WO2017045655A1

WO2017045655A1 - An amorphous form of vortioxetine hydrobromide stabilized by a cyclodextrin

Info

Publication number: WO2017045655A1
Application number: PCT/CZ2016/000099
Authority: WO
Inventors: Pavel ZVATORA; Ondrej Dammer; Hana TOZICKOVA; Pavel KOVACIK
Original assignee: Zentiva, K.S.
Priority date: 2015-09-16
Filing date: 2016-09-06
Publication date: 2017-03-23
Also published as: CZ2015633A3

Abstract

The object of the invention is amorphous vortioxetine hydrobromide stabilized by cyclodextrin as a suitable carrier while the ratio of the active pharmaceutical ingredient to cyclodextrin is 1:4. Another object is a method of its preparation and use for a pharmaceutical composition.

Description

An amorphous form of vortioxetine hydrobromide stabilized by a cyclodextrin Field of the Invention

This invention relates to a novel stabilized amorphous form of l-(2-((2,4- dimethylphenyl)thio)phenyl)piperazine hydrobromide, known as vortioxetine hydrobromide of formula I

(I)

The invention further comprises various preparation methods of 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 and their use in a pharmaceutical composition are described and characterized. A new application, WO 2014/177491, describes amorphous forms of vortioxetine hydrobromide stabilized by adsorbents such as AI₂0₃, CaC0₃, MgO, Si0₂, Ti0₂ and ZnO.

The patent application WO 2015/044963 describes amorphous forms of the free base of vortioxetine and vortioxetine hydrobromide stabilized by polyvinyl pyrrolidone, hydroxypropyl methylcellulose and hypromellose acetate succinate. These amorphous forms generally have a higher solubility and biological availability than crystalline forms of vortioxetine. In the case of stabilization of vortioxetine hydrobromide by means of Si0₂ (Syloid® 72 FP) its solubility in water with pH 1.2 was about 1.5 times higher than the solubility of crystalline vortioxetine hydrobromide of form beta.

The present solution wherein the amorphous form of vortioxetine hydrobromide is stabilized by means of cyclodextrin as a suitable carrier exhibits approx. 2.2 times higher solubility than crystalline vortioxetine hydrobromide of form beta under identical conditions (water, pH 1.2).

Disclosure of the Invention

The object of the invention is amorphous vortioxetine hydrobromide stabilized by a cyclodextrin as a suitable carrier, a method of its preparation and use for a pharmaceutical composition.

Brief description of the Drawings Figure 1 : X-ray powder pattern of vortioxetine hydrobromide with β-cyclodextrin - preparation by evaporation of the solvent on a rotary vacuum evaporator.

Figure 2: X-ray powder pattern of vortioxetine hydrobromide with β-cyclodextrin - preparation by spray drying

Detailed description of the Invention

The invention relates to new solid forms of l-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine hydrobromide, known as vortioxetine hydrobromide, in the form of a stable amorphous substance with a cyclodextrin and methods of their preparation. A crystalline structure is characterized by a long-distance structure arrangement. On the other hand, amorphous solid substances do not exhibit this arrangement. Compared to crystalline solid substances, amorphous solid substances have a larger surface area, and therefore they exhibit a higher solubility. If the solubility and biological availability of active pharmaceutical ingredients needs to be increased, they should be preferably prepared in an amorphous form. If the temperature of a crystalline material reaches the melting point, its phase changes from the solid phase to the liquid phase. 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 subcooled solution. The subcooled solution is cooled to achieve the glass transition (Tg), the molecules are kinetically frozen and the subcooled liquid solidifies and passes into the vitreous state. Molecules in a subcooled 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^nd 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 cannot be prepared with the use of common laboratory procedures. For this reason, the amorphous form of vortioxetine and vortioxetine hydrobromide must be stabilized to prevent re-crystallization.

Amorphous forms of vortioxetine or vortioxetine hydrobromide may be stabilized by addition of other substances. A number of substances may be used as stabilizers of the amorphous form. The application WO 2014/177491, describes amorphous forms of vortioxetine hydrobromide stabilized by adsorbents (AI₂0₃, CaC0₃, MgO, Si0₂, Ti0₂, ZnO).

Another possibility of stabilization of the amorphous form of vortioxetine in the base or salt form is the use of a suitable polymer. The patent application WO 2015/044963 describes amorphous forms of the free base of vortioxetine and vortioxetine hydrobromide stabilized by polyvinyl pyrrolidone, hydroxypropyl methylcellulose and hypromellose acetate succinate.

The present invention uses a cyclodextrin as a suitable carrier for stabilization of vortioxetine hydrobromide, especially β-cyclodextrin.

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 method. In a common dissolution method 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 methanol, ethanol, ethyl acetate, isopropyl alcohol, acetone, dichloromethane, tetrahydrofuran etc. may be mentioned. 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 is produced. The solvent can be removed by means of a rotary vacuum evaporator, fluid granulation, spray drying, electrospinning, solvent freezing etc.

Other options of preparation of stabilized amorphous substances are methods without the use of a solvent.

This invention focuses on the preparation of an amorphous form of vortioxetine hydrobromide in a mixture with cyclodextrin as a suitable carrier wherein this mixture can be used for a pharmaceutical formulation. For the preparation of the cyclodextrin-stabilized amorphous solid form of vortioxetine hydrobromide hydrated β-cyclodextrin with the molecular weight of approx. 1333 Da (g/mol) can advantageously be used. Cyclodextrins are cyclic oligosaccharide derivatives of starch. They form 6-, 7-, 8-membered rigid structures with a central cavity that is suitable for complexation of hydrophobic parts of molecules and formation of inclusion complexes. For these properties they are frequently used in pharmacy to increase solubility, biological availability and physical stabilization of a number of active pharmaceutical ingredients. Cyclodextrins are also widely used in pharmacy to disguise unpleasant taste.

For the preparation of amorphous solid forms of vortioxetine hydrobromide stabilized by β-cyclodextrin a method has been used wherein the solvent is removed by means of a rotary vacuum evaporator and a spray drier (BUCHI B290). An advantage of the present method is that the amorphous form of cyclodextrin-stabilized vortioxetine hydrobromide can be prepared by evaporation of an aqueous solution without the use of organic solvents. The advantages of this method are that it is easy to carry out and at the same time. The X-ray powder analysis results have shown that both the above mentioned procedures of aqueous solution evaporation can be used to prepare amorphous forms of vortioxetine hydrobromide. 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 and storage at 25°C/0% RH for the test period of at least 30 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 was registered, which was also the case of storage at 25°C/75% RH (see Table 1).

Table 1: Stabilities of the prepared amorphous solid forms of vortioxetine hydrobromide with β-cyclodextrin (weight ratio 1:4, API: β-cyclodextrin)

The prepared amorphous solid forms of vortioxetine hydrobromide stabilized by cyclodextrin in accordance with this invention, which are stable, highly soluble, easy to prepare under environment-friendly conditions, can be advantageously used for the preparation of pharmaceutical compositions, especially solid drug forms, e.g. tablets. Such pharmaceutical compositions can contain at least one excipient from the group of fillers (e.g. lactose), binders (e.g. microcrystalline cellulose, mannitol), disintegrants (e.g. sodium salt of croscarmellose, hydroxypropyl cellulose), 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 embodiment examples below. These examples, which illustrate the preparation of novel amorphous forms of 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

Spray drying

The removal of the solvent with the use of spray drying was carried out by means of a BUCHI B290 laboratory spray drier. Carrier gas flow 40 m³/h, inlet temperature 120°C, outlet temperature 55°C, solution dosage rate 20%, aspirator 85%, condensation loop temperature 0°C.

X-ray powder analysis

The diffractograms were obtained using an X ERT PRO MPD PANalytical powder diffractometer, used radiation CuKa (λ=0.1542 nm (1.5142 A)), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, 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.

UV-VIS spectrometric analysis

The content of dissolved vortioxetine hydrobromide was analyzed with the use of a UV-VIS Cary 60 Agilent Technologies device in the range of 200 to 500 nm, with the increment of 1 nm. The measurement was carried out in a cuvette with the cuvette space length of 2 mm. The absorbance peak was read at 230 nm. Dissolution of the samples

The samples were dissolved in 1ml glass vials with the use of a shaker (Eppendorf Thermomixer comfort) at 21 Hz and the temperature of 37°C for 60 min. The undissolved solid fraction was removed by means of filtration through a nylon filter with the pore size of 0.2 μιη. The content of dissolved vortioxetine hydrobromide was determined by using the calibration line method.

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 hydrobromide with β-cyclodextrin by evaporation of the solvent using a rotary vacuum evaporator.

400 mg of β-cyclodextrin and 100 mg of crystalline vortioxetine hydrobromide (form β) were dosed into a 100 ml round flask with a ground joint. This mixture was dissolved in 25 ml of distilled water, being stirred on a magnetic stirrer at 25°C. The solution was stirred for 20 min, and after this time period the solvent was evaporated on a vacuum evaporator at 70°C and the pressure of 1.5 kPa. The resulting product was left to dry in a vacuum dryer at the temperature of 40°C and the pressure of 20 kPa for 12 hours. X-ray powder pattern in Fig. 1.

Example 4

Preparation of the amorphous solid form of vortioxetine hydrobromide with β-cyclodextrin by evaporation of the solvent using a spray dryer. 3.2 mg of β-cyclodextrin and 0.8 mg of crystalline vortioxetine hydrobromide (form β) were dosed into a 250 ml round flask with a ground joint. This mixture was dissolved in 200 ml of distilled water, being stirred in a magnetic stirrer at 25°C. The solution was stirred for 20 min, and after this time period the solvent was evaporated using the BUCHI B290 spray dryer. This way, the amount of 2.4 g of the product (yield 60%) was obtained. X-ray powder pattern in Fig. 2.

Example 5

Comparison of solubility of crystalline vortioxetine hydrobromide and the prepared amorphous form of vortioxetine hydrobromide stabilized by β-cyclodextrin. The solubility of the solid forms of vortioxetine hydrobromide was studied in an aqueous solution of 67 mmol-dm-3 HCl and 33 mmol-dm-3 NaCl with pH 1.2 at 37°C (simulation of the alimentary tract conditions). The solution was stirred using a shaker for 60 min. The undissolved solid fraction was removed by means of filtration through a nylon filter with the pore size of 0.2 μηι. The supernatants were analyzed by using a UV-Vis spectrometer. The concentration of the dissolved vortioxetine hydrobromide was determined based on the peaks of the absorption bands at 230 nm with the use of a calibration line. The calibration series of vortioxetine hydrobromide was in the prepared range of 0.2 - 1.5 mg/ml and in this interval the peak positions of the absorption bands exhibited a linear dependence on the concentration. Under these conditions, the solubility of crystalline vortioxetine hydrobromide (form β) was 0.60 g/ml. In the case of using the amorphous solid form of vortioxetine hydrobromide stabilized by β-cyclodextrin the solubility of vortioxetine hydrobromide was 1.34 mg/ml). This experiment proved a considerably higher solubility of amorphous voritoxetine hydrobromide stabilized by β-cyclodextrin as compared to its crystalline form.

Claims

1. Amorphous vortioxetine hydrobromide stabilized by a cyclodextrin.

2. The amorphous vortioxetine hydrobromide in accordance with claim 1 wherein the cyclodextrin is β-cyclodextrin.

3. The amorphous vortioxetine hydrobromide in accordance with claims 1 and 2 exhibiting the characteristic amorphous halo with the use of X-ray CuKa radiation.

4. The amorphous vortioxetine hydrobromide in accordance with claims 1 to 3 wherein the weight ratio of the active pharmaceutical ingredient - API: cyclodextrin is 1 :4.

5. A method for preparing the amorphous vortioxetine hydrobromide stabilized by a cyclodextrin characterized in claims 1 to 4, characterized in that it comprises dissolution of vortioxetine hydrobromide with cyclodextrin in water or a mixture of water and an organic solvent miscible with water selected from the group of C1-C4 alcohols and subsequent removal of the solvent, producing an amorphous mixture.

6. The method for preparing in accordance with claim 5, characterized in that the used solvent is water.

7. The method for preparing in accordance with claim 5, characterized in that the solvent is removed from the solution by means of spray drying or in a vacuum evaporator, preferably with spray drying.

8. Use of vortioxetine hydrobromide characterized in claims 1 to 4 for the preparation of a pharmaceutically acceptable composition.