Amorphous Vortioxetine Hydrobromide

Abstract

The present invention relates to a pharmaceutical composition comprising amorphous vortioxetine hydrobromide, a process for the preparation thereof, use thereof and a method for stabilizing said pharmaceutical composition.

Claims

1. A pharmaceutical composition comprising a solid solution or solid dispersion of amorphous vortioxetine hydrobromide in at least one organic carrier, and at least one further ingredient being contained in an amount of about 0.01 to about 80% by weight relative to the weight of the solid solution or solid dispersion.

2. The pharmaceutical composition according to claim 1, wherein the organic carrier is selected from an organic polymer or co-polymer.

3. The pharmaceutical composition according to claim 1, wherein the organic carrier comprises at least one compound selected from the group consisting of a hydroxyalkylcellulose, hydroxyalkylalkycellulose, and a polyvinylcaprolactam—polyvinyl acetate—polyethylene glycol graft copolymer.

4. The pharmaceutical composition according to claim 1, wherein the solid solution or solid dispersion further comprises microcrystalline cellulose.

5. The pharmaceutical composition according to claim 1, wherein the solid solution or solid dispersion is applied to a substrate.

6. The pharmaceutical composition according to claim 1, wherein the amorphous vortioxetine hydrobromide is present in an amount of 20-50% (w/v), based on the total weight of the solid solution or solid dispersion.

7. A process for the preparation of the pharmaceutical composition according to claim 1, comprising a process step selected from (i) subjecting vortioxetine hydrobromide, the at least one organic carrier and optional further ingredients to solvent-evaporation; (ii) subjecting vortioxetine hydrobromide, the at least one organic carrier and optional further ingredients to melt extrusion; and (iii) spray drying a solution or dispersion comprising vortioxetine hydrobromide, the at least one organic carrier and optional further ingredients; in order to obtain a solid solution or solid dispersion.

8. The process according to claim 7, said process comprising (i) dissolving or dispersing vortioxetine hydrobromide and the at least one organic carrier and optional further ingredients in a protic solvent, an aprotic solvent, or a mixture of a protic solvent and an aprotic solvent; (ii) mixing in a fluidized bed; and (iii) removing the solvent.

9. The process according to claim 7, said process comprising (i) mixing vortioxetine hydrobromide with the at least one organic carrier and optional further ingredients; (ii) melt-extruding the mixture; and (iii) subjecting the extrudate to spheronizing, pelletizing, milling or direct shaping.

10. The process according to claim 7, said process comprising (i) dissolving or dispersing vortioxetine hydrobromide and the at least one organic carrier and optional further ingredients in a protic solvent, an aprotic solvent, or a mixture of a protic solvent and an aprotic solvent; (ii) mixing; and (iii) spray drying the mixture.

11. The process according to claim 7, wherein the solid solution or solid dispersion is applied to a substrate.

12. A pharmaceutical composition according to claim 7 for use in the treatment of a disease selected from affective disorders, depression, major depressive disorder, postnatal depression, depression associated with bipolar disorder, Alzheimer's disease, psychosis, cancer, age or Parkinson's disease, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, panic attacks, phobia, social phobia, agoraphobia, stress urinary incontinence, emesis, irritable bowel syndrome, eating disorders, chronic pain, partial responders, treatment resistant depression, Alzheimer's disease, cognitive impairment, attention deficit hyperactivity disorder, melancholia, posttraumatic stress disorder, hot flushes, sleep apnea, alcohol, nicotine or carbohydrate craving, substance abuse and alcohol or drug abuse.

13. A method for stabilizing amorphous vortioxetine hydrobromide in a pharmaceutical composition, characterized in that the amorphous vortioxetine hydrobromide is formulated in a solid solution or solid dispersion in at least one organic carrier, and at least one further ingredient being contained in an amount of about 0.01 to about 80% by weight relative to the weight of the solid solution or solid dispersion.

Description

[0087] FIG. 1 relates to solid dispersions prepared by hot melt extrusion according to example 1.

[0088] FIG. 1A shows XRPD patterns of vortioxetine hydrobromide in Soluplus as organic carrier (A) and of Soluplus without vortioxetine hydrobromide (B).

[0089] FIG. 1B shows XRPD patterns of vortioxetine hydrobromide crystalline form β (A) and the product obtained in example 1 after milling the melt extruded product (B).

[0090] FIG. 1C shows XRPD patterns of the final tablets prepared in example 1 (A) and of correspondingly prepared tablets without vortioxetine hydrobromide (B).

[0091] FIG. 2 relates to solid dispersions with HPMC prepared by solvent evaporation according to example 2

[0092] FIG. 2A shows XRPD patterns of vortioxetine hydrobromide crystalline form β (B) and of the end product of example 2 (A).

[0093] FIG. 2B shows XRPD patterns of vortioxetine hydrobromide crystalline form β (C) and of the solid dispersions with HPMC immediately after the preparation (A) and after 1 week at room temperature (B).

[0094] FIG. 3 shows XRPD patterns for compressed tablets with adsorbate Neusilin US2/adsorbate Syloid 244FP according to reference examples 6+7

[0095] The present invention will be explained in more detail with the following examples, which are not to be interpreted as limiting.

EXAMPLES

Example 1: Solid Solution/Dispersion Prepared by Hot Melt Extrusion

[0096] Any physical form of vortioxetine (e.g., produced as described in WO 2003/029232, WO 2007/144005 or WO 2014/044721) can be used to prepare a solid solution or solid dispersion of amorphous vortioxetine hydrobromide.

[0097] 5.0 g of the vortioxetine hydrobromide salt and 15.0 g of Soluplus (polyvinyl caprolactam—polyvinyl acetate—polyethylenglycole graft copolymer) were mixed for 10 min in a suitable bin blender. The mixture was passed through a DSM Xplore 5×15 Micro Compounder at 225° C. and 50 rpm. 1.24 g of the resulting granules were passed through a mill with screen 1.0 mm and mixed together with 12.2 g Mannitol, 1.0 g hydroxypropyl cellulose (KLUCEL EF), 5.08 g microcrystalline cellulose and 0.98 g sodium starch glycolate (type A). Following lubrication of the blend by mixing with 0.26 g magnesium stearate the powder blend was transferred to a tablet press. Tablets having a target core weight of 125 mg and a diameter of 6.5 mm were prepared to obtain tablets with a target content of the hydrobromide salt corresponding to 5 mg of the free base.

[0098] In FIGS. 1A, 1B and 1C it has been shown that the solid solution/dispersion obtained in example 1 contains amorphous vortioxetine hydrobromide.

[0099] FIG. 1A shows XRPD's of Soluplus alone (B) and of the solid solution/dispersion (A) obtained after the melt extrusion. It can be seen that no crystalline compounds are present.

[0100] FIG. 1B shows XRPD's of vortioxetine hydrobromide crystalline form β (A) and of the solid solution/dispersion after the milling step (B). It can be seen that the vortioxetine hydrobromide in the solid solution/dispersion stays in the amorphous form even after the milling step.

[0101] FIG. 1C shows the XRPD's of a blank tablet (no vortioxetine hydrobromide) (B) and of the corresponding tablet containing vortioxetine hydrobromide (A). Both tablets were prepared by the method of example 1. It can be seen, that the XRPD's of both tablets are identical, which means that the vortioxetine hydrobromide in the finished tablets is amorphous.

Example 2: Solid Solution/Dispersion with HPMC Prepared by Solvent Evaporation

[0102] 1 g of the vortioxetine hydrobromide salt and 2 g of hydroxypropylmethylcellulose (Pharmacoat 603) were solved under stirring in an appropriate amount of methanol; after clear solution occurred 3 g of microcrystalline cellulose were added and stirred over a period of 30 min until homogenous suspension was reached. The solvent was removed by evaporation under rotation followed by vacuum drying at 40° C./25 mbar 24 h.

[0103] In FIGS. 2A and 2B it has been shown that the solid solution/dispersion obtained in example 2 contains amorphous vortioxetine hydrobromide.

[0104] FIG. 2A shows XRPD's of vortioxetine hydrobromide crystalline form β (B) and of the solid solution/dispersion (A). It can be seen that the vortioxetine hydrobromide in the solid solution/dispersion is amorphous.

[0105] FIG. 2B shows XRPD's of vortioxetine hydrobromide crystalline form β (C), of the solid solution/dispersion immediately after preparation (A) and after 1 week at room temperature (B). It can be seen, that the vortioxetine hydrobromide in the solid solution/dispersion immediately after preparation and also after storage for 1 week at room temperature is amorphous.

Example 3: Solid Solution/Dispersion with HPMC Prepared with Fluid Bed Granulation

[0106] 100 g of the vortioxetine hydrobromide salt and 200 g of hydroxypropylmethylcellulose (Pharmacoat 603) is dissolved under stirring in 1667 ml methanol; the solution is sprayed on 300 g of microcrystalline cellulose during continuous fluidization in a fluid bed granulation Typ Glatt GPCG 1. The final granules are further treated over 24 h at 40° C./25 mbar in a vacuum chamber.

Example 4: Solid Dispersion with an Adsorbate

[0107] The adsorbate of vortioxetine hydrobromide on magnesium aluminometasilicate grade US2 (Neusilin US2) was prepared as described in Example 8 (amorphous vortioxetine HBr on Neusilin US2 and HPMC).

[0108] 11.62 g of the solid dispersion, 25.03 g Mannitol, 2.0 g HPC (KLUCEL EF), 18.8 g microcrystalline cellulose and 2.02 g Sodium Starch glycolate (Type A) were mixed for 20 min in a suitable bin blender. Following lubrication of the blend by mixing with 0.6 g magnesium stearate the powder blend was transferred to a tablet press. Tablets having a target core weight of 150 mg and a diameter of 8 mm were prepared to obtain tablets with a target content of the hydrobromide salt corresponding to 5 mg of the free base.

Example 5: Solid Dispersion with an Adsorbate

[0109] The adsorbate of vortioxetine hydrobromide on magnesium aluminometasilicate grade US2 (Neusilin US2) was prepared as described in Example 8 (amorphous vortioxetine HBr on Neusilin US2 and HPMC).

[0110] 12.06 g of the solid dispersion, 25.90 g Mannitol and 2.08 g hydroxypropylcellulose (KLUCEL EF) were mixed for 2 min in a suitable mixing device. 18.1 g water were added under continuous stirring over 2 min, followed by 2 min kneading. The wet mass were sieved through a sieve of 2 mm, followed by tray drying at 42° C. over 1 h. 30.8 g of the resulting granules were mixed together with 15.08 g microcrystalline cellulose, 1.62 g Sodium starch glycolate for 10 min. Following lubrication of the blend by mixing with 0.48 g magnesium stearate the powder blend was transferred to a tablet press. Tablets having a target core weight of 150 mg and a diameter of 7 mm were prepared to obtain tablets with a target content of the hydrobromide salt corresponding to 5 mg of the free base.

Example 6: Adsorbate (Neusilin US2) Tablets (Reference)

[0111] The adsorbate of vortioxetine hydrobromide was prepared as described in Example 8.

[0112] 23.88 g of the vortioxetine hydrobromide adsorbate (vortioxetine hydrobromide on magnesium aluminometasilicate grade US2 (Neusilin US2)), 70.50 g Mannitol, 5.67 g hydroxypropylcellulose (KLUCEL EF), were mixed for 2 min in a suitable mixing device. 50.0 g water were added under continuous stirring over 5 min, followed by 2 min kneading. The wet mass were sieved through a sieve of 2 mm, followed by tray drying at 42° C. over 90 min. 81.70 g of the resulting granules were mixed together with 27.75 g microcrystalline cellulose, 4.64 g Sodium starch glycolate for 10 min. Following lubrication of the blend by mixing with 1.15 g magnesium stearate the powder blend was transferred to a tablet press. Tablets having a target core weight of 125 mg and a diameter of 6.5 mm were prepared to obtain tablets with a target content of the hydrobromide salt corresponding to 5 mg of the free base.

Example 7: Adsorbate (Syloid 244FP) (Reference)

[0113] The adsorbate of vortioxetine hydrobromide was prepared as described in Example 8.

[0114] 23.9 g of the vortioxetine hydrobromide adsorbate (vortioxetine hydrobromide on silica (Syloid 244FP)), 70.47 g Mannitol, 5.70 g hydroxypropylcellulose (KLUCEL EF), were mixed for 2 min in a suitable mixing device. 45.0 g water were added under continuous stirring over 5 min, followed by 2 min kneading. The wet mass were sieved through a sieve of 2 mm, followed by tray drying at 42° C. over 80 min. 82.90 g of the resulting granules were mixed together with 28.15 g microcrystalline cellulose, 4.68 g Sodium starch glycolate for 10 min. Following lubrication of the blend by mixing with 1.18 g magnesium stearate the powder blend was transferred to a tablet press. Tablets having a target core weight of 125 mg and a diameter of 6.5 mm were prepared to obtain tablets with a target content of the hydrobromide salt corresponding to 5 mg of the free base.

[0115] FIG. 3 shows XRPD's of the tablets obtained in examples 6 and 7 and XRPD's of corresponding blank tablets without vortioxetine hydrobromide. All XRPD's are essentially identical showing that the adsorbates contain amorphous vortioxetine hydrobromide.

Example 8

[0116] Preparation methods of vortioxetine HBr adsorbates are presented below. Alternatively, the methods according to the non-prepublished copending patent application PCT/EP2014/058546 may be used (incorporated herein with reference).

Preparation of Amorphous Vortioxetine HBr on Neusilin US2

[0117] Vortioxetine HBr (1.0 g) was dissolved in dichloromethane (100 mL) at room temperature. In the obtained clear solution Neusilin US2 was added. The mixture was further stirred for 1 h and then the solvent was completely evaporated on a rotary evaporator under reduced pressure at room temperature. The dry product was analyzed by DSC and PXRD and found to be amorphous as shown in Table 1 below.

TABLE-US-00001 TABLE 1 Neusilin US2 Loading [g] [%] Form 2.30 30 amorphous 2.05 33 amorphous 1.65 38 amorphous .sup.a Evaporator under reduced pressure at a bath temperature 40° C.

Preparation of Amorphous Vortioxetine HBr on Neusilin US2

[0118] Vortioxetine HBr (1.0 g) was dissolved in dichloromethane (30 mL) at reflux. In the obtained clear solution Neusilin US2 was added, heating was then turned off. Obtained mixture was stirred for 19 h at room temperature and then the slurry was filtered. The cake was dried overnight in vacuum at 30° C. The dry product was analyzed by DSC and PXRD and found to be amorphous as shown in Table 2 below.

TABLE-US-00002 TABLE 2 Neusilin US2 Loading [g] [%] Form 1.5 29 amorphous 1.0 30 amorphous

Preparation of Amorphous Vortioxetine HBr on Neusilin US2 and HPMC

[0119] Vortioxetine HBr (7.6 g) was dissolved in dichloromethane (380 mL) at room temperature. In the obtained clear solution Neusilin US2 (18.7 g) and HPMC (7.7 g) were added. The mixture was further stirred for 1.5 h and then the solvent was completely evaporated on a rotary evaporator under reduced pressure at room temperature. The dry product was analyzed by DSC and PXRD and found to be amorphous.

Preparation of Amorphous Vortioxetine HBr on Syloid 244 FP

[0120] Vortioxetine HBr was dissolved in dichloromethane at room temperature. In the obtained clear solution Syloid 244 FP was added. The mixture was further stirred for a certain time and then the solvent was completely evaporated on a rotary evaporator under reduced pressure. The dry product was analyzed by DSC and PXRD and found to be amorphous as shown in Table 3 below.

TABLE-US-00003 TABLE 3 Vortioxetine Syloid HBr 244 FP CH.sub.2Cl.sub.2 Stirring time Loading [g] [g] [mL] [h] [%] Form 0.2 0.3 20 21 40 amorphous 1 2.3 50 1 30 amorphous

Preparation of Amorphous Vortioxetine HBr on Syloid 244 FP

[0121] Vortioxetine HBr (0.2 g) was dissolved in dichloromethane (10 mL) at room temperature. In the obtained clear solution Syloid 244 FP was added. Obtained mixture was stirred at room temperature for a certain time and then the slurry was filtered. The cake was dried overnight in vacuum at 30° C. The dry product was analyzed by DSC and PXRD and found to be amorphous as shown in Table 4 below.

TABLE-US-00004 TABLE 4 Neusilin US2 Stirring time Loading [g] [h] [%] Form 0.2 7 30 amorphous 1.3 26 38 amorphous