WO2011063773A2

WO2011063773A2 - Crystalline and amorphous forms of almorexant and a method of their preparation

Info

Publication number: WO2011063773A2
Application number: PCT/CZ2010/000119
Authority: WO
Inventors: Stanislav Radl; Josef Cerny; Hana Brusova
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2009-11-25
Filing date: 2010-11-24
Publication date: 2011-06-03
Anticipated expiration: 2012-05-25
Also published as: CZ2009791A3; WO2011063773A3

Abstract

The invention relates to crystalline and amorphous forms of (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl] -3,4-dihydro- 1H-isoquinolin-2-yl} -N-methyl-2-phenyl- acetamide hydrochloride (I) (almorexant) and a method of their preparation.

Description

Crystalline and amorphous forms of almorexant and a method of their preparation Technical Field

The invention relates to crystalline and amorphous forms of (2R)-2-{(15)-6,7-dimethoxy-l-[2- (4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-lH-isoquinolm-2-yl}-N-methyl-2-phenyl- acetamide hydrochloride (I) (almorexant) and a method of their preparation.

The compound of formula (I) acts as a selective antagonist of the 0X1 and 0X2 orexetin receptors and is effective in treatment of sleep disorders. Almorexant is currently in the phase III of clinical tests (RESTORA 1). The project is being developed by the Actelion Company in cooperation with the GlaxoSmitliKline Company.

Background Art The basic document WO2005/118548 Al described preparation of almorexant in several ways. It was isolated in the form of the free base or hydrochloride. Preparation of almorexant hydrochloride was also described in the patent application no. WO2009/083899 A2. Neither of the above-mentioned patents specifies the form of the hydrochloride in more detail. Disclosure of Invention

The invention provides crystalline and amorphous forms of (2R)-2-{(l₁S)-6,7-dimethoxy-l-[2- (4-trifluoiOmethyl-phenyl)-ethyl] -3 ,4-dihydro- lH-isoquinolin-2-yl} -N-methyl-2-phenyl- acetamide hydrochloride (almorexant) (I) and a method of their preparation. The thus obtained Form A has the advantage of an easy method of preparation consisting in crystallization from suitable solvents or mixtures of solvents. The form obtained in this manner exhibits high stability, high chemical as well as polymorphous purity, and low contents of residual solvents. The amorphous form has the advantage of very good solubility, which is suitable for the manufacture of medical dosage forms.

Detailed description of the invention

During the development of the substance (2R)-2-{(liy)-6,7-dimethoxy-l-[2-(4-trifluoromethyl- phenyl)-ethyl] -3 ,4-dihydro- lH-isoquinolin-2-yl} -N-methyl-2-phenyl-acetamide hydrochloride (almorexant) (I) we tried to develop suitable forms, which could be used for the formulation of solid dosage forms. As a result we have obtained two suitable forms of almorexant hydrochloride (I), namely the crystalline form A and an amorphous form. The preparation method of almorexant hydrochloride (I) of form A developed by us consists in dissolving the almorexant base in an organic solvent, such as ethers, e.g. diethyl ether, methyl-i-butyl ether, tetrahydrofuran, or dioxane, chlorinated solvents, e.g. dichloromethane, dichloro ethane, chloroform, or tetrachloromethane, aromatic hydrocarbons, e.g. benzene, toluene, or xylene, or in solvents such as acetone, 2-butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide, hydrocarbons, e.g. heptane, cyclohexane, methylcyclohexane, or (Ci-C₆) alcohols, e.g. methanol, ethanol, 2-propanol, 1- propanol, 1-butariol, 2-butanol, either in anhydrous solvents or their mixtures, or in solvents or their mixtures with addition of water. To thus prepared solution is added an anhydrous solution of hydrogen chloride gas in an organic solvent, such as (Ci-C₆) alcohols, e.g. methanol, ethanol, 2-propanol, 1-propanol, 1-butanol, 2-butanol, ethers, e.g. diethyl ether, methyl-i-butyl ether, tetrahydrofuran, or dioxane, or in acetic acid esters, such as ethyl acetate, isopropyl acetate, isobutyl acetate, or butyl acetate. It is also possible to add aqueous hydrochloric acid, preferably with a concentration of 1 to 37% (by weight), to the prepared solution of almorexant base (I) to obtain almorexant hydrochloride (I).

What proved to be especially advantageous is dissolving the almorexant base in ethyl acetate followed by dropwise addition of an equivalent of a solution of gaseous hydrogen chloride in ethyl acetate with a concentration of 1% to 30% by weight at a temperature of 20 to 60 °C for 5 to 30 minutes. After addition of the solution of gaseous hydrogen chloride the reaction mixture was stirred at a temperature of from 25 to 80 °C for 10 minutes to 2 hours. After cooling of the reaction mixture to a temperature of from -10 to 30 °C the product was aspirated, washed with ethyl acetate and dried in a vacuum drier.

A very suitable method of preparation of almorexant hydrochloride of form A is also represented by crystallization of other forms (amorphous form as well) from (Ci-Ce) alcohols, e.g. methanol, ethanol, 2-propanol, 1-propanol, 1-butanol, 2-butanol or their mixtures both in anhydrous solvents and in solvents containing water, which may be at a concentration from 0.01% to 15%) by weight.

Form A prepared in this manner contains less than 5% by weight of other polymorphous forms, usually less than 1% of other polymorphous forms. Crystalline form A manifests in an X-ray powder pattern characteristic peaks in the following positions: 4.69; 9.40; 9.81; 14.50; 15.01 ; 16.26; 18.89; 22.22; 22.51; 23.18; 25.24; 26.05; 29.41; 29.83; 38.85 ° 20 ± 0.1° 2Θ, which corresponds to the X-ray pattern (figure 1). The main peaks were observed at 4.69; 9.40; 15.01 ; 16.26; 18.89; 25.24° 2Θ ± 0.1° 2Θ. Further, DSC was measured for form A. The temperature programme used was 50-250 °C, the heat-up rate 10 °C/min in a nitrogen atmosphere. The obtained thermogram has one significant endotherm, corresponding to melting of the substance. The endothemi is characterized by the values of onset 206 °C and peak 213 °C (average values obtained from more measurements), which corresponds to the record (figure 3). Form A exhibits high stability, decomposition does not occur even at a relatively high temperature (90 °C) and is also stable in the light. Good physical characteristics of form A also represent a great advantage. It is very easy to filter, wash and dry. After drying in a vacuum drier at 30 °C for 6 hours the contents of residual solvents are within the admissible limits.

Another suitable form of almorexant hydrochloride is represented by the amorphous form. The preparation method of amorphous almorexant hydrochloride (I) developed by us consists in dissolving almorexant hydrochloride in a suitable solvent, such as ethers, e.g. diethyl ether, methyl-r-butyl ether, tetrahydrofuran, or dioxane, chlorinated solvents, e.g. dichloromethane, dichloro ethane, chloroform, or tetrachloromethane, aromatic hydrocarbons, e.g. benzene, toluene, or xylene, or in solvents such as acetone, 2-butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, acetonitnle, (Ci-C₆) alcohols, e.g. methanol, ethanol, 2-propanol, 1-propanol, 1-butanol, 2-butanol, or their mixtures, and spraying the solution prepared in this manlier into the hot stream of an inert gas, followed by settling and isolating (spray drying) of the amorphous particles.

Another method of preparation of amorphous almorexant hydrochloride consists in dissolving almorexant hydrochloride in a suitable solvent, such as chlorinated solvents, e.g. dichloromethane, dichloroethane, chloroform, or tetrachloromethane, ethers, e.g. diethyl ether, methy -butyl ether, tetrahydrofuran, or dioxane, aromatic hydrocarbons, e.g. benzene, toluene, or xylene, or in solvents such as acetone, 2-butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, acetonitnle or their mixtures, followed by evaporation of the solvent at a reduced pressure. Amorphous almorexant hydrochloride can also be prepared by dissolving almorexant hydrochloride in a suitable solvent, such as chlorinated solvents, e.g. dichloromethane, dichloroethane, chloroform, or tetrachloromethane, ethers, e.g. diethyl ether, methyl-i-butyl ether, tetrahydrofuran, or dioxane, or in solvents such as acetone, 2-butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, acetonitnle, or their mixtures, and precipitating by addition of another solvent to the solution. Suitable solvents for the precipitation mainly include C5-C16 aliphatic or alicyclic hydrocarbons such as pentane, hexane, heptane, cyclohexane, methylcyclohexane, decalin, and the like, or mixtures thereof such as petroleum ether, petrol, petroleum, and the like. The amorphous product prepared using this method contains less than 5% by weight of the other polymorphous forms, usually less than 1% by weight of other polymorphous forms. An X-ray patterns confirms that it is an amorphous form of almorexant hydrochloride (figure 2). Further, DSC was measured for the amorphous form. The temperature programme employed was 50 -250 °C, heat-up rate 10 °C/min in a nitrogen atmosphere. The obtained thermogram has one significant exotherm and one significant endotherm. The exotherm is characterized by the values of onset 153 °C and peak 160 °C and the endotherm is characterized by the values of onset 212 °C and peak 215 °C (average values obtained from more measurements), which corresponds to the record (figure 4). Besides these significant energy manifestations there is also seen a glass transition (Tg) around the temperature of 114 °C (figure 5). Amorphous almorexant hydrochloride exhibits very good solubility and it is known from earlier published papers (Konno T., Chem. Pharm. Bull. 1990, 38, 2003-2007) that amorphous forms exhibit high bioavailability, which makes it suitable for pharmaceutical formulations.

The invention is described in a more detailed way in the examples below. These examples, which illustrate the improvement of the procedure of the invention, have merely an illustrative character and do not limit the scope of the invention in any respect. Brief Description of Drawings

Figure 1 - X-ray powder pattern of almorexant hydrochloride, form A

Figure 2 - X-ray powder pattern of amorphous almorexant hydrochloride

Figure 3 - DSC of almorexant hydrochloride, form A

Figure 4 - DSC of amorphous almorexant hydrochloride

Figure 5 - Tg (glass transition) of amorphous almorexant hydrochloride

Examples Example 1

(2R)-2-{(15)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-i

isoquinolin-2-yl}-N-methyl-2-phenyl-acetamide hydrochloride (I) - almorexant, form A (16 -6,7-Dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-l,2,3,4-tetrahydroisoquinoline hydrochloride (50 g) was suspended in 2-butanone (250 ml) under stirring at the laboratory temperature.^' After 5 minutes Na₂C0₃ (30.3 g) was added and the suspension was stirred at the laboratory temperature for another 10 minutes. After adding of (S)-methylcarbamoyl-phenyl- methylester of toluene-4-sulfonic acid (51.7 g) the reaction mixture was heated up to reflux and refluxed while being stirred for 16 hours. Then, most of the solvent (ca. 200 ml) was removed by distillation and the residue was co-distilled with ethyl acetate (3 x 50 ml). Then, the mixture was diluted with 150 ml of ethyl acetate and the solid fraction was aspirated and washed with 100 ml of ethyl acetate. The solution was washed with water (2 x 100 ml) and brine (50 ml). After drying with MgSC*4 the solution was heated up to 60 °C. A solution of HCl(g) in ethyl acetate (8.9%, 51 g) was added dropwise within 30 minutes. After heating up to reflux and stirring for 30 minutes the solution was cooled down to 0 °C and aspirated. 63 g (92%) of almorexant hydrochloride, form A, were obtained (confirmed by an XRPD analysis). Example 2

(2R)-2-{(l₁S}-6,7-Dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-lH- isoquinolin-2-yl}-N-methyl-2-phenyl-acetamide hydrochloride (I) - almorexant, form A (l>S)-6,7-Dimethoxy-l-[2-(4-trifiuoromethylphenyl)ethyl]-l,2,3,4-tetrahydroisoquinoline hydrochloride (15 g) was suspended in 2-butanone (75 ml) while being stirred at the laboratory temperature. After 5 minutes Na₂C0₃ (9.1 g) was added and the suspension was stirred at the laboratory temperature for another 10 minutes. After adding of (S)- methylcarbamoyl-phenyl-methyl ester of toluene-4-sulfonic acid (15.5 g) the reaction mixture was heated up to reflux and refluxed under stirring for 16 hours. Then, the solid fraction was aspirated and the solution was evaporated until dry. The evaporation product was dissolved in 100 ml of ethyl acetate, washed with water (2 x 50 ml) and brine (50 ml). After drying with MgS0₄ the solution was evaporated until dry. The evaporation residue was crystallized from isopropyl alcohol (150 ml). 17.8 g (87%) of almorexant hydrochloride, form A, were obtained (confirmed by an XRPD analysis).

Example 3

(2R)-2-{(1 )-6,7-Dimethoxy^^2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro H- isoquinolin-2-yl}-N-methyl-2-phenyl-acetamide hydrochloride (I) - almorexant, form A

(15)-6,7-Dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-l,2,3,4-tetrahydroisoquinoline hydrochloride (5 g) was suspended in 2-butanone (30 ml) under stirring at the laboratory temperature. After 5 minutes Na₂C0₃ (3 g) was added and the suspension was stirred at the laboratory temperature for another 10 minutes. After adding of ( }-methylcarbamoyl-phenyl- methyl ester of toluene-4-sulfonic acid (5.1 g) the reaction mixture was heated up to reflux and refluxed while being stirred for 16 hours. Then, the solid fraction was aspirated and the solution was evaporated until dry. The evaporation residue was dissolved in 100 ml of ethyl acetate, washed with water (2 x 50 ml) and brine (50 ml). After drying with MgS0₄ 1.5 ml of 35% hydrochloric acid was added to the solution. After removal of water by azeotropic distillation the reaction mixture was cooled to 0 °C and aspirated. After drying 6.0 g (88%>) of almorexant hydrochloride, form A, were obtained (confirmed by an XRPD analysis).

Example 4

(2R)-2- {(1^-6,7-Dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-lH- isoquinolin-2-yl}-N-methyl-2-phenyl-acetamide hydrochloride (I) - almorexant, form A

Almorexant hydrochloride (50 g) was dissolved in 400 ml of isopropyl alcohol under boiling. Being intensively stirred the solution was cooled down to 60 °C. After inoculation with 0.5 g of form A the product starts to precipitate. Under stirring the suspension was cooled down to 0 °C and stirred for 1 hour. Then, the product was aspirated, washed with 50 ml of ice-cold isopropyl alcohol and dried in a vacuum drier at 30 °C. 45 g (90%) of almorexant hydrochloride, form A, were obtained (confirmed by an XRPD analysis).

Example 5 (2R)-2- {( 1 £ 6,7-Dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro- 1H- isoquinolin-2-yl} -N-methyl-2-phenyl-acetamide hydrochloride (I) - almorexant, form A

Almorexant hydrochloride (5 g) was dissolved in a mixture of 20 ml of isopropyl alcohol and 5 ml of ethanol under boiling. Being intensively stirred the solution was cooled down to 60 °C. After inoculation with 0.1 g of form A the product starts to precipitate. Being stirred the suspension was cooled down to 0 °C and stirred for 1 hour. Then, the product was aspirated, washed with 5 ml of ice-cold isopropyl alcohol and dried in a vacuum drier at 30 °C. 4.3 g (86%) of almorexant hydrochloride, form A, were obtained (confirmed with an XRPD analysis). Example 6

(2^)-2- {(l¾-6_;7-Dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihyd^

isoquinolin-2-yl}-N-methyl-2-phenyl-acetamide hydrochloride (I) - almorexant, form A

Almorexant hydrochloride (3 g) was dissolved in 20 ml of acetone. Being intensively stirred the solution was cooled down to 60 °C. After inoculation with 0.1 g of form A the product starts to precipitate. Being stirred the suspension was cooled down to 0°C and stirred for 1 hour. Then, the product was aspirated, washed with 3 ml of ice-cold acetone and dried in a vacuum drier at 30 °C. 2.5 g (82%) of almorexant hydrochloride, form A were obtained (confirmed with an XRPD analysis)

Example 7 (2^)-2-{(l^-6,7-Dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-lH- isoquinolin-2-yl}-N-methyl-2-phenyl-acetamidu hydrochloride (I) - almorexant, form A

Almorexant hydrochloride (5 g) was dissolved in a mixture of 10 ml of 2-butanone and 20 ml of ethyl acetate under boiling. Being intensively stirred the solution was cooled down to 60 °C. After inoculation with 0.1 g of form A the product starts to precipitate. Being stirred the suspension was cooled down to 0 °C and stirred for 1 hour. Then, the product was aspirated, washed with 5 ml of ice-cold acetone and dried in a vacuum drier at 30 °C. 4.4 g (87%) of almorexant hydrochloride, form A, were obtained (confirmed with an XRPD analysis). Example 8

(2R)-2-{(l^-6,7-Dimethoxy-l-[2-(4 rifluoromethyl-phenyl)-ethyl]-3,4-dihydro-lH- isoquinolin-2-yl}-N-methyl-2-phenyl-acetamide hydrochloride (I) - amorphous form (1 )-6,7-Dimethoxy-l -[2-(4-trifluormethylphenyl)ethyl]-l,2,3,4-tetrahydroisoquinoline hydrochloride (15 g) was suspended in 2-butanone (75 ml) under stirring at the laboratory temperature. After 5 minutes Na₂C0₃ (9.1 g) was added and the suspension was stirred at the laboratory temperature for another 10 minutes. After adding of (^-methylcarbamoyl-phenyl- methyl ester of toluene-4-sulfonic acid (15.5 g) the reaction mixture was heated up to reflux and refiuxed while being stirred for 16 hours. Them the solid fraction was aspirated and the solution was evaporated until dry. The evaporation residue was dissolved in 100 ml of dichloromethane, washed with water (2 x 50 ml) and brine (50 ml). After drying with MgS0₄ the solution was evaporated until dry. 19.38 g (94%) of amorphous almorexant hydrochloride were obtained (confirmed with an XRPD analysis).

Example 9 (2i?)-2-{(l₁S)-6,7-Dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-lH- isoquinolin-2-yl}-N-methyl-2-phenyl-acetamide hydrochloride (I) - amorphous form

Almorexant hydrochloride (50 g) was dissolved in 300 ml of dichloromethane. The solution was sprayed into the stream of a hot inert gas, whereupon the amorphous particles were settled and isolated (spray drying). 48 g (96%) of amorphous almorexant hydrochloride were obtained (confirmed with an XRPD analysis).

Example 10 (2R)-2- {(l£)-6,7-Dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro- 1H- isoquinolin-2-yl}-N-methyl-2-phenyl-acetamide hydrochloride (I) - amorphous form

Almorexant hydrochloride (5 g) was dissolved in 30 ml of methanol. The solution was sprayed into the stream of a hot inert gas, whereupon the amorphous particles were settled and isolated (spray drying). 4.5 g (90%) of amorphous almorexant hydrochloride were obtained (confirmed with an XRPD analysis). Example 11

{2R)-2- { ( 1 S)-6_s7-Dimet oxy- 1 - [2-(4-trifluoromethyl-phenyl)-ethyl] -3 ,4-dihydro- 1H- isoquinolin-2-yl}-N-methyl-2-phenyl-acetamidue hydrochloride (I) - amorphous form

Almorexant hydrochloride (3 g) was dissolved in 10 ml of dichloromethane. The solution was sprayed into intensively stirred pentane (100 ml). The precipitate was aspirated, washed with 10 ml of pentane and dried in a vacuum drier. 2.6 g (86%) of amorphous almorexant hydrochloride were obtained (confirmed with an XRPD analysis).

Experimental part

X-ray diffraction analysis: The diffraction pattern was obtained with an X'PERT PRO MPD PANalytical diffractometer with a graphite monochromator, radiation used: CuKa (λ=1.542Α), excitation voltage: 45 kV, anodic current: 40 niA, measured range: 4 - 40^° 2Θ, increment: 0,008° 2Θ; the measurements were carried out on a flat sample with the area/thickness of 10/ 0.5 mm. DSC analysis: the thermogram was obtained with a Pyris 1 DSC Perkin Elmer device. The sample was measured in the temperature range of from 50 to 300 °C with the heat-up rate of 10 °C/min in a nitrogen stream. The measurement was performed in standard Al pans.

Claims

C L A I M S

1. Polymorphous form A of almorexant hydrochloride of formula (I), exhibiting the following characteristic peaks in an X-ray powder diffraction pattern: 4.69; 9.40; 15.01 ; 16.26; 18.89; 25.24° 2Θ ± 0. 2Θ.

2. The polymorphous form A of almorexant hydrochloride according to claim 1, exhibiting the following characteristic peaks in an X-ray powder diffraction pattern: 4.69; 9.40; 9.81; 14.50; 15.01; 16.26; 18.89; 22.22; 22.51; 23.18; 25.24; 26.05; 29.41; 29.83; 38.85 ° 2Θ ± 0.1° 2Θ.

3. The polymorphous form A of almorexant hydrochloride according to claims 1-2, containing less than 5% by weight of other polymorphous forms.

4. The polymorphous form A of almorexant hydrochloride according to claims 1-3, containing less than 1 % by weight of other polymorphous forms.

5. Amorphous almorexant hydrochloride.

6. The amorphous almorexant hydrochloride according to claim 5, containing less than 5% by weight of other polymorphous forms.

7. The amorphous almorexant hydrochloride according to claims 5 or 6, containing less than 1% of weight of other polymorphous forms.

8, A method for the manufacture of the polymorphous form A of almorexant hydrochloride of formula I according to claims 1 -A, characterized in that it consists of the following steps:

a) Dissolving the almorexant base in an organic solvent selected from the group consisting of ethers, chlorinated solvents, aromatic hydrocarbons, acetone, 2- butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, acetonitrile, dimethylformamide, dimethylacetamide, N- methylpyiTolidone, dimethyl sulfoxide and (Ci-C₅) alcohols, and mixtures thereof, optionally with addition of water;

b) Adding aqueous hydrochloric acid or hydrogen chloride; and

c) Isolating the product by filtering and removing the solvent from the product, after optional removing of water.

9. The method according to claim 8, characterized in that aqueous hydrochloric acid having a concentration of 1-37% by weight is added in step (b).

10. The method according to claim 8, characterized in that a solution of gaseous HCl in an organic solvent, selected from the group consisting of ethers acetone, 2-butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, and (C]-C₆) alcohols is added in step (b).

11. A method for the manufacture of the polymorphous form A of almorexant hydrochloride of formula I according to claims 1-4, characterized in that it consists of the following steps:

Crystallizing almorexant hydrochloride in an organic solvent, selected from the group consisting of ethers, chlorinated solvents, aromatic hydrocarbons, acetone, 2- butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, acetonitrile, dimethylformamide, dimethylacetamide, N- methylpyrrolidone or dimethyl sulfoxide, and (Ci-C₆) alcohols, and mixtures thereof, optionally with addition of water.

12. A method for the manufacture of the amorphous almorexant hydrochloride according to claims 5-7, characterized in that it consists of the following steps:

a) Dissolving the almorexant base in an organic solvent selected from the group consisting of ethers, chlorinated solvents, aromatic hydrocarbons, acetone, 2- butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, acetonitrile, dimethylformamide, dimethylacetamide, N- methylpyrrolidone, dimethyl sulfoxide and (Ci-C₆) alcohols, and mixtures thereof, optionally with addition of water;

b) Adding aqueous hydrochloric acid or hydrogen chloride; and

c) Removing the solvent and obtaining the amorphous product.

13. The method according to claim 12, characterized in that a solution of gaseous HCl in an organic solven, selected from the group consisting of ethers, acetone, 2-butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, and (Ci-Ce) alcohols is added in step (b).

14. A method for the manufacture of the amorphous almorexant hydrochloride according to claims 5-7, characterized in that it consists of the following steps:

a) Dissolving almorexant hydrochloride in an organic solvent selected from the group consisting of ethers, chlorinated solvents, aromatic hydrocarbons, acetone, 2- butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, acetonitrile, dimethylformamide, dimethylacetamide, N- methylpyrrolidone, dimethyl sulfoxide and (Ci-C₆) alcohols, and mixtures thereof, optionally with addition of water; and

b) Isolating the amorphous particles.

15. The method according to claim 14, characterized in that isolation in step (b) is carried out by spraying the solution into a stream of a hot inert gas.

16. The method according to claim 14, characterized in that isolation in step (b) is carried out by evaporating the solvent and isolating the amorphous product.

17. The method according to claim 14, characterized in that isolation in step (b) is carried out by precipitating by addition of another solvent; and filtering and obtaining the amorphous product by removal of the solvent.

18. The method according to claim 17, characterized in that the precipitation is carried out by adding at least one C5-C16 aliphatic or alicyclic hydrocarbon selected form the group consisting of pentane, hexane, heptane, cyclohexane, methylcyclohexane, decalin, petroleum ether, petrol and petroleum.

19. A medical dosage form, characterized in that it comprises the polymorphous form A of almorexant hydrochloride of formula I according to claims 1-4 and at least one pharmaceutically acceptable excipient.

20. A medical dosage form, characterized in that it comprises the amorphous form of almorexant hydrochloride of formula I according to claims 5-7 and at least one pharmaceutically acceptable excipient.