WO2014177491A1

WO2014177491A1 - New solid form of 1-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine hydrobromide

Info

Publication number: WO2014177491A1
Application number: PCT/EP2014/058546
Authority: WO
Inventors: Borut ZUPANCIC; Polona MULEC
Original assignee: Lek Pharmaceuticals D.D.
Priority date: 2013-04-29
Filing date: 2014-04-28
Publication date: 2014-11-06

Abstract

Title: New Solid Form of 1-(2-((2,4-Dimethylphenyl)thio)phenyl)piperazine Hydrobromide The present invention relates to 1-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine hydrobromide (vortioxetine hydrobromide,a drug for the treatment of depression and anxiety) in amorphous form and in association with an adsorbent. The invention further relates to pharmaceutical compositions comprising amorphous 1-(2-((2,4-dimethylphenyl)thio)phenyl)- piperazinehydrobromidein association with an adsorbent, processes for the manufacture of such pharmaceutical compositions and their use as medicaments.

Description

New Solid Form of 1 -(2-((2,4-Dimethylphenyl)thio)phenyl)piperazine Hydrobromide

Field of the Invention This invention relates to a new solid form of 1 -(2-((2,4-dimethylphenyl)thio)phenyl)piperazine hydrobromide (vortioxetine hydrobromide) a drug for the treatment of depression and anxiety The invention further relates to pharmaceutical compositions comprising this new solid form, processes for the manufacture thereof and their use as medicaments.

Background of the Invention

The preparation of crystalline vortioxetine hydrobromide (HBr) and its use in the preparation of pharmaceutical compositions is described in WO 2007/144005 A1. The solubility of the alpha and beta crystalline forms of vortioxetine hydrobromide in water is described as 2 mg/ml and 1.2 mg/ml respectively. Given the relatively poor aqueous solubility of vortioxetine hydrobromide, there is a need for an alternative solid form of vortioxetine hydrobromide having improved solubility and bioavailability. In addition, there remains a need for improved pharmaceutical compositions comprising vortioxetine hydrobromide which have advantages in terms of tablet size and patient convenience.

Summary of the Invention

Described herein is a stabilised amorphous form of vortioxetine hydrobromide which shows improved solubility relative to crystalline vortioxetine hydrobromide. The amorphous vortioxetine hydrobromide is stabilised by means of an adsorbent. As demonstrated herein, surprisingly high levels of active pharmaceutical agent (API) loading on the adsorbent can be achieved, translating into smaller tablet size when formulating the API into a pharmaceutical composition. Processes for the manufacture of pharmaceutical compositions comprising amorphous vortioxetine hydrobromide and their use as medicaments are also described.

Description of the Figures

Figure 1 : XRPD of amorphous vortioxetine hydrobromide in association with Syloid 72 FP

(17.63% loading) Figure 2: XRPD of amorphous vortioxetine hydrobromide in association with Syloid 72 FP (34.75% loading)

Figure 3: SEM images at 10,000x (Figure 3a) and 1 ,000x (Figure 3b) magnifications of

Syloid 72 FP adsorbent in the absence of vortioxetine hydrobromide

Figure 4: SEM images at 10,000x (Figure 4a) and 1 ,000x (Figure 4b) magnifications of amorphous vortioxetine hydrobromide in association with Syloid 72 FP adsorbent (35% loading)

Figure 5: SEM images at 10,000x (Figure 5a) and 1 ,000x (Figure 5b) magnifications of crystalline vortioxetine hydrobromide (50%) mixed with Syloid 72 FP (50%)

Figure 6: Dissolution kinetics for amorphous vortioxetine HBr on Syloid 72 FP versus

crystalline vortioxetine HBr (media pH = 1 .2, 37°C)

Detailed Description of the Invention

Embodiments and examples of the present invention are described below. Embodiment 1 . Amorphous vortioxetine hydrobromide in association with an adsorbent.

Embodiment 2. Amorphous vortioxetine hydrobromide according to Embodiment 1

wherein the adsorbent is selected from Al₂0₃, CaC0₃, MgO, Si0₂, Ti0₂ and ZnO.

Embodiment 3. Amorphous vortioxetine hydrobromide according to Embodiment 1

wherein the adsorbent comprises silicon.

Embodiment 4. Amorphous vortioxetine hydrobromide according to any one of

Embodiments 1 to 3 wherein the adsorbent is Si0₂.

Embodiment 5. Amorphous vortioxetine hydrobromide according to any one of

Embodiments 1 to 4 wherein the adsorbent is a silica gel. Embodiment 6. Amorphous vortioxetine hydrobromide according to Embodiment 1 or

Embodiment 3 wherein the adsorbent is a silicate.

Embodiment 7. Amorphous vortioxetine hydrobromide according to Embodiment 6

wherein the adsorbent is Neusilin. Embodiment 8. Amorphous vortioxetine hydrobromide according to any one of

Embodiments 1 to 4 wherein the adsorbent is selected from Aerosil and Syloid.

Embodiment 9. Amorphous vortioxetine hydrobromide according to Embodiment 8 wherein the adsorbent is selected from Aerosil 200, Aerosil 380, Syloid AL1 , Syloid 72 FP and Syloid 244 FP.

Embodiment 10. Amorphous vortioxetine hydrobromide according to any one of

Embodiments 1 to 9 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is over 20%. Embodiment 1 1 . Amorphous vortioxetine hydrobromide according to any one of

Embodiments 1 to 9 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is over 25%.

Embodiment 12. Amorphous vortioxetine hydrobromide according to any one of

Embodiments 1 to 9 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is over 30%.

Embodiment 13. Amorphous vortioxetine hydrobromide according to any one of

Embodiments 1 to 9 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is over 35%.

Embodiment 14. Amorphous vortioxetine hydrobromide according to any one of

Embodiments 1 to 9 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is over 40%.

Embodiment 15. Amorphous vortioxetine hydrobromide according to any one of

Embodiments 1 to 9 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is over 45%. Embodiment 16. Amorphous vortioxetine hydrobromide according to any one of

Embodiment 10 to 15 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is less than 60%.

Embodiment 17. Amorphous vortioxetine hydrobromide according to any one of

Embodiment 10 to 15 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is less than 55%.

Embodiment 18. A pharmaceutical composition comprising amorphous vortioxetine hydrobromide as defined in any one of Embodiments 1 to 17. Embodiment 19. A pharmaceutical composition according to Embodiment 18 comprising at least one pharmaceutically acceptable excipient.

Embodiment 20. A process for the preparation of a pharmaceutical composition comprising amorphous vortioxetine hydrobromide in association with an adsorbent which comprises:

(i) dissolving crystalline vortioxetine hydrobromide in a protic solvent, an aprotic solvent, or a mixture of a protic solvent and an aprotic solvent;

(ii) adding the adsorbent to the solution;

(iii) mixing the adsorbent and vortioxetine hydrobromide solution; and (iv) removing the solvent.

The skilled person would understand that steps (i) and (ii) of Embodiment 20 could be carried out in the reverse order.

Embodiment 21 . A process according to Embodiment 20 wherein the adsorbent is selected from Al₂0₃, CaC0₃, MgO, Si0₂, Ti0₂ and ZnO. Embodiment 22. A process according to Embodiment 21 wherein the adsorbent is Si0₂.

Embodiment 23. A process according to any one of Embodiments 20 to 22 wherein the adsorbent is a silica gel.

Embodiment 24. A process according to Embodiment 23 wherein the silica gel is selected from Aerosil and Syloid. Embodiment 25. A process according to Embodiment 24 wherein the silica gel is selected from Aerosil 200, Aerosil 380, Syloid AL1 , Syloid 72 FP and Syloid 244 FP.

Embodiment 26. A process according to Embodiment 20 wherein the adsorbent is a silicate.

Embodiment 27. A process according to Embodiment 26 wherein the silicate is Neusilin. Embodiment 28. A process according to any one of Embodiments 20 to 27 wherein the solvent used in step (i) is a protic solvent selected from Ci-C₆ alcohols.

Embodiment 29. A process according to Embodiment 28 wherein the CrC₆ alcohol is 1 - butanol. Embodiment 30. A process according to any one of Embodiments 20 to 27 wherein the solvent used in step (i) is dichloromethane.

Embodiment 31 . A process according to any one of Embodiments 20 to 30 wherein step (i) is carried out at a temperature of 0 to 100°C. Embodiment 32. A process according to any one of Embodiments 20 to 30 wherein step (i) is carried out at a temperature of 20 to 30°C.

Embodiment 33. A process according to any one of Embodiments 20 to 32 wherein in step

(iii) the adsorbent and vortioxetine hydrobromide solution are mixed for at least 1 minute. Embodiment 34. A process according to any one of Embodiments 20 to 33 wherein in step

(iv) the solvent is removed by filtration or evaporation. Embodiment 35. A pharmaceutical composition according to Embodiment 18 or

Embodiment 19 for use as a medicament. Embodiment 36. A pharmaceutical composition according to Embodiment 18 or

Embodiment 19 for use in the treatment of mood disorders; major depressive disorder; general anxiety disorder; post-traumatic stress disorder; depression associated with cognitive impairment, Alzheimer's disease or anxiety; depression with residual symptoms; chronic pain; or eating disorders. For the purposes of interpreting the terms used in the description of the invention, the following definitions will apply. All other terms as used herein are to be interpreted in accordance with their everyday meaning to the person of ordinary skill in the art.

As used herein, the term "amorphous vortioxetine hydrobromide" is intended to mean a noncrystalline form of vortioxetine hydrobromide as determined by differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD) analysis or by using a scanning electron microscope (SEM).

As used herein, the term "in association with" is intended to mean that the amorphous vortioxetine hydrobromide forms an adsorbate on the surface of the adsorbent. The difference between amorphous vortioxetine hydrobromide in association with an adsorbent and crystalline vortioxetine hydrobromide simply mixed with an adsorbent can be clearly seen using a SEM (for example see Figure 4b versus Figure 5b). As used herein, the term "adsorbent" is intended to mean any substance onto which amorphous vortioxetine hydrobromide is adsorbed. Adsorption of amorphous vortioxetine hydrobromide onto an adsorbent serves to stabilise the vortioxetine hydrobromide in its amorphous form. Examples of adsorbents include, but are not limited to, Si0₂, Al₂0₃, Ti0₂, MgO, synthetic and amorphous silicas such as Aerosil, for example Aerosil 200, Aerosil 380 (Evonik Industries), Syloid, for example Syloid AL1 , Syloid 72 FP and Syloid 244 FP (W. R. Grace & Co. -Conn), and synthetic and amorphous silicates such as Neusilin and in particular Neusilin UFL2 (Fuji Chemical industry Co., Ltd.).

As used herein, the term "silica gel" is intended to mean a granular, porous form of Si0₂. Examples of silica gels include, but are not limited to, Syloid AL1 , Syloid 72 FP and Syloid 244 FP.

As used herein, the term "silicate" is intended to mean a compound comprising silicon, oxygen and one or more metals. An example of a silicate includes, but is not limited to, Neusilin. As used herein, the percentage loadings of amorphous vortioxetine hydrobromide on the adsorbent are calculated as follows: loading = ((mass of vortioxetine hydrobromide weighed at the beginning)-(mass of vortioxetine hydrobromide remaining in the filtrate))/((mass of vortioxetine hydrobromide weighed at the beginning)-(mass of vortioxetine hydrobromide remaining in the filtrate)+(mass of adsorbent)). The weight of amorphous vortioxetine hydrobromide remaining in the filtrate is determined by weighing the amount of vortioxetine hydrobromide in the filtrate after solvent evaporation or by HPLC analysis of the filtrate.

As used herein, the term "aprotic solvent" is intended to mean any solvent which contains no hydrogen atom that is capable of hydrogen bonding. Examples of aprotic solvents include, but are not limited to, DMSO, DMF and CH₂CI₂. As used herein, the term "protic solvent" is intended to mean any solvent which contains one or more hydrogen atoms that are capable of hydrogen bonding. Examples of protic solvents include, but are not limited to, Ci-C₆ alcohols and acetic acid.

As used herein, the term "pharmaceutical composition" is intended to mean any mixture or solution containing amorphous vortioxetine hydrobromide in association with an adsorbent suitable for administration to a mammal, preferably a human, in order to prevent, treat or control a particular disease or condition affecting the mammal.

As used herein, the term "pharmaceutically acceptable excipient" refers to a

pharmaceutically acceptable ingredient that is commonly used in the pharmaceutical industry for preparing granulate and/or solid oral dosage formulations. Examples of categories of excipients include, but are not limited to, antioxidants, binders, buffering agents, Bulking agents, disintegrants, diluents, fillers, glidants, lubricants, preservatives, surfactants and cosurfactants. One of ordinary skill in the art may select one or more of the aforementioned excipients with respect to the particular desired properties of the granulate and/or solid oral dosage form by routine experimentation and without any undue burden. The amount of each excipient used may vary within ranges conventional in the art. The following references disclose techniques and excipients used to formulate oral dosage forms (see The Handbook of Pharmaceutical Excipients, 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2000).

As used herein, the term "subject" refers to an animal. Typically the animal is a mammal. In a preferred embodiment the subject is a human.

As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically or in quality of life from such treatment. As used herein, the term "a therapeutically effective amount" of amorphous vortioxetine hydrobromide refers to an amount of amorphous vortioxetine hydrobromide that will elicit the biological or medical response of a subject, ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent disease.

As used herein, the term "treat", "treating" or "treatment" of any disease or disorder refers to ameliorating, alleviating or modulating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).

WO 2007/144005 A1 states that vortioxetine, and pharmaceutically acceptable salts thereof, exert a combination of serotonin transporter (SERT), 5-HT₃ antagonism and 5-HT_1A partial agonism. As such, the amorphous vortioxetine hydrobromide of the present invention is expected to be of use in the treatment of mood disorders; major depressive disorder; general anxiety disorder; post-traumatic stress disorder; depression associated with cognitive impairment, Alzheimer's disease or anxiety; depression with residual symptoms; chronic pain; and eating disorders.

In accordance with the foregoing, in one aspect, the invention relates to a pharmaceutical composition comprising amorphous vortioxetine hydrobromide in association with an adsorbent for use as a medicament. In one embodiment, the invention relates to a

pharmaceutical composition comprising amorphous vortioxetine hydrobromide in association with an adsorbent for use in the treatment of mood disorders; major depressive disorder; general anxiety disorder; post-traumatic stress disorder; depression associated with cognitive impairment, Alzheimer's disease or anxiety; depression with residual symptoms; chronic pain; or eating disorders.

In a further aspect, the invention relates to the use of amorphous vortioxetine hydrobromide as an active pharmaceutical ingredient in a medicament. In one embodiment, the invention relates to the use of amorphous vortioxetine hydrobromide as an active pharmaceutical ingredient in a medicament for the treatment of mood disorders; major depressive disorder; general anxiety disorder; post-traumatic stress disorder; depression associated with cognitive impairment, Alzheimer's disease or anxiety; depression with residual symptoms; chronic pain; or eating disorders. In a further aspect, the invention relates to the use of amorphous vortioxetine hydrobromide for the manufacture of a medicament for the treatment mood disorders; major depressive disorder; general anxiety disorder; post-traumatic stress disorder; depression associated with cognitive impairment, Alzheimer's disease or anxiety; depression with residual symptoms; chronic pain; or eating disorders. In a further aspect, the invention relates to a method for the treatment of mood disorders; major depressive disorder; general anxiety disorder; post-traumatic stress disorder;

depression associated with cognitive impairment, Alzheimer's disease or anxiety; depression with residual symptoms; chronic pain; or eating disorders, in a subject in need of such treatment, which method comprises administering to such subject a therapeutically effective amount amorphous vortioxetine hydrobromide.

For the above-mentioned indications, the appropriate dosage will vary depending on, for example, the host, the mode of administration, the nature and severity of the condition, disease or disorder or the effect desired. Amorphous vortioxetine hydrobromide may be conveniently administered in a unit dose form comprising about 1 to 50 mg of the API. The total daily dose is expected to be in the range of about 1 to 20 mg of API.

In a further aspect, the invention relates to a pharmaceutical composition comprising amorphous vortioxetine hydrobromide as API in association with an adsorbent and

comprising at least one pharmaceutically acceptable excipient. Examples of categories of excipients include, but are not limited to, antioxidants, binders, buffering agents, bulking agents, disintegrants, diluents, fillers, glidants, lubricants, preservatives, surfactants and cosurfactants.

Typical excipients include antioxidants. Antioxidants may be used to protect ingredients of the composition from oxidizing agents that are included within or come in contact with the composition. Examples of antioxidants include water soluble antioxidants such as ascorbic acid, sodium sulfite, metabisulfite, sodium miosulfite, sodium formaldehyde, sulfoxylate, isoascorbic acid, isoascorbic acid, cysteine hydrochloride, 1 ,4-diazobicyclo-(2,2,2)-octane, and mixtures thereof. Examples of oil-soluble antioxidants include ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, potassium propyl gallate, octyl gallate, dodecyl gallate, phenyl-a-napthyl-amine, and tocopherols such as a-tocopherol.

Examples of pharmaceutically acceptable binders include, but are not limited to, starches; celluloses and derivatives thereof; copolymer of 1 -vinyl-2-pyrrolidone and vinyl acetate;

sucrose; dextrose; corn syrup; polysaccharides; and gelatin. Examples of celluloses and derivatives thereof include for example, microcrystalline cellulose, e.g., AVICEL PH from FMC (Philadelphia, PA), hydroxypropyl cellulose hydroxylethyl cellulose and

hydroxylpropylmethyl cellulose METHOCEL from Dow Chemical Corp. (Midland, Ml); HP- Cellulose 100 (Klucel LF). Copolymer of 1 -vinyl-2-pyrrolidone and vinyl acetate can be purchased as Kollidon VA64 from BASF.

Buffering agents may be used to maintain an established pH of the composition. Examples of buffering agents included sodium citrate, calcium acetate, potassium metaphosphate, potassium phosphate monobasic, and tartaric acid.

Bulking agents are ingredients which may provide bulk to a pharmaceutical composition. Examples of bulking agents include, without limitation, PEGs, mannitol, trehalose, lactose, sucrose, polyvinyl pyrrolidone, sucrose, glycine, cyclodextrins, dextran and derivatives and mixtures thereof.

Surfactants are agents used to stabilize multi-phasic compositions, e.g., used as wetting agents, antifoam agents, emulsifiers, dispersing agents, and penetrants. Surfactants include, but are not limited to, fatty acid and alkyl sulfonates; benzethanium chloride, e.g., HYAMINE 1622 from Lonza, Inc. (Fairlawn, NJ); polyoxyethylene sorbitan fatty acid esters, e.g., the TWEEN Series from Uniqema (Wilmington, DE); and natural surfactants, such as sodium taurocholic acid, 1 -palmitoyl-2-Sn-glycero-3-phosphocholine, lecithin and other

phospholipids. Such surfactants, e.g., minimize aggregation of lyophilized particles during reconstitution of the product. Surfactants, if present, are typically used in an amount of from about 0.01 % to about 5% w/v.

A cosurfactant is a surface-active agent that acts in addition to the surfactant by further lowering the interfacial energy but that cannot form micellar aggregates by itself.

Cosurfactants can be, for example, hydrophilic or lipophilic. Examples of a cosurfactant include, but are not limited to, cetyl alcohol and stearyl alcohol.

Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches, e.g. (sodium carboxymethyl starch); clays; celluloses, e.g. low substitute hydroxy propyl cellulose; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone or crospovidone, e.g., POLYPLASDONE XL from International Specialty

Products (Wayne, NJ); cross-linked sodium carboxymethylcellulose or croscarmellose sodium, e.g., AC-DI-SOL from FMC; and cross-linked calcium carboxymethylcellulose; soy polysaccharides; and guar gum.

Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc.

Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose. Typically, a lubricant may be present in an amount from about 0.1 % to about 5% by weight of the composition; whereas, the glidant, e.g., may be present in an amount from about 0.1 % to about 10% by weight.

Preservatives may also be used to protect the composition from degradation and/or microbial contamination. Examples of preservatives include liquipar oil, phenoxyethanol, methyl paraben, propyl paraben, butyl paraben, isopropyl paraben, isobutyl paraben, diazolidinyl urea, imidazolidinyl urea, diazolindyl urea, benzalkonium chloride, benzethonium chloride, phenol, and mixtures thereof (e.g., liquipar oil).

The pharmaceutical compositions of the present invention are preferably in solid oral dosage form. Solid oral dosage forms include, but are not limited to, tablets, hard or soft capsules, caplets, lozenges, pills, mini-tablets, pellets, beads, granules (e.g. packaged in sachets), or powders. The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.

Suitable compositions for oral administration include an effective amount of amorphous vortioxetine hydrobromide in association with an adsorbent in the form of tablets, hard or soft capsules, caplets, lozenges, pills, mini-tablets, pellets, beads, granules (e.g. packaged in sachets), or powders. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

In one embodiment, the pharmaceutical composition of the invention is in the form of a tablet or capsule.

In one embodiment, the pharmaceutical compositions are tablets or gelatin capsules comprising amorphous vortioxetine hydrobromide in association with an adsorbent together with

a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;

b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol;

and for tablets also

c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, copolymers of 1 -vinyl-2-pyrrolidone and vinyl acetate, sodium carboxymethylcellulose and/or polyvinylpyrrolidone;

and optionally

d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; celluloses; cross-linked polymers; and/or

e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methods known in the art.

Tablets can be optionally coated with a functional or non-functional coating as known in the art. Examples of coating techniques include, but are not limited to, sugar coating, film coating, microencapsulation and compression coating. Types of coatings include, but are not limited to, enteric coatings, sustained release coatings, controlled-release coatings. Anhydrous pharmaceutical compositions and dosage forms can also be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.

As used herein, a unit dosage form is a single dosage form which has the capacity of being administered to a subject to be effective, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising the active ingredient.

Tablets may be manufactured by direct compression or granulation.

In the process of direct compression, the powdered materials included in the solid dosage form are typically compressed directly without modifying their physical nature. Usually, the active ingredient, excipients such as a glidant to improve the rate of flow of the tablet granulation, and lubricant to prevent adhesion of the tablet material to the surface of the dies and punches of the tablet press, are blended in a twin shell blender or similar low shear apparatus before being compressed into tablets.

Granulation is a process in which granulates are formed. These granulates are then subjected to direct compression in order to form a tablet or encapsulated for a capsule. The granulates may be formed by wet granulation which includes: a) forming a powder mixture of the active ingredient and at least one

pharmaceutically acceptable excipient; b) adding a granulation liquid to the powder blend under agitation to form a wet mass; c) granulating the wet mass to form moist granulates; d) drying the moist granulates to form granulates; e) sieving the granulates.

Alternatively, the granulates may be formed by fluid-bed granulation which includes:

a) suspending particles of a material (e.g., an inert material or the active ingredient) with, e.g., a rising airstream in a vertical column;

spraying a granulating material into the column; c) allowing the particles to be coated with the granulating material resulting in granulates.

Another alternative for producing granulates includes melt granulation. This process includes:

a) forming a mixture of an active ingredient with at least one release retardant, e.g. a release retarding polymer, and optionally, a plasticizer;

b) granulating the mixture using an extruder or other suitable equipment, for

example a jacketed high shear mixer, while heating the mixture to a temperature above the softening temperature of the release retardant; as used herein, the "softening temperature" refers to the temperature at which the release retardant experiences a change in the rate of viscosity decrease as a function of temperature; and

c) cooling the granules to room temperature, for example, at a controlled rate.

Another alternative for producing granulates includes dry granulation which may include roller compaction or slugging. Roller compaction is a process in which uniformly mixed powders are compressed between two counter-rotating roll pairs to form a compressed sheet or ribbon that is then milled (granulated). Slugging is a process in which uniformly mixed powders are compressed into large tablets which are subsequently comminuted into the desired size.

Capsules as used herein refer to a formulation in which the amorphous vortioxetine hydrobromide in association with an adsorbent may be enclosed in either a hard or soft, soluble container or shell, often formed from gelatin.

A hard gelatin capsule, also known as a dry-filled capsule, is composed of two sections, one slipping over the other, thus completely surrounding (encapsulating) the drug formulation.

A soft elastic capsule has a soft, globular, e.g., gelatin shell.

Examples

Analytical Methods:

X-Rav Powder Diffraction (XRPD)

X-ray powder diffraction patterns were obtained by methods known in the art using Philips X'Pert PRO diffracto meter with X'Celerator detector using CuKa radiation (tube operating at 45 kV and 40 mA) in the Bragg-Brentano (reflection) geometry. Data were recorded from 2 to 40 °2Θ in steps of 0.033 °2Θ and a measurement time of 50 seconds per step. Variable divergence and antiscatter slits were used to maintain 10 mm of sample length irradiated.

Differential Scanning Calorimetry (DSC)

DSC thermograms were obtained using a Mettler Toledo DSC822e differential scanning calorimeter. The sample (1 -10 mg) was placed in an unsealed aluminium pan with a hole and heated at 10°C/min in the temperature range from 30 °C to 250 °C.

Scanning Electron Microscopy

The samples were mounted on stubs with double faced adhesive tape and sputter coated with a 3 nm gold layer in a high vacuum sputter coater (Leica EM SCD 500). Surface topography was analyzed with a scanning electron microscope (JSM FE SEM 7001 , Jeol, Tokyo, Japan) using secondary electron imaging (SEI) detector and different magnifications (100 - 20 OOOx). An acceleration voltage of 2 kV and a working distance of 5 mm were used.

Example 1 : Preparation of amorphous vortioxetine HBr on Syloid 72 FP Crystalline vortioxetine HBr was dissolved in dichloromethane at room temperature (a temperature range of about 21 °C to 26°C). Syloid 72 FP was added, the mixture stirred for 15 minutes at room temperature and the slurry then filtered. The dry product was analyzed by DSC and XPRD and found to be amorphous as shown in Table 1 below.

Table 1

Vortioxetine HBr Syloid 72 FP CH₂CI₂ Loading

Form

[g] [g] [mL] [%]

0.2 0.2 5 17.6 amorphous³

0.2 0.3 5 16.1 amorphous

0.2 0.4 5 16.8 amorphous

0.2 0.5 5 16.8 amorphous

0.2 0.6 5 16.4 amorphous

1 .0 5.0 50 15.4 amorphous^b

^a Figure 1 shows an XRPD of amorphous vortioxetine HBr in association with Syloid 72 FP when 0.2 g of vortioxetine HBr was dissolved in 5 mL dichloromethane and mixed with 0.2 g Syloid 72 FP to achieve a 17.6% loading. Similar XRPDs indicative of amorphous material were obtained for the other preparations listed in Table 1. The XRPDs obtained for amorphous vortioxetine HBr are in sharp contrast to those disclosed in WO 2007/144005 A1 for crystalline forms of vortioxetine HBr. ^b The cake was washed with 4 mL of CH₂CI₂ and dried under reduced pressure at 30°C. Example 2: Preparation of amorphous vortioxetine HBr on Syloid 72 FP

Crystalline vortioxetine HBr (0.2 g) was dissolved in 1 -butanol (10 mL) at 90°C. Syloid 72 FP (0.2 g) was added and the mixture stirred for 15 minutes. After cooling to room temperature the slurry was filtered. The product was dried under reduced pressure at 40°C. The dry product was analyzed by DSC: amorphous. Example 3: Preparation of amorphous vortioxetine HBr on Syloid 72 FP

Crystalline vortioxetine HBr was dissolved in 1 -butanol at 100°C. After cooling to room temperature Syloid 72 FP was added, the mixture stirred for 15 minutes and the slurry filtered. The product was then dried under reduced pressure. The dry product was analyzed by DSC and found to be amorphous as shown in Table 2 below. Table 2

Vortioxetine HBr Syloid 72 FP 1 -butanol Drying

Form

[g] [g] [mL] [°C]

0.2 0.2 20 30 amorphous

1 .0 5.0 50 40 amorphous

Example 4: Preparation of amorphous vortioxetine HBr on Syloid 72 FP

0.2 g of crystalline vortioxetine HBr was dissolved in 10 mL of 2-propanol at 79°C and 0.2 g of Syloid 72 FP added. The mixture was stirred for 15 minutes at 79°C and the hot slurry filtered. The cake was washed with 2 mL of 2-propanol and then dried under reduced pressure at 40°C. The dry product was analyzed by DSC: amorphous.

Example 5: Preparation of amorphous vortioxetine HBr on Syloid 72 FP

0.2 g of crystalline vortioxetine HBr was dissolved in 25 mL of n-pentanol at 33°C and 0.2 g of Syloid 72 FP added. The mixture was stirred for 15 minutes at 33°C and the slurry filtered. The cake was washed with 1 mL of n-pentanol and dried under reduced pressure at 40°C. The dry product was analyzed by DSC: amorphous.

Example 6: Preparation of amorphous vortioxetine HBr on Syloid 72 FP

Crystalline vortioxetine HBr (0.2 g) was dissolved in dichloromethane (20 mL) at room temperature (a temperature range of about 21 °C to 26°C) and Syloid 72 FP added. The mixture was stirred for 1 hour at room temperature. The solvent was then completely evaporated on a rotary evaporator under reduced pressure and at a bath temperature of 40°C. The dry product was analyzed by DSC or XPR) and found to be amorphous as shown in Table 3 below. Table 3

Syloid 72 FP Loading

Form

[g] [%]

0.30 34.8 amorphous^c

0.37 30.3 amorphous

0.46 26.2 amorphous

0.60 23.7 amorphous

0.80 17.5 amorphous

1 .10 14.2 amorphous

1 .80 8.9 amorphous

3.80 NT amorphous

NT = not tested ^c Figure 2 shows an XRPD of amorphous vortioxetine HBr in association with Syloid 72 FP when 0.2 g of vortioxetine HBr was dissolved in 20 mL dichloromethane and mixed with 0.3 g Syloid 72 FP to achieve a 34.8% loading. Similar XRPDs indicative of amorphous material were obtained for the other preparations listed in Table 3. SEM images of amorphous vortioxetine hydrobromide in association with Syloid 72 FP adsorbent at a 35% loading are shown in Figure 4.

Example 7: Preparation of amorphous vortioxetine HBr on Syloid AL-1

Crystalline vortioxetine HBr (0.2 g) was dissolved in dichloromethane (10 mL) at room temperature (a temperature range of about 21 °C to 26°C) and Syloid AL-1 added. The mixture was stirred for 15 hours at room temperature and the slurry filtered. The product was dried under reduced pressure at 50°C and the dry product analyzed by DSC and found to be amorphous as shown in Table 4 below.

Table 4

Syloid AL-1

Form

[g]

0.2 amorphous

0.3 amorphous

Example 8: Stability of amorphous vortioxetine HBr on Syloid 72 FP

The stability of amorphous vortioxetine HBr on Syloid 72 FP at various % loadings prepared as described in the above Examples was measured by DSC and XRPD. The various loadings of amorphous vortioxetine HBr on Syloid 72 FP were found to be stable for at least the length of the periods listed below in Table 5. Table 5

% Loading Stability DSC Stability XRPD

10.0 NT 2 weeks and 6 days

15.4 7 weeks and 4 days 4 weeks and 6 days

16.4 9 weeks 10 days

17.2 10 weeks and 3 days 10 days

17.6 1 1 weeks and 1 day 2 weeks

20.0 5 weeks and 5 days 3 weeks

30.0 4 weeks and 4 days 1 week and 6 days

40.0 4 weeks and 4 days 1 week and 6 days

NT = not tested

Example 9: Preparation of amorphous vortioxetine HBr on carrier

Crystalline vortioxetine HBr (0.2 g) was dissolved in dichloromethane (10 mL) at room temperature (a temperature range of about 21 °C to 26°C) and then carrier added. The mixture was stirred for 1 hour at room temperature. The solvent was then completely evaporated on a rotary evaporator under reduced pressure and a bath temperature of 40°C. The dry product was analyzed by DSC and found to be amorphous as shown in Table 6 below.

Table 6

Carrier Carrier Loading

Form

[g] [%]

Syloid 244 FP 0.20 50 amorphous

Syloid 244 FP 0.30 40 amorphous

Aerosil 380 0.30 40 amorphous

Neusilin^* UFL2 0.20 50 amorphous

Neusilin^* UFL2 0.30 40 amorphous

MgO 0.30 40 amorphous

^*Neusilin is synthetic magnesium aluminometasilicate (chemical formula

AI₂0₃-MgO- 1 .7Si0₂- xH₂0)

Example 10: Preparation of amorphous vortioxetine HBr on Syloid 72 FP

Crystalline vortioxetine HBr (0.2 g) was dissolved in 1 -butanol (10 mL) at 90°C and then Syloid 72 FP added. The mixture was stirred for 15 minutes. After cooling to room temperature the slurry was filtered. The product was dried under reduced pressure at 40°C and analyzed by DSC and found to be amorphous as shown in Table 7 below.

Table 7

Syloid 72 FP Loading

Form

[g] [%]

0.2 5.1 amorphous

0.3 28.2 amorphous

0.4 21.5 amorphous

0.5 17.5 amorphous

Example 11 : Preparation of amorphous vortioxetine HBr on Syloid 72 FP Crystalline vortioxetine HBr (0.2 g) was dissolved in 2-propanol (10 mL) at 81 °C and Syloid 72 FP added. The mixture was stirred for 15 minutes at 81 °C and the hot slurry filtered. The product was dried under reduced pressure at 40°C and analyzed by DSC and found to be amorphous as shown in Table 8 below. Table 8

Syloid 72 FP Loading

Form

[g] [%]

0.2 1 .5 amorphous

0.3 4.3 amorphous

0.4 4.7 amorphous

0.5 4.8 amorphous

Example 12: Preparation of amorphous vortioxetine HBr on Neusilin UFL2

Crystalline vortioxetine HBr (0.2 g) was dissolved in dichloromethane (10 mL) at room temperature (a temperature range of about 21 °C to 26°C) and Neusilin UFL2 (0.2 g) was then added. The mixture was stirred for 15 minutes at room temperature. The slurry was filtered and the dry product analyzed by DSC: amorphous. Loading = 23%.

Example 13: Solubility comparison between amorphous vortioxetine HBr on Syloid 72 FP and crystalline vortioxetine HBr Dissolution kinetics studies were performed in 0.1 M hydrochloric acid with pH = 1 .2 (simulated gastric fluid) at 37 °C using a shaking flask (Thermo Scientific MaxQ 4000 Apparatus) at 400 rpm. The tested sample was added directly to a preheated 40 mL solution of 0.1 M hydrochloric acid to a final concentration of approximately 1 mg/mL. Aliquots, each of 1 mL, were withdrawn from the dissolution medium at time intervals of 5, 15, 30, 60 and 180 minutes. The sample aliquots were withdrawn through a syringe, filtered through Millipore filter (0.45 μηη, PVDF) and diluted. The sample aliquots were analyzed for the dissolved vortioxetine HBr content using reversed-phase HPLC. The concentration of dissolved vortioxetine HBr was determined from the area of vortioxetine HBr peak using a preformed calibration curve. A standard curve for vortioxetine HBr was measured over a range of 200 - 0.1 μg/mL and shown to be linear. Amorphous vortioxetine HBr on Syloid 72 FP was found to be more soluble than crystalline vortioxetine HBr (Figure 6).

Claims

1 . Amorphous vortioxetine hydrobromide in association with an adsorbent.

2. Amorphous vortioxetine hydrobromide according to Claim 1 wherein the adsorbent is selected from Al₂0₃, CaC0₃, MgO, Si0₂, Ti0₂ and ZnO.

3. Amorphous vortioxetine hydrobromide according to Claims 1 or Claim 2 wherein the adsorbent is Si0₂.

4. Amorphous vortioxetine hydrobromide according to any one of Claims 1 to 3 wherein the adsorbent is a silica gel.

5. Amorphous vortioxetine hydrobromide according to Claim 1 wherein the adsorbent is selected from Aerosil, Neusilin and Syloid.

6. Amorphous vortioxetine hydrobromide according to any one of Claims 1 to 5 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is over 20%.

7. Amorphous vortioxetine hydrobromide according to any one of Claims 1 to 5 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is over 25%.

8. Amorphous vortioxetine hydrobromide according to any one of Claims 1 to 5 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is over 30%.

9. Amorphous vortioxetine hydrobromide according to any one of Claims 1 to 5 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is over 35%.

10. Amorphous vortioxetine hydrobromide according to any one of Claim 6 to 9 wherein the loading of amorphous vortioxetine hydrobromide on the adsorbent is less than 60%.

1 1 . A pharmaceutical composition comprising amorphous vortioxetine hydrobromide as defined in any one of Claims 1 to 10.

12. A pharmaceutical composition according to Claim 1 1 comprising at least one

pharmaceutically acceptable excipient.

13. A process for the preparation of a pharmaceutical composition comprising amorphous vortioxetine hydrobromide in association with an adsorbent which comprises:

(ii) adding the adsorbent to the solution; (iii) mixing the adsorbent and vortioxetine hydrobromide solution; and

(iv) removing the solvent.

14. A pharmaceutical composition according to Claim 1 1 or Claim 12 for use as a

medicament.

15. A pharmaceutical composition according to Claim 1 1 or Claim 12 for use in the

treatment of mood disorders; major depressive disorder; general anxiety disorder; posttraumatic stress disorder; depression associated with cognitive impairment,

Alzheimer's disease or anxiety; depression with residual symptoms; chronic pain; or eating disorders.