, or    b) a suspension of the amorphous form of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a mixture of water and optionally at least one solvent as a carrier, is stirred at a temperature between 20° C. and 60° C., preferably at a temperature between 20° C. and 30° C., and subsequently the remaining water or solvent is removed.
The invention also includes a crystalline form V of 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of formula (1), obtainable by one of the processes described above.
Due to its favorable overall profile of properties, 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride, in particular 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride in the crystalline forms II and V, is outstandingly suitable as an active substance for pharmaceutical compositions and quite particularly suitable for pain-relieving medicaments. Accordingly, the invention also includes the use of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of formula (1) as an active substance in a pharmaceutical composition or medicament, preferably as an active substance in an analgesic.
Preferred here also, as in the entire application, are diastereomers or mixtures of enantiomeric diastereomers with trans configuration of the phenyl ring and of the dimethylaminomethyl group (1R,2R configuration and 1S,2S configuration, respectively), the enantiomer with the absolute configuration (1R,2R) being quite particularly preferred.
The invention also includes a pharmaceutical composition containing a pharmacologically effective amount of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of formula (1) and at least one pharmaceutical carrier or diluent.
In the composition the compound of the formula (1) may be present as crystalline form I, II, III, IV, V or as a mixture of forms I, II, III, IV and V. The crystalline form II and/or I and/or V is preferably included. The crystalline form II and/or V is particularly preferably included.
The conversion of the compounds of the crystalline form II into the crystalline form I in pharmaceutical compositions can be prevented through the use of pharmaceutically acceptable ingredients and components or through the use of suitable formulation auxiliaries known to a person skilled in the art.
The quantity of the compounds of the formula (1) depends substantially on the type of formulation and on the desired dosage during the period of administration. The quantity of the respective compounds of the formula (1) to be administered to the patient may vary and is, for example, dependent on the weight or age of the patient and also on the manner of administration, on the indication and on the degree of severity of the illness. Preferably 0.005 mg/kg to 5000 mg/kg, particularly preferably 0.05 mg/kg to 500 mg/kg, quite particularly preferably 0.5 mg/kg to 100 mg/kg, still more preferably 2 mg/kg to 20 mg/kg of body weight of the patient of at least one such compound are administered.
Oral formulations may be solid formulations, for example tablets, capsules, pills and pastilles, but oral formulations may also be liquid formulations, for example solutions, suspensions, syrups or elixirs. Liquid and solid formulations also encompass the incorporation of the compounds of the formula (1) into solid or liquid foodstuffs. Furthermore, liquids also encompass solutions for parenteral applications, such as, for example, solutions for infusion or injection.
The compounds of the formula (1) and the crystalline forms can be used directly as powders (micronized particles), granulates, suspensions or solutions, or they may be mixed with other pharmaceutically acceptable ingredients and components and then pulverized, in order then to fill the powders into capsules consisting of hard or soft gelatin, to press tablets, pills or pastilles, or in order to suspend or dissolve the powders in a carrier for the purpose of preparing suspensions, syrups or elixirs. Tablets, pills or pastilles can be provided with a coating after pressing.
Pharmaceutically acceptable ingredients and components for the various types of formulation are known as such. It may, for example, be a question of binding agents such as synthetic or natural polymers, medicinal carriers, lubricating agents, surfactants, sweetening agents and flavoring agents, coating agents, preserving agents, dyestuffs, thickening agents, ancillary agents, antimicrobial agents and carriers for the various types of formulation.
Examples of suitable binding agents include gum arabic, gum tragacanth, acacia gum and biodegradable polymers such as homopolyesters or copolyesters of dicarboxylic acids, alkylene diols, polyalkylene glycols and/or aliphatic hydroxycarboxylic acids; homopolyamides or copolyamides of dicarboxylic acids, alkylenediamines and/or aliphatic aminocarboxylic acids; corresponding polyester-polyamide copolymers, polyanhydrides, polyorthoesters, polyphosphazenes and polycarbonates. The biodegradable polymers may be linear, branched or crosslinked. Specific examples are polyglycolic acid, polylactic acid and poly-d,l-lactic/glycolic acid. Other examples of polymers are water-soluble polymers such as, for example, polyoxaalkylenes (polyoxyethylene, polyoxypropylene and mixed polymers thereof), polyacrylamides and hydroxyl-alkylated polyacrylamides, polymaleic acid and esters or amides thereof, polyacrylic acid and esters or amides thereof, polyvinyl alcohol and esters or ethers thereof, polyvinyl imidazole, polyvinyl pyrrolidone and natural polymers, such as chitosan, for example.
Examples of medicinal carriers include phosphates, such as dicalcium phosphate.
Examples of suitable lubricating agents include natural or synthetic oils, fats, waxes or fatty-acid salts such as magnesium stearate.
Surfactants (surface-active agents) may be anionic, cationic, amphoteric or neutral. Examples of useful surfactants include lecithin, phospholipids, octyl sulfate, decyl sulfate, dodecyl sulfate, tetradecyl sulfate, hexadecyl sulfate and octadecyl sulfate, sodium oleate or sodium caprate, 1-acylaminoethane-2-sulfonic acids such as 1-octanoylaminoethane-2-sulfonic acid, 1-decanoylaminoethane-2-sulfonic acid, 1-dodecanoylaminoethane-2-sulfonic acid, 1-tetradecanoylamino-ethane-2-sulfonic acid, 1-hexadecanoylaminoethane-2-sulfonic acid and 1-octadecanoylaminoethane-2-sulfonic acid, bile acids, salts and derivatives thereof, such as, for example, cholic acid, deoxycholic acid, taurocholic acid, taurodeoxycholic acid and sodium glycocholates, sodium caprate, sodium laurate, sodium oleate, sodium lauryl sulfate, sodium cetyl sulfate, sulfated castor oil, sodium dioctyl sulfosuccinate, cocamidopropyl betaine and lauryl betaine, fatty alcohols, cholesterols, glycerin monostearate or distearate, glycerin monooleate or dioleate, glycerin monopalmitate or dipalmitate and polyoxyethylene stearate.
Examples of suitable sweetening agents include sucrose, fructose, lactose and aspartame.
Examples of useful flavoring agents include peppermint, oil of wintergreen or fruit flavor such as cherry or orange flavor.
Examples of suitable coating agents include gelatins, waxes, shellac, sugars and biodegradable polymers.
Examples of preservation agents include methylparaben or propylparaben, sorbic acid, chlorobutanol and phenol.
Examples of ancillary agents include aromatic principles.
Examples of suitable thickening agents include synthetic polymers, fatty acids, fatty-acid salts, fatty-acid esters and fatty alcohols.
Examples of suitable liquid carriers include water, alcohols (ethanol, glycerol, propylene glycol, liquid polyethylene glycols), polytriazines and oils. Examples of solid carriers are talc, aluminas, microcrystalline cellulose, silicon dioxide, aluminium oxide and similar solid substances.
The composition according to the invention may also contain isotonic agents such as, for example, sugars, physiological buffers and sodium chloride.
The composition according to the invention may also be formulated as an effervescent tablet or effervescent powder which decomposes in an aqueous environment, thereby formulating solutions or suspensions for drinking.
A syrup or a elixir may contain the compound of the formula (1), a sugar such as sucrose or fructose by way of sweetening agent, a preserving agent (such as methylparaben), a dyestuff and a flavoring agent (such as flavoring substances).
The composition according to the invention may also be a formulation with delayed and/or controlled release of the active substance upon contact with body fluids of the gastrointestinal tract, in order to achieve a substantially constant and effective level of the active substance in the blood plasma. For this purpose the compounds of the formula (1) can be embedded in a polymer matrix of a biodegradable polymer, of a water-soluble polymer or of both types of polymers, optionally together with a suitable surfactant. In this context, 'embedding' may signify the incorporation of microparticles into the polymer matrix. Formulations with delayed and controlled release of active substance can also be obtained by encapsulation of dispersed microparticles or emulsified microdroplets with the aid of known techniques for coating dispersions and emulsions.
The compounds of the formula (1) can also be used together with at least one further pharmaceutical active substance for combination therapies. To this end, at least one further active substance may be additionally dispersed or dissolved in the composition according to the invention.
The invention also relates to the use of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride of formula (1) for preparing a pharmaceutical composition, in particular for the treatment of pain.
The invention thus also relates to a process for treating pain conditions, wherein an effective quantity of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of the formula (1) is administered to a patient suffering from pain.
The medicament or pharmaceutical composition according to the invention preferably is suitable for the treatment or inhibition of pain, preferentially pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain; of migraine; depressions; neurodegenerative diseases, preferentially selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease and multiple sclerosis; cognitive illnesses, preferentially cognitive deficiency conditions, particularly preferably attention-deficit syndrome (ADS), panic attacks; epilepsy; coughing; urinary incontinence; diarrhea; pruritus; schizophrenia; cerebral ischemias; muscular spasms; cramps; food-intake disorders, preferentially selected from the group consisting of bulimia, cachexia, anorexia and obesity; abuse of alcohol and/or drugs (in particular, nicotine and/or cocaine) and/or medicaments; dependence on alcohol and/or drugs (in particular, nicotine and/or cocaine) and/or medicaments, preferentially for the prophylaxis and/or reduction of withdrawal symptoms in the case of dependence on alcohol and/or drugs (in particular, nicotine and/or cocaine) and/or medicaments; development of tolerance phenomena in relation to medicaments, particularly in relation to opioids; gastro-oesophageal reflux syndrome; for diuresis; for antinatriuresis; for influencing the cardiovascular system; for anxiolysis; for heightening wakefulness; for heightening libido, for modulating motor activity and for local anaesthesia.
In particularly preferred manner, the pharmaceutical composition according to the invention is suitable for the treatment and/or inhibition of pain, preferentially of acute pain, chronic pain, neuropathic pain or visceral pain; depressions; epilepsy; Parkinson's disease; abuse of alcohol and/or drugs (in particular, nicotine and/or cocaine) and/or medicaments; dependence on alcohol and/or drugs (in particular, nicotine and/or cocaine) and/or medicaments; preferentially for the prophylaxis and/or reduction of withdrawal symptoms in the case of dependence on alcohol and/or drugs (in particular, nicotine and/or cocaine) and/or medicaments; of the development of tolerance phenomena in relation to medicaments, in particular in relation to opioids, or for anxiolysis.
In quite particularly preferred manner, the medicament according to the invention is suitable for the treatment and/or inhibition of pain, preferentially of acute pain, chronic pain, neuropathic pain or visceral pain.
Particularly preferred is the use of at least one salt according to the invention, in each case optionally in the form of a purified or isolated stereoisomer, in particular enantiomers or diastereomers, or a racemate or in the form of a mixture of stereoisomers, in particular of the enantiomers and/or diastereomers, in an arbitrary mixing ratio, and also, optionally, of one or more pharmaceutically compatible ancillary substances for preparing a pharmaceutical composition for treating and/or inhibiting pain, preferentially pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain, or for the treatment and/or inhibition of migraine, depression, neurodegenerative diseases, preferentially a neurodegenerative disease selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease and multiple sclerosis, cognitive illnesses, preferentially cognitive deficiency conditions, particularly preferably of attention-deficit syndrome (ADS), panic attacks, epilepsy, coughing, urinary incontinence, diarrhea, pruritus, schizophrenia, cerebral ischemias, muscular spasms, cramps, food-intake disorders, preferentially selected from the group consisting of bulimia, cachexia, anorexia and obesity, abuse of alcohol and/or drugs (in particular, nicotine and/or cocaine) and/or medicaments; dependence on alcohol and/or drugs (in particular, nicotine and/or cocaine) and/or medicaments; preferentially for the prophylaxis and/or reduction of withdrawal symptoms in the case of dependence on alcohol and/or drugs (in particular, nicotine and/or cocaine) and/or medicaments; development of tolerance phenomena in relation to drugs and/or medicaments, particularly in relation to opioids, gastro-oesophageal reflux syndrome, for diuresis, for antinatriuresis, for influencing the cardiovascular system, for anxiolysis, for heightening wakefulness, for heightening libido, for modulating motor activity and for local anaesthesia.
The pharmaceutical composition according to the invention may exist as a liquid, semisolid or solid medicinal form, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols, or in multiparticulate form, for example in the form of pellets or granulates, optionally pressed into tablets, filled in capsules or suspended in a liquid, and may also be administered as such.
In addition to at least one salt according to the invention, optionally in the form of an isolated and/or purified stereoisomer, in particular enantiomers or diastereomers, its racemate or in the form of mixtures of the stereoisomers, in particular of the enantiomers or diastereomers, in an arbitrary mixing ratio, the pharmaceutical composition according to the invention) ordinarily contains further physiologically compatible pharmaceutical ancillary substances, which may preferably be selected from the group consisting of carrier materials, fillers, solvents, diluents, surface-active substances, dyestuffs, preserving agents, disintegrants, lubricating agents, lubricants, flavors and binding agents.
The selection of the physiologically compatible ancillary substances and also the quantities of such substances to be employed depend on whether the pharmaceutical composition is to be administered orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example onto infections on the skin, of the mucous membranes and in the eyes. Particularly suitable for oral administration are preparations in the form of tablets, dragées, capsules, granulates, pellets, drops, juices and syrups; for parenteral, topical and inhalational application, solutions, suspensions, dry preparations capable of being reconstituted easily and also sprays.
Suitable preparations for percutaneous application include also sustained-release preparations in dissolved form or in a plaster, optionally with addition of agents which promote the penetration of the skin.
Orally or percutaneously administrable forms of preparation are able to release the respective salts according to the invention in delayed manner.
The pharmaceutical compositions according to the invention are prepared using conventional means, appliances and methods, following processes well-known from the state of the art, such as are described, for example, in Remington's Pharmaceutical Sciences, editor A. R. Genarro, 17th Edition, Mack Publishing Company, Easton, Pa., 1985, in particular in Part 8, Chapters 76 to 93, which chapters are hereby incorporated by reference as part of the original disclosure.
The quantity of the respective salts according to the invention to be administered to the patient may vary and will depend, for example, on the weight or age of the patient and also on the manner of administration, on the indication and on the degree of severity of the illness. Ordinarily, 0.005 mg/kg to 5000 mg/kg, preferentially 0.05 mg/kg to 500 mg/kg, of body weight of the patient of at least one such compound are applied.

HCI polymorphs of 3-((2-(dimethylamino)methyl(cyclohex-1-yl)) phenol


A system and method for using service impact analysis (SIA) to provide a telecommunications network carrier with improved real-time information on network failures. The system monitors a network for faults by collecting fault data. The system assess the fault data to determine the actual service impact at a particular instant in time and the likely cause of the fault. The system also predicts future service impact based on collected historical data of the telecommunications network. The system thus associates equipment failures with actual and potential call traffic impact to provide both customer and network support operations with additional perspective on the service impact of a network equipment failure. This customer oriented view, rather that the traditional network oriented view, is significant in providing imported telecommunications service availability with limited human resources.

1. Field of the Invention
The present invention relates generally to wireless cellular network systems. More particularly, the present invention relates to assessing network service impact from a customer perspective rather than the traditional network perspective and indicating results of the assessment as part of an alarm notification.
2. Related Art
Traditionally, telecommunications network operators use extensive network management systems to collect, process, and display equipment alarm data for network management engineers. Equipment alarm data normally indicates an equipment malfunction. An equipment malfunction is also referred to as a fault. For example, network equipment may be designed to indicate when a card, circuit, or chassis has failed. Even in relatively simple networks, equipment alarms can generate a large quantity of complex, often interrelated, data. The data must be processed to prevent significant customer service discontinuities.
To help organize the volume and complexity of the incoming network fault data, network operators use sophisticated analysis engines or knowledge-based systems to convert the raw alarm data into usable, real-time information. In spite of this processing, however, network management users must have significant experience and insight into the network to understand the significance of alarm data and identify the criticality of a failure. Thus, what is required is a system to simplify the task of assessing the incoming network fault data.

Method and system of service impact analysis in a communications network


The system and method speeds up the image composition process based upon the blurring function and the blurring function determination process; facilitates the confirmation and correction of the blurring function determination results; determines the relative position of image data and to enable the position match for the difficult image data that is corrected for the zoom ratio; and facilitates the confirmation and the correction of the image data relative positioning results.

A number of techniques has been proposed to generate a universally focused pan focus image data based upon a plurality of images data by capturing a common scenery at a different focal point. These techniques are generally grouped into "interactive reconstruction methods" and "select and merge methods." As an example of the select and merge method, Japanese Patent Laid Publication Hei 3-80676 discloses a process where each of a plurality of the input images is divided into blocks and the corresponding blocks are compared for an amount of high frequency portion. Based upon the comparison, the brightness is determined, and an image block containing more of the high frequency portion is selected and merged into a universally focused image. Another example of the select and merge method is Japanese Patent Laid Publication Hei 8-307756, which discloses a technique where a bright portion is selected based upon a change in intensity from a first image that is focused upon an object with a short focal length. The selected bright portion is merged into a corresponding portion of a second image that is focused on another object with a long focal length. In the alternative, an image portion is selected from the first image based upon brightness, and the selected bright portion is merged into the second image at a corresponding position. The selected portion is merged by taking an average of intensity or a change rate in intensity of the corresponding first and second image portions.
Yet another example of the select and merge method in prior art is disclosed in a publication entitled, "Enhanced Image Acquisition by Using Multiple Differently Focused Images" by Naito et al. Electronics and Information Communication Academy D-II Vol. 579-D-II, No. 6, pp 1046–1053 (1996). Each pixel in a first image is compared to a corresponding one in a second image, and the focus of the pixel in the first image is adjusted by applying a predetermined function until it substantially matches with that of the second image. If there is a substantial match, it is assumed that the adjusted pixel of the first image was originally in focus before the adjustment. This process is repeated to determine an in-focus area. The original pixel intensity value is used when the pixel is merged into the universally focused image.
Examples of the interactive reconstruction method includes the publication entitled, "Acquisition of an All-Focused Image by the Use of Multiple Differently Focused Images" by Kodama et al. Electronics and Information Communication, D-II, Vol 80-D-II, No. 9, pp 2298–2307, (1977). The prior art reference discloses a derivation for an equation for generating a universally focused image having multiple focal points at various depths in a scene. The equation is iteratively applied to generate the universally focused image. Similarly, another example. "Arbitrarily focused image from Multiple Images," Kodama et al., Image Media Symposium, IMS 96, 1-8.18 discloses a technique for generating an image having arbitrarily determined blurness for each depth.
To further illustrate the above iterative reconstruction method by Kodama et al., the following equations are given. It is assumed that a near image and a far image are respectively expressed by f(x) and g(x) while captured images are expressed by I1(x) and I2(x). The whole image I(x) is expressed:
                              f                                (            x            )                          =                  {                                                                                I                                                                          (                          x                          )                                                                                (                                                                        d                                                                                (                            x                            )                                                                          =                                                  d                          1                                                                    )                                                                                0                                                                                (                                                                        d                                                                                (                            x                            )                                                                          =                                                  d                          2                                                                    )                                                                                g                                                  (                  x                  )                                                      =                          {                                                                                0                                                                                (                                                                        d                                                                                (                            x                            )                                                                          =                                                  d                          1                                                                    )                                                                                I                                                                          (                          x                          )                                                                                (                                                                        d                                                                                (                            x                            )                                                                          -                                                  d                          2                                                                    )                                                                                (        1        )            where the depth of the image is d(x)=d1 or d2I(x)=f(x)+g(x)  (2)then,I1(x)=f(x)+h2g(x)  (3)I2(x)=h1f(x)+g(x)  (4)where h1 and h2 are blur functions. According to this model, equations (2) and (4) lead toG(x)=HI(x)  (5)andG(x)=(h1−1)I1(x)+(h2−1)I2(x)  (6)thus, the following equation is obtained.H=h1h2−1  (7)For each input image; if the blur functions h1 and h2 are known, using the initially reconstructed image I0=I1 or I2.In+1=(H+1)In−G  (8)By iteration, the universally focused image is obtained.
Similarly, an arbitrarily focused image Iab is expressed as follows when blur functions ha and hb are respectively used for a near image f(x) and a far image g(x).Iab(x)=haf(x)+hbg(x)  (9)Instead of Equation (8),Gab=(hbh1−ha)Ii(x)+(hah2−hb)I2(x)  (10)is consideredIn+1=(H+1)In−Gab  (11)for the iterative process for generating the universally focused image. Furthermore, the Kodama et al. reference discloses two ways to determine the blurring function. The first one uses predetermined image capturing conditions including the focal point and at each distance, the blur function is measured for an object. The second way is that the blur function is estimated by adjusting the blurness of each pixel as described in the Naito et al. reference.
The above described two groups of prior art techniques are susceptible to errors in generating a universally focused image. In general, the conventional select and merge methods are subject to selection errors, which cause an inferior merged image. The errors are particularly likely near edges where the intensity changes are larger in an out-of-focus image portion than an in-focus image portion.
For the prior-art iterative reconstruction methods, in general, substantially no selection errors are involved. The iterative reconstruction methods do not need information on the location of blurness, and it is possible to generate not only a universally focused image but also an arbitrarily focused image. On the other hand, it is not clear how many iterations are necessary to converge although the Kodama reference discloses only about three iterations. For a large number of iterations, an amount of calculation increases, and it takes a substantial amount of time. In addition, the two proposed techniques for determining the blurring functions also have the following problems. For the first measurement technique, it is necessary to measure the characteristics of the camera as well as other information on each input image such as the focal point length and exposure which affect the blurring function. For these reasons, images taken by an auto focus camera are not usually appropriate for the measurement technique since the auto focus camera generally does not provide information such as the focal point length. The other technique to determine the blurring function based upon the estimation from the image generally requires a large amount of calculation, and it takes a large amount of time. Furthermore, it is difficult for the user to adjust the blurring function.
In addition to the above-described undesirable problems, the prior-art methods also have the following difficulties. Since the zoom ratios usually change as the focal point length is changed, it is necessary to correct at least the zoom ratio of each image before the portions of the images are merged into one composite image. For example, after an auto focus camera is positioned and captures a first image in which a predetermined object is centered, to prepare for capturing a second image, the camera is turned away from the predetermined object and the background scene is focused with the release button for example. Then, with the above described focus, the camera is turned back towards the predetermined object, and the second image is captured. The second image is centered around the predetermined object. These two images have not only different zoom ratios but also slightly different orientations and positions. The ratio correction alone does not allow the precise positioning of image portions. Images taken by a regular camera without a beam splitter and two CCD's require a high degree of flexible re-positioning technique which includes parallel and rotational movements.
In order to solve the above-described problems, it is desired to quickly generate a high-quality pan focus composite image data from a plurality of common images captured by a generally available auto focus and auto exposure camera. To accomplish the above objectives, it is desired 1) to speed up the image composition process based upon the use of a blurring function, 2) to speed up the blurring function determination process, 3) to facilitate the confirmation and correction of the results by the blurring function, 4) to speculate the relative position of image data and to enable the position match for the difficult image data that is corrected for the zoom ratio, and 5) to facilitate the confirmation and the correction of the image data and the relative positioning results.

This patent is subject to a terminal disclaimer.

Method and system for composing universally focused image from multiple images


The present invention relates to a nitride semiconductor device and a method for fabricating the same. According to the present invention, there is an advantage in that trenches isolating respective nitride semiconductor unit devices from one another are filled with crack-inhibiting walls to remove voids, thereby minimizing cracks or damage that may occur in the nitride semiconductor unit devices during a laser lift-off process.

1. Field of the Invention
The present invention relates to a nitride semiconductor device and a method for fabricating the same, and more particularly, to a nitride semiconductor device and a method for fabricating the same, wherein a crack or damage that may occur in a nitride semiconductor unit device during a laser lift-off process can be minimized.
2. Description of the Related Art
Generally, a sapphire substrate is mainly employed as a substrate for nitride semiconductor growth. However, there are many difficulties in fabricating devices using nitrides due to the inherent conductivity of sapphire. Further, since the thermal conductivity of the sapphire is greatly inferior to other materials, it causes significant problems in driving the devices.
To solve these problems, a laser lift-off (LLO) method has been used conventionally.
The LLO method also has a disadvantage in that an entire sapphire substrate cannot be removed at a time due to limitations on the size and uniformity of a laser beam. Thus, a uniform but small sized laser beam is radiated on the sapphire substrate in a scanning manner to sequentially remove the substrate little by little.
However, non-uniformity is produced at an area of a separated device on which the laser beam has been radiated overlappingly. Thus, a crack produced due to this non-uniformity propagates into other areas of the device.
To prevent such a phenomenon, there has been used a method in which a part of a nitride layer is etched to separate each device that in turn is bonded to a Si substrate, a GaAs substrate, a metallic plate or the like, and a sapphire substrate is then removed therefrom.
However, air remaining in voids, which have been formed in trenches between the respective devices after the bonding process, expands due to intense laser energy and then creates cracks in the devices.

Nitride semiconductor device and method for fabricating the same that minimizes cracking

Abstract: In addition, there is an advantage in that the devices are bonded through a bonding-reinforcing plate or the crack-inhibiting walls to a carrier substrate with a bonding member coated thereon, thereby maintaining a strong bonding force to the carrier substrate.


A protective helmet comprising an outer helmet shell of rigid material and having a fastener mounted into the outer helmet shell. The fastener comprises a rivet and a washer. More particularly, the rivet includes a flanged head portion at a first end of the rivet, a post part at a second end of the rivet, and a section having an obround cross-sectional shape intermediate the flanged head portion and the post part. The post part can be flattened against the washer to form a compound flanged structure abutting against the helmet shell. The fastener further comprises an elongated aperture extending longitudinally from the post part to the flanged head portion. The aperture is threaded to accept a screw-type securing means that can be used to retain accessories such as a face shield onto the protective helmet. The obround section of the fastener locks with the helmet shell so as to prevent the fastener from turning when the screw-type securing means is engaged therein.

The use of protective helmets in various types of sports or hazardous activities is well known. Protective helmets generally include a number of different accessories such as earpieces, or visor shields or the like, many of which are fastened onto the protective helmet. Common fastening means include screws which threadedly engage nuts. Both the screw and the nut have flanged end portions that abut, respectively, the accessory and the inner surface of the helmet shell.
One of the problems associated with the use of such fastening means arises when tightening or loosening the latter to adjust the accessory. Two hand tools are required to engage each of the screw and nut, respectively, so as to prevent the nut from rotating when the screw is being turned. This is not practical because two hand tools are not always available.
Another disadvantage that relates to helmets which incorporate such fastening means resides in the large number of fastener pieces that must be collected and stored upon removal of an accessory from the protective helmet. The accessory may require a plurality of screws and locking nuts that if lost may result in a situation where the user can no longer attach the accessory.
Thus, there is a need in the industry to provide a protective helmet that comprises an improved fastener mounted to the helmet and capable of receiving a screw-type securing means for retaining accessories to the protective helmet .


The invention concerns image-recording apparatus, which records an image onto a sheet-film. The image-recording apparatus includes a mainframe; a main/sub-scanning unit that includes a main-scanning unit to expose a light-beam onto a sheet-film by scanning the light-beam in a main-scanning direction and a sub-scanning unit to convey the sheet-film in a sub-scanning direction; and a supporting member to mount and support the main/sub-scanning unit onto the mainframe at a supporting position. The height of the supporting position is substantially the same as that of a center of gravity of the main/sub-scanning unit. The sub-scanning unit is detachably integrated with the main-scanning unit to form the main/sub-scanning unit.

The present invention relates to an apparatus, which irradiates a light-beam onto a sheet-film.
There has been well-known such a system that records an image onto a sheet-film, comprising a photosensitive material, such as a heat-processable photosensitive material, etc., by scanning a laser beam on the sheet-film under a drive controlling operation based on image data, radiographed by a medical image radiographing apparatus such as the X-ray CT or the MRI, etc., and transmitted to an image-recording apparatus, such as the Laser-Imager, etc.
Further, there has been developed and introduced into medical facilities such an image-recording apparatus that comprises both an image recording section to irradiate a laser beam onto the sheet-film and a processing section to develop the sheet-film.
In the abovementioned image-recording apparatus, a quality of the recorded image considerably depends on a scanning accuracy of a main-scanning unit for scanning the laser beam and a conveyance accuracy of a sub-scanning unit for conveying the sheet-film. Specifically, among the optical-parts comprising the main-scanning unit, a polygon mirror rotating at a high-velocity is sensitive to external vibrations, and is liable to induce unevenness of its rotating velocity. As a result, such the unevenness of rotating velocity of the polygon mirror causes unevenness of the recorded image.
For the purpose of solving the troubles stated above, there is proposed TOKKAISHO No. 61-230465 that discloses an image-recording apparatus having a construction in which an optical system (main-scanning unit) and a conveyance system (sub-scanning unit) are supported by the same supporting plate.
However, when there is employed the construction to support the optical system and the conveyance system with the same supporting plate, mass of the overall unit is increased, a height of the center of gravity of the overall unit is increased, and a position of the center of gravity of the overall unit on which the units are mounted is much higher than a height of a supporting position at which a supporting member supports the overall unit, and thereby, external vibrations cause the unit to make a pendulum-like turn, resulting in a concern of occurrence of the problems such as writing unevenness, etc.
For the problems mentioned above, there is proposed a construction to solve the problems by combining a plurality of vibration isolating members and regulating members in TOKKAIHEI No. 2-271136. However, this construction has not enough to be a satisfactory measure for the problems that external vibrations cause a main/sub-scanning unit to make a pendulum-like turn because a height of the center of gravity of the unit is increased and much higher than a height of supporting position at which a supporting member supports the unit, and has another problem that a space for providing plural supporting members is needed and low frequency vibrations are caused by a large-sized unit.
To suppress low frequency vibrations, there have been made attempts for lightening by dividing a sub-scanning unit and for lightening by thinning a wall thickness of a part and by changing to the resin materials, which are suggested in TOKKAISHO No. 58-17767. However, use of parts lightened excessively sometimes leads to a cost increase, and dispersion of accuracy created by a difference in thermal expansion caused by use of combined different materials is a problem, which cannot be ignored for forming minute images.
In the past, the vibration isolating member has been provided under the optical unit of a writing system, which has caused a height of the center of gravity of the optical unit to be much higher than a height of the vibration isolating member in many cases, and thereby, the optical unit has been caused by vibrations to tend to reciprocate linearly in the vertical, from-side-to-side and diagonal directions, and to make a pendulum-like turn. This pendulum-like turn has a tendency to be generated generally under the low frequency, and its decay time is longer than that of the vibration caused by the linear reciprocating motion.
In particular, in the case of the construction to have a film conveyance mechanism on the lower side of the optical unit, and in the case of the construction to have a film conveyance mechanism on the upper side of the optical unit, the height of the center of gravity of the optical unit grows greater, and the pendulum-like turn grows greater accordingly. To achieve stability of the unit under such construction, it is necessary to broaden intervals for attaching vibration isolating members, which leads to the large-sized apparatus.
Further, the scanning section that is made of various materials and employs a laser beam has resulted in unstable mass balance in many cases, because of the restriction in arrangement of functional parts derived from insurance of an optical path and of unbalance in materials and specific gravity.
Though there is proposed, in TOKKAISHO No. 61-230465, the construction to achieve stability of a unit by arranging respectively an optical unit and a film conveyance mechanism on both upper and lower sides of the same supporting plate, by supporting the supporting plate with a leg member to have an angle, and by supporting the lower portion of the leg member with the vibration isolating member, it is impossible to avoid the pendulum-like turn caused by vibrations because a position of the center of gravity of the optical unit is high and is away from the vibration isolating member located at the lower portion for mounting on the main body. Further, it is difficult, because of the structure of the leg member, to make the optical unit and the film conveyance mechanism to be capable of being mounted and dismounted, thus, maintenance work is still difficult, and it is impossible to avoid that the unit is made to be large in size and its mass increases.
Further, when mass of the unit grows greater, low frequency vibrations of the unit are increased, and it is necessary to use an elastic member such as rubber with low hardness to suppress the low frequency vibrations. Nevertheless, there is generated a shake of the unit caused by the vibrations, which has resulted in a fear of the problem that the unit comes in contact with surrounding members of the conveyance system. Even in the case of transportation of the unit, there have been problems including damages of precision optical parts caused by the excessive shake of the unit and damages caused by the contact between the unit and surrounding members of the conveyance system.

Scanning unit of image-recording apparatus


An apparatus and method are provided for continuously and automatically protecting an electrical device (22) from a potential threat of damaging voltage. levels. The apparatus includes a detector (24) for the threat and a protection switching circuit (30) for grounding the electrical device and the detector upon detection. Grounding occurs for a predetermined time interval, after which the detector is again automatically re-activated. Embodiments of detectors include detectors which detect the degree of electrical changes in a surrounding field and detectors comprising a tuned radio receiver. One embodiment includes a device utilization monitor (222) and a detector disable circuit (224) for disabling the detector, and thereby precluding grounding, while a device such as a radio frequency transmitter is being utilized.

1. Field of Invention
This invention pertains to the protection of electrically operated devices from damaging voltage levels, particularly high voltage levels attending atmospheric disturbances such as lightning.
2. Prior Art and Other Considerations
Prudent practice suggests that electrical and electronic devices should be protected from high voltage levels lest the devices sustain inordinate if not irreparable damage. Electrical disturbances in the atmosphere have long posed perilous problems to electrical devices, and are nowadays particularly troublesome for communications and computer devices.
The conventional approach for protecting electrical devices from damaging voltage levels involves utilization of passive portection devices. These passive devices cause disconnection of the protected devices after high voltage levels or spikes are actually detected, i.e., after a storm has already reached a magnitude that can damage or destroy electrical devices. Numerous passive detectors have been employed, including metal oxide varistors, thyrectors, gas discharge tubes, and ground rods. Lacking in the prior art is a protection system that protects electrical equipment before a storm reaches a perilous magnitude.
The passive protection devices described above disconnect the protected device and keep the protected device disconnected until a human intervenes to re-connect the protected device. Sustained disconnection in his manner occasions unnecessary down time for devices which otherwise might profitably be communicating with the outside world after the threat of damaging voltage levels has subsided.
Passive protection devices cannot ascertain when, despite the threat of damaging voltage levels, the continued use of the protected device should nevertheless be accommodated. Such discretion would be particularly advantageous, for example, in the field of radio communications wherein an opportunity should be provided to continue transmissions in progress at the time of detection of the potential threat of high voltage levels.
Accordingly, it is an object of the present invention to provide method and apparatus for protecting an electrical device from a potential threat of damaging voltage levels.
An advantage of the present invention is the provision of method and apparatus which selectively disconnects and re-connects a protected a device in accordance with a sensed potential of damaging voltage levels.
A further advantage of the present invention is the provision of method and apparatus which protects an electrical device from a potential of damaging voltage levels but which also accommodates continued utilization of the device under desirable conditions.

Incipient lightning detection and device protection


Optical network devices, optical receivers, Automatic Gain Control (AGC) circuits, and power detection systems are provided for detecting power of optical signals within an optical communication system. An optical network device, according to one implementation, includes a receiver configured to receive an optical signal. The optical network device also includes a low bandwidth path configured to detect a low-band power component of the optical signal within a channel of interest and a broad bandwidth path arranged in parallel with the low bandwidth path. The broad bandwidth path is configured to detect a broad-band power component of the optical signal within broad-band channels including at least the channel of interest. A power detection output is derived from the low-band power component and the broad-band power component.

Conventional optical receivers typically include only one digital power detector after an Analog-to-Digital Converter (ADC). The digital power detector may include a power monitor bandwidth up to approximately the Nyquist frequency. Typically, there are ways to re-center an Automatic Gain Control (AGC) loop via performance parameters discovered in a Digital Signal Processor (DSP). However, this process is slow, and it cannot compensate and re-adjust AGC targets during input signal transients. Some commercial DSPs have a very rudimentary power detector and are not particularly accurate or precise. A problem exists in that these concepts are traditionally the only options in the field of optical receivers.
FIG. 1 is a schematic diagram of a conventional AGC loop 10 used for power detection in an optical system. A receiver 12 is configured to receive optical signals. An ADC 14 converts the analog optical signals to digital samples. A squaring device 16 and Broad-Band (BB) accumulator 18 are configured to detect the power of the received optical signal. This power reported may be applied to an AGC loop that includes a multiplier 20, summer 22, and integrator 24. The AGC loop includes a feedback signal to the receiver 12. Thus, the AGC loop is configured to set the Rx gain properly to fill the ADC input.
FIGS. 2A-2C are graphs showing sampled power versus frequency for a channel of interest and a channel adjacent to the channel of interest. The adjacent channel has a band of frequencies greater than the channel of interest. The receiver 12 may have a bandwidth (BWElectrical). The ADC 14 may have a Nyquist frequency
  (            f              A                D                C              2    )and is closely matched to the input target signal bandwidth
      (                  f                  B                    a                    u                    d                    2        )    .Even when an adjacent channel is present, the adjacent channel's signal is largely not detected by the receiver 12 of the power detector.
FIGS. 3A-3C are graphs showing sampled power versus frequency of the channel of interest and the adjacent channel. When the receiver bandwidth
  (      B              W      Electrical        )and ADC Nyquist frequency
  (            f              A                D                C              2    )are greater man me input target signal bandwidth
      (                  f                  B                    a                    u                    d                    2        )    ,a single power detector will observe both the target signal power and a portion of the adjacent channel power. In this case, the power detector reports different power depending on the presence and the power spectrum level of the adjacent channel;
      P          P            w            r            D            e            t        =                    ∫        0                              f                          A                            D                            C                                2                                                        S                          P                            r                            o                            b                            e                                                      (            f            )                                  df              +                  ∫        0                              f                          A                            D                            C                                2                                                        S                          A                            d                            j                            a                            c                            e                            n                            t                                                      (            f            )                                  d                          f          .
Another shortcoming of the conventional systems is that a single power detector cannot discriminate between the signal power of a channel of interest and an adjacent channel. Therefore, with the receiver (Rx) AGC loop locking onto a fixed target, the signal power at the ADC input can vary depending on the adjacent channel power appearing at the ADC input. Therefore, there is a need in the field of optical receivers, AGC circuits, and power detection systems to overcome the deficiencies of the conventional systems.

Detecting power of low-bandwidth and broad-bandwidth optical signals