WO2012096632A1

WO2012096632A1 - New addition salts of ziprasidone, a process for the preparation thereof and use thereof in therapy

Info

Publication number: WO2012096632A1
Application number: PCT/SI2011/000044
Authority: WO
Inventors: Rudolf RUČMAN; Pavel Zupet
Original assignee: Silverstone Pharma AG
Current assignee: Silverstone Pharma AG
Priority date: 2011-01-13
Filing date: 2011-08-11
Publication date: 2012-07-19
Anticipated expiration: 2013-07-13
Also published as: SI23610A

Abstract

The invention discloses new addition salts of ziprasidone, namely sulfamates and N- substituted sulfamates in amorphous and crystal form and in the form of hydrates. The processes for their preparation comprise the reaction of 1 mol of ziprasidone base with 1 mol of sulfamic acids, and the method for the isolation of these salts in solid form. The invention further comprises a process for the preparation of granulate for tabletting and incapsulation, wherein ziprasidone salt finely distributed on an inert carrier is obtained. According to the invention, the new salts of ziprasidone are used for the treatment and prevention of psychotic disorders and diseases.

Description

New addition salts of ziprasidone, a process for the preparation thereof and use thereof in therapy

Technical Field

The present invention belongs to the field of pharmaceutical chemistry and refers to the new addition salts of ziprasidone - derivatives of sulphamic acid and hydrates thereof of general formula (I):

(I) wherein R means hydrogen, an alkyl or a cycloalkyl group having 1 to 6 carbon atoms, and n means 0 to 2.

The present invention further describes a process for the preparation of these compounds and use thereof in the manufacturing of pharmaceutical preparations in the treatment of psychotic conditions like schizophrenia and anxiety. Technical Problem

The main problem of pharmaceutical preparations containing as the active ingredient ziprasidone or the addition salts thereof, especially hydrochloride, is high hydrophobicity and very poor solubility in water and consequently very low bioavailability. A very high dosage of the active ingredient must therefore be used in order to achieve a good therapeutic effect, which is related to more considerable side effects and high cost of therapy.

So there is a need for new addition salts with improved water solubility, which would contribute to better resorption and higher bioavailability.

Prior Art

Ziprasidone is a heterocyclic compound of formula (II):

(Π)

Ziprasidone has the chemical name 5-[2-[4-(l,2-benzisothiazol-3-yl)-l- piperazinyl]ethyl]-6-chloro- 1 ,3-dihydro-2H-indol-2-one. Ziprasidone is used in the treatment of psychotic disorders like schizophrenia and anxiety. It exhibits a high affinity for dopamine D₂ and D₃ receptors, serotonin 5HT₂A, 5HT_1A, 5HT_1D and οΐχ adrenergic receptors.

Ziprasidone hydrochloride is used in an oral pharmaceutical formulation, whereas a mesylate salt in the form of a trihydrate is more suitable for intramuscular use.

A synthesis of ziprasidone was researched by the Pfizer company, who applied for patents US 4,831,031 and EP 0 281 309, wherein an entire range of addition salts of ziprasidone is disclosed, of which only ziprasidone hydrochloride is documented in detail. The synthesis is performed by reacting a ziprasidone base with a gaseous hydrogen chloride. Depending on the solvent used, the formed hydrochloride can be in amorphous or crystalline form.

A reaction in organic solvents in the presence of some water also yields hydrates, which is disclosed in the patent US 5,312,925. Amorphous ziprasidone hydrochloride is formed in the reaction of a ziprasidone base, suspended in n-hexane, or n-heptane, when dry, gaseous hydrogen chloride is introduced.

European patents EP 0 584 903 and EP 1 029 861 describe a preparation of addition salts of ziprasidone by the reaction of a ziprasidone base suspension with one equivalent of a pharmaceutically acceptable acid, such as hydrochloric acid or methanesulphonic acid.

Patents EP 0 918 772 in EP 0 904 273 protect mesylates in the form of dihydrates and trihydrates, which are claimed to have better solubility in water.

Patent application WO 2006/034964 discloses a synthesis of addition salts, like acetate and maleate with a reaction in a polar solvent, such as acetonitrile.

Patent application WO 2005/065660 A2 of the American company Alpharm Inc. discloses several pharmaceutical formulations with a hydrochloride hydrate and dihydrate and with various particle sizes.

Patent EP 0 965 343 Bl discloses pharmaceutical formulations of ziprasidone hydrochloride dihydrate with various particle sizes, especially those smaller than 85 μιη and with addition of surfactants that enhance solubility. In its patent EP 0 900 088 the Pfizer company discloses inclusion complexes with cyclodextrins containing ziprasidone hydrochloride. This is claimed to enhance solubility and opportunity for use in the form of intramuscular injections.

Various polymorphic crystal forms of ziprasidone hydrochloride are disclosed also in other patents and patent applications, e.g. WO 2004/050655 Al (Dr. Reddy Labs), WO 2004/089948 Al (Hetero Drugs) and WO 2005/015325 A2 (TEVA).

Patent application US 2005/0059680 A discloses polymorphic crystal forms of ziprasidone hydrochloride with a specific surface of particles exceeding 4 m /g.

Canadian patent 2 245 269 discloses the preparation of a pharmaceutical granulate containing a ziprasidone free base by spraying the suspension of ziprasidone base in a solution of hydroxypropyl cellulose acetate and succinate and drying in a warm air stream.

Canadian patent 2 252 896 discloses the preparation of ziprasidone mesylates and hydrates thereof.

The extensive patent application WO 2006/098834 A2 describes the preparation of various crystal forms of mesylates and their hydrates.

Patent application WO 2008/015005 describes a synthesis of ziprasidone sulfate and hydrogen sulfate and their hydrates. A pharmaceutical formulation in the form of a capsule containing ziprasidone hydrogen sulphate dihydrate is disclosed as well.

In some methods mentioned in literature, a reaction of salt formation (of hydrochloride) is carried out by reacting a solid ziprasidone base suspended in a solvent with a gaseous hydrogen chloride. As no mother liquor is obtained in crystallization, the obtained crystals are less pure (since the impurities are not removed).

Based on known data and efforts to improve solubility of ziprasidone salts, there still exists a need for the preparation of new addition salts with better physical and chemical properties and increased bioavailability. The Technical Solution

A problem of high hydrophobicity, poor water solubility of the active ingredient and consequently low bioavailability can be solved by introducing a new addition salt, another crystalline form, reducing particle size, also converting the salt to an amorphous form or even by adding a surfactant.

Within the meaning of the invention new addition salts of ziprasidone with sulfamic acid and N-substituted sulfamic acids were synthetized. The salts were prepared in crystalline form, in the form of hydrates and in amorphous state. Ziprasidone salts with sulfamic acids tend to crystallize.

The present invention thus relates to ziprasidone sulfamates and hydrates thereof of general formula (I):

(I)

wherein R means hydrogen, an alkyl or a cycloalkyl group having 1 to 6 carbon atoms, and n means 0 to 2.

The present invention also relates to a process for the preparation of ziprasidone sulfamates and the hydrates thereof, represented by general formula I, wherein ziprasidone base of formula (II):

is reacted with sulfamic acids of general formula:

R-NH-SO₃H wherein R means hydrogen, an alkyl or a cycloalkyl group having 1 to 6 carbon atoms, in molar ratio 1 : 1 in a polar solvent at a temperature of 50-90 °C, preferably 70-80 °C, the obtained salt is isolated in solid form by drying, crystallization, precipitation or lyophilisation.

The present invention further relates to a process for the preparation of a granulate for tabletting or incapsulation containing a fine distributed ziprasidone salt, wherein an aqueous/alcohol solution of ziprasidone sulfmate or hydrate thereof of general formula I is sprayed onto inert components and fillers for granulate preparation with simultaneous drying in counterstream of warm air with a temperature between 30 °C and 80 °C.

The present invention further relates to the process wherein the solution for spraying is prepared by dissolving ziprasidone base and sulfamic or N-alkylsulfamic acid in a molar ratio 1 : 1 in an aqueous/alcohol mixture. The present invention further relates to the use of ziprasidone sulfamates and hydrates thereof for the preparation of solid pharmaceutical preparations for the treatment and prevention of psychotic conditions, such as shizophrenia, bipolar disorders, psychotic depression and anxiety disorders.

Detailed description of the invention

Ziprasidone sulfaminates are prepared from ziprasidone base and suitable sulfamic acid or N-alkylsulfamic acid with a reaction in a suitable solvent and in a ratio 1 mol of sulfamic acid per 1 mol of ziprasidone base. Solvents used are polar organic solvents such as: lower alcohols, dioxane, 1,3-dioxolane, acetonitrile, acetone, tetrahydrofuran, dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide and their mixtures with water. To promote crystallization and for precipitation even less polar organic solvents, in which ziprasidone salt is very poorly soluble, such as aliphatic ethers having 4-6 carbon atoms, e. g. diethyl ether, methyl tert-butyl ether and similar can be added.

The reaction is normally performed in a temperature range from 50-90 °C, preferably at 70-80 °C.

After the reaction is completed, the ziprasidone salts are crystallized from the reaction mixture, unless we want to obtain them in amorphous form.

The amorphous substance is obtained by fine filtering of the salt solution after the reaction is over (in order to remove particles that would be cores for crystallization), quick cooling to get a frozen solution and then by lyophilization. Solubility of amorphous salts is normally considerably better than solubility of crystal salts.

Several N-substituted sulfamic acids are not commercially available. We have therefore also prepared methods for the synthesis thereof. They are obtained by a reaction of chlorosulfonic acid with an appropriate amine dissolved in 1,2- dichloroethane at a temperature of -20 °C. The solvent is then evaporated, the solid substance dissolved in water and poured through an ion-exchange column. The eluate is dried in vacuum by water evaporation and the obtained solid substance is then crystallized from acetone.

The composition and structure of new salts was proved with elemental analysis, mass and 1H-NMR spectra.

Melting points were determined with a Kofler method. The crystal structure was determined with X-ray powder diffraction with the difractograph X' Pert PRO with alpha configuration, CuKa radiation, in the range 3-35 degrees 2 theta. 1H-NMR spectra were recorded with the NMR spectrometer Bruker Advance DPX 300 MHz in DMSO. The mass spectra were recorded with AutoSpec Q spectrometer. Elemental analyses were performed using Perkin Elmer instrument, type 240. Crystal water content was determined using the Karl Fischer method with titration.

According to the present invention, the sulfamic salts of ziprasidone have a surprisingly better solubility in water, especially when in amorphous form. The solubility of amorphous ziprasidone sulfamate at 20 °C is 100 mg/100 mL of water, and that of ziprasidone N-n-propylsulfamate is 75 mg/100 mL of water.

Additionally, the size of particles can be considerably influenced by conditions of crystallization: concentration, speed of crystallization, stirring or solvent selection. The obtained crystals can be mechanically milled to the size ranging 20 μιη to 10 μιη. Wet milling in an inert, poorly volatile organic solvent (such as octane or decane) followed by filtration, rinsing with easily volatile inert solvent and drying is especially adequate. The solubility can thus be increased up to ten times.

Ziprasidone sulfamates, prepared by the described process, are used for the prevention and treatment of psychotic conditions such as schizophrenia, bipolar disorders, psychotic depression and anxiety conditions. Usual therapeutic doses in the treatment of said diseases range from 20 mg to 80 mg (calculated per ziprasidone base).

Pharmaceutical formulations are available in a variety of solid forms, such as tablets, capsules, powder or granules. They are prepared by conventional known methods, in which pharmaceutically acceptable fillers, such as lactose, microcrystalline cellulose, dibasic calcium phosphate, various sugars and mixtures thereof are used. Binders must be present as well, such as polyvinylpirrolidone, carboxymethyl cellulose, gelatine and others. As disintegrants sodium croscarmellose, crospovidone, starch and derivatives thereof are added. As lubricants or glidants magnesium stearate, stearic acid, talc, polyethylene glycols and silica can be used.

The granulate for the preparation of tablets or capsules may be prepared by spraying an aqueous/alcohol solution of ziprasidone sulfamate or N-alkylsulfamate onto inert granulate ingredients and simultaneously drying in a counterstream of warm air with a temperature between 30 °C and 80 °C. In this way the obtained ziprasidone in the form of salt is very finely distributed on the carrier. Very tiny particles dissolve much more easily in a therapeutic application.

Brief Description of Figures

Fig. 1. 1H-NMR spectrum of ziprasidone sulfamate.

Fig. 2. 1H-NMR spectrum of ziprasidone N-cyclohexylsulfamate.

Fig. 3. 1H-NMR spectrum of ziprasidone N-n-propylsulfamate.

Fig. 4. 1H-NMR spectrum of ziprasidone N-cyclopropylsulfamate.

Fig. 5. 1H-NMR spectrum of ziprasidone N-tert-butylsulfamate.

The invention is explained in more detail by the following examples intended to illustrate the methods and are not intended to limit the scope of the invention in any manner.

EXAMPLE 1. Ziprasidone sulf ornate mono hydrate

Ziprasidone base (5 g, 12.1 mmol) and sulfamic acid (1.18 g, 12.1 mmol) were suspended in 70 mL of ethanol and 30 mL of water. The mixture was heated to 80 °C and intensively stirred to complete dissolution. The solution was filtered, cooled and crystallized overnight at -15 °C. The crystals were filtered off and dried in vacuum at 50 °C. 6.05 g (95.5 %) of reddish crystals with the melting point of 244 °C (decomposition) were obtained.

Elemental analysis corresponds to the formula C₂₁H₂₄ClN₅O₄S₂ H₂0:

calculated: C: 47.76 % H: 4.96 % N: 13.26 %

found: C: 47.41 % H: 5.19 % N: 12.70 %

Water content according to . Fischer method was 3.41 %, which corresponds to monohydrate.

Mass spectrum: MS TOF ES⁺: 413.1, 415.1, (MH⁺, base),

MS TOF ES^": 96.1 (M FT, acid).

1H-NMR spectrum (Fig. 1) recorded in DMSO (dimethylsulfoxide) corresponds to the structure.

X-ray powder diffractogram represented by the following 2 Θ- values and relative intensities:

No. Position [2Θ/°] Spacing [d/A] Relative intensity [%]

1 7.3133 12.07791 8.50

2 12.8124 6.90380 3.98

3 14.6293 6.05017 3.30

4 16.2193 5.46049 71.43

5 17.3335 5.1 1191 49.02

6 18.7029 4.74058 9.80

7 19.9887 4.43846 11.59

8 20.2788 4.37562 6.39

9 21.2019 4.18713 14.64

10 21.9870 4.03938 100.00

11 24.0433 3.69836 6.53

12 24.4496 3.63781 9.87

13 25.1488 3.53823 25.32 14 25.7515 3.45677 19.53

15 27.3383 3.25963 20.46

16 31.0822 2.87501 4.27

17 31.7111 2.81941 6.71

18 32.7022 2.73618 11.57

EXAMPLE 2. Ziprasidone sulfamate - amorphous

Ziprasidone sulfamate monohydrate (0.65 g) was dissolved in 47 mL of dioxane and 32 mL of water at 80 °C. While still warm, the solution was filtered through a filter with the pore size 0,22 μηι in order to filter off potential crystallisation cores. The clear solution was rapidly frozen and lyophilized. After drying in high vacuum 0.62 g (99.7 %) of amorphous substance with a melting point of 180 °C (decomposition) was obtained.

Elemental analysis corresponds to formula C2iH₂₄ClN₅O₄S₂:

calculated: C: 49.45 % H: 4.74% N: 13.73 %

found: C: 50.00 % H: 4.72% N: 13.69 %

Ή-NMR spectrum (Fig. l) corresponds to this structure, whereas the X-ray powder diffractogram shows no sharp reflexes, which is typical of amorphous substance.

EXAMPLE 3. Ziprasidone N-cyclohexylsulfamate dihydrate

Ziprasidone base (5 g, 12.1 mmol) and N-cyclohexylsulfamic acid (2.17 g, 12.1 mmol) were suspended in 100 mL of ethanol and 35 mL of water, then heated to 80 °C and stirred to complete dissolution. The reaction mixture was filtered, cooled and crystallized overnight at -15 °C. 7.03 g (95.2 %) of reddish crystals with a melting point of 209-215 °C were obtained.

Elemental analysis corresponds to the formula C2₇H₃₄ClN₅O₄S2-2H₂O:

calculated: C: 53.15 % H: 5.94 % N: 11.48 %

found: C: 52.57 % H: 6.06 % N: 11.01 %

Water content according to K. Fischer was 5.70 % (theoret.: 5.9 %), which corresponds to dihydrate. Mass spectrum: MS TOF ES⁺: 413.1, 415.1 (MH⁺), base,

MS TOF ES^": 178.1 (M-H)^", acid.

1H-NMR spectrum (Fig. 2) corresponds to said structure.

No. Position[26y°] Spacing [d/A] Relative intensity [%]

1 6.3420 13.92535 4.46

2 9.5048 9.29747 57.87

3 13.8441 6.39153 4.76

4 15.8473 5.58781 13.93

5 17.2901 5.12464 15.03

6 19.0358 4.65842 100.00

7 23.2830 3.81738 6.50

8 23.5461 3.77531 3.12

9 28.701 1 3.10788 6.49

10 29.5264 3.02286 4.73

11 31.9312 2.80048 5.27

12 32.7476 2.73250 5.44

13 34.9873 2.56254 3.13

EXAMPLE 4. Ziprasidone N-n-propylsulfamate dihydrate a) Synthesis of N-n-propylsulfamic acid

n-Propylamine (5.9 g, 0.1 mol) was dissolved in 25 mL of 1,2-dichloroethane and cooled to -20 °C. While stirring, chlorosulfonic acid (2.2 ml, 0.033 mol) was then slowly added dropwise and the solvent was evaporated in vacuum for the solid residue to crystallize. The crystal mass was dissolved in water and the obtained solution was poured through a column (diameter 4 cm and length 10 cm) filled with a cation exchanger in H⁺ form (Amberlyt^® IR-120). The acidic eluate was collected and evaporated in vacuum to the solid residue. It was dissolved in hot acetone and crystallized. 3.23 g (45.8 %) of N-n-propylsufamic acid with a melting point of 189— 193 °C were obtained. b) Ziprasidone N-n-propylsulfamate dihydrate

Ziprasidone base (2.5 g, 6.054 mmol) and N-n-propylsulfamic acid (0.85 g, 6.11 mmol) were dissolved at 70 °C in a mixture of 50 mL of acetone and 25 mL of water. While hot, the reaction mixture was filtered (5 μπι filter), and cooled to crystallize. 3.03 g (89 %) of reddish crystals with a melting point of 128-130 °C were obtained. Elemental analysis corresponds to the formula: C₂₄H₃oClN₅O₄S₂-2H2O:

calculated: C: 49.09 % H: 5.78 % N: 11.82 %

found: C: 49.02 % H: 5.81 % N: 11.90 %

Water content according to K. Fischer was 5.31 %, which corresponds to dihydrate. Mass spectrum: MS TOF ES⁺: 413.1 , 415.1 (MH)⁺, base

MS TOF ES^": 138. 0 (M H)- 277.1 (2M_rH)^~ acid.

Ή-ΝΜΙ spectrum (Fig. 3) corresponds to the structure.

No. Position [2Θ/⁰] Spacing [d/A] Relative intensity [%]

10.0775 8.77040 15.44

2 11.8601 7.45586 21.96

3 12.5472 7.04910 34.44

4 17.0272 5.20316 82.63

5 17.3572 5.10497 21.70

6 17.7535 4.99109 14.76

7 18.2241 4.86405 85.29

8 19.5437 4.53851 32.47

9 22.2301 3.99576 17.95

10 22.6119 3.89514 17.83

11 23.4066 3.79751 15.70

12 23.7825 3.73832 22.83

13 25.0644 3.54996 100.00

14 26.5369 3.35622 41.11

15 27.0695 3.29139 13.84

16 27.7046 3.21736 29.08

17 28.0894 3.17415 11.94

18 29.7782 2.99787 23.12

19 30.7244 2.90767 37.36

20 31.5390 2.83440 14.92 21 32.2178 2.77622 30.42

22 34.1844 2.62086 25.05

23 35.9891 2.49347 17.78

24 36.7090 2.44620 11.61

EXAMPLE 5. Ziprasidone N-n-propylsulfamate

Ziprasidone base (1.25 g, 3.026 mmol) and N-n-propylsulfamic acid (0.425 g, 3.026 mmol) were dissolved in 11 mL of Ν,Ν-dimethylformamide at 70 °C. To this solution a total of 20 mL of methyl tert-butyl ether was added slowly while stirring. The solution was cooled and crystallized over night. It was filtered and the crystals washed thoroughly with methyl tert-butyl ether and dried in vacuum at 50 °C. 1.63g (97 %) of reddish crystals with a melting point of 160-163 °C were obtained.

Elemental analysis corresponds to the formula C24H₃₀ClN₅O4S2:

calculated: C: 52.21 % H: 5.48 % N: 12.68 %

found: C: 51.67 % H: 5.60 % N: 12.53 %

Mass spectrum: MS TOF ES⁺: 413.1, 415.1 (MH)⁺, base,

MS TOF ES^": 138.0 (M_rH)^", 277.1 (M_rH)^~, acid.

X-ray powder diffractogram represented by the following 2 (9- values and relative intensities:

No. Position [2 <9/°] Spacing [d/A] Relative intensity [%]

1 5.5178 16.00333 20.75

2 5.9092 14.94428 14.16

3 10.9719 8.05740 30.41

4 11.8696 7.44996 16.17

5 13.7032 6.45694 29.00

6 15.6498 5.65789 19.90

7 16.6178 5.33042 35.55

8 17.8630 4.96155 100.00

9 18.2467 4.85807 29.52

10 18.5526 4.77867 32.31

11 19.4003 4.57173 23.71

12 22.9521 3.87167 23.49

13 23.4233 3.79482 72.96 14 23.6162 3.76427 26.57

15 23.9710 3.70935 33.86

16 24.1480 3.68256 31.99

17 25.0439 3.55281 24.48

18 27.0418 3.29470 24.48

19 29.9866 2.97750 60.28

20 34.6850 2.58117 22.07

EXAMPLE 6. Ziprasidone N-cyclopropylsulfamate monohydrate a) The synthesis of N-cyclopropylsulfamic acid

N-cyclopropylsulfamic acid was prepared according to the process described in Example 4 a). The yield is 32.6 %. The acid melts at 166-168 °C. b) Ziprasidone N-cyclopropylsulfamate monohydrate

Ziprasidone base (2.5 g, 6.054 mmol) and N-cyclopropylsulfamic acid (0.83 g, 6.054 mmol) were suspended in 52 mL of acetone and 25 mL of water at 70 °C. The reaction mixture was stirred to dissolve. While hot, it was filtered and cooled overnight to +5 °C to crystallize. 2. 80 g (89.9 %) of reddish crystals with a melting point of 184-186 °C were obtained.

Elemental analysis corresponds to the formula C₂4H₂₈CiN₅O₄S₂ H₂O:

calculated: C: 50.75 % H: 5.32 % N: 12.33 %

found: C: 51.26 % H: 5.16 % N: 12.37 %

Water content according to K. Fischer was 3.4 % (theoret.: 3.2 %), which corresponds to monohydrate.

Mass spectrum: MS TOF ES⁺: 413.1, 415.1 (MH⁺), base,

MS TOF ES^~: 136.0 (M,-H)^", acid.

1H-NMR spectrum (Fig.4) corresponds to this structure.

X-ray powder diffractogram represented by the following 2 Θ- values and relative intensities: No. Position [26>/°] Spacing [d/A] Relative intensity [%]

1 4.1220 21.41892 26.92

2 8.2590 10.69697 26.05

3 16.551 1 5.35174 46.94

4 17.1250 5.17367 14.73

5 17.4376 5.08162 18.89

6 18.9650 4.67566 1 1.12

7 20.7261 4.28218 100.00

8 21.0724 4.21258 12.52

9 21.7273 4.08706 15.41

10 24.2023 3.67443 14.01

1 1 25.9876 3.42590 17.92

12 26.4147 3.37146 12.36

13 27.0840 3.28966 14.41

14 29.1733 3.05864 92.09

15 31.4309 2.84390 12.58

16 35.4323 2.53137 9.37

EXAMPLE 7. Ziprasidone N-tert-butylsulfamate monohydrate a) The synthesis of N-tert-butylsulfamic acid

N-tert-butylsulfamic acid was prepared according to the process described in Example 4 a). The crystals from acetone melted at 169-171 °C. The yield of the synthesis was 52 %. b) Ziprasidone N-tert-butylsulfamate monohydrate

Ziprasidone base (2.5 g, 6.054 mmol) and N-tert-butylsulfamic acid (0.93 g, 6.054 mmol) were suspended in the mixture acetone/ethanol/water = 100/80/150 and stirred at 80 °C to complete dissolution. The reaction mixture was cooled and crystallized at -15 °C overnight. 2.98 g (84.2 %) of crystals with a melting point of 169-171 °C were obtained.

Elemental analysis corresponds to the formula C₂5H3₂ClN₅O₄S2-H₂0:

calculated: C: 51.40 % H: 5.86 % N: 1 1.99 %

found: C: 51.60 % H: 5.65 % N: 11.89 %

Water content was 3.23 % (theoret.: 3.1 %), which corresponds to monohydrate. Mass spectrum: MS TOF ES⁺: 413.2 , 415.1 (MH)⁺, base,

MS TOF ES-: 152.0 (Mj-H)^", acid.

1H-NMR spectrum (Fig. 5) corresponds to this structure.

No. Position [20/°] Spacing [d/A] Relative intensity [%]

1 7.6370 11.56674 26.49

2 14.8358 5.96644 32.02

3 15.3026 5.78547 100.00

4 16.3077 5.43107 10.29

5 16.8899 5.24515 16.20

6 17.8119 4.97568 22.22

7 21.5275 4.12453 11.63

8 24.0264 3.70093 17.05

9 24.7410 3.59562 38.00

10 24.9270 3.56921 14.97

11 25.1972 3.53154 6.44

12 25.5853 3.47886 5.81

13 27.9682 3.18763 5.81

14 29.3857 3.03701 10.00

15 29.7182 3.00379 14.97

16 31.5594 2.83261 6.52

EXAMPLE 8. Granulate preparation with spray drying

The solution prepared from ziprasidone base and sulfamic acid in a mixture of 5700 mL of ethanol and 2000 mL of water containing 255 g ziprasidone sulfamate was finely sprayed onto a mixture of inert fillers consisting of 1940 g of dibasic calcium phosphate dihydrate and 2160 g of corn starch. As the fillers were intensively whirled, the granulate was dried in counterstream of warm air at 50 °C. The granulate was then finally sieved through a sieve with openings of 1 mm and homogeneously mixed with 80 g of magnesium stearate and tabletted. Tablet composition:

Ingredient: Quantity, mg/tablet:

Ziprasidone sulfamate hydrate 25.5^*

Dibasic calcium phosphate dihydrate 194.0

Corn starch 22.5

Magnesium stearate 8 )

Mass of the tablet 250 mg

EXAMPLE 9. Capsule composition

Ingredient: Quantity, mg/capsule:

Ziprasidone N-n-propylsulfamate dihydrate 28.5^*

Lactose monohydrate 69 .0

Starch 1500 pregelatinized 10.0

Polyvinylpyrrolidone 1.5

Magnesium stearate L0

HO mg

^* corresponds to 20 mg of ziprasidone

Claims

1. Ziprasidone sulfamates and hydrates thereof of general formula (I):

2. Ziprasidone sulfamates according to claim 1 in amorphous form.

3. Ziprasidone sulfamates according to claim 1 in crystalline form.

4. Ziprasidone sulfamate monohydrate according to claim 1 , characterised by the X- ray powder diffractogram represented by the following 2 lvalues and relative intensities:

No. Position[2<9/°] Spacing [d/A] Relative intensity [%

1 7.3133 12.07791 8.50

2 12.8124 6.90380 3.98

3 14.6293 6.05017 3.30

4 16.2193 5.46049 71.43

5 17.3335 5.11 191 49.02

6 18.7029 4.74058 9.80

7 19.9887 4.43846 1 1.59

8 20.2788 4.37562 6.39

9 21.2019 4.18713 14.64

10 21.9870 4.03938 100.00

1 1 24.0433 3.69836 6.53

12 24.4496 3.63781 9.87

13 25.1488 3.53823 25.32

14 25.7515 3.45677 19.53

15 27.3383 3.25963 20.46

16 31.0822 2.87501 4.27

17 31.71 1 1 2.81941 6.71

18 32.7022 2.73618 11.57

5. Ziprasidone N-cyclohexylsulfamate dihydrate according to claim 1, characterised by the X-ray powder diffractogram represented by the following 2 Θ- values and relative intensities:

No. Position [2(9/°] Spacing [d/A] Relative intensity [%]

1 6.3420 13.92535 4.46

2 9.5048 9.29747 57.87

3 13.8441 6.39153 4.76

4 15.8473 5.58781 13.93

5 17.2901 5.12464 15.03

6 19.0358 4.65842 100.00

7 23.2830 3.81738 6.50

8 23.5461 3.77531 3.12

9 28.7011 3.10788 6.49

10 29.5264 3.02286 4.73

1 1 31.9312 2.80048 5.27

12 32.7476 2.73250 5.44

13 34.9873 2.56254 3.13

6. Ziprasidone N-n-propylsulfamate according to claim 1, characterised by the X-ray powder diffractogram represented by the following 2(9- values and relative intensities:

Position [2(9/°] Spacing [d/A] Relative intensity [%]

5.5178 16.00333 20.75

2 5.9092 14.94428 14.16

3 10.9719 8.05740 30.41

4 1 1.8696 7.44996 16.17

5 13.7032 6.45694 29.00

6 15.6498 5.65789 19.90

7 16.6178 5.33042 35.55

8 17.8630 4.96155 100.00

9 18.2467 4.85807 29.52

10 18.5526 4.77867 32.31

11 19.4003 4.57173 23.71

12 22.9521 3.87167 23.49

13 23.4233 3.79482 72.96

14 23.6162 3.76427 26.57

15 23.9710 3.70935 33.86

16 24.1480 3.68256 31.99

17 25.0439 3.55281 24.48

18 27.0418 3.29470 24.48

19 29.9866 2.97750 60.28

20 34.6850 2.58117 22.07

7. Ziprasidone N-n-propylsulfamate dihydrate according to claim 1, characterised by the X-ray powder diffractogram represented by the following 2 lvalues and relative intensities:

No. Position [2 >/°] Spacing [d/A] Relative intei

1 10.0775 8.77040 15.44

2 11.8601 7.45586 21.96

3 12.5472 7.04910 34.44

4 17.0272 5.20316 82.63

5 17.3572 5.10497 21.70

6 17.7535 4.99109 14.76

7 18.2241 4.86405 85.29

8 19.5437 4.53851 32.47

9 22.2301 3.99576 17.95

10 22.6119 3.89514 17.83

11 23.4066 3.79751 15.70

12 23.7825 3.73832 22.83

13 25.0644 3.54996 100.00

14 26.5369 3.35622 41.11

15 27.0695 3.29139 13.84

16 27.7046 3.21736 29.08

17 28.0894 3.17415 11.94

18 29.7782 2.99787 23.12

19 30.7244 2.90767 37.36

20 31.5390 2.83440 14.92

21 32.2178 2.77622 30.42

22 34.1844 2.62086 25.05

23 35.9891 2.49347 17.78

24 36.7090 2.44620 1 1.61

8. Ziprasidone N-cyclopropylsulfamate monohydrate according to claim 1, characterised by the X-ray powder diffractogram represented by the following 2Θ- values and relative intensities:

No. Position [2 >/°] Spacing [d/A] Relative intensity [%]

1 4.1220 21.41892 26.92

2 8.2590 10.69697 26.05

3 16.551 1 5.35174 46.94

4 17.1250 5.17367 14.73

5 17.4376 5.08162 18.89

6 18.9650 4.67566 11.12

7 20.7261 4.28218 100.00

8 21.0724 4.21258 12.52

9 21.7273 4.08706 15.41

10 24.2023 3.67443 14.01

1 1 25.9876 3.42590 17.92

12 26.4147 3.37146 12.36

13 27.0840 3.28966 14.41

14 29.1733 3.05864 92.09

15 31.4309 2.84390 12.58

16 35.4323 2.53137 9.37

9. Ziprasidone N-tert-butylsulfamate monohydrate according to claim 1 characterised by the X-ray powder diffractogram represented by the following 2 Θ- values and relative intensities: o

Position [2 >/°] Spacing [d/A] Relative intensity [%]

1 7.6370 11.56674 26.49

2 14.8358 5.96644 32.02

3 15.3026 5.78547 100.00

4 16.3077 5.43107 10.29

5 16.8899 5.24515 16.20

6 17.81 19 4.97568 22.22

7 21.5275 4.12453 1 1.63

8 24.0264 3.70093 17.05

9 24.7410 3.59562 38.00

10 24.9270 3.56921 14.97

11 25.1972 3.53154 6.44

12 25.5853 3.47886 5.81

13 27.9682 3.18763 5.81

14 29.3857 3.03701 10.00

15 29.7182 3.00379 14.97

16 31.5594 2.83261 6.52

10. Process for the preparation of ziprasidone sulfamates and hydrates thereof in amorphous and crystal forms of general formula (I):

(I) wherein R means hydrogen, an alkyl or a cycloalkyl group having 1 to 6 carbon atoms, and n means 0 to 2,

characterised in that a ziprasidone base of formula (II):

(Π) is reacted with sulfamic acids of general formula:

11. Process according to claim 10, characterized in that a lower aliphatic alcohol having 1 to 4 carbon atoms, acetonitrile, acetone, dioxane, tetrahydrofuran, 1,3- dioxolane, N,N-dimethylformamide or N-methylpyrrolidone are used as a solvent.

12. Process according to claims 10 and 11, characterized in that another solvent is used to enhance crystallization or for precipitation, in which solvent ziprazidone salt is very poorly soluble, such as aliphatic ethers having 4 to 6 carbon atoms.

13. Process for the preparation of a granulate for tabletting or incapsulation containing fine distributed ziprasidone salt, characterised in that an aqueous/alcohol solution of ziprasidone salt according to claim 1 is sprayed onto inert components and fillers for granulate preparation with simultaneous drying in counterstream of warm air with a temperature between 30 °C and 80 °C.

14. Process according to claim 13, characterized in that the solution for spraying is prepared by dissolution of ziprasidone base and sulfamic or N-alkylsulfamic acid in a molar ratio 1 : 1 in an aqueous/alcohol mixture.

15. Use of ziprasidone sulfamates and hydrates thereof according to claims 1 to 9 for the preparation of solid pharmaceutical form for the treatment and prevention of psychotic conditions, such as shizofrenia, bipolar disorders, psychotic depression and anxiety disorders.