WO2016116077A1

WO2016116077A1 - Polymer-stabilized amorphous forms of vortioxetine

Info

Publication number: WO2016116077A1
Application number: PCT/CZ2016/000008
Authority: WO
Inventors: Pavel ZVATORA; Ondrej Dammer; Michal Benes; Lukas KREJCIK; Jaroslava SVOBODOVA; Robert Klvana
Original assignee: Zentiva, K.S.
Priority date: 2015-01-21
Filing date: 2016-01-15
Publication date: 2016-07-28
Also published as: CZ201531A3

Abstract

The present invention relates to an amorphous mixture of vortioxetine of formula I or its hydrobromide salt with a polymer, characterized in that the polymer is selected from derivatives of polyacrylates, polymethacrylates, cellulose or polyvinyls. Also included is a method of preparing said amorphous mixture, comprising dissolution of vortioxetine in the base form or in the hydrobromide salt form and a suitable polymer in a suitable organic solvent, and subsequent removal of the solvent to produce an amorphous mixture. Another method consists in mixing vortioxetine in the base form or in the hydrobromide salt form with a suitable polymer, and subsequent heating of this mixture to produce a melt and than an amorphous mixture.

Description

Polymer-stabilized amorphous forms of vortioxetine Technical Field

This invention relates to new amorphous forms of l-(2-((2,4-dimethylphenyl)- thio)phenyl)piperazine, known as vortioxetine (formula I)

and to an amorphous form of vortioxetine hydrobromide. The invention further encompasses various methods of preparing the amorphous forms and their use for a pharmaceutical composition.

Background Art

Vortioxetine is used in pharmacy for the treatment of depression and anxiety. Its synthesis and use were first described in the application WO 03029232. In a more recent application, WO 2007/144005, various crystalline salts of vortioxetine are described and characterized, as well as their use in a pharmaceutical composition. In particular, e.g. solubilities of crystalline forms of vortioxetine hydrobromide alpha (2 mg/ml) and beta (1.2 mg/ml) are compared.

A new application, WO 2014/177491, describes amorphous forms of vortioxetine hydrobromide stabilized by adsorbents such as A1₂0₃, CaC0₃, MgO, Si0₂, Ti0₂ and ZnO. These amorphous forms have a higher solubility and biological availability than crystalline vortioxetine hydrobromide.

The present invention, wherein the amorphous forms of vortioxetine or vortioxetine hydrobromide are stabilized by means of a polymer, is more advantageous, compared to the use of adsorbents of WO 2014/177491, mainly in that the solubility of polymers is dependent on the pH value of the solution, which means that their use makes it possible to influence releasing of the pharmaceutically active substance depending on pH of the alimentary tract.

Disclosure of Invention

The invention provides amorphous mixtures of vortioxetine and vortioxetine hydrobromide with suitable polymeric carriers such as cellulose derivatives, polyacrylates or methacrylates and poly vinyl derivatives, processes of their preparation and their use for a pharmaceutical composition.

Brief Description of Drawings

Figure 1: X-ray powder pattern of vortioxetine base with Eudragit L 100 (weight ratio 1:2, API: polymer)

Figure 2: X-ray powder pattern of vortioxetine base with Eudragit S 100 (weight ratio 1 :2, API: polymer)

Figure 3 : X-ray powder pattern of vortioxetine base with HPMCAS LF (weight ratio 1 :2, API: polymer)

Figure 4: X-ray powder pattern of vortioxetine hydrobromide with Eudragit L 100 (weight ratio 1:2, API: polymer)

Figure 5: X-ray powder pattern of vortioxetine hydrobromide with Eudragit S 100 (weight ratio 1:2, API: polymer)

Figure 6: X-ray powder pattern of vortioxetine hydrobromide with HPMCAS LF (weight ratio 1:2, API: polymer)

Figure 7: X-ray powder pattern of vortioxetine hydrobromide with PVP K30 (weight ratio 1 :2, API: polymer) Figure 8: X-ray powder pattern of vortioxetine hydrobromide with Methocel E5 (weight ratio 1:2, API: polymer)

Figure 9: DSC record of vortioxetine hydrobromide with UPMCAS LF (weight ratio 1:2, API: polymer)

Detailed description of the invention

The invention relates to new solid forms of l-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine, known as vortioxetine, and to vortioxetine hydrobromide, in the form of a stable amorphous mixture with a polymer, and to methods of preparing the same.

A crystalline solid is characterized by a long-distance structure arrangement. On the other hand, amorphous solids do not exhibit this arrangement. The molecular arrangement of an amorphous solid may be represented by a "frozen liquid" with rheological properties of a solid.

In this invention, the term "solid dispersion" is used, which represents any solid composition consisting of at least two components. In this case, the solid dispersion contains the pharmaceutically active ingredient (vortioxetine, or its salt), which is dispersed in at least one component, e.g. in a polymer.

The term "molecular dispersion", used in this invention, refers to dispersion of a component (e.g. vortioxetine) with a polymeric matrix. In some cases, vortioxetine or its salt may be dispersed in the polymeric matrix in such a way that they are immobilized in this matrix in their amorphous form. In case of the molecular dispersion the resulting solid only has one glass transition temperature (Tg) and in this invention it is referred to as a vitreous solution.

In case the component (vortioxetine, or its salt) is dispersed in the polymeric matrix in the form of amorphous clusters, this solid dispersion is referred to as a vitreous suspension. The resulting vitreous suspension has two or more glass transitions, which belong to the amorphous active pharmaceutical substance and to the particular polymer or polymers.

As mentioned above, compared to crystalline solids, amorphous solids have a different internal structure and a larger surface area, and therefore they exhibit a higher solubility. If the solubility and biological availability of pharmaceutically active substances needs to be increased, they should be preferably prepared in an amorphous form.

If the temperature of a crystalline material reaches the melting point, a change of the state from the solid phase to the liquid phase occurs. When this melt is cooled again, the crystalline structure is restored. However, if the melt is cooled at a sufficiently high rate, crystallization may be prevented by formation of a undercooled solution. The undercooled solution is cooled to achieve the glass transition (Tg), the molecules are kinetically frozen and the undercooled liquid solidifies into glass. The molecules in an undercooled liquid have a much higher mobility than in the vitreous state, as described by Remington in the publication: The Science and Practice of Pharmacy, Pharmaceutical Press, 21 ^d edition.

Since molecules in the vitreous state also exhibit certain mobility, it is advantageous for the glass transition temperature to be at least 20°C, preferably 30°C and most preferably at least 40°C above the temperature of the actual storage conditions.

Amorphous vortioxetine, which is not stabilized, has a low glass transition temperature (-8°C). In the case of vortioxetine hydrobromide the glass transition temperature of the amorphous non- stabilized form is 64°C. These non-stabilized amorphous forms re-crystallize during storage. For this reason, the amorphous forms of vortioxetine and vortioxetine hydrobromide must be stabilized by increasing of the glass transition temperature (Tg) to prevent re-crystallization.

Amorphous forms of vortioxetine or vortioxetine hydrobromide can be stabilized by addition of other substances. A number of substances may be used as stabilizers of the amorphous state. The application WO 2014/17749, describes amorphous forms of vortioxetine hydrobromide stabilized with the adsorbents AI₂0 , CaC0_3} MgO, Si0₂, Ti0₂, ZnO.

Another possibility of stabilization of the amorphous state of vortioxetine in the base or salt form is the use of a suitable polymer. These polymers may come from the groups of water-soluble or water-insoluble polymers. Typical water-soluble polymers for stabilization of vortioxetine and vortioxetine hydrobromide are polyvinyl pyrrolidone (povidone), copovidone, polyvinyl alcohol, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, polyethylene glycol, copolymers of polyvinyl caprolactam, polyvinyl acetate - polyethylene glycol (Soluplus™) etc. Typical water-insoluble polymers for stabilization of vortioxetine and vortioxetine hydrobromide are methylcellulose, ethylcellulose, polymethacrylates, hypromellose, phthalate, hypromellose succinate, hypromellose acetate succinate (HPMCAS), cellulose acetate phthalate, carboxymethyl cellulose etc. An advantage of these polymers is the fact that their solubility is dependent on the pH value of the solution and their use makes it possible to influence releasing of the pharmaceutically active ingredient depending on pH of the alimentary tract.

There are a number of preparation methods of stabilized amorphous forms of vortioxetine and vortioxetine hydrobromide.

One of the preparation methods of stabilized amorphous forms of vortioxetine and vortioxetine hydrobromide is the dissolution process. In a common dissolution process the active substance is dissolved in a solvent or in any mixture of solvents. The solvent may be water or any organic solvent. As an example of suitable organic solvents one can mention methanol, ethanol, ethyl acetate, isopropyl alcohol, acetone, dichloromethane, tetrahydrofuran etc.. In the next step, a substance stabilizing the active pharmaceutical ingredient is added to this solution or suspension. The solvent is quickly removed and amorphous solid matter results. The solvent can be removed by means of a rotary vacuum evaporator, fluid granulation, spray drying, electrosp inning, solvent freezing etc.

Other options of preparation of stabilized amorphous substances are methods without the use of a solvent. In these processes the active pharmaceutical ingredient (vortioxetine or its salt) is mixed with a stabilizing substance (polymer). This mixture is heated up and melted, producing a melt. Common temperatures for the formation of a melt vary in the range of 20°C - 40°C above the temperature Tg, when the mixture is melted and has a suitable viscosity for its processing. The melt is subsequently cooled down, which produces an amorphous solid. As some examples of these methods one can mention hot melt extrusion, hot melt granulation, high shear mixer, solvent-free fluid bed granulation etc.

This invention is focused on preparation of an amorphous mixture of vortioxetine and vortioxetine hydrobromide with a polymer, which can be used in a pharmaceutical formulation. The following polymers can be advantageously used for the preparation of polymer-stabilized amorphous solid forms of vortioxetine or vortioxetine hydrobromide: polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (Methocel), polymethacrylate derivatives (Eudragit LI 00, Eudragit SlOO) and hypromellose acetate succinate (HPMCAS).

The most commonly used polymers in this invention are polyvinyl pyrrolidone (PVP K30) with the molecular, weight of approx. 50,000 Da (g/mol), Methocel E5 with the molecular weight of approx. 22,000 Da (g/mol), Eudragit SlOO with the molecular weight of approx. 125,000 Da (g/mol), Eudragit L100 with the molecular weight of approx. 125,000 Da (g/mol) and hypromellose acetate succinate (HPMCAS-LF).

The solvent removal method with the use of a rotary vacuum evaporator has been used for the preparation of the amorphous solid forms of vortioxetine or vortioxetine hydrobromide. The products prepared this way are summarized in Table 1 together with the results of the DSC and X- ray powder analyses.

The results of the X-ray powder analysis have shown that the free base of vortioxetine forms stable amorphous solid forms with the polymers Eudragit LI 00, Eudragit SI 00 and HP CAS LF. In the case of vortioxetine hydrobromide amorphous solid forms were prepared with the polymers Eudragit L100, Eudragit SI00, HPMCAS LF, PVP K30 and Methocel E5.

The differential scanning calorimetry (DSC) measurement makes it possible to distinguish a solid dispersion and a molecular dispersion, wherein the amorphous solid only exhibits one glass transition value. The prepared amorphous solids in the weight ratio of 1 :2 (API : polymer) formed stable solid dispersions or molecular dispersions whose stability increases with the increasing Tg value (Hancock and Zografi, 1997).

A comparison of the Tg values from the DSC measurements has shown that the most stable molecular dispersion was formed by vortioxetine in the basic form with the polymer Eudragit LI 00 (Tg = 173°C); in the case of vortioxetine hydrobromide this polymer also formed the most stable molecular dispersion with the glass transition temperature (Tg = 116⁰C).

According to the results of the X-ray powder analyses, the prepared samples were stable in all the cases of storage at 50°C/0 % relative humidity (RH) for the test period of 3 days. In the case of the storage conditions of 50°C/75% RH for the test period of 3 days, re-crystallization of vortioxetine hydrobromide has been observed when the polymers HPMCAS, PVP K30 and Methocel E5 were used. The samples with the polymers Eudragit LI 00 and Eudragit SI 00 were stable under all the test conditions (see Table 1). Table 1: Stabilities of the prepared amorphous solids of vortioxetine and vortioxetine hydrobromide (weight ratio 1:2), API : polymer)

The prepared amorphous solids containing vortioxetine or vortioxetine hydrobromide stabilized with polymers in accordance with this invention can be used for the preparation of pharmaceutical compositions, especially solid dosage forms, e.g. tablets. Such pharmaceutical compositions can contain at least one excipient from the group of fillers (e.g. lactose), binders (e.g. macrocrystalline cellulose), disintegrants (e.g. sodium salt of croscarmellose), lubricants (e.g. magnesium stearate), surfactants etc. These tablets can be coated with common coating compounds, e.g. polyvinyl alcohol or polyethylene glycol.

The invention is clarified in a more detailed way using the working examples below. These examples, which illustrate the preparation of novel amorphous forms of vortioxetine or vortioxetine hydrobromide in accordance with the invention, only have an illustrative character and do not restrict the scope of the invention in any respect.

Experimental part

X-ra powder analysis

The diffractograms were obtained using an X'PERT PRO MPD PANalytical powder diffractometer, used radiation Cu a (λ=1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 20, increment: 0.01° 2Θ at the dwell time at a reflection of 0.5 s, the measurement was carried out with a flat sample with the area/thickness of 10/0.5 mm. For the correction of the primary array 0.02 rad Soller slits, a 10mm mask and a 1/4° fixed anti-dispersion slit were used. The irradiated area of the sample is 10 mm, programmable divergence slits were used. For the correction of the secondary array 0.02 rad Soller slits and a 5.0 anti-dispersion slit were used.

Differential Scanning Calorimetry (DSC)

The DSC records were measured using a Discovery DSC device made by TA Instruments. The sample charge in a standard Al pot (40 μί) was between 4-5 mg and the heating rate was 5°C/min. The temperature program that was used consists of 5 min of stabilization at the temperature of -10°C and then of heating up to 225°C for the vortioxetine free base and 250°C for vortioxetine hydrobromide at the heating rate of 5°C/min (Amplitude = 0.8°C and Period = 60 s). As the carrier gas 5.0 N₂ was used at the flow rate of 50 ml/min. HPLC analysis

The content of dissolved vortioxetine hydrobromide was analyzed using a UPLC Aquity Waters device. A BECH C8 (1.7 um, 1 = 0.10 m,□ = 2.1 mm) column was used. The gradient elution was carried out by mixing of the mobile phase (A), 10 mmol/1 solution of ammonium carbonate in water, pH 10, (B) methanol. Composition of the mobile phase in time, see Table 2:

Table 2: Gradient elution

The content was detected using a spectrophotometric measurement at 230 nm. Sample injection volume 1 μΐ. Injected sample temperature 37°C.

Dissolution of the samples

The samples were dissolved in plastic Eppendorf tubes having the volume of 2 ml with the use of a shaker (Eppendorf Thermomixer comfort) at 21 Hz and the temperature of 37°C.

Centrifugation

The undissolved fraction was removed by means of a centrifuge (Centrifuge MPW-65E) at 14,000 rpm for 5 min and the temperature of 37°C.

Examples

Example 1

The crystalline free base of vortioxetine was prepared in accordance with the method described in the application (WO 2007/144005), Example 3b. Example 2

The crystalline salt of vortioxetine hydrobromide, form β was prepared in accordance with the method described in the application (WO 2007/144005), Example 4c.

Example 3

Preparation of the amorphous solid form of vortioxetine with Eudragit L100

402.9 mg of Eudragit LI 00 and 200.5 mg of the crystalline free base of vortioxetine were dosed into a 100ml round flask with a ground joint. This mixture was dissolved in 15 ml of a dichloromethane : ethanol mixture (1 :1, V:V), being stirred in a magnetic stirrer at 45°C. The solution was stirred for 20 min, and after this time period the solvent was evaporated in a vacuum evaporator at the temperature of 45 °C and the pressure of 2 kPa. The resulting product was left to dry in a vacuum drier at the temperature of 40°C and the pressure of 20 kPa for 12 hours. X-ray powder pattern in Fig. 1. The glass transition temperature of the molecular dispersion according to DSC was 173°C.

Example 4

Preparation of the amorphous solid form of vortioxetine with Eudragit S100

398.5 mg of Eudragit S100 and 200.2 mg of the crystalline free base of vortioxetine were dosed into a 100ml round flask with a ground joint. This mixture was dissolved in 15 ml of a dichloromethane : ethanol mixture (1 :1, V V), being stirred in a magnetic stirrer at 45°C. The solution was stirred for 20 min, and after this time period the solvent was evaporated in a vacuum evaporator at the temperature of 45°C and the pressure of 2 kPa. The resulting product was left to dry in a vacuum drier at the temperature of 40° C and the pressure of 20 kPa for 12 hours. X-ray powder pattern in Fig. 2. The glass transition temperature of the molecular dispersion according to DSC was 146°C.

Example 5

Preparation of the amorphous solid form of vortioxetine with HPMCAS LF

434.3 mg of HPMCAS LF and 216.5 mg of the crystalline free base of vortioxetine were dosed into a 100ml round flask with a ground joint. This mixture was dissolved in a 15ml dichloromethane : ethanol mixture (1 :1, V:V), being stirred in a magnetic stirrer at 45°C. The solution was stirred for 20 min, and after this time period the solvent was evaporated in a vacuum evaporator at the temperature of 45°C and the pressure of 2 kPa. The resulting product was left to dry in a vacuum drier at the temperature of 40°C and the pressure of 20 kPa for 12 hours. X-ray powder pattern in Fig. 3. The glass transition temperature of the molecular dispersion according to DSC was 84°C.

Example 6

Preparation of the amorphous solid form of vortioxetine hydrobromide with Eudragit LI 00 420 mg of Eudragit L100 and 210.3 mg of crystalline vortioxetine hydrobromide (form β) were dosed into a 100ml round flask with a ground joint. This mixture was dissolved in 15 ml of a dichloromethane : ethanol mixture (1 :1, V:V), being stirred in a magnetic stirrer at 45°C. The solution was stirred for 20 min, and after this time period the solvent was evaporated in a vacuum evaporator at the temperature of 45°C and the pressure of 2 kPa. The resulting product was left to dry in a vacuum drier at the temperature of 40"C and the pressure of 20 kPa for 12 hours. X-ray powder pattern in Fig. 4. The glass transition temperature of the molecular dispersion according to DSC was 116°C with re-crystallization of the sample at 140°C.

Example 7

Preparation of the amorphous solid form of vortioxetine hydrobromide with Eudragit S100 414 mg of Eudragit SI 00 and 206 mg of crystalline vortioxetine hydrobromide (form β) were dosed into a lOOml round flask with a ground joint. This mixture was dissolved in 15 ml of a dichloromethane : ethanol mixture (1 :1, V:V), being stirred in a magnetic stirrer at 45°C. The solution was stirred for 20 min, and after this time period the solvent was evaporated in a vacuum evaporator at the temperature of 45°C and the pressure of 2 kPa. The resulting product was left to dry in a vacuum drier at the temperature of 40°C and the pressure of 20 kPa for 12 hours. X-ray powder pattern in Fig. 5. The glass transition temperature of the molecular dispersion according to DSC was 116°C with re-crystallization of the sample at 140°C. Example 8

Preparation of the amorphous solid form of vortioxetine hydrobromide with HPMCAS LF 403 mg of HPMCAS LF and 203 mg of crystalline vortioxetine hydrobromide (form β) were dosed into a 100ml round flask with a ground joint. This mixture was dissolved in 15 ml of a dich!oromethane : ethanol mixture (1 : 1, V:V), being stirred in a magnetic stirrer at 45°C. The solution was stirred for 20 min, and after this time period the solvent was evaporated in a vacuum evaporator at the temperature of 45°C and the pressure of 2 kPa. The resulting product was left to dry in a vacuum drier at the temperature of 40°C and the pressure of 20 kPa for 12 hours. X-ray powder pattern in Fig. 6. The glass transition temperature of the molecular dispersion according to DSC was 62°C with re-crystallization of the sample at 140°C (see Fig. 9).

Example 9

Preparation of the amorphous solid form of vortioxetine hydrobromide with PVP 30

403 mg of PVP K30 and 203 mg of crystalline vortioxetine hydrobromide (form β) were dosed into a 100ml round flask with a ground joint. This mixture was dissolved in 15 ml of a dichloromethane : ethanol mixture (1 :1, V:V), being stirred in a magnetic stirrer at 45°C. The solution was stirred for 20 min, and after this time period the solvent was evaporated in a vacuum evaporator at the temperature of 45°C and the pressure of 2 kPa. The resulting product was left to dry in a vacuum drier at the temperature of 40°C and the pressure of 20 kPa for 12 hours. X-ray powder pattern in Fig. 7. The glass transition temperature of the molecular dispersion according to DSC was 45°C.

Example 10

Preparation of the amorphous solid form of vortioxetine hydrobromide with Methocel E5

403.4 mg of Methocel E5 and 202 mg of crystalline vortioxetine hydrobromide (form β) were dosed into a 100ml round flask with a ground joint. This mixture was dissolved in 15 ml of a dichloromethane : ethanol mixture (1 :1, V:V), being stirred in a magnetic stirrer at 45°C. The solution was stirred for 20 min, and after this time period the solvent was evaporated in a vacuum evaporator at the temperature of 45 °C and the pressure of 2 kPa. The resulting product was left to dry in a vacuum drier at the temperature of 40°C and the pressure of 20 kPa for 12 hours. X-ray powder pattern in Fig. 8, The glass transition temperatures of the solid dispersion according to DSC were 52°C and 135°C.

Example 1 1

Comparison of solubility of crystalline vortioxetine hydrobromide and the prepared amorphous forms of vortioxetine hydrobromide stabilized by polymers

The solubility kinetics was studied in an aqueous solution of 0.1 mo 1/1 HC1 with pH 1.2 at 37°C (simulation of conditions in the alimentary tract). The solution was stirred by means of a shaker. The solutions were prepared in such a way that the final concentration could correspond to 1.5 mg/ml. The undissolved solid fraction was removed by centrifugation after 5, 15, 30 and 1440 min. The supernatant was analyzed with reverse-phase HPLC. The concentration of the dissolved vortioxetine hydrobromide was determined based on the peak area of vortioxetine hydrobromide with the use of a calibration line. The calibration series of vortioxetine hydrobromide was in the prepared range of 0.02 - 1.5 mg/1 and in this interval the peak areas exhibited a linear dependence on the concentration. The solubility kinetics of crystalline vortioxetine hydrobromide and the prepared amorphous forms of vortioxetine hydrobromide stabilized by polymers is shown in Fig. 10. When the polymers Eudragit L 100, Eudragit SI 00 and HPMCAS LF were used, a lower content of vortioxetine hydrobromide was measured in the acidic environment after 24 hours than in the case of solubility of the crystalline form. When the polymers PVP K30 and Methocel E5 were used, after 24 hours the content of vortioxetine hydrobromide in the supernatant was higher than in the case of solubility of crystalline vortioxetine hydrobromide (see Table 3). This experiment has proved that suitable selection of the polymer that stabilizes amorphous vortioxetine hydrobromide can significantly influence its solubility.

Claims

1. An amorphous mixture of vortioxetine or its hydrobromide salt with a polymer, characterized in that the polymer is selected from derivatives of polyacrylates, (poly)methacrylates, cellulose, or from derivatives of (poly)vinyl.

2. The amorphous mixture of vortioxetine or its hydrobromide salt with a polymer according to claim 1, characterized in that it exhibits a glass transition temperature Tg >40°C.

3. The amorphous mixture of vortioxetine or its hydrobromide salt with a polymer according to claims 1 and 2, characterized in that the polymer is selected from the group of polymethacrylate derivatives, polyvinyl pyrrolidone, hydroxypropyl methylcellulose and hypromellose acetate succinate.

4. The amorphous mixture of vortioxetine or its hydrobromide salt with a polymer according to claim 3, which exhibits the characteristic amorphous halo with the use of the CuKa X-ray radiation.

5. The amorphous mixture of vortioxetine or its hydrobromide salt with a polymer according to claims 1-4, characterized in that it is prepared in the weight ratio of 1:2 - active pharmaceutical ingredient - API : polymer.

6. The amorphous mixture of vortioxetine or its hydrobromide salt with a polymer according to any of the previous claims, characterized in that the polymer is a polymethacrylate derivative.

7. The amorphous mixture of vortioxetine or its hydrobromide salt with a polymer according to any of the previous claims, characterized in that the polymer is hydroxypropyl methylcellulose.

8. The amorphous mixture of vortioxetine or its hydrobromide salt with a polymer according to any of the previous claims, characterized in that the polymer is polyvinyl pyrrolidone.

9. The amorphous mixture of vortioxetine or its hydrobromide salt with a polymer according to any of the previous claims, characterized in that the polymer is hypromellose acetate succinate.

10. A method of preparing the amorphous mixture of vortioxetine or its hydrobromide salt with a polymer as defined in claims 1 to 9, comprising dissolution of vortioxetine in the base form or in the hydrobromide salt form with a suitable polymer selected from the group consisting of polymethacrylate derivatives, polyvinyl pyrrolidone, hydroxypropyl methylcellulose and hypromellose acetate succinate in a suitable organic solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, ethyl acetate, acetone, dichloromethane, tetrahydrofuran or their mixtures, followed by removal of the solvent to obtain an amorphous mixture.

11. The method of preparing the amorphous mixture of vortioxetine or its hydrobromide salt with a polymer according to claim 10, characterized in that the solvent is a mixture of dichloromethane and ethanol.

12. The method according to claim 11, characterized in that vortioxetine hydrobromide is dissolved with the polymethacrylate derivatives in a dichloromethane : ethanol mixture with the volume ratio of 1:1 and subsequently the solvent is removed, producing an amorphous mixture.

13. A method of preparing the amorphous mixture of vortioxetine or its hydrobromide salt with a polymer as defined in claims 1 to 9, comprising mixing of vortioxetine in the base form or in the hydrobromide salt form with a suitable polymer selected from the group consisting of polymethacrylate derivatives, polyvinyl pyrrolidone, hydroxypropyl methylcellulose and hypromellose acetate succinate and subsequent heating of this mixture, producing a melt and an amorphous mixture.

14. Use of the amorphous mixture of vortioxetine or its hydrobromide salt with a polymer as defined in claims 1 to 9 for the preparation of a pharmaceutically acceptable composition.