PROCESS FOR THE PREPARATION OF VORTIOXETINE SALTS
20170114034 ยท 2017-04-27
Assignee
Inventors
- Istvan Ling (Budapest, HU)
- Gyorgy Jeges (Vilonya, HU)
- Gyorgyi Kovanyine Lax (Budapest, HU)
- Balazs Volk (Budapest, JE)
- Peter Gregor (Szekesfehervar, HU)
- Jeno Peter Seres (Budapest, HU)
- Andras Dancso (Budapest, HU)
- Zoltan Varga (Budapest, HU)
- Eva SZABO (Budapest, HU)
Cpc classification
C07D295/096
CHEMISTRY; METALLURGY
C07C309/29
CHEMISTRY; METALLURGY
A61P25/28
HUMAN NECESSITIES
A61P25/18
HUMAN NECESSITIES
International classification
C07D295/096
CHEMISTRY; METALLURGY
C07C309/29
CHEMISTRY; METALLURGY
Abstract
The invention relates to an improved process for the preparation of pharmaceutical active ingredients and also to high purity salts and pharmaceutical compositions prepared by said process. More particularly the invention relates to an economical process for the preparation of the compound having the international non-proprietary name (INN) vortioxetine and the chemical nomenclature 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine. Vortioxetine corresponds to the following Formula
##STR00001##
Still more particularly the invention relates to the preparation of high purity vortioxetine L-(+)-mandelate salt of the Formula IX, the conversion of this salt into other highly pure salts and also to the formulation of said salts.
Claims
1. Process for the preparation of vortioxetine salts of the general Formula VII ##STR00002## by reacting the compound of the Formula V ##STR00003## with a compound of the general Formula VI ##STR00004## (wherein X stands for chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy or hydroxy; H.sub.nA represents an organic or inorganic mono- or polybasic acid, A is an acid residue and n is the number of the hydrogen atoms, preferably 1, 2 or 3 which comprises converting the vortioxetine base of the Formula I ##STR00005## formed in the L-(+)-mandelic acid salt of the Formula IX, ##STR00006## if necessary setting free the base from the salt and converting the same in another salt of the general Formula VII (wherein H.sub.nA stands for a mono- or polybasic organic or inorganic acid; n is 1, 2 or 3 and A represents an acid residue ion).
2. Process according to claim 1 which comprises carrying out the reaction of the compounds of the Formulae V and VI in a solvent, preferably an aprotic solvent; and/or using as aprotic solvent an aromatic or aliphatic hydrocarbon, an ether, an acid amide, an urea derivative, a nitrile, an ester or a mixture thereof; and/or using as aprotic solvent an aromatic solvent, preferably toluene, xylene, ethyl benzene; an aliphatic solvent preferably pentane, hexane, cyclohexane, octane or petrolether; an ether preferably an aliphatic or cyclic ether, more advantageously diethyl ether, diisopropyl ether, dibutyl ether, methyl tert.butyl ether, diethylene glycol dimethyl ether or diethylene glycol monoethyl ether; an acid amide preferably dimethyl- or diethyl-formamide, dimethyl- or diethyl-acetamide or -propionamide; an urea derivative preferably 1,3-dimethyl-2-imidazolidinone (DMI); an ester preferably esters of acetic acid or propionic acid formed with C.sub.1-4 alcohols, preferably ethyl acetate, propyl acetate, ethyl propionate, butyl acetate or a mixture of said solvents; and/or using as solvent a mixture of an aromatic solvent and an amide type solvent, preferably a mixture of toluene and DMI, whereby the ratio of toluene and DMI is 5:1-1:5, preferably 2:1-1:2, more advantageously 1:1.
3-5. (canceled)
6. Process according to claim 1 which comprises carrying out the reaction of the compounds of the Formulae V and VI in the presence of an organic or inorganic base; and optionally comprises using an organic base, preferably a tertiary amine and/or aromatic amine; as tertiary amine preferably triethyl amine (TEA), N,N-diisopropyl ethyl amine (DIPEA), tributyl amine (TBA), N,N-dimethyl ethyl amine; and as aromatic amine pyridine or a pyridine derivative; and/or optionally comprises using as inorganic base an alkali or alkaline earth metal carbonate or hydrocarbonate, preferably an alkali carbonate, more advantageously potassium carbonate.
7-8. (canceled)
9. Process according to claim 1 which comprises carrying out the reaction of the compounds of the Formulae V and VI at 100-200 C., preferably at 170-180 C., at the boiling point of the solvent or the solvent mixture or in a closed vessel; and/or reacting the compounds of the Formulae V and VI for 6-20 hours, preferably for 9-15 hours.
10. (canceled)
11. Process according to claim 1 which comprises isolating the vortioxetine base of the Formula I after the reaction of the compounds of the Formulae V and VI has been completed; and optionally comprises a) evaporating the reaction mixture partially or completely, reacting the residue with an aqueous alkali, preferably ammonium hydroxide or a potassium or sodium hydroxide solution, more advantageously with an ammonium hydroxide solution and separating the precipitated vortioxetine base from the liquid phase, or b) adding to the reaction mixture an apolar aprotic solvent, preferably an aromatic solvent, more advantageously toluene in a 2-15, preferably 3-12, more advantageously 5-fold volume amount, related to the volume of the reaction mixture, cooling the mixture thus obtained, reacting with an aqueous base, preferably a sodium or potassium hydroxide solution, separating the organic phase and if desired drying and evaporating said organic phase, and dissolving the vortioxetine base prepared according to process a) or b) in a dipolar aprotic solvent, preferably acetone, adding to the solution L-(+)-mandelic acid or a solution thereof formed with a dipolar aprotic solvent, isolating the salt and if desired recrystallizing the L-(+)-mandelate salt thus obtained from a protic solvent, preferably methanol or 2-propanol.
12. (canceled)
13. Process according to claim 1 which comprises isolating the vortioxetine base from the reaction mixture in form of a solution and adding to the solution containing the vortioxetine base a calculated amount of L-(+)-mandelic acid and separating the precipitated L-(+)-mandelate salt from the solution; and optionally comprises adding to the reaction mixture after the reaction has been completed an apolar aprotic solvent, preferably an aromatic solvent, more advantageously toluene in a 2-15, preferably 3-12, more advantageously 5 fold volume amount, related to the volume of the reaction mixture, reacting the mixture thus obtained with an aqueous base, preferably a sodium or potassium hydroxide solution, separating the organic phase, if necessary drying the same and heating to 50-100 C., preferably to 50-80 C., more advantageously to 55-65 C., adding a calculated amount of L-(+)-mandelic acid, allowing the mixture to cool, separating the precipitated L-(+)-mandelate salt from the solution and optionally filtering and drying the precipitated crystals.
14. (canceled)
15. Process according to claim 1 which comprises suspending the isolated crystalline vortioxetine L-(+)-mandelate salt thus obtained in water, adding to the mixture a water non-soluble solvent, preferably an aromatic solvent, more advantageously toluene; a halogenated solvent, preferably dichloro methane; an ether type solvent, preferably diethyl ether or diisopropyl ether, adding to the mixture thus obtained an inorganic base, preferably an alkali or alkaline earth metal hydroxide or carbonate in an amount sufficient to make the pH of the aqueous phase alkaline, thereafter separating the organic phase and drying and evaporating the same and if necessary subjecting the vortioxetine base thus obtained to the following steps: a) recrystallizing; or b) dissolving or suspending in a dipolar aprotic solvent, preferably a nitrile, ketone or ester type solvent, more advantageously in acetonitrile as nitrile or in acetone as ketone or in ethyl acetate as ester, reacting with an organic acid, preferably salicylic acid, citric acid, malonic acid, oxalic acid, L-malic acid, benzenesulfonic acid, acetic acid, succinic acid or L-mandelic acid or a solution thereof formed with an organic solvent, or with an inorganic acid, preferably hydrogen bromide or an aqueous solution thereof, particularly with citric acid or oxalic acid or a solution thereof formed with an organic solvent preferably acetone or ethyl acetate or with an aqueous hydrogen bromide solution and if necessary recrystallizing the salts thus obtained; or reacting the compounds of the Formulae V and VI in a 1:2-2:1, preferably 1:1 by weight ratio mixture of toluene and DMI in a closed vessel at 150-200 C., preferably at 170-180 C. for 10-16 hours, preferably 12 hours, cooling the mixture, filtering the precipitated inorganic salts, washing the united organic phases free from toluene, pouring the residue into an aqueous ammonium hydroxide solution, filtering the precipitated crystalline vortioxetine base, suspending the same in acetone, warming the suspension thus obtained to 60 C., adding a calculated amount of an acetone solution of L-(+)-mandelic acid, cooling the mixture, separating the precipitated vortioxetine L-(+)-mandelate salt, suspending said salt in water, adding dichloromethane, making the aqueous phase alkaline with a potassium or sodium carbonate solution or an alkali hydroxide, preferably sodium or potassium hydroxide solution, separating the dichloro methane phase, drying and evaporating the same and optionally subjecting the vortioxetine base of the Formula I to the following steps: a) allowing to crystallize or recrystallizing from acetonitrile; or b) crystallizing or recrystallizing the base of the Formula I and/or suspending or dissolving said base in a dipolar aprotic solvent, preferably acetone or ethyl acetate, adding at 60 C. a calculated amount of salicylic acid, citric acid, malonic acid, oxalic acid, L-malic acid, benzenesulfonic acid, acetic acid, succinic acid or L-amygdalic acid dissolved in acetone or ethyl acetate, more preferably citric acid or oxalic acid or an aqueous hydrogen bromide solution and thereafter separating the corresponding vortioxetine salt by cooling; or reacting the compounds of the Formulae V and VI in a 1:2-2:1, preferably 1:1 parts by weight mixture of toluene and DMI, in a closed vessel, preferably at 150-200 C., preferably at 170-180 C. for 6-12 hours, thereafter adding to the reaction mixture a 2-15, preferably 3-12, more advantageously 5 fold amount of toluene, related to the volume of the reaction mixture, the mixture thus obtained is cooled, reacted with an aqueous base, preferably a sodium or potassium hydroxide solution, the organic phase is separated, if necessary dried, warmed to 50-100 C., preferably 50-80 C., most preferably 55-65 C., then a calculated amount of L-(+)-mandelic acid is added, the mixture is allowed to cool, the precipitated crystals are filtered, dried, the L-(+)-mandelate salt thus obtained is optionally suspended in water, dichloro methane is added, the aqueous layer is made alkaline with potassium or sodium carbonate or an alkali hydroxide, preferably a sodium potassium or potassium hydroxide solution, the dichloro methane phase is separated, dried and evaporated, the vortioxetine base of the Formula I thus obtained is optionally a) allowed to crystallize or recrystallized from acetonitrile; or b) the base of the Formula I is optionally crystallized or recrystallized by suspending and/or dissolving in a dipolar aprotic solvent, preferably in acetone or ethyl acetate and adding to the mixture at 60 C. a calculated amount of salicylic acid, citric acid, malonic acid, oxalic acid, L-malic acid, benzenesulfonic acid, acetic acid, succinic acid or L-amygdalic acid dissolved in acetone or ethyl acetate, more particularly citric acid or oxalic acid or an aqueous hydrogen bromide solution and thereafter separating the corresponding vortioxetine salt by cooling; or preparing the compound of the Formula V by reacting the nitro compound of the general Formula II (wherein Z stands for fluorine, chlorine, bromine or iodine) with the diol of the Formula III and reducing the compound of the Formula IV thus obtained into the amine of the Formula V.
16-17. (canceled)
18. Process according to claim 15 which comprises carrying out the reaction of the compounds of the Formulae V and VI in the presence of potassium or sodium carbonate, preferably potassium carbonate.
19. (canceled)
20. A salt of the vortioxetine base of the Formula I ##STR00007## formed with salicylic acid, citric acid, malonic acid, oxalic acid, L-malic acid, benzenesulfonic acid, acetic acid, succinic acid or L-amygdalic acid of uniform morphology, preferably the vortioxetine salicylate salt of the Formula XIII, ##STR00008## the vortioxetine monocitrate anhydrate salt of the Formula XX, ##STR00009## the vortioxetine monocitrate hydrate salt of the Formula XIV, ##STR00010## the vortioxetine hemicitrate salt of the Formula XI, ##STR00011## the vortioxetine malonate salt of the Formula XV, ##STR00012## the vortioxetine hemioxalate salt of the Formula XVI, ##STR00013## the vortioxetine monooxalate salt of the Formula X, ##STR00014## the vortioxetine malate salt of the Formula XVII, ##STR00015## the vortioxetine benzenesulfonate salt of the Formula XVIII, ##STR00016## the vortioxetine acetic acid salt of the Formula XIX, ##STR00017## the vortioxetine succinic acid salt of the Formula XII ##STR00018## and the vortioxetine L-(+)-mandelate salt of the Formula IX ##STR00019## or a polymorph thereof.
21. Vortioxetine salts according to claim 20 having a HPLC purity larger than 99.5%, preferably larger than 99.8% and/or containing less than 0.5%, preferably less than 0.2% of the impurity of the Formula VIII.
22. A polymorph of the following vortioxetine salts: the polymorph of the vortioxetine succinic acid (1:1) salt of the Formula XII ##STR00020## having the following characteristic X-ray powder diffraction peaks: 2 (0.2 2): 11.33; 15.32; 17.03; 17.91; 23.44; 24.00; the polymorph of the vortioxetine salicylate salt of the Formula XIII ##STR00021## having the following characteristic X-ray powder diffraction peaks: 2 (0.2 2): 13.73; 14.39; 16.60; 16.84; 18.61; the polymorph of the vortioxetine monocitrate monohydrate (1:1) salt of the Formula XIV ##STR00022## having the following characteristic X-ray powder diffraction peaks: 2 (0.2 2): 11.66; 13.89; 16.36; 17.00; 22.65; 24.09; the polymorph of the vortioxetine monocitrate anhydrate (1:1) salt of the Formula XX ##STR00023## having the following characteristic powder X-ray powder diffraction peaks: 2 (0.2 2): 5.52; 12.38; 16.26; 16.61; 18.12; 20.89; the polymorph of the vortioxetine malonate salt of the Formula XV ##STR00024## having the following characteristic X-ray powder diffraction peaks: 2 (0.2 2): 5.11; 10.46; 11.93; 15.21; 18.71; 20.42; the polymorph of the vortioxetine hemioxalate (2:1) salt of the Formula XVI ##STR00025## having the following characteristic X-ray powder diffraction peaks: 2 (0.2 2): 15.43; 16.32; 16.96; 17.48; 22.85; 25.14; the polymorph of the vortioxetine L-malate (1:1) salt of the Formula XVII ##STR00026## having the following characteristic X-ray powder diffraction peaks: 2 (0.2 2): 12.08; 13.4; 13.58; 16.97; 19.58; 24.26; the polymorph of the vortioxetine benzenesulfonate salt of the Formula XVIII ##STR00027## having the following characteristic X-ray powder diffraction peaks: 2 (0.2 2): 14.79; 15.63; 17.61; 18.51; 19.54; 23.53; or the polymorph of the vortioxetine acetate salt of the Formula XIX ##STR00028## having the following characteristic X-ray powder diffraction peaks: 2 (0.2 2): 13.08; 14.06; 15.68; 18.26; 21.06; 22.44.
23. The polymorph of the morphologically uniform vortioxetine L-(+)-mandelate salt of the Formula IX according to claim 20 having the following characteristic powder diffraction peaks: 2 (0.2o 2): 11.86; 13.29; 16.52; 16.93; 17.17; 23.46; and/or having the following characteristic X-ray powder diffraction peaks: 2 (0.2 2): 4.25; 11.69; 11.86; 13.29; 16.52; 16.93; 17.17; 18.47; 23.46; 24.29; 26.21.
24. (canceled)
25. Polymorphs of the vortioxetine L-(+)-mandelate salt according to claim 20 having the characteristic X-ray powder diffraction data disclosed in the following Table: TABLE-US-00036 Relative intensity Peak 2 () d () (%) 1 4.25 20.76 16 2 11.69 7.56 22 3 11.86 7.46 24 4 12.25 7.22 10 5 13.29 6.66 32 6 14.42 6.14 16 7 16.52 5.36 65 8 16.93 5.23 100 9 17.17 5.16 26 10 17.58 5.04 11 11 18.47 4.8 17 12 18.81 4.71 2 13 19.54 4.54 7 14 20.55 4.32 2 15 20.78 4.27 5 16 22.18 4 2 17 22.39 3.97 2 18 23.15 3.84 9 19 23.46 3.79 38 20 23.94 3.71 15 21 24.29 3.66 18 22 24.59 3.62 5 23 24.95 3.57 4 24 25.42 3.5 8 25 26.21 3.4 24 26 26.93 3.31 13 27 28.28 3.15 5 28 28.71 3.11 3 29 29 3.08 3 30 30.18 2.96 3 31 31.32 2.85 4 32 31.82 2.81 2 33 32.58 2.75 3 34 33.1 2.7 2 35 33.36 2.68 2
26. Polymorph of the vortioxetine hemicitrate (2:1) salt of the Formula XI according to claim 20 having the following characteristic X-ray powder diffraction peaks: 2 (0.2 2): 5.24; 13.79; 16.52; 17.31; 18.15; 20.35; and/or having the following characteristic X-ray powder diffraction peaks: 2 (0.2 2): 5.24; 13.79; 15.76; 16.52; 17.31; 17.65; 18.15; 20.35; 20.6; 21.00; 23.01.
27. (canceled)
28. Polymorph of the vortioxetine hemicitrate (2:1) salt according to claim 20 having the characteristic X-ray powder diffraction data disclosed in the following Table: TABLE-US-00037 Relative intensity Peak 2 () d () (%) 1 5.24 16.85 100 2 10.26 8.61 36 3 10.5 8.41 10 4 10.94 8.08 9 5 11.43 7.74 14 6 12.1 7.31 16 7 13.02 6.8 21 8 13.79 6.41 93 9 14.28 6.2 8 10 14.67 6.03 10 11 15.76 5.62 41 12 16.52 5.36 73 13 17.31 5.12 48 14 17.65 5.02 39 15 18.15 4.88 50 16 18.77 4.72 27 17 19.04 4.66 13 18 20.01 4.43 21 19 20.35 4.36 53 20 20.6 4.31 44 21 21 4.23 40 22 21.45 4.14 21 23 22 4.04 14 24 23.01 3.86 42 25 23.2 3.83 31 26 24.31 3.66 13 27 24.71 3.6 15 28 25.12 3.54 11 29 25.39 3.51 10 30 25.85 3.44 18 31 26.37 3.38 17 32 26.71 3.34 4 33 27.3 3.26 5 34 27.75 3.21 18 35 28.22 3.16 3 36 28.84 3.09 6 37 30 2.98 6 38 31.07 2.88 7
29. Polymorph of the vortioxetine monooxalate (1:1) salt of the Formula X according to claim 20 having the following characteristic X-ray powder diffraction data: 2 (0.2 2): 14.48; 17.8; 18.97; 20.38; 23.87; 27.57; and/or having the following characteristic X-ray powder diffraction data 2 (0.2 2): 13.67; 14.48; 16.01; 17.8; 18.15; 18.46; 18.97; 20.38; 23.87; 27.57; 28.15.
30. (canceled)
31. Polymorph of the vortioxetine monooxalate (1:1) salt according to claim 20 having the characteristic X-ray powder diffraction data disclosed in the following table: TABLE-US-00038 Relative intensity Peak 2 () d () (%) 1 10.16 8.7 9 2 13.67 6.47 41 3 14.48 6.11 96 4 15.38 5.76 3 5 16.01 5.53 28 6 16.98 5.22 8 7 17.8 4.98 51 8 18.15 4.88 32 9 18.46 4.8 18 10 18.97 4.67 100 11 19.54 4.54 7 12 20.38 4.36 48 13 21.1 4.21 10 14 21.72 4.09 3 15 22.16 4.01 4 16 22.75 3.91 3 17 23.16 3.84 10 19 24.36 3.65 5 20 24.89 3.57 2 21 25.35 3.51 3 22 26.1 3.41 6 23 26.81 3.32 16 24 27.15 3.28 4 25 27.57 3.23 57 26 28.15 3.17 29 27 29.32 3.04 10 28 29.73 3 3 29 30.65 2.91 2 30 31.63 2.83 8 31 31.96 2.8 3 32 32.33 2.77 12 33 32.74 2.73 3 34 33.37 2.68 4 35 34.44 2.6 10
32. Pharmaceutical composition comprising as active ingredient a morphologically uniform vortioxetine salt according to claim 20 formed with salicylic acid, citric acid, malonic acid, oxalic acid, L-malic acid, benzenesulfonic acid, acetic acid, succinic acid or L-mandelic acid, preferably the vortioxetine salicylate salt of the Formula XIII, the vortioxetine monocitrate anhydrate salt of the Formula XX, the vortioxetine monocitrate hydrate salt of the Formula XIV, the vortioxetine hemicitrate salt of the Formula XI, the vortioxetine malonate salt of the Formula XV, the vortioxetine hemioxalate salt of the Formula XVI, the vortioxetine monooxalate salt of the Formula X, the vortioxetine malate salt of the Formula XVII, the vortioxetine benzenesulfonate salt of the Formula XVIII, the vortioxetine acetic acid salt of the Formula XIX, the vortioxetine succinic acid salt of the Formula XII or the vortioxetine L-(+)-mandelate salt of the Formula IX or polymorphs thereof in admixture with at least one auxiliary agent.
33. Pharmaceutical composition according to claim 32 wherein the HPLC purity of the active ingredient is larger than 99.5%, preferably larger than 99.8% and/or contains less than 0.5%, preferably less than 0.2% of the impurity of the Formula VIII; and/or which comprises one of the following active ingredients: polymorph of the vortioxetine L-(+)-mandelate salt having the following characteristic X-ray powder diffraction peaks: 2 (0.2 ): 4.25; 11.69; 11.86; 13.29; 16.52; 16.93; 17.17; 18.47; 23.46; 24.29; 26.21. polymorph of the vortioxetine-hemicitrate (2:1) salt having the following characteristic X-ray powder diffraction peaks: 2 (0.2 ): 5.24; 13.79; 16.52; 17.31; 18.15; 20.35; polymorph of the vortioxetine monooxalate (1:1) salt having the following characteristic X-ray powder diffraction peaks: 2 (0.2 2): 14.48; 17.8; 18.97; 20.38; 23.87; 27.57; and/or which comprises as auxiliary agent a filler and optionally a glidant, an antiadhesive, a binder, a disintegrant and a lubricant.
34-35. (canceled)
36. Process for the preparation of pharmaceutical compositions according to claim 32 comprising admixing a salt of vortioxetine formed with salicylic acid, citric acid, malonic acid, oxalic acid, L-malic acid, benzenesulfonic acid, acetic acid, succinic acid or L-mandelic acid, preferably the vortioxetine monooxalate of the Formula X, the vortioxetine L-(+)-mandelate of the Formula IX, the vortioxetine hemicitrate of the Formula XI or the vortioxetine hydrobromide or a mixture thereof with pharmaceutically acceptable solid or liquid diluents and/or auxiliary agents and bringing the mixture to a galenic form; and/or a) admixing the active ingredient with suitable pharmaceutical acceptable carriers in the desired ratio: or b) subjecting the active ingredient with a portion of the auxiliary agents to dry or wet granulation and if necessary drying the granules thus obtained, and tableting the mixture thus obtained or filling the same in capsules; and/or admixing 2-23% by weight, preferably 5-20% by weightcalculated on the filling weight of the tablet or capsuleof the L-(+)-mandelate salt, hemicitrate salt or oxalate salt according to the present invention with 40-90% by weight, preferably 60-80% by weight of mannitol, 5-15% by weight, preferably 9-12% by weight of microcrystalline cellulose, 1-4% by weight, preferably 2-3% by weight of sodium carboxymethyl starch (Primojel), granulating the mixture in a fluid granulator with a 3-10% by weight, preferably 4-8% by weight, more advantageously 6% by weight solution of hydroxypropyl cellulose (Klucel EXF), drying the granules thus obtained in a fluidization apparatus, regranulating the granules on a 1 mm oscillating sieve, adding the residual 2-5% by weight of microcrystalline cellulose and preferably 0.5-1.5% by weight of magnesium stearate and tableting the mixture thus obtained on a rotating tableting machine.
37-38. (canceled)
Description
LIST OF THE FIGURES
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[0203] Drawing 15 (
[0204] Drawing 16 (
[0205] Drawings 17 and 18 (
[0206] Further details of the present invention are to be found in the following examples without limiting the scope of protection to said examples.
Example 1
Preparation of 2,4-dimethyl-1-/(2-nitrophenyl)-phenylsulfanyl/-benzene (compound of the Formula IV)
[0207] 31.5 g (0.2 mole) of 2-chloro-nitrobenzene (II) (wherein Z stands for chlorine) and 27.65 g (0.2 mole) of 2,4-dimethylthiophenol (III) are dissolved in 500 ml of dimethyl formamide whereupon to the solution 30.35 g (0.22 mole) of potassium carbonate are added under vigorous stirring. The reaction mixture is stirred at an internal temperature of 100 C. in an inert atmosphere for 2.5 hours. The reaction mixture is evaporated. The viscous resin thus obtained is treated with 250 ml of water. The yellow crystalline substance thus obtained is filtered, washed with 250 ml of water. The yellow crystalline product thus obtained is filtered, washed three times with 50 ml of water each and dried. Thus 51.76 g (99.79%) of a yellow crystalline product are obtained, which melts at 82-89 C. (HPLC purity 99.89%). The product can be used in the next step without purification.
[0208] Elementary analysis C.sub.14H.sub.13NO.sub.2S (259.33) calculated for the Formula:
TABLE-US-00008 Calc [%] C: 64.48 H: 5.05 N: 5.40 S: 12.36 Found [%] C: 64.71 H: 5.06 N: 5.35 S: 12.44
[0209] IR (KBr): 1517, 1331, 1302, 810, 732 cm.sup.1.
[0210] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.25 (m, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.31 (m, 1H), 7.21 (s, 1H), 7.19 (m, 1H), 7.11 (d, J=7.6 Hz, 1H), 6.70 (m, 1H), 2.40 (s, 3H), 2.30 (s, 3H) ppm.
Example 2
Preparation of 2-[(2,4-dimethyl-phenyl)-sulfanyl]-aniline (V)
[0211] A solution of 51.9 g (0.2 mole) of 2,4-dimethyl-1-[(2-nitro-phenyl)-sulfanyl]-benzene (IV) and 200 ml ethanol is placed in a hydrogenating autoclave whereupon 5.2 g of a 10% palladium/charcoal catalyst are added. The closed autoclave is rinsed, placed under a hydrogen pressure of 10 bar and stirred in a 80 C. oil bath for 6 hours (if the internal pressure decreases to 0 bar, the autoclave is put again under a hydrogen pressure of 10 bar). The heating is stopped and the autoclave is allowed to stand at room temperature overnight. The catalyst is filtered, washed with ethanol and the filtrate is evaporated. Thus 45.87 g (theoretical yield 45.85 g) of a yellow-brown oily product are obtained (HPLC purity 96%). The product is used in the next step without purification.
[0212] Elementary analysis C.sub.14H.sub.15NS (229.35) calculated for the Formula:
TABLE-US-00009 Calc [%] C: 73.32 H: 6.59 N: 6.11 Found [%] C: 73.02 H: 6.56 N: 6.14
[0213] IR (film): 3473, 3374, 1609, 1479, 751 cm.sup.1.
[0214] .sup.1H-NMR (CDCl.sub.3, 500 MHz): 7.34 (m, 1H), 7.19 (m, 1H), 6.98 (s, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.74 (m, 1H), 6.72 (m, 1H), 6.70 (d, J=7.9 Hz, 1H), 4.19 (b, 2H), 2.37 (s, 3H), 2.25 (s, 3H) ppm.
Example 3
Preparation of the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine L-(+)-mandelic acid salt of the Formula IX
[0215] 1.0 g (4.36 millimoles) of 2-[(2,4-dimethyl-phenyl)-sulfanyl]-aniline, 0.91 g (5.0 millimoles) of bis-(2-chloroethyl-amine)-hydrochloride and 0.72 g (5.2 millimoles) of potassium carbonate are suspended in a mixture of 10 ml of toluene and 10 ml of DMI. The suspension is placed in a hermetically closed Teflon vessel and heated in an oil bath at 170-180 C. for 12 hours under stirring. The reaction mixture is cooled every 3 hours, whereupon bis-(2-chloroethyl)-amine hydrochloride and potassium carbonate are added in an amount disclosed above. Heating is continued. The reaction having been completed the suspension is filtered, the inorganic salt mixture is washed successively with 5 ml of toluene and three times with 5 ml of dichloro methane each. The united filtrates are poured in a mixture of 100 g of ice and 5 ml of ammonium hydroxide, then evaporated dichloro methane and toluene free. The precipitated resin is solidified by rubbing. The solid substance is filtered, washed with water until neutral and dried. Thus about 0.94 g (72%) of sticky crystals are obtained from which a 0.3 g (about 1.0 millimole) portion is suspended in 6 ml of acetone. The suspension is warmed to 60 C. whereupon at this temperature a solution of 0.15 g (1.0 millimole) of L-(+)-mandelic acid and 2 ml of acetone is added dropwise. After some minutes the precipitation of crystals begins. The precipitated salt is filtered, washed three times whit 2 ml of cold acetone each and dried. Thus 0.35 g (78%) of the desired compound is obtained. Mp.: 155-158 C., HPLC purity 99.9%.
[0216] IR (KBr): 2736, 2517, 1716, 1594, 1471, 1370, 1232, 1187 cm.sup.1.
[0217] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.50 (m, 2H), 7.36 (d, J=7.8 Hz, 1H), 7.32 (m, 2H), 7.21 (m, 1H), 7.19 (s, 1H), 7.09 (m, 1H), 7.05 (m, 1H), 6.92 (m, 1H), 6.91 (m, 1H), 6.52 (m, 1H), 4.95 (s, 1H), 3.06 (m, 2H), 3.02 (m, 4H), 2.95 (m, 2H), 2.38 (s, 3H), 2.31 (s, 3H) ppm.
[0218] The characteristic X-ray powder diffraction peaks of the salt thus obtained are shown on
TABLE-US-00010 Relative Peak 2 () d () intensity (%) 1 4.25 20.76 16 2 11.69 7.56 22 3 11.86 7.46 24 4 12.25 7.22 10 5 13.29 6.66 32 6 14.42 6.14 16 7 16.52 5.36 65 8 16.93 5.23 100 9 17.17 5.16 26 10 17.58 5.04 11 11 18.47 4.80 17 12 18.81 4.71 2 13 19.54 4.54 7 14 20.55 4.32 2 15 20.78 4.27 5 16 22.18 4.00 2 17 22.39 3.97 2 18 23.15 3.84 9 19 23.46 3.79 38 20 23.94 3.71 15 21 24.29 3.66 18 22 24.59 3.62 5 23 24.95 3.57 4 24 25.42 3.50 8 25 26.21 3.40 24 26 26.93 3.31 13 27 28.28 3.15 5 28 28.71 3.11 3 29 29.00 3.08 3 30 30.18 2.96 3 31 31.32 2.85 4 32 31.82 2.81 2 33 32.58 2.75 3 34 33.10 2.70 2 35 33.36 2.68 2
Example 3/A
Preparation of the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazin L-(+)-mandelic acid salt of the Formula (IX)
[0220] 3.4 g (14.8 millimoles) of 2-[(2,4-dimethyl-phenyl)-sulfanyl]-aniline and 2.9 g (16.25 millimoles) of bis-(2-chloroethyl)-amine hydrochlorideare suspended in a mixture of 3.4 ml of toluene and 3.4 ml of DMI. The suspension is heated to boiling in an inert atmosphere for 4 hours under stirring. The reaction mixture is cooled and washed until free from toluene, whereupon one proceeds as described in Example 3.
Example 3/B
Preparation of 1-/2-(2,4-dimethyl-phenylsulfanyl)-phenyl/-piperazine L-(+)-mandelic acid salt (IX)
[0221] 3.4 g (14.8 millimoles) of 2-[(2,4-dimethyl-phenyl)-sulfanyl]-aniline and 2.9 g (16.25 millimoles) of bis-(2-chloroethyl-amine)-hydrochloride are dissolved in a mixture of 3.4 ml of toluene and 3.4 ml of DMI. The solution is heated to boiling in an oil bath at 170-180 C. for 6 hours under stirring. To the warm reaction mixture 34 ml of toluene are added. The mixture is allowed to cool to room temperature and 20 ml of a 1 n sodium hydroxide solution are added. The mixture is stirred until clear phases are formed. The phases are separated, the organic layer is washed four times with 10 ml of water each, warmed to 60 C. and 2.25 g (14.8 millimoles) of L-(+)-mandelic acid are added and the reaction mixture is stirred at this temperature until the L-(+)-mandelic acid is dissolved. On cooling the precipitation of crystals begins. The crystal suspension is placed in a refrigerator overnight, the precipitated salt is filtered, washed twice with 3 ml of cold toluene each and three times with 5 ml of acetone each and dried. Thus 4.3 g (64.4%) of the desired L-(+)-mandelic acid salt are obtained. Mp.: 154-157 C. HPLC yield 99.91%.
Example 3/C
1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine L-(+)-mandelic acid salt (IX) (from vortioxetine base by salt formation)
[0222] 6.0 g (20.0 millimoles) of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine base are suspended in 120 ml of acetone. The suspension is warmed to reflux temperature. A solution is obtained. To the hot solution 3.0 g (20.0 millimoles) of L-(+)-mandelic acid in 40 ml of acetone are added. The precipitation of crystals immediately begins. The suspension is stirred at room temperature for 6 hours and allowed to stand at 4 C. overnight. The crystals are filtered, washed with cold acetone and dried under an infrared lamp until constant weight. Yield 8.31 g (92.2%). The HPLC purity of the white crystals is >99.9% (HPLC).
[0223] The characteristic X-ray powder diffraction peaks of the salt are shown on
Example 4
Preparation of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine from the L-(+)-mandelic acid salt of the Formula IX
[0224] 5.26 g (11.67 millimoles) of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine L-(+)-mandelic acid salt prepared according to any of examples 3, 3/A or 3/B are suspended in 175 ml of dichloro methane, whereupon 175 ml of a 1 M sodium hydroxide solution are added. The mixture is cooled until clear pure phases are formed. The layers are separated; the organic phase is washed three times with 100 ml of water each, dried over sodium sulphate and evaporated in vacuo. The crystalline residue is suspended in 50 ml of water, washed three times with 20 ml of water each and dried. Thus 3.5 g (yield about 100%) of the desired product are obtained. Mp.: 112-115 C.
Example 5
Preparation of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine monooxalate salt (X)
[0225] One proceeds as described in Example 3 except that to the suspension a solution of 0.09 g (1.0 millimoles) of oxalic acid in 2 ml of acetone is added at 60 C. Thus 0.33 g (85%) of the desired monooxalate salt is obtained. Mp.: 185-188 C., HPLC purity 97.85%.
[0226] IR (KBr): 3434, 3016, 2510, 1715, 1652, 1474, 1209, 705 cm.sup.1.
[0227] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 7.33 (d, J=7.8 Hz, 1H), 7.25 (s, 1H), 7.14 (m, 2H), 7.10 (m, 1H), 6.95 (m, 1H), 6.41 (m, 1H), 3.17 (m, 4H), 3.13 (m, 4H), 2.33 (s, 3H), 2.24 (s, 3H) ppm.
[0228] .sup.13CNMR (DMSO-d.sub.6, 100 MHz): 163.39, 148.06, 141.79, 139.44, 135.86, 133.56, 131.92, 128.22, 127.05, 126.18, 126.00, 125.25, 120.46, 48.42, 43.56, 20.87, 20.23 ppm.
[0229] The characteristic X-ray powder diffraction peaks of the salt are shown on
TABLE-US-00011 Relative Peak 2 () d () intensity (%) 1 10.16 8.70 9 2 13.67 6.47 41 3 14.48 6.11 96 4 15.38 5.76 3 5 16.01 5.53 28 6 16.98 5.22 8 7 17.80 4.98 51 8 18.15 4.88 32 9 18.46 4.80 18 10 18.97 4.67 100 11 19.54 4.54 7 12 20.38 4.36 48 13 21.10 4.21 10 14 21.72 4.09 3 15 22.16 4.01 4 16 22.75 3.91 3 17 23.16 3.84 10 18 23.87 3.72 100 19 24.36 3.65 5 20 24.89 3.57 2 21 25.35 3.51 3 22 26.10 3.41 6 23 26.81 3.32 16 24 27.15 3.28 4 25 27.57 3.23 57 26 28.15 3.17 29 27 29.32 3.04 10 28 29.73 3.00 3 29 30.65 2.91 2 30 31.63 2.83 8 31 31.96 2.80 3 32 32.33 2.77 12 33 32.74 2.73 3 34 33.37 2.68 4 35 34.44 2.60 10
Example 6
Preparation of the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hemicitrate salt (XI)
[0231] One proceeds as described in Example 3 except that to the suspension 0.115 g (0.6 millimole) of citric acid dissolved in 2 ml of acetone is added at 60 C. Thus 0.32 g (79%) of the desired hemicitrate salt is obtained. Mp.: 183-186 C., HPLC purity 98.93%.
[0232] IR (KBr): 2491, 1603, 1474, 1280, 764 cm.sup.1.
[0233] .sup.1H-NMR (CD.sub.3OD-CDCl.sub.3, 500 MHz): 7.31 (d, J=7.8 Hz, 1H), 7.18 (d, J=0.6 Hz, 1H), 7.13 (m, 1H), 7.11 (m, 1H), 7.05 (m, 1H), 6.92 (m, 1H), 6.54 (dd, J1=0.9 Hz, J2=7.7 Hz, 1H), 3.30 (m, 4H), 3.24 (m, 4H), 2.81 (d, J=15.4 Hz, 0.5*2H), 2.73 (d, J=15.4 Hz, 0.5*2H), 2.36 (s, 3H), 2.29 (s, 3H) ppm.
[0234] The X-ray powder diffraction data are shown on
[0235] The X-ray powder mixture diffraction of the citric acid (1:2) salt are shown in the following Table 2:
TABLE-US-00012 TABLE 2 Relative Peak 2 () d () intensity (%) 1 5.24 16.85 100 2 10.26 8.61 36 3 10.50 8.41 10 4 10.94 8.08 9 5 11.43 7.74 14 6 12.10 7.31 16 7 13.02 6.80 21 8 13.79 6.41 93 9 14.28 6.20 8 10 14.67 6.03 10 11 15.76 5.62 41 12 16.52 5.36 73 13 17.31 5.12 48 14 17.65 5.02 39 15 18.15 4.88 50 16 18.77 4.72 27 17 19.04 4.66 13 18 20.01 4.43 21 19 20.35 4.36 53 20 20.60 4.31 44 21 21.00 4.23 40 22 21.45 4.14 21 23 22.00 4.04 14 24 23.01 3.86 42 25 23.20 3.83 31 26 24.31 3.66 13 27 24.71 3.60 15 28 25.12 3.54 11 29 25.39 3.51 10 30 25.85 3.44 18 31 26.37 3.38 17 32 26.71 3.34 4 33 27.30 3.26 5 34 27.75 3.21 18 35 28.22 3.16 3 36 28.84 3.09 6 37 30.00 2.98 6 38 31.07 2.88 7
[0236] The X-ray powder diffraction data of the vortioxetine citric acid (1:2) salt [0237] (relative intensities>2%)
Example 7
1-/2-[(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide salt (beta polymorph
[0238] One proceeds as described in Example 3 except that to the suspension 0.113 ml (1.0 millimole) of an aqueous 48% hydrogen bromide solution is added at 60 C. Thus 0.26 g (69%) of the desired hydrobromide salt ( polymorph) is obtained. Mp.: 224-229 C., HPLC purity 97.72%.
[0239] elementary analysis C.sub.18H.sub.23BrN.sub.2S (379.37) calculated for the Formula:
TABLE-US-00013 Calc [%] C: 56.99 H: 6.11 N: 7.38 S: 8.45 Br: 21.06 Found [%] C: 56.31 H: 5.98 N: 7.30 S: 8.22 Br: 21.08
[0240] IR (KBr): 2704, 2460, 1440, 1041, 927 cm.sup.1.
[0241] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 8.77 (b, 2H), 7.34 (d, J=7.8 Hz, 1H), 7.25 (s, 1H), 7.16 (m, 1H), 7.15 (m, 1H), 7.11 (m, 1H), 6.97 (m, 1H), 6.43 (m, 1H), 3.25 (m, 4H), 3.19 (m, 4H), 2.33 (s, 3H), 2.25 (s, 3H) ppm.
Preparation of Salts of High Purity Via the Base Formed from the Mandelic Acid Salt
Example 8
Preparation of the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine citric acid (2:1) salt (vortioxetine hemicitrate of the Formula XI)
[0242] 300 mg (1.0 millimoles) of the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine base prepared according to Example 4 are dissolved in 6 ml of acetone under reflux whereupon to the hot solution 114 mg (0.6 millimole) of citric acid in 2 ml of acetone is added. From the hot solution the precipitation of crystals immediately begins. The suspension is stirred at room temperature for 6 hours and allowed to stand at 4 C. overnight. The crystals are filtered, washed with cold acetone and dried. Yield 350 mg (71%). The white crystals melt at 183-186 C., HPLC purity 99.9%.
[0243] The NMR and XRPD data of the product correspond to those disclosed in Example 6.
Example 8/A
Preparation of the 1-[1-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine citric acid (2:1) salt (vortioxetine hemicitrate of the Formula XI)
[0244] 6.0 g (20.0 millimoles) of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine base are suspended in 120 ml of acetone. The suspension is heated to reflux temperature. To the hot solution 2.31 g (12.0 millimoles) of citric acid dissolved in 225 ml of acetone is added. The precipitation of crystals immediately begins. On manual treatment the oily product becomes crystalline and can be easily stirred. The suspension is stirred at room temperature for 6 hours and thereafter allowed to stand at 4 C. overnight. The crystals are filtered, washed with cold acetone and dried. Yield 7.2 g (88.6%). The white crystals melt at 183-186 C. Purity: >99.9%.
[0245] The NMR and XRPD data of the product correspond to those disclosed in Example 6.
Example 9
Preparation of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine oxalic acid (1:1) salt (X) (vortioxetine monooxalate)
[0246] 300 mg (1.0 millimole) of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine base obtained according to Example 4 are dissolved in 6 ml of acetone under reflux. To the hot solution 108 mg (1.2 millimoles) of oxalic acid dissolved in 2 ml of acetone are added. From the hot solution the precipitation of crystals immediately begins. The suspension is stirred at room temperature for 3 hours and thereafter allowed to stand at 4 C. overnight. The crystals are filtered, washed with cold acetone and dried. Yield 360 mg (93%). The white crystals melt at 185-188 C., HPLC purity larger than 99.9%.The NMR and XRPD data of the product correspond to those disclosed in Example 6.
Example 9/A
Preparation of the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine monooxalate salt of the Formula X
[0247] 6.0 g (20.0 millimoles) of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine base prepared according to Example 4 are suspended in 120 ml of acetone. The suspension is heated under reflux. To the hot solution thus obtained 2.06 g (24.0 millimoles) of oxalic acid dissolved in 25 ml of acetone are added. An abundant crystal precipitation immediately starts. The suspension is stirred at room temperature for 6 hours and thereafter allowed to stand at 4 C. overnight. The crystals are filtered, washed with cold acetone and dried to constant weight. Yield 7.19 g (92.5%). The white crystals melt at 185-188 XC. HPL purity larger than 99.9%. The NMR and XRPD data correspond to those disclosed in Example 5.
Example 10
Preparation of the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide salt (beta polymorph)
[0248] 300 mg (1.0 millimole) of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine base prepared according to Example 4 are dissolved in 6 ml of acetone under reflux. To the hot solution thus obtained 0.113 g (1.0 millimole) of a 48% aqueous hydrobromic acid solution is added. From the hot solution the precipitation of crystals immediately begins. The suspension is stirred at room temperature for 3 hours and then allowed to stand at 4 C. overnight. The crystals are filtered, washed with cold acetone and dried. Yield 0.27 g (70.6%). Mp.: 226-228 C. HPLC purity 99.81%. The NMR and XRPD data of the product correspond to those disclosed in Example 7.
Example 11
Preparation of the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine salicylic acid (1:1) salt (vortioxetine salicylate of the Formula XIII)
[0249] 400 mg (1.34 millimole) of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine base are dissolved in 8 ml of acetone under reflux. To the hot solution thus obtained 185 mg (1.34 millimole) of salicylic acid dissolved in 2 ml of acetone are added. The reaction mixture is cooled to room temperature; the solvent is evaporated in vacuo. The residue is crystallized from 1 ml of acetone. The crystals obtained are filtered, washed with cold acetone and dried in a refrigerator at 80 C. for 6 hours. The white crystals melt at 179-184 C., yield 510 mg (87%).
[0250] IR (KBr): 2488, 1638, 1474, 1457, 1381, 763 cm.sup.1.
[0251] 1H-NMR (CDCl3, 400 MHz): 7.94 (m, 1H), 7.36 (m, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.14 (s, 1H), 7.05 (m, 1H), 7.02 (m, 1H), 6.97 (m, 1H), 6.95 (m, 1H), 6.91 (m, 1H), 6.86 (m, 1H), 6.53 (dd, J1=1.2 Hz, J2=7.9 Hz, 1H), 3.41 (m, 4H), 3.29 (m, 4H), 2.35 (s, 3H), 2.29 (s, 3H) ppm.
[0252] The X-ray powder diffraction data of the vortioxetine salicylic acid (1:1) salt are disclosed in the following Table (relative intensities>2%).
TABLE-US-00014 Relative Peak 2 () d () intensity (%) 1 8.44 10.47 18 2 11.66 7.58 27 3 12.41 7.12 7 4 13.22 6.69 22 5 13.73 6.45 71 6 14.39 6.15 64 7 16.60 5.34 100 8 16.84 5.26 47 9 17.57 5.04 23 10 17.83 4.97 34 11 18.61 4.76 51 12 19.03 4.66 6 13 19.57 4.53 14 14 19.81 4.48 42 15 20.30 4.37 39 16 21.55 4.12 10 17 21.82 4.07 9 18 32.10 2.79 10 19 29.04 3.07 9 20 22.05 4.03 17 21 22.60 3.93 30 22 23.06 3.85 28 23 21.07 4.21 12 24 17.08 5.19 19 25 10.21 8.65 3 26 23.45 3.79 17 27 24.00 3.71 25 28 24.24 3.67 13 29 24.96 3.56 8 30 25.24 3.53 26 31 25.63 3.47 7 32 26.06 3.42 28 33 27.30 3.26 23 34 27.66 3.22 7 35 27.99 3.18 23 36 28.47 3.13 8 37 28.80 3.10 22 38 29.28 3.05 3 39 29.98 2.98 8 40 30.57 2.92 5 41 30.90 2.89 6 42 32.38 2.76 4 43 33.57 2.67 3 44 33.87 2.64 5
Example 12
Preparation of the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine citric acid [1:1] salt (vortioxetine monocitrate monohydrate of the Formula XIV
[0253] 100 mg (0.335 millimole) of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine base are dissolved in a mixture of 2 ml of acetone and 0.2 ml of water under reflux. To the hot solution 320 mg (1.67 millimole) of citric acid in 2 ml of acetone are added. From the hot solution the precipitation of crystals immediately begins. The suspension thus obtained is stirred at room temperature for 6 hours and then allowed to stand at 4 C. overnight. The crystals are filtered, washed with cold acetone and dried. Yield 90 mg (53%). The white crystals melt at 126-129 C.
[0254] IR (KBr): 3454, 2528, 1702, 1679, 1582, 1311, 1234 cm.sup.1.
[0255] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 10.46 (b, 3H), 7.33 (d, J=7.8 Hz, 1H), 7.25 (s, 1H), 7.16 (m, 1H), 7.15 (m, 1H), 7.11 (m, 1H), 6.97 (m, 1H), 6.42 (m, 1H), 3.23 (m, 4H), 3.16 (m, 4H), 2.55 (d, J=15.1 Hz, 2H), 2.48 (d), 2.33 (s, 3H), 2.24 (s, 3H) ppm.
[0256] The loss of weight of the product obtained according to the process amounts to 3.3% by weight measured by TG (calc. 3.6% by weight).
[0257] The characteristic X-ray powder diffraction data of the citric acid [1:1] salt (vortioxetine monocitrate monohydrate) are disclosed in the following Table: [0258] (relative intensities> than 2%)
TABLE-US-00015 Relative Peak 2 () d () intensity (%) 1 11.66 7.58 90 2 11.97 7.39 5 3 12.76 6.93 10 4 13.89 6.37 48 5 14.17 6.24 15 6 14.98 5.91 45 7 16.36 5.42 52 8 17.00 5.21 100 9 18.17 4.88 11 10 18.58 4.77 7 11 19.8 4.48 11 12 20.82 4.26 9 13 21.27 4.17 6 14 22.04 4.03 3 15 22.65 3.92 81 16 23.42 3.79 4 17 24.09 3.69 48 18 24.84 3.58 6 19 25.61 3.48 5 20 26.98 3.3 10 21 27.26 3.27 10 22 28.42 3.14 8 23 29.09 3.07 9 24 29.63 3.01 3 25 30.42 2.94 4 26 30.82 2.90 3 27 32.69 2.74 6 28 33.54 2.67 7 29 34.36 2.61 13 30 34.68 2.58 6
Example 13
Preparation of the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine citric acid [1:1] salt (vortioxetine monocitrate anhydrate of the (Formula XX)
[0259] 100 mg (0.335 mole) of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine base are dissolved in 2 ml of acetone under reflux whereupon to the hot solution thus obtained 320 mg (1.67 millimoles) of citric acid dissolved in 2 ml of acetone are added. From the hot solution the precipitation of crystals starts immediately. The suspension is stirred at room temperature for 6 hours and thereafter allowed to stand at 4 C. overnight. The crystals are filtered, washed with cold acetone and dried. Yield 120 mg (73%). The white crystals melt at 152-154 C.
[0260] IR (KBr): 3351, 3139, 2518, 1735, 1686, 1628, 1440, 1403, 1199, 1044 cm.sup.1.
[0261] .sup.1H-NMR (CD.sub.3OD-CDCl.sub.3, 500 MHz): 7.29 (d, J=7.8 Hz, 1H), 7.20 (bs, 1H), 7.17 (m, 1H), 7.13 (m, 1H), 7.06 (m, 1H), 6.93 (m, 1H), 6.54 (m, 1H), 3.37 (m, 4H), 3.28 (m, 4H), 2.83 (d, J=15.5 Hz, 2H), 2.74 (d, J=15.4 Hz, 2H), 2.35 (s, 3H), 2.28 (s, 3H) ppm.
[0262] The characteristic X-ray diffraction data of the citric acid (1:1) salt (vortioxetine monocitrate anhydrate) are summarized in the following Table: [0263] (relative intensities>2%)
TABLE-US-00016 Relative Peak 2 () d () intensity (%) 1 5.52 16.01 100 2 10.33 8.56 6 3 10.94 8.08 3 4 12.38 7.14 71 5 13.20 6.70 15 6 13.91 6.36 13 7 14.56 6.08 29 8 15.62 5.67 10 9 16.26 5.45 47 10 16.61 5.33 93 11 18.12 4.89 78 12 18.83 4.71 6 13 20.68 4.29 20 14 20.89 4.25 33 15 21.34 4.16 6 16 22.10 4.02 13 17 22.91 3.88 24 18 23.41 3.80 17 19 24.37 3.65 11 20 24.85 3.58 33 21 25.60 3.48 26 22 26.37 3.38 16 23 27.93 3.19 15 24 28.45 3.13 13 25 29.37 3.04 7 26 31.15 2.87 11 27 31.97 2.80 4 28 32.89 2.72 7
Example 14
Preparation of the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine malonic acid [1:1] salt (vortioxetine malonate of the Formula XV)
[0264] 300 mg (1.0 mole) of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine base are dissolved in 6 ml acetone at room temperature whereupon to the hot solution thus obtained 100 mg (1.0 millimole) of malonic acid dissolved in 2 ml of acetone are added. The reaction mixture is cooled to room temperature; the solvent is evaporated in vacuo. The oily residue is crystallized from 1 ml of acetone. The crystals are filtered, washed with cold acetone and dried in a refrigerator under a pressure of 8 mbar in vacuo at 80 C. for 6 hours. Yield 350 mg (87%). The white crystals melt at 126-129 C.
[0265] IR (KBr): 3478, 3029, 2490, 1718, 1580, 1469, 1374 cm.sup.1.
[0266] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 7.33 (d, J=7.8 Hz, 1H), 7.25 (s, 1H), 7.15 (m, 2H), 7.11 (m, 1H), 6.97 (m, 1H), 6.42 (m, 1H), 3.23 (m, 4H), 3.17 (m, 4H), 2.72 (s, 2H), 2.33 (s, 3H), 2.24 (s, 3H) ppm.
[0267] The characteristic X-ray powder diffraction peaks of the vortioxetine malonic acid [1:1] salt are summarized in the following Table [0268] (relative intensity> than 2%)
TABLE-US-00017 Peak 2 () d () Relative intensity (%) 1 5.11 17.26 71 2 10.46 8.45 59 3 11.93 7.41 34 4 14.77 5.99 24 5 15.21 5.82 63 6 16.05 5.52 31 7 16.58 5.34 11 8 17.35 5.11 15 9 17.91 4.95 25 10 18.30 4.84 28 11 18.71 4.74 100 12 19.64 4.52 9 13 19.98 4.44 16 14 20.42 4.35 76 15 20.64 4.30 28 16 20.93 4.24 9 17 21.58 4.12 9 18 22.53 3.94 7 19 22.79 3.90 20 20 23.03 3.86 8 21 24.22 3.67 28 22 24.60 3.62 7 23 25.77 3.45 19 24 26.44 3.37 14 25 26.95 3.31 10 26 27.19 3.28 10 27 27.66 3.22 12 28 29.23 3.05 8 29 29.45 3.03 11 30 30.66 2.91 8 31 30.95 2.89 8 32 31.79 2.81 7
Example 15
Preparation of the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine oxalic acid [2:1] salt (vortioxetine hemioxalate of the Formula XVI)
[0269] 300 mg (1.0 millimole) of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine base are dissolved in 6 ml of acetone under reflux and to the hot solution thus obtained 54 mg (0.6 millimole) of oxalic acid dissolved in 1.2 ml of acetone are added. From the hot solution the precipitation of crystals immediately begins. The suspension is stirred at room temperature for 5 hours and then allowed to stand overnight. The crystals are filtered, washed with cold acetone and dried. Yield 270 mg (93%). The white crystals melt at 199-208 C.
[0270] IR (KBr): 2756, 2509, 1915, 1653, 1474, 1209, 705 cm.sup.1.
[0271] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 7.33 (d, J=7.8 Hz, 1H), 7.25 (s, 1H), 7.14 (m, 2H), 7.10 (m, 1H), 6.95 (m, 1H), 6.41 (m, 1H), 3.17 (m, 4H), 3.13 (m, 4H), 2.33 (s, 3H), 2.24 (s, 3H) ppm.
[0272] .sup.13CNMR (DMSO-d.sub.6, 100 MHz): 163.39, 148.06, 141.79, 139.44, 135.86, 133.56, 131.92, 128.22, 127.05, 126.18, 126.00, 125.25, 120.46, 48.42, 43.56, 20.87, 20.23 ppm.
[0273] X-ray powder diffraction data of the vortioxetine oxalic acid [1:2] salt: [0274] (relative intensities>2%)
TABLE-US-00018 Peak 2 () d () Relative intensity (%) 1 11.67 7.58 6 2 12.00 7.37 17 3 13.79 6.42 7 4 14.27 6.20 17 5 15.43 5.74 97 6 16.32 5.43 24 7 16.96 5.22 50 8 17.48 5.07 100 9 18.42 4.81 7 10 18.85 4.70 14 11 19.89 4.46 18 12 20.43 4.34 13 13 20.89 4.25 11 14 21.71 4.09 4 15 22.08 4.02 4 16 22.85 3.89 57 17 23.22 3.83 13 18 23.41 3.80 10 19 23.85 3.73 6 20 24.49 3.63 22 21 25.14 3.54 23 22 25.72 3.46 10 23 26.33 3.38 3 24 28.12 3.17 6 25 28.51 3.13 6 26 29.49 3.03 3 27 29.97 2.98 5 28 30.38 2.94 3 29 30.92 2.89 4 30 31.62 2.83 2 31 32.50 2.75 3 32 32.90 2.72 4 33 34.59 2.59 3 34 34.81 2.57 5
Example 16
Preparation of the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine L-malic acid [1:1] salt (vortioxetine L-malate of the Formula XVII)
[0275] 300 mg (1.0 millimole) of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine base are dissolved in 6 ml of acetone under reflux, whereupon to the hot solution 130 mg (1.0 millimole) of L-malic acid in 2 ml of acetone are added. From the hot solution the precipitation of crystals immediately begins. The suspension is stirred at room temperature for 6 hours and then allowed to stand at room temperature overnight. The crystals are filtered, washed with cold acetone and dried. Yield 380 mg (88%). The white crystals melt at 127-130 C.
[0276] IR (KBr): 2492, 1716, 1634, 1472, 1454, 1228, 1045 cm.sup.1.
[0277] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 9.75 (br s, 4H), 7.33 (d, J=7.8 Hz, 1H), 7.25 (s, 1H), 7.15 (m, 1H), 7.14 (m, 1H), 7.10 (m, 1H), 6.95 (m, 1H), 6.42 (m, 1H), 3.87 (dd, J1=3.8 Hz, J2=10.2 Hz, 1H), 3.18 (m, 4H), 3.12 (m, 4H), 2.50 (m, 1H), 2.33 (s, 3H), 2.32 (m, 1H), 2.24 (s, 3H) ppm.
[0278] X-ray powder diffraction data of the vortioxetine L-malic acid [1:1] salt [0279] (relative intensities>2%)
TABLE-US-00019 Peak 2 () d () Relative intensity (%) 1 4.05 21.78 44 2 8.06 10.96 19 3 12.08 7.32 100 4 12.57 7.04 23 5 13.40 6.60 46 6 13.58 6.52 76 7 14.36 6.17 5 8 15.65 5.66 11 9 16.13 5.49 16 10 16.97 5.22 49 11 18.12 4.89 28 12 19.58 4.53 84 13 20.63 4.30 14 14 21.77 4.08 15 15 22.61 3.93 43 16 23.49 3.78 33 17 23.96 3.71 24 18 24.26 3.67 48 19 25.29 3.52 16 20 27.08 3.29 15 21 27.72 3.22 17 22 28.34 3.15 18
Example 17
Preparation of the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine benzenesulfonic acid [1:1] salt of the Formula XVIII
[0280] 300 mg of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine base are dissolved in 6 ml of acetone whereupon to the hot solution 160 mg (1.0 millimole) of benzenesulfonic acid dissolved in 2 ml of acetone are added. From the hot solution the crystallization of crystals immediately begins. The suspension is stirred at room temperature for 6 hours and thereafter allowed to stand at 4 C. overnight. The crystals are filtered, washed with cold acetone and dried. Yield 430 mg (94%). The white crystals melt at 178-181 C.
[0281] IR (KBr): 3050, 2496, 1224, 1192, 1124, 1016, 611 cm.sup.1.
[0282] .sup.1H-NMR (CDCl.sub.3, 400 MHz): 9.10 (br s, 2H), 7.95 (m, 2H), 7.44 (m, 3H), 7.32 (d, J=7.8 Hz, 1H), 7.14 (s, 1H), 7.05 (m, 1H), 7.02 (m, 1H), 6.97 (m, 1H), 6.90 (m, 1H), 6.52 (dd, J1=1.5 Hz, J2=7.9 Hz, 1H), 3.44 (m, 4H), 3.29 (m, 4H), 2.35 (s, 3H), 2.28 (s, 3H) ppm.
[0283] The X-ray powder diffraction data of the vortioxetine benzene sulfonic acid [1:1] salt are summarized in the following Table: [0284] (relative intensities>2%)
TABLE-US-00020 Peak 2 () d () Relative intensity (%) 1 5.83 15.15 18 2 7.81 11.31 49 3 8.04 10.99 17 4 11.19 7.90 10 5 11.64 7.60 7 6 13.49 6.56 24 7 14.30 6.19 13 8 14.79 5.98 100 9 15.35 5.77 19 10 15.63 5.67 58 11 16.08 5.51 43 12 16.56 5.35 33 13 17.61 5.03 66 14 18.28 4.85 35 15 18.51 4.79 66 16 19.54 4.54 83 17 20.44 4.34 17 18 20.83 4.26 3 19 21.27 4.17 6 20 21.55 4.12 20 21 22.03 4.03 17 22 22.53 3.94 37 23 22.79 3.90 28 24 23.53 3.78 62 25 24.11 3.69 12 26 24.71 3.60 12 27 24.92 3.57 24 28 25.76 3.46 15 29 26.22 3.40 4 30 26.46 3.37 3 31 27.03 3.30 23 32 27.50 3.24 6 33 28.28 3.15 7 34 28.77 3.10 9
Example 18
Preparation of the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine acetic acid salt (vortioxetine acetate of the Formula XIX)
[0285] 300 mg (1.0 millimole) of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine base are dissolved in 6 ml of acetone under reflux whereupon to the hot solution 0.06 ml (1.0 millimole) of acetic acid dissolved in 2 ml of acetone is added. The solution is cooled to room temperature, whereby slow precipitation of crystals begins. The suspension is stirred at room temperature for 6 hours and thereafter allowed to stand at 4 C. overnight. The crystals are filtered, washed with cold acetone and dried. Yield 140 mg (39%). The white crystals melt at 106-108 C.
[0286] IR (KBr): 2398, 1580, 1470, 1440, 1040, 759 cm.sup.1.
[0287] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 7.32 (d, J=7.8 Hz, 1H), 7.23 (s, 1H), 7.10 (m, 2H), 7.08 (m, 1H), 6.88 (m, 1H), 6.38 (d, J=7.7 Hz, 1H), 2.89 (m, 4H), 2.85 (m, 4H), 2.32 (s, 3H), 2.23 (s, 3H), 1.90 (s, 3H) ppm.
[0288] The X-ray powder diffraction data of the acetic acid salt are shown on
TABLE-US-00021 TABLE 10 Peak 2 () d () Relative intensity (%) 1 6.59 13.41 5 2 7.22 12.23 27 4 11.07 7.99 8 5 11.83 7.47 11 6 12.34 7.17 5 7 12.79 6.92 8 8 13.08 6.76 54 9 14.06 6.30 53 10 14.87 5.95 8 11 15.68 5.65 100 12 16.06 5.52 7 13 16.59 5.34 24 14 16.87 5.25 8 15 17.41 5.09 45 16 17.96 4.93 16 17 18.26 4.85 50 20 19.44 4.56 10 21 19.82 4.48 33 22 20.25 4.38 20 23 20.42 4.35 14 24 21.06 4.21 80 25 21.52 4.13 7 27 22.44 3.96 81 28 22.98 3.87 6 29 23.77 3.74 16 31 24.95 3.57 20 32 25.38 3.51 7 34 26.30 3.39 6 36 27.21 3.27 11 37 27.87 3.20 7 40 29.16 3.06 5 42 30.32 2.95 6 44 31.69 2.82 6 45 32.12 2.78 14 46 32.40 2.76 7 47 33.52 2.67 6 48 33.75 2.65 6
[0289] X-ray powder diffraction data of the vortioxetine acetic acid salt (1:1) [0290] (relative intensities>2%)
Example 19
Preparation of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine succinic acid salt (vortioxetine succinate of the Formula XII)
[0291] 300 mg (1.0 millimole) of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine are dissolved in 6 ml of acetone under reflux whereupon to the hot solution 120 mg (1.0 millimole) of succinic acid dissolved in 2 ml of acetone are added. From the hot solution the precipitation of crystals begins. The suspension is stirred at room temperature for 6 hours and thereafter allowed to stand at 4 C. overnight. The crystals are filtered, washed with cold acetone and dried. Yield 370 mg (89%). Melting point: 146-149 C.
[0292] Elementary analysis C.sub.22H.sub.28N.sub.2O.sub.4S (416.54) calculated for the Formula:
TABLE-US-00022 Calc [%] C: 63.44 H: 6.78 N: 6.73 S: 7.70 Found [%] C: 63.11 H: 6.78 N: 6.63 S: 7.60
[0293] IR (KBr): 2739, 2529, 1720, 1632, 1581, 1472, 1043 cm.sup.1.
[0294] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 7.33 (d, J=7.8 Hz, 1H), 7.24 (s, 1H), 7.13 (m, 2H), 7.09 (m, 1H), 6.92 (m, 1H), 6.40 (m, 1H), 3.03 (s, 8H), 2.33 (s, 3H), 2.33 (s, 4H), 2.24 (s, 3H) ppm.
[0295] The X-ray powder diffraction data of the vortioxetine succinic acid (1:1) salt [0296] (relative intensities>2%)
TABLE-US-00023 Peak 2 () d () Relative intensity (%) 1 4.90 18.02 13 2 5.10 17.32 19 3 9.36 9.45 7 4 11.33 7.80 100 5 12.29 7.19 15 6 13.00 6.80 7 7 13.70 6.46 13 8 14.39 6.15 4 9 14.91 5.94 26 10 15.32 5.78 47 11 16.37 5.41 13 12 17.03 5.20 65 13 17.91 4.95 85 14 18.27 4.85 10 15 19.05 4.66 27 16 19.64 4.52 9 17 19.99 4.44 19 18 20.26 4.38 8 19 21.28 4.17 40 20 21.90 4.06 3 21 22.46 3.96 18 22 22.81 3.90 16 23 23.08 3.85 19 24 23.44 3.79 77 25 24.00 3.71 84 26 24.42 3.64 38 27 24.72 3.60 31 28 25.08 3.55 21 29 25.81 3.45 10 30 27.32 3.26 5 31 27.59 3.23 10 32 28.50 3.13 5 33 28.90 3.09 9 34 29.75 3.00 5 35 30.03 2.97 6 36 32.67 2.74 3 37 33.33 2.69 5 38 34.74 2.58 11
Example 20/A
Preparation of Vortioxetine Mandelate (Compound of the Formula IX) Containing Tablets
(Strength: Corresponds to 20 mg of Vortioxetine Base)
[0297]
TABLE-US-00024 Name of the product: Vortioxetine 20 mg tablet Batch Number: Batch size: 015 UA 1114 about 1 050 g Weight mg/tablet weight (g) Vortioxetine-mandelate ground 30.196 211.37 Microcrystalline cellulose (Avicel PH 13.620 95.34 101 (FMC)) Mannitol (Pearlitol SD 200) 88.884 622.19 Sodium carboxymethyl starch 4.500 31.50 (Primojel) Hydroxypropyl cellulose (Klucel EXF) 4.50 31.50 Purified water 0 493.50 0 0 Avicel PH 101 (FMC) 6.80 47.60 Magnesium stearate 1.50 10.50 0 0 Total: 150.0 1050.0
[0298] Brief description of the manufacturing process: [0299] a) The components of the internal phase vortioxetine mandelate, microcrystalline cellulose (Avicel PH 101, FMC), mannitol (Pearlitol SD 200) and sodium carboxymethyl starch (Primojel) are admixed, homogenized and granulated with a solution of hydroxypropyl cellulose (Klucel EXF) in a fluidized granulating apparatus (Glatt GPCG 1). The granules thus obtained are dried and regranulated on an oscillating sieve (Frewitt 1.0 mm). [0300] b) The components of the external phase microcrystalline cellulose (Avicel PH 101 FMC) and magnesium stearate are admixed with the granules prepared according to paragraph a). The mixture thus obtained is homogenized. [0301] c) The homogenized mixture prepared according to paragraph b) is pressed on a rotating tableting machine to lentiform tablets (size 9.54.5 mm, weight 150 mg). Pressing strength: min. 30N. The chemical stability and dissolution of the tablets thus obtained are tested:
[0302] a) Chemical Stability of the Tablets Obtained:
TABLE-US-00025 Amount of the impurity expressed in the percentage of the active ingredient Total amount of impurities [%] (>0.03%) Storing Average total. known unknown Sample conditions content % [%] [%] [%] Mandelate Starting 102.94 <0.03 <0.03 <0.03 salt 40 C./75RH 102.38 <0.03 <0.03 <0.03 containing %-2 weeks tablet 40 C./75RH 99.37 0.03 <0.03 0.03 (015UA1114) %-4 weeks
[0303] (The results are calculated from 2 parallels measurements. The average content is expressed in the percentage of the theoretical content calculated from the measured value). It can be seen from the Table that the chemical stability of the tablets is excellent.
[0304] b) Dissolution Test
[0305] The dissolution of the tablets meets the requirements of the immediate release tablets. On advancement of time the dissolution of the tablets does not significantly change which is shown on Drawing 13 and in Table 13:
TABLE-US-00026 Time of sampling (minutes)dissolution (%) 015UA1114 5 10 15 20 30 45 60 starting Average 100.72 101.99 101.81 101.89 102.05 102.35 102.29 (%) SD 3.48 3.11 3.16 3.01 2.99 2.96 3.08 RSD[%] 3.44 3.04 3.10 2.95 2.93 2.89 3.00 2 weeks Average 101.56 103.00 102.85 102.83 103.02 102.85 102.66 40 C./75% RH (%) SD 2.43 1.91 2.06 1.89 1.74 2.00 1.87 RSD[%] 2.39 1.85 1.99 1.83 1.68 1.94 1.82 4 weeks Average 101.66 102.89 102.93 103.10 103.11 103.04 103.09 40 C./75% RH (%) SD 2.43 2.47 2.38 2.13 2.32 2.39 2.33 RSD[%] 2.38 2.40 2.30 2.06 2.24 2.31 2.25
Example 20/B
Preparation of Vortioxetine Mandelate (Compound of the Formula IX) Containing Capsules
(Strength: Corresponds to 20 mg of Vortioxetine Base)
[0306] One proceeds as described in steps a) and b) of Example 20A except that in step c) the homogenized mixture is not pressed to tablets but filled in soft gelatine capsules.
Example 21
Preparation of Vortioxetine Hydrobromide Containing Tablets
(Strength: Corresponds to 20 mg of Vortioxetine Base)
Composition:
[0307]
TABLE-US-00027 Name of the product: Vortioxetine 20 mg tablet Batch number: Batch size: 012 UA 1114 about 1 050 g Name of component mg/tablet weight (g) Vortioxetine-hydrobromide ground 25.42 177.94 Microcrystalline cellulose (Avicel PH 14.212 99.48 101 (FMC)) Mannitol (Pearlitol SD 200) 92.768 649.38 Sodium carboxymethyl cellulose 4.500 31.5 (Primojel) Hydroxypropyl cellulose (Klucel EXF) 4.50 31.5 Purified water 0 493.5 0 0 Avicel PH 101 (FMC) 7.10 49.7 Magnesium stearate 1.50 10.5 0 0 Total: 150.0 1050
[0308] The tablets are prepared according to the process of example 20/A except that the components are used in the amounts corresponding to the above composition.
[0309] The chemical stability and dissolution of the tablets obtained is tested.
[0310] a) Chemical Stability of the Tablets Obtained:
TABLE-US-00028 Amount of the impurity expressed in the percentage of the active ingredient Total amount of impurities[%] (>0.03%) Storing Average total known unknown Sample Conditions content % [%] [%] [%] Tablet Starting 98.20 <0.03 <0.03 <0.03 containing 40 C./75RH 100.98 <0.03 <0.03 <0.03 the HBr salt %-2 weeks (012UA1114) 40 C./75RH 102.77 <0.03 <0.03 <0.03 %-4 weeks
[0311] (The results are calculated from two parallel measurements. The average value is expressed as a percentage of the theoretical content calculated from the measured value.)
[0312] It can be seen from the Table that the chemical stability of the tablets is excellent.
[0313] b) Dissolution Tests
[0314] The dissolution of the tablets meets the requirements of the immediate release tablets. On the advancement of time the dissolution of the tablets does not significantly change as shown on Drawing 13 and
TABLE-US-00029 Time of sampling (minutesdissolution (%) 012UA1114 5 10 15 20 30 45 60 Starting Average 96.87 99.45 99.98 100.33 100.84 101.53 102.03 (%) SD 1.96 2.01 1.96 2.01 2.08 2.35 2.43 RSD[%] 2.05 2.04 1.99 2.03 2.09 2.35 2.41 2 weeks Average 96.45 99.19 99.94 100.53 101.31 101.96 102.12 40 C./75% RH (%) SD 2.14 2.40 2.59 2.51 2.50 2.74 2.85 RSD[%] 2.25 2.45 2.63 2.52 2.50 2.72 2.83 4 weeks Average 96.78 99.63 100.45 100.84 101.53 102.31 102.49 40 C./75% RH (%) SD 2.41 2.29 2.28 2.27 2.45 2.34 2.25 RSD[%] 2.52 2.32 2.30 2.28 2.45 2.32 2.23
Example 22
Preparation of Tablets Containing Vortioxetine Hemicitrate of the Formula XI
(Strength: Corresponds to 20 mg of Vortioxetine Base)
Composition:
[0315]
TABLE-US-00030 Name of the product: Vortioxetine 20 mg tablet Batch number: Batch size: 013 UA 1114 ca. 1 050 g Weight of the component mg/tablet Weight (g) Vortioxetine hemicitrate ground 26.034 182.24 Microcrystalline cellulose (Avicel PH 14.098 98.68 101 (FMC)) Mannitol (Pearlitol SD 200) 92.268 645.88 Sodium carboxymethyl starch 4.5 31.5 (Primojel) Hydroxypropyl cellulose (Klucel EXF) 4.5 31.5 Purified water 0 493.5 0 0 Avicel PH 101 (FMC) 7.1 49.7 Magnesium stearate 1.5 10.5 0 0 Total: 150 1050
[0316] The tablets are prepared as described in example 20 except that the amount of the components corresponds to the above composition.
[0317] The chemical stability and the dissolution of the tablets obtained are tested.
[0318] a) Chemical Stability of the Tablets:
TABLE-US-00031 Impurity content expressed in the percentage of the active ingredient Total amount of impurities [%] (>0.03%) Storing Average total known unknown Sample conditions content % [%] [%] [%] Hemicitrate Starting 97.03 <0.03 <0.03 <0.03 containing 40 C./75RH 97.49 <0.03 <0.03 <0.03 tablets %-2 weeks (013UA1114) 40 C./75RH 95.93 0.03 <0.03 0.03 %-4 weeks
[0319] (The results are calculated from two parallel measurements. The average content is expressed in the percentage of the theoretical content obtained from the measured value)
[0320] It can be seen from the Table that the chemical stability of the tablets is excellent.
[0321] b) Dissolution Test
[0322] The dissolution of the tablets meets the requirements of the immediate release tablets.
[0323] On advancement of time the dissolution of the tablets does not change significantly as shown on the following Drawing 14 and
TABLE-US-00032 Time of sampling (minutesdissolution (%) 013UA1114 5 10 15 20 30 45 60 starting Average 95.02 97.69 97.86 97.65 97.54 97.70 97.65 (%) SD 1.85 0.91 1.03 0.88 0.88 0.84 0.88 RSD[%] 1.93 0.92 1.04 0.89 0.89 0.85 0.89 2 weeks Average 96.64 98.08 98.38 98.47 98.83 98.57 98.57 40 C./75% RH (%) SD 1.81 1.30 1.38 1.38 1.51 1.31 1.31 RSD[%] 1.85 1.31 1.38 1.39 1.51 1.31 1.32 4 weeks Average 96.33 98.06 98.25 98.29 98.28 98.51 98.51 40 C./75% RH (%) SD 1.45 1.11 1.20 1.11 1.27 1.20 1.30 RSD[%] 1.48 1.12 1.21 1.12 1.28 1.20 1.30
Example 23
Preparation of Tablets Containing Vortioxetine Monooxalate of the Formula X
(Strength: Corresponds to 20 mg of Vortioxetine Base)
Composition:
[0324]
TABLE-US-00033 Name of component: Vortioxetine 20 mg tablet Batch number: Batch size: 014 UA 1114 about 1 050 g Weight of the component mg/tablet Weight (g) Vortioxetine monooxalate ground 26.034 182.24 Microcrystalline cellulose (Avicel PH 14.098 98.68 101 (FMC)) Mannitol (Pearlitol SD 200) 92.268 645.88 Sodium carboxymethyl starch 4.5 31.5 (Primojel) Hydroxypropyl cellulose (Klucel EXF) 4.5 31.5 Purified water 0 493.5 0 0 Avicel PH 101 (FMC) 7.1 49.7 Magnesium stearate 1.5 10.5 0 0 Total: 150 1050
[0325] The tablets are prepared according to the process of example 20 except that the components are used in an amount corresponding to the above composition.
[0326] The chemical stability and dissolution of the tablets obtained are tested:
[0327] a) Chemical Stability of the Tablets Obtained:
TABLE-US-00034 Amount of the impurity expressed in the percentage of the active ingredient Total impurities [%] (>0.03%) Storing Average total known unknown Sample conditions content % [%] [%] [%] Monooxalate Starting 99.74 <0.03 <0.03 <0.03 salt 40 C./75RH 98.42 <0.03 <0.03 <0.03 containing %-2 weeks tablet 40 C./75RH 99.38 <0.03 <0.03 <0.03 (014UA1114) %-4 weeks
[0328] (The results are calculated from 2 parallel measurements. The average content is expressed in % of the theoretical content calculated from the measured value.) It can be seen from the Table that the chemical stability of the tablets is excellent.
[0329] b) Dissolution Tests:
[0330] After storing the dissolution of the tablets meets the requirements of immediate release tablets. On advancement of time the dissolution of the tablets does not change significantly as shown in the following Table and on Drawing 14 and
TABLE-US-00035 Time of sampling (minutesdissolution (%) 014UA1114 5 10 15 20 30 45 60 starting Average 102.31 103.17 103.06 103.02 102.93 102.94 103.15 (%) SD 2.14 2.34 2.39 2.24 2.33 2.34 2.31 RSD[%] 2.18 2.36 2.41 2.26 2.35 2.36 2.33 2 weeks Average 102.37 103.09 103.27 103.04 103.25 103.18 103.25 40 C./75% RH (%) SD 2.09 2.12 2.14 2.16 2.14 2.18 2.17 RSD[%] 2.12 2.13 2.16 2.18 2.15 2.19 2.18 4 weeks Average 102.61 103.57 103.55 103.64 103.56 103.83 103.72 40 C./75% RH (%) SD 2.07 2.18 2.07 1.99 2.12 2.17 2.03 RSD[%] 2.10 2.19 2.08 2.00 2.13 2.18 2.03