WO2003042161A1

WO2003042161A1 - Venlafaxine hydrochloride polymorphs

Info

Publication number: WO2003042161A1
Application number: PCT/HU2002/000121
Authority: WO
Inventors: József Barkóczy; Péter KÓTAY NAGY; Gyula Simig; Károly HORVÁTH; Zsuzsa SZENT KIRÁLLYI; Béla FARKAS; Tamás GREGOR; Kálmán NAGY; György Krasznai
Original assignee: Egyt Gyogyszervegyeszeti Gyar; Egis Pharmaceuticals PLC
Current assignee: Egyt Gyogyszervegyeszeti Gyar; Egis Pharmaceuticals PLC
Priority date: 2001-11-13
Filing date: 2002-11-13
Publication date: 2003-05-22
Anticipated expiration: 2004-05-13
Also published as: HUP0104872A2; HU0104872D0; HUP0104872A3

Abstract

The invention relates to new crystalline forms I, II and III (±)-1-[2-dimethylamino-1-(4-methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride of the Formula (I) and hydrates thereof. The new polymorphs are of uniform morphology and can be used in therapy as antidepressant.

Description

VENLAFAXINE HYDROCHLORIDE POLYMORPHS

Technical field of the invention

The invention relates to new polymorphs of venlafaxine hydrochloride, a process for the preparation thereof, pharmaceutical compositions containing the new polymorphs and use thereof for the treatment of depression.

More particularly the invention is concerned with new crystalline forms I, II and III of venlafaxine hydrochloride, a process for the preparation thereof, pharmaceutical compositions containing the new polymorphs and use thereof for the treatment of depression.

Background of the invention

It is known that (±)-l-[2-dimethylamino-l-(4-methoxy-phenyl)- ethyl]-cyclohexanol-hydrochloride having the INN (International Non-Proprietory Name) venlafaxine hydrochloride is an antidepressant acting by a serotonine or noradrenaline reuptake inhibitor mechanism.

Venlafaxine was first described in EP 112,669 which corresponds to HU 199,204. According to this patent specification venlafaxine base is prepared by chromatography and the base is converted into the hydrochloride salt by reacting with an isopropanol solution of hydrogen chloride. No reference is made to any crystalline form ofthe product.

According to Journal of Medicinal Chemistry Vol. 33-, No. 10. 2899-2905 (1990) venlafaxine base is dissolved in ethyl acetate and a solution of hydrogen chloride in 2-propanol is added to the solution. There is no teaching relating to the polymorphy of the product obtained.

Also according to GB 2,227,743 venlafaxine hydrochloride is prepared by reacting the base with a solution of hydrogen chloride in 2-propanol. The patent specification is silent in teaching further details ofthe process or the crystalline form of the product.

According to EP 797,991 venlafaxine hydrochloride is a polymorph substance. Two polymorphs are mentioned, one of them being regarded as a kinetical product of the crystallization process. It is also disclosed that on heating in the crystallization solvent one of the polymers is transformed into the other polymorph. It is not disclosed, however, which solvent is used for recrystallization. According to a further disclosure the polymorphs differ from each other in their IR spectrum and X- ray power diffraction pattern. However neither the IR spectra nor the X-ray powder-diffraction patterns are given. The text is completely silent in teaching the conditions used in the preparation ofthe polymorphs (solvent etc).

According to Acta Cryst. C56, 1009-1010, (2000) racemic venlafaxine hydrochloride exists in the form of two polymorphs and the single crystal X-ray diffraction pattern of one of the polymorphs could be prepared. However no details of the preparation ofthe single crystal are disclosed and there is no disclosure ofthe X-ray powder-diffraction patterns either.

Thus (±)- 1 -[2-dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]- cyclohexanol-hydrochloride polymorphs of uniform morphology, characterized by infrared spectrum and X-ray powder-diffraction pattern have not been disclosed in prior art. A reproducible process for the preparation thereof has not been described either.

In pharmaceutical industry there is a strong need for (±)-l-[2- dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]-cyclohexanol- hydrochloride of uniform morphology meeting the requirements of pharmaceutical compositions. It is known that important properties of various polymorphs (e.g. dissolution velocity, bioavailability, chemical stability) are considerably different. Technological aspects also require morphologically uniform products which can be prepared in a reproducible manner because polymorphs show considerably different and changing properties during working-up (e.g. filtrability, drying properties, solubility, tabletting etc).

It is the object ofthe present invention to provide new venlafaxine polymorphs which are morphologically uniform and can be prepared in a reproducible manner on industrial scale too.

The above object is solved by the new (±)-l-[2-dimethylamino- l-(4-methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride polymorphs of the present invention.

Summary of the invention

According to the present invention there are provided crystalline form I (±)-l-[2-dimethylamino-l-(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride ofthe Formula

and hydrates thereof characterized by the X-ray powder diffraction pattern expressed in Table 1 and Figure 1 :

Table 1

Position of diffraction lines and relative intensities

(>15 % of polymorph I)

According to a further aspect ofthe present invention there are provided crystalline form II (±)-l-[2-dimethylamino-l-(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride of the Formula I and hydrates thereof characterized by the X-ray diffraction pattern expressed in Table 2 and Figure 2:

Table 2

Position of diffraction lines and relative intensities (>15 % of polymorph II)

According to a still further aspect ofthe present invention there are provided crystalline form III (±)-l-[2-dimethylamino-l-(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride of the Formula I and hydrates thereof characterized by the X-ray powder diffraction pattern expressed in Table 3 and Figure 3 :

Table 3

Position of diffraction lines and relative intensities

(>10 % of polymorph III)

Detailed description of the invention

The powder diffraction pattern ofthe new crystalline polymorphs ofthe present invention is determined under the following conditions:

Equipment: PHILIPS - XPERT PW 3710 powder diffractometer

Radiation: CuKα (λ: 1.54190A)

Monochromator: graphite

Exciting voltage: 40 kV Anode current: 30 Ma

Standard reference substance: SRM 675

Mica Powder (synthetic fluorographite), Ser. No.: 981307.

The measurement is continuous: Θ/2Θ scan: 4.5° - 40.00° 2Θ

Step size: 0.02°

Sample: surface plain, width 0.5 mm, in quartz sample holder, measured and stored at room temperature.

Crystalline form I (±)-l-[2-dimethylamino-l-(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride ofthe Formula I and hydrates thereof are prepared by recrystallizing or suspending amorphous or crystalline form II or III (±)-l-[2-dimethylamino- l-(4-methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof from a mixture of a lower alkanol and water, or a mixture of a water-miscible dipolar aprotic organic solvent and water.

As lower alkanol preferably methanol, ethanol, n-propanol, 2- propanol, n-butanol or tert. butanol, particularly ethanol or 2- propanol can be used. As dipolar aprotic solvent preferably acetonitrile or acetone can be used. The mixture of lower alkanol and water or the mixture ofthe dipolar aprotic solvent and water can contain 0.01-5 by weight % of water. Recrystallization can be preferably carried out by dissolving amorphous or crystalline form II or III (±)-l-[2-dimethylamino- l-(4-methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof in the solvent under heating, and thereafter cooling the solution under stirring, preferably to 0-5 °C. It is preferred to heat the solution to 60-65 °C. The suspending procedure can be accomplished by suspending amorphous or crystalline form II or III (±)-l-[2-dimethylamino-l-(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof in the solvent at about room temperature, stirring the suspension and thereafter filtering or centrifuging the product. The suspension is preferably stirred for 2-120 hours.

Crystalline form II (±)-l-[2-dimethylamino-l-(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride ofthe Formula I and hydrates thereof are prepared by recrystallizing crystalline form I or III (±)-l-[2-dimethylamino-l-(4-methoxy-phenyl)-ethyl]- cyclohexanol-hydrochloride or a hydrate thereof from an anhydrous lower alkanol or an anhydrous mixture of a dipolar aprotic solvent and a lower alkanol.

As lower alkanol preferably methanol, ethanol, n-propanol, 2- propanol, n-butanol or tert. butanol, particularly 2-propanol can be used. As a mixture of a dipolar aprotic solvent and a lower alkanol preferably a mixture of ethyl acetate and methanol or ethyl acetate and 2-propanol can be used. One may proceed particularly preferably by using a 4:1 vol. mixture of ethyl acetate and methanol.

Recrystallization can be carried out by dissolving crystalline form I or III (±)-l-[2-dimethylamino-l-(4-methoxy-phenyl)- ethyl]-cyclohexanol-hydrochloride or a hydrate thereof in the solvent under heating, cooling the solution and isolating the crystalline form II polymorph. One may proceed preferably by heating the solution to the boiling point of the solvent, thereafter cooling to 0-5°C and isolating the precipitated crystalline form II (±)-l-[2-dimethylamino-l-(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride.

Crystalline form III (±)-l-[2-dimethylamino-l-(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride ofthe Formula I and hydrates thereof are prepared by recrystallizing or suspending crystalline form I or II (±)-l-[2-dimethylamino-l-(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof from a mixture of a dipolar aprotic organic solvent and water.

As aprotic solvent preferably a halogenated aliphatic hydrocarbon (e.g. dichloro ethane, dichloro methane or chloroform) or an ester (e.g. ethyl acetate) can be used. One may proceed preferably by using dichloro methane, dichloro ethane or ethyl acetate as aprotic solvent. The mixture ofthe aprotic solvent and water can contain preferably 2-5 by weight % of water.

The process can be preferably carried out by dissolving or suspending crystalline form I or II (±)-l-[2-dimethylamino-l- (4-methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof in the solvent at 20-40°C, stirring and thereafter isolating the crystalline form III (±)-l-[2-dimethylamino-l-(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride polymorph. Stirring can be continued for a longer period of time, preferably for 20-240 hours. The precipitated crystalline form III polymorph is isolated, preferably by filtration or centrifuging.

According to a further aspect of the invention there is provided a pharmaceutical composition comprising as active ingredient crystalline form I, II or III (±)-l-[2-dimethylamino-l-(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof in admixture with inert solid or liquid pharmaceutical carriers and/or auxiliary agents.

The pharmaceutical composition according to the present invention can be administered preferably orally or parenterally. Oral pharmaceutical compositions may be e.g. tablets, capsules, dragees, solutions, elixirs, suspensions or emulsions. For parenteral administration preferably intravenous or intramuscular injections can be used.

The pharmaceutical composition according to the present invention can contain conventional pharmaceutically acceptable carriers and/or auxiliary agents. As carrier e.g. magnesium carbonate, magnesium stearate, talc, lactose, pectine, dextrine, starch gelatine, tragacanth, methyl cellulose, sodium carboxy methyl cellulose, lower melting wax, cocoa butter etc. can be used. Soft gelatine capsules can also be prepared without a carrier whereby the capsule material plays the role ofthe carrier. Oral pharmaceutical compositions can be preferably prepared in the form of tablets, powders, capsules, cachets, pills, losenges.

The suppositories preferably contain as carrier a lower melting wax (e.g. a mixture of fatty acid triglycerides or cocoa butter). Suppositories are prepared preferably by melting the wax and uniformly distributing the active ingredient in the melt. The homogenous melt mixture is poured into a form of suitable size and allowed to solidify under cooling. Tablets can be prepared by admixing the active ingredient with suitable carriers and auxiliary agents and pressing the mixture into tablets ofthe desired weight and size.

Powders can be prepared by admixing the finally powdered active ingredient with the finely powdered carriers.

The liquid compositions can be solutions, suspensions or emulsions. The active ingredient can also be released from the composition in a controlled or sustained manner.

It is preferred to prepare aqueous or aqueous propylene glycol solutions. Liquid compositions for parenteral administration can be preferably prepared in the form of aqueous polyethylene glycol solutions.

Orally administrable liquid solutions can be prepared by dissolving the active ingredient in water in the presence of further additives e.g. stabilizers, emulsifiers, wetting agents, colourants, thickening agents etc.

Liquid compositions for oral administration can be prepared by suspending the active ingredient in water in the presence of viscous additives (e.g. natural or synthetic gums, resins, methyl cellulose, sodium carboxy methyl cellulose or other known suspending agents).

An other group ofthe solid pharmaceutical compositions ofthe present invention is converted into a liquid composition immediately before administration. The liquid compositions can be solutions, suspensions or emulsions which contain in addition to the active ingredient further additives, e.g. colourants, flavourants, stabilizers, buffers, synthetic or natural sweeteners, dispersing agents, thickening agents etc.

The pharmaceutical compositions according to the present invention can be preferably prepared in dosage unit form. Such dosage units contain the desired amount of the active ingredient. The dosage units can be put on the market in packaged form which contain discrete amounts ofthe composition (e.g. packaged tablets, capsules, vials or ampoules which contain a powder). The term "dosage unit" relates to the tablets, capsules, losenges per se and also to the packaged form which contains the desired number of dosage units.

According to a further aspect ofthe present invention there is provided a process for the preparation of the pharmaceutical composition described above which comprises admixing crystalline form I, II or III (±)-l-[2-dimethylamino-l-(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof with inert solid or liquid pharmaceutical carriers and/or auxiliary agents and bringing the mixture to galenic form.

The pharmaceutical compositions can be prepared by methods of pharmaceutical industry known per se.

The pharmaceutical compositions ofthe present invention can contain in addition to crystalline form I, II or III (±)-l-[2- dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]-cyclohexanol- hydrochloride or a hydrate thereof further compatible pharmaceutical active ingredients.

The daily dose of crystalline form I, II or III (±)-l-[2- dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]-cyclohexanol- hydrochloride or a hydrate thereof depends on various factors (e.g. the age, condition and body weight ofthe patient, the seriousness of the disease to be treated, the form of administration) and is determined by the physician.

According to a further aspect of the invention there is provided crystalline form I, II or III (±)-l-[2-dimethylamino-l-(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof, for use as pharmaceutical active ingredient. According to a further aspect ofthe invention there is provided the crystalline form I, II or III (±)-l-[2-dimethylamino-l-(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof, for use as antidepressant.

According to a still further aspect ofthe present invention there is provided use of crystalline form I, II or III (±)-l-[2- dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]-cyclohexanol- hydrochloride or a hydrate thereof for the treatment of depression.

According to a still further aspect ofthe present invention there is provided a method of treatment of depression which comprises administering to the patient in need of such treatment a therapeutically efficient amount of crystalline form I, II or III (±)- 1 -[2-dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]- cyclohexanol-hydrochloride or a hydrate thereof.

The advantage ofthe present invention is that the new (±)-l-[2- dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]-cyclohexanol- hydrochloride polymorphs are of a uniform morphology and therefore possess well reproducible properties in relation to dissolution velocity, bioavailability, chemical stability and working-up (filtrability, drying, tabletting). The new polymoφhs ofthe present invention can be manufactured in a reproducible manner on industrial scale too.

Further details of the present invention are to be found in the Examples without limiting the scope of protection to said Examples.

Example 1

Preparation of crystalline form I venlafaxine hydrochloride from venlafaxine hydrochloride containing mixed polymorphs I and II

Into a 500 ml glass duplicator equipped with an Anker type stirrer of variable speed of rotation 20 g of venlafaxine hydrochloride of mixed crystalline form and 400 ml of 2- propanol are weighed in. The mixture is heated to 60-62°C under stirring, and kept at this temperature for half an hour. The substance goes completely into solution. The solution is then heated to 32°C with a cooling rate of l°C/minute at 120 r.p.m. The solution is inoculated at this temperature with 1.0 g of crystals of crystalline form I venlafaxine hydrochloride. The crystalline suspension is cooled with the above cooling speed to 0-5°C and stirred at this temperature for half an hour. Stirring is stopped. The suspension is filtered, washed with 20 ml of cold (0-5°C) 2-propanol and dried at 35-40°C until constant weight. Thus 15 g of the crystalline form I polymoφh are obtained.

Example 2

Preparation of crystalline form I venlafaxine hydrochloride from venlafaxine hydrochloride containing crystalline form II polymorph

Into a 100 ml round-bottomed flask equipped with a reflux condenser and a thermometer 7 g of crystalline form II venlafaxine hydrochloride and 56 ml of 2-propanol are weighed in. Taking into consideration the water content of the solvent, the water content is adjusted to 0.01 % by weight. The stirring ofthe suspension is started at 20-25°C with a magnetic stirrer. The suspending procedure is continued at this temperature for 110 hours. Stirring is then stopped, the suspension filtered, washed with cold (0-5°C) 2-propanol and dried at 35-40°C until constant weight. Thus 5.6 g ofthe crystalline form I polymoφh are obtained.

Example 3

Into a 100 ml round-bottomed flask equipped with a reflux condenser and a thermometer 7 g of crystalline form II venlafaxine hydrochloride and 56 ml of 2-propanol are weighed in. Taking into consideration the water content ofthe solvent, the water content is adjusted to 0.42 % by weight. The stirring ofthe suspension is started at 20-25°C with a magnetic stirrer. The suspending procedure is continued at this temperature for 110 hours. Stirring is then stopped, the suspension filtered, washed with cold (0-5°C) 2-propanol and dried at 35-40°C until constant weight. Thus 4.6 g ofthe crystalline form I polymoφh are obtained. Example 4

Into a 100 ml round-bottomed flask equipped with a reflux condenser and a thermometer 7 g of crystalline form II venlafaxine hydrochloride and 56 ml of 2-propanol are weighed in. Taking into consideration the water content ofthe solvent, the water content is adjusted to 2.0 % by weight. The stirring of the suspension is started at 20-25°C with a magnetic stirrer. The suspending procedure is continued at this temperature for 110 hours. Stirring is then stopped, the suspension filtered, washed with cold (0-5°C) 2-propanol and dried at 35-40°C until constant weight. Thus 4.2 g ofthe crystalline form I polymoφh are obtained.

Example 5

Preparation of crystalline form II venlafaxine hydrochloride from venlafaxine hydrochloride containing crystalline form I polymorph

Into a 500 ml flask glass flask equipped with an Anker type stirrer of variable speed of rotation 45 g of crystalline form I venlafaxine hydrochloride and 450 ml of 2-propanol are weighed in. The mixture is heated to 80°C under stirring and kept at this temperature for half an hour; the substance goes completely into solution. The solution is cooled to 70°C with a cooling rate of 0.5°C/minutes at 200 r.p.m and thereafter to 20°C with a cooling rate of 5°C/minute. Cooling is continued with a smaller cooling rate (1.5°C/minute) until crystallization begins. The crystalline suspension is cooled to 2-4°C within a further half an hour. Cooling is then stopped, the suspension filtered, the product washed with 20 ml of cold (0-5°C) 2- propanol and dried at 35-40°C until constant weight. Thus 36 g of crystalline form II venlafaxine hydrochloride are obtained.

Example 6

Preparation of crystalline form I venlafaxine hydrochloride from venlafaxine hydrochloride containing crystalline form II

Into a 250 ml round-bottomed flask 10 g of crystalline form II venlafaxine hydrochloride and 100 ml of acetonitrile are weighed in. Taking into consideration the water content ofthe solvent, the water content is adjusted to 2.0 weight %. The stirring ofthe suspension is started at 20-25°C with a magnetic stirrer. The suspending procedure is continued at this temperature for 48 hours. Stirring is then stopped, the suspension filtered, the product washed with cold (0-5°C) acetonitrile and dried at 35-40°C until constant weight. Thus 5.3 g of crystalline form I polymoφh are obtained. Example 7

Into a 250 ml round-bottomed flask 10 g of crystalline form II venlafaxine hydrochloride and 100 ml of acetone are weighed in. Taking into consideration the water content ofthe solvent, the water content is adjusted to 2.0 weight %. The stirring ofthe suspension is started at 20-25°C with a magnetic stirrer. The suspending procedure is continued at this temperature for 72 hours. Stirring is then stopped, the suspension filtered, the product washed with cold (0-5°C) acetone and dried at 35-40°C until constant weight. Thus 8.7 g of crystalline form I polymoφh are obtained.

Example 8

Into a 250 ml round-bottomed flask 10 g of crystalline form II venlafaxine hydrochloride and 50 ml of ethanol are weighed in. Taking into consideration the water content of the solvent, the water content is adjusted to 0.12 weight %. The stirring ofthe suspension is started at 20-25°C with a magnetic stirrer. The suspending procedure is continued at this temperature for 100 hours. Stirring is then stopped, the suspension filtered, the product washed with cold (0-5°C) ethanol and dried at 35-40°C until constant weight. Thus 4.4 g of crystalline form I polymoφh are obtained.

Example 9

Preparation of crystalline form III venlafaxine hydrochloride from venlafaxine hydrochloride containing crystalline form II

Into a 250 ml round-bottomed flask 10 g of crystalline form II venlafaxine hydrochloride, 100 ml of dichloro ethane and 2.3 ml of water are weighed in. The solid substance is dissolved at 40°C under stirring, whereupon the cloudy solution is filtered over a perlite bed. The filtrate is stirred at 20-25°C for 26 hours. The precipitation of a fluffy crystalline product begins after some minutes. Stirring is stopped, the suspension filtered and dried at 35-40°C until constant weight. Thus 7.3 g of the crystalline form III polymoφh are obtained.

Example 10

Preparation of crystalline form MI venlafaxine hydrochloride from venlafaxine hydrochloride containing crystalline form II polymorph

Into a 250 ml round-bottomed flask 10 g of crystalline form II venlafaxine hydrochloride, 97 ml of ethyl acetate and 3.0 ml of water are weighed in. The stirring ofthe suspension is started with a magnetic stirrer at 20-25°C. The suspending procedure is carried out at this temperature for 224 hours. Stirring is stopped, the suspension filtered, the product washed with cold (0-5°C) ethyl acetate and dried at 35-40°C until constant weight. Thus 8.5 g of the crystalline form III polymoφh are obtained.

Example 11

Preparation of crystalline form II venlafaxine hydrochloride from venlafaxine hydrochloride containing crystalline form III polymorph

Into a 500 ml round bottomed flask equipped with a reflux condenser and a thermometer 10 g of crystalline form III venlafaxine hydrochloride and 200 ml of 2-propanol are weighed in. The mixture is refluxed for 30 minutes, cooled to 0-5°C and stirred at this temperature for an hour. Stirring is stopped, the suspension filtered, the product washed with cold (0-5°C) 2-propanol and dried at 35-40°C until constant weight. Thus 6.2 g of crystalline form II polymoφh are obtained. Example 12

Into a 250 ml round bottomed flask equipped with a reflux condenser and a thermometer 10 g of crystalline form III venlafaxine hydrochloride and 100 ml of a 4: 1 mixture of ethyl acetate and methanol are weighed in. The mixture is refluxed for 30 minutes, cooled to 0-5°C and stirred at this temperature for an hour. Stirring is stopped, the suspension filtered, the product washed with a cold (0-5°C) 4:1 mixture of ethyl acetate and methanol and dried at 35-40°C until constant weight. Thus 4.2 g of crystalline form II polymoφh are obtained.

Example 13

Into a 250 ml round bottomed flask equipped with a reflux condenser and a thermometer 10 g of crystalline form I venlafaxine hydrochloride and 100 ml of a 4:1 mixture of ethyl acetate and methanol are weighed in. The mixture is refluxed for 30 minutes, cooled to 0-5°C and stirred at this temperature for an hour. Stirring is stopped, the suspension filtered, the product washed with cold (0-5°C) 4:1 mixture of ethyl acetate and methanol and dried at 35-40°C until constant weight. Thus 6.0 g of crystalline form II polymoφh are obtained.

Example 14

Preparation of crystalline form I venlafaxine hydrochloride from venlafaxine hydrochloride containing crystalline form III polymorph

Into a 250 ml round bottomed flask 10 g of crystalline form III venlafaxine hydrochloride, 100 ml of acetonitrile and 1.6 ml of water are weighed in. The stirring ofthe suspension is started at 20-25°C with a magnetic stirrer. The suspending procedure is continued at this temperature for 24 hours. Stirring is stopped, thus suspension filtered, the product washed with cold (0-5°C) acetonitrile and dried at 35-40°C until constant weight. Thus 6.5 of crystalline form I polymoφh are obtained.

Example 15

Into a 100 ml round bottomed flask 10 g of crystalline form III venlafaxine hydrochloride, 50 ml of ethanol and 0,7 ml of water are weighed in. The stirring ofthe suspension is started at 20- 25°C with a magnetic stirrer. The suspending procedure is continued at this temperature for 24 hours. Stirring is stopped, thus suspension filtered, the product washed with cold (0-5°C) ethanol and dried at 35-40°C until constant weight. Thus 2.0 of crystalline form I polymorph are obtained.

Example 16

Preparation of crystalline form III venlafaxine hydrochloride from venlafaxine hydrochloride containing crystalline form I polymorph

Into a 250 ml round bottomed flask 10 g of crystalline form I venlafaxine hydrochloride, 97 ml of ethyl acetate and 3.0 ml of water are weighed in. The stirring ofthe suspension is started at 20-25°C with a magnetic stirrer. The suspending procedure is continued at this temperature for 26 hours. Stirring is stopped, thus suspension filtered, the product washed with cold (0-5°C) ethyl acetate and dried at 35-40°C until constant weight. Thus 9.1 of crystalline form III polymoφh are obtained.

Example 17

Into a 250 ml round bottomed flask 10 g of crystalline form I venlafaxine hydrochloride, 100 ml of dichloro ethane and 2.3 ml of water are weighed in. The solid substance is dissolved under stirring at 40°C, whereupon the solution is filtered over a perfile bed. The solution is stirred at.20-25°C for 26 hours. Stirring is stopped, the suspension is filtered and dried at 35-40°C until constant weight. Thus 6.2 g of crystalline form III polymorph are obtained.

Claims

What we claim is,

1. Crystalline form I (±)- 1 -[2-dimethylamino- 1 -(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride of the Formula

Table 1

Position of diffraction lines and relative intensities (>15 % of polymorph I)

2. Process for the preparation of crystalline form I (±)-l-[2- dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]-cyclohexanol- hydrochloride of the Formula I according to Claim 1 and hydrates thereof which comprises recrystallizing or suspending amoφhous or crystalline form II or III (±)-l-[2-dimethylamino- l-(4-methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof from a mixture of a lower alkanol and water, or a mixture of a water-miscible dipolar aprotic organic solvent and water.

3. Process according to Claim 2 which comprises using ethanol or 2-propanol as lower alkanol.

4. Process according to Claim 2 which comprises using acetonitrile or acetone as dipolar aprotic solvent.

5. Process according to any of Claims 2-4 which comprises using a mixture of a lower alkanol and water, or a dipolar aprotic solvent and water containing 0.01-5 by weight % of water.

6. Process according to any of Claims 2-5 which comprises carrying out recrystallization by dissolving amoφhous or crystalline form II or III (±)-l-[2-dimethylamino-l-(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof in the solvent under heating, cooling the solution and isolating the crystalline form I polymoφh.

7. Process according to any of Claims 2-5 which comprises suspending amoφhous or crystalline form II or III (±)-l-[2- dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]-cyclohexanol- hydrochloride or a hydrate thereof in the solvent at about room temperature and isolating the crystalline form I polymoφh from the suspension after stirring.

8. Process according to Claim 7 which comprises stirring the suspension for 2-120 hours.

9. Pharmaceutical composition comprising as active ingredient crystalline form I (±)-l-[2-dimethylamino-l-(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof in admixture with inert solid or liquid pharmaceutical carriers and/or auxiliary agents.

10. Process for the preparation of the pharmaceutical composition according to Claim 9 which comprises admixing crystalline form I (±)-l-[2-dimethylamino-l-(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof with inert solid or liquid pharmaceutical carriers and/or auxiliary agents and bringing the mixture to galenic form.

11. Crystalline form I (±)- 1 -[2-dimethylamino- 1 -(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof, for use as pharmaceutical active ingredient.

12. Crystalline form I (±)- 1- [2-dimethylamino- 1 -(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof, for use as antidepressant.

13. Use of crystalline form I (±)- 1 -[2-dimethylamino- 1 -(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof for the treatment of depression.

14. Method of treatment of depression which comprises administering to the patient in need of such treatment a therapeutically efficient amount of crystalline form I (±)-l-[2- dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]-cyclohexanol- hydrochloride or a hydrate thereof.

15. Crystalline form II (±)-l -[2-dimethylamino- 1 -(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride of the Formula I and hydrates thereof characterized by the X-ray diffraction pattern expressed in Table 2 and Figure 2:

Table 2

Position of diffraction lines and relative intensities (>15 % of polymorph II)

16. Process for the preparation of crystalline form II (±)- 1 - [2-dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]-cyclohexanol- hydrochloride ofthe Formula I according to Claim 15 and hydrates thereof which comprises recrystallizing crystalline form I or III (±)-l -[2-dimethylamino- l-(4-methoxy-phenyl)- ethylj-cyclohexanol-hydrochloride or a hydrate thereof from an anhydrous lower alkanol or an anhydrous mixture of a dipolar aprotic solvent and a lower alkanol.

17. Process according to Claim 16 which comprises using 2- propanol as lower alkanol.

18. Process according to Claim 16 which comprises using a mixture of ethyl acetate and methanol, or ethyl acetate and 2- propanol as a mixture of a dipolar aprotic solvent and a lower alkanol.

19. Process according to Claim 18 which comprises using a 4: 1 volume mixture of ethyl acetate and methanol.

20. Process according to any of Claims 16-19 which comprises carrying our recrystallization by dissolving crystalline form I or III (±)-l- [2-dimethylamino- l-(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof in the solvent under heating, cooling the solution and isolating the crystalline form II polymoφh.

21. Pharmaceutical composition comprising as active ingredient crystalline form II (±)-l -[2-dimethylamino- 1 -(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof in admixture with inert solid or liquid pharmaceutical carriers and/or auxiliary agents.

22. Process for the preparation ofthe pharmaceutical composition according to Claim 21 which comprises admixing crystalline form II (±)-l- [2-dimethylamino- l-(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof with inert solid or liquid pharmaceutical carriers and/or auxiliary agents and bringing the mixture to galenic form.

23. Crystalline form II (±)- 1 -[2-dimethylamino- 1 -(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof, for use as pharmaceutical active ingredient.

24. Crystalline form II (±)- 1 -[2-dimethylamino- 1 -(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof, for use as antidepressant.

25. Use of crystalline form II (±)- 1 -[2-dimethylamino- 1 -(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof for the treatment of depression.

26. Method of treatment of depression which comprises administering to the patient in need of such treatment a therapeutically efficient amount of crystalline form II (±)-l-[2- dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]-cyclohexanol- hydrochloride or a hydrate thereof.

27. Crystalline form III (±)- 1- [2-dimethylamino- 1 -(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride of the Formula I and hydrates thereof characterized by the X-ray powder diffraction pattern expressed in Table 3 and Figure 3 : Table 3

Position of diffraction lines and relative intensities

(>10 % of polymorph III)

28. Process for the preparation of crystalline form III (±)- 1 - [2-dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]-cyclohexanol- hydrochloride of the Formula I according to Claim 27 and hydrates thereof which comprises recrystallizing or suspending crystalline form I or II (±)-l- [2-dimethylamino- l-(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof from a mixture of a dipolar aprotic organic solvent and water.

29. Process according to Claim 28 which comprises using dichloro ethane or ethyl acetate as aprotic organic solvent.

30. Process according to Claim 28 or 29 which comprises using a mixture of an aprotic solvent and water containing 1-5 weight % of water.

31. Process according to any of Claims 28-30 which comprises dissolving or suspending crystalline form I or II (±)-

1 -[2-dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]-cyclohexanol- hydrochloride or a hydrate thereof in the solvent at 20-60°C, stirring and thereafter isolating the crystalline form III polymoφh.

32. Process according to Claim 31 which comprises carrying out stirring for 20-240 hours.

33. Pharmaceutical composition comprising as active ingredient crystalline form III (±)-l -[2-dimethylamino- 1 -(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof in admixture with inert solid or liquid pharmaceutical carriers and/or auxiliary agents.

34. Process for the preparation ofthe pharmaceutical composition according to Claim 33 which comprises admixing crystalline form III (±)- 1- [2-dimethylamino- 1 -(4-methoxy- phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof with inert solid or liquid pharmaceutical carriers and/or auxiliary agents and bringing the mixture to galenic form.

35. Crystalline form III (±)- 1 -[2-dimethylamino- 1 -(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a . hydrate thereof, for use as pharmaceutical active ingredient.

36. Crystalline form III (±)- 1 -[2-dimethylamino- 1 -(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof, for use as antidepressant.

37. Use of crystalline form III (±)- 1- [2-dimethylamino- 1 -(4- methoxy-phenyl)-ethyl]-cyclohexanol-hydrochloride or a hydrate thereof for the treatment of depression.

38. Method of treatment of depression which comprises administering to the patient in need of such treatment a therapeutically efficient amount of crystalline form III (±)-l-[2- dimethylamino- 1 -(4-methoxy-phenyl)-ethyl]-cyclohexanol- hydrochloride or a hydrate thereof.