SI23610A - New addition salts of ziprasidone, process for their preparation and their use in therapy - Google Patents

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 ziprasidone addition salts, process for their preparation and use in therapy.

The field of technology.

The present invention is in the field of pharmaceutical chemistry and relates to novel addition salts of ziprasidone - sulfamic acid derivatives and their hydrates of the general formula I /.

I.

wherein R represents a hydrogen, alkyl or cycloalkyl group of 1 to 6 carbon atoms, and n represents 0 to 2.

The present invention also provides a process for the preparation of these compounds and their use for the manufacture of pharmaceutical compositions for the treatment of psychotic conditions such as schizophrenia, anxiety, acute cases of mania and various conditions associated with dipolar disorders.

A technical problem.

The main problem of pharmaceutical preparations containing as active ingredient ziprasidone or its addition salts is high hydrophobicity and very poor water solubility and associated very low bioavailability. Therefore, to achieve good therapeutic effect, a very high dose of the active substance should be used, which in turn is associated with higher side effects and high cost of therapy.

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

• ·

The state of the art.

Ziprasidone is a heterocyclic compound of formula II:

Ziprasidone is chemically 5- [2- [4- (1,2-benzoisothiazol-3-yl) -1-piperazinyl] ethyl] -6-chloro 1,3,3-dihydro-2H-indol-2-one.

Ziprasidone is used to treat psychiatric conditions such as schizophrenia and in the form of intramuscular injections for acute attacks of schizophrenia and mania and for various conditions associated with dipolar disorders.

It has a high affinity for dopamine, serotonin and alpha-adrenergic receptors and a moderate affinity for histamine receptors, where it is likely to act as an antagonist. It appears to inhibit the susceptibility of synapses to serotonin and norepinephrine, although the clinical relevance of this cannot be explained. The mechanism of action of ziprasidone is unknown. The cause of the antipsychotic activity is thought to be primarily the dopamine receptor specific antagonism, specifically D ₂ . Serotonin antagonism plays a role in the effect of ziprasidone, the significance of 5-HT ₂ a antagonism is unclear. It is probably the most selective affinity for the 5-HT ^ receptors with respect to the D ₂ and 5-HT _2C receptors as with all neuroleptics. Antagonism to histamine and alpha adrenergic receptors may also explain its side effects, such as sedation and orthostasis.

In the oral pharmaceutical formulation, ziprasidone hydrochloride is used, and intramuscular administration is preferable to the trihydrate mesylate salt.

The synthesis of ziprasidone has been investigated by Pfizer and has filed US Patent Nos. 4,831,031 and EP 0281309, which lists the full range of various addition salts, of which only ziprasidone hydrochloride is documented. The synthesis is carried out by reaction of ziprasidone base with hydrogen chloride gas. Depending on the solvent used, hydrochloride in amorphous or crystalline form may be formed. Hydrogen reactions are also formed in the reaction of organic solvents in the presence of some water, which is disclosed in US Patent 5,322,925. Amorphous ziprasidone hydrochloride is formed by the reaction of ziprasidone base suspended in n-hexane or nheptane if dry, hydrogen chloride gas is introduced.

European Patents EP 0584903 and EP 1 029 861 address the preparation of ziprasidone addition salts by reacting a ziprasidone base suspension with one equivalent of a pharmaceutically acceptable acid, for example hydrochloric or methanesulfonic acid.

Patents EP 0 918 772 and EP 0 904 273 protect mesylates in the form of dihydrates and trihydrates, for which they provide slightly better water solubility.

WO 2006/034964 describes the synthesis of addition salts such as acetate and maleate by reaction in a polar solvent such as acetonitrile.

Alpharm Inc., USA in its patent application WO 2005/065660 A2 deals with various pharmaceutical formulations with hydrochloride hydrate and dihydrate and with different particle sizes.

EP 0 965 343 B1 discloses pharmaceutical formulations of ziprasidone hydrochloride dihydrate with variously sized particles, in particular smaller than 85 [mu] m, and with the addition of surfactants to improve solubility.

In patent application EP 0 900 088, Pfizer protects inclusion complexes with cyclodextrins containing ziprasidone hydrochloride. This is intended to increase solubility and the potential for use in the form of intramuscular injections.

The various polymorphic crystalline forms of ziprasidone hydrochloride are also cited by other patents and patent applications such as, for example, WO 2004/050655 A1 (Dr. Reddy Labs), WO 2004/089948 A1 (Hetero Drugs) and WO 2005/01 5325 A2 (TEVA).

US patent application 2005/0059680 A deals with polymorphic crystalline forms of ziprasidone hydrochloride with a specific particle area of more than 4 m ² / g.

As described in Canadian Patent 2 245 269, a pharmaceutical granulate containing a ziprasidone base is prepared by spraying a ziprasidone base suspension in a solution of hydroxypropyl cellulose acetate and succinate and drying under warm air.

Canadian Patent 2 252 896 describes the preparation of ziprasidone mesylates and their hydrates. The extensive patent application PCT WO 2006/098834 A2 deals with the preparation of various crystalline forms of mesylates and their hydrates.

Patent application WO 2008/015005 describes the synthesis of ziprasidone sulfate and hydrogen sulfate and their hydrates. A pharmaceutical capsule formulation containing ziprasidone hydrogen sulphate dihydrate is also indicated.

Given the known data and efforts to improve the solubility of ziprasidone • 9 salts, there is still a need to prepare new addition salts with better physicochemical properties and increased bioavailability.

Description of solution to a technical problem.

The problem of high hydrophobicity and poor solubility of the active substance in water and consequently low bioavailability can be solved by introducing a new addition salt, with another crystalline form, by reducing the particle size, including by converting the salt into an amorphous form, or even by adding a surfactant.

According to the invention, new ziprasidone addition salts with sulfamic acid and N-substituted sulfamic acids have been synthesized. The salts were prepared in crystalline, hydrate and amorphous form. Siprasidone salts with sulfamic acids are very much crystallized. In some of the previous processes, the above-mentioned methods carry out the reaction of solubilization (hydrochloride) such that the solid ziprasidone base suspended in the solvent reacts with hydrogen chloride gas. Because crystallization does not produce a mother liquor, the crystals obtained are less pure (since impurities are not removed).

Ziprasidone sulfaminates are prepared from the ziprasidone base and the corresponding sulfamic acid by reaction in a suitable solvent and in a ratio of 1 mol of sulfamic acid to 1 mol of ziprasidone base. Polar organic solvents such as: lower alcohols, dioxane, 1,3-dioxolane, acetonitrile, acetone, tetrahydrofuran, dimethylformamide, N-methylpyrrolidone and dimethylsulfoxide, also mixed with water, are used as a solvent. To accelerate crystallization, less polar solvents can also be added. such as diethyl ether, methyl tert.butyl ether and the like. The reaction is generally carried out in the temperature range from 50 to 90 ° C, preferably at 70 to 80 ° C.

After completion of the reaction, the ziprasidone salts are crystallized from the reaction mixture, unless desired in amorphous form. The amorphous substance is obtained by fine filtration of the salt solution after the reaction (to remove particles which would be nuclei for crystallization), rapidly cooled to freeze and then lyophilized. The solubility of amorphous salts is usually significantly better than crystalline ones.

Some N-substituted sulfamic acids are not commercially available. Therefore, we have also developed procedures for their synthesis. They are obtained by reaction of chlorosulfonic acid with the corresponding amine dissolved in 1,2-dichloroethane at -20 ° C, then the solvent is evaporated, the solid is dissolved in water and passed through an ion exchanger column. The eluate was dried in vacuo by evaporation of water, and the solid was then crystallized from acetone.

The composition and structure of the new salts were demonstrated by elemental analysis, mass and ¹ H-NMR spectra. Melting points were determined by the Kofler method. The crystal structure was determined by X-ray powder diffraction with an X 'Pert PRO diffractor with an alpha configuration, CuKa radiation, in the range of 3-35 degrees 2 theta. ¹ H-NMR spectra were recorded with a Bruker Advance DPX 300 MHz NMR spectrometer in DMSO. Mass spectra were recorded with an AutoSpec Q spectrometer. Elemental analyzes were performed with a Perkin Elmertip 240 apparatus, and crystalline water content by Karl Fischer method with titration.

According to the invention, the ziprasidone sulfamine salts have surprisingly better water solubility, especially when in amorphous form. The solubility of amorphous ziprasidone sulfaminate at 20 ° C is 100 mg / 100 ml water and ziprasidone N-propylsulfaminate 75 mg / 100 ml.

On the other hand, the particle size can be significantly affected by the conditions of crystallization: concentration, crystallization rate, mixing or type of solvent. The crystals already obtained can also be mechanically ground to a size of 20 to 10 pm. Wet milling in an inert, highly volatile organic solvent (for example in octane or decane) is particularly appropriate, followed by filtration, washing with a light volatile inert solvent and drying. Thus, the solubility can also be increased tenfold.

Ziprasidone sulfaminates obtained by the described procedure are used for the prevention and treatment of psychotic conditions such as schizophrenia, bipolar disorders, psychotic depression and anxiety conditions. The usual doses in the treatment of these diseases range from 20 to 80 mg (calculated on the ziprasidone base).

The pharmaceutical formulations are in various solid forms such as tablets, capsules, powder or granules. They are prepared according to usual, known procedures. Pharmaceutically acceptable fillers such as lactose, microcrystalline cellulose, dibasic calcium phosphate, various sugars and mixtures thereof are used. Mass-binding agents such as polyvinylpyrrolidone, carboxymethylcellulose, gelatin and others must also be present. Croscarmellose sodium, crospovidone, starch and their derivatives are added as disintegrants. As lubricants or lubricants. better glide take magnesium starate, stearic acid, talc, polyethylene glycols and silica (aerosil).

The granules for tablet or capsule preparation can also be made by spraying an aqueous / alcoholic solution of ziprasidone sulfaminate or N-alkylsulfaminate on the inert constituents of the granulate and simultaneously drying in hot air. In this way, ziprasidone in the form of salts is very finely divided on the carrier. Very fine particles are much easier to dissolve in therapeutic applications.

Short description of the pictures.

FIG. 1. ¹ H.NMR spectrum of ziprasidone sulfaminate.

FIG. 2. ¹ H-NMR spectrum of ziprasidone N-cyclohexylsulfaminate.

FIG. 3. ¹ H-NMR spectrum of ziprasidone Nn-propylsulfaminate.

FIG. 4. ¹ H-NMR spectrum of ziprasidone N-cyclopropylsulfaminate.

FIG. 5. ¹ H-NMR spectrum of ziprasidone N-tert. of butylsulfaminate.

The invention is illustrated by the following embodiments, which are intended to illustrate the methods and in no way limit the invention.

EXAMPLE 1. Ziprasidone sulfaminate monohydrate.

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, warmed to 80 ° C and stirred vigorously to dissolve everything. The solution was filtered, cooled and crystallized overnight at -15 ° C. The crystals were filtered off and dried in vacuo at 50 ° C. 6.05 g (95.5%) of reddish crystals are obtained with a melting point of 244 ° C (decomposition).

Elemental analysis corresponds to the formula C21H24CIN5O4S2 H2O and is; calculated: C: 47.76% H: 4.96% N: 13.26% found: C: 47.41% H: 5.19% N: 12.70%

The determination of water by the K. Fischer method gives a content of 3.41%, which corresponds to the monohydrate. Mass spectrum: MS TOF ES ⁺ : 413.1 and 415.1, (MH ⁺ , base),

MS TOF ES ': 96.1 (Mi - H', acid).

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

X-ray powder diffraction pattern (XRPD): No .: Position [2 theta / ° j Distance [d / Α] 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 5,11191 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 sulfaminate - amorphous.

Ziprasidone sulfamate monohydrate (0.65 g) was dissolved in 47 ml of dioxane and 32 ml of water at 80 ° C. The solution was further warmly filtered through a 0.22 µm pore filter to remove potential crystallization nuclei. The clear solution was quickly frozen and lyophilized.

Finally dry in high vacuum. 0.62 g (99.7%) of an amorphous substance are obtained with a melting point of 180 ° C (decomposition).

Elemental analysis corresponds to the formula C21H24CIN5O4S2 and is: calculated: C: 49.45% H: 4.74% N: 13.73% found: C: 50.00% H: 4.72% N: 13.69%

This structure also corresponds to the ¹ H-NMR spectrum (Fig. Fig. 1), and the X-ray powder diffractogram does not show any sharp reflexes, which is characteristic of amorphous substances.

EXAMPLE 3 Ziprasidone N-cyclohexylsulfaminate 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. Heat to 80 ° C and stir to dissolve. It is filtered, cooled and crystallized overnight at -15 ° C. 7.03 g (95.2%) of reddish crystals were obtained with a melting point of 209-215 ° C.

Elemental analysis corresponds to composition C27H34CIN5O4S2. 2 H ₂ O and is:

calculated: C: 53.15% H: 5.94% N: 11.48% found: C: 52.57% H: 6.06% N: 11.01%

The water content according to K. Fischer is 5.70% (theory 5.9%) which corresponds to the dihydrate.

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

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

^{The 1} H-NMR spectrum corresponds to the structure indicated (Figure 2).

X-ray powder diffraction pattern:

No. Position [2 theta / ⁰ ] Distance [d / A] Rel. 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 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-propylsulfaminate 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. Chlorosulfonic acid (2.2 ml, 0.033 mol) was slowly added dropwise while stirring, the solvent was evaporated in vacuo to crystallize the solid residue. The crystalline mass was dissolved in water and the solution was passed through a column of 4 cm diameter, 10 cm long, filled with a cation exchanger in H ⁺ form (Amberlyt IR120, ®). The acidic eluate was collected and evaporated in vacuo to a solid residue. It is dissolved in hot acetone and crystallized. 3.23 g (45.8%) of Nn-propylsulfamic acid are obtained with a melting point of 189-193 ° C.

b. Ziprasidone N-n-propylsulfaminate - 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. Hot filter (5 pm filter) and cool to crystallize. 3.03 g (89%) of reddish crystals are obtained with a melting point of 128 - 130 ° C.

Elemental analysis corresponds to the formula C24H30CIN5O4S2.2 H ₂ O and is: calculated: C: 49.09% H: 5.78% N: 11.82% found: C: 49.02% H: 5.81% N: 11 , 90%

According to K. Fischer analysis, 5.31% of water corresponds to the dihydrate. Mass spectrum: MS TOF ES ⁺ : 413.1, 415.1 (MH) ⁺ , base,

MS TOF ES ': 138.0 (M1-H)', 277.1 (2M ¹ -H) ', acid. ^{The 1} H-NMR spectrum corresponds to the structure and is shown in Fig. Fig.3.

X-ray powder diffraction pattern:

No. Position [2 theta / ⁰ ] Distance [d / A] Relat. intensity 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 280894 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-propylsulfaminate.

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 N, N-dimethylformamide at 70 ° C. A total of 20 ml of methyl tert.butyl ether was slowly added to this solution while stirring, cooled and crystallized overnight. It was filtered and the crystals were thoroughly washed with methyl tert-butyl ether and dried in vacuo at 50 ° C. 1.63 g (97%) of reddish crystals with a melting point of 160-163 ° C are obtained.

Elemental analysis corresponds to the formula C24H30CIN5O4S2 and is;

calculated C: 52.21% H: 5.48% N: 12,68% found: C: 51.67% H. 5.60% N: 12.53% Mass spectra: MSTOF ES ⁺ : 413.1 , 415.1 (MH) ⁺ , base, MS TOF ES ': 138.0 (MrH)', 277.1 (MH +) i-H) ', acid. X-ray powder diffraction pattern: No. Position [2 theta / ⁰ ] Distance [d / A] Rel. 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-cyclopropylsulfaminate monohydrate. a. Synthesis of N-cyclopropylsulfamine xyline.

N-Cyclopropylsulfamic acid was prepared according to the procedure described in Example 4.a. The yield is 32.6%. The acid melts at 166-168 ° C.

b. Ziprasidone N-cyclopropylsulfaminate hydrate.

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 and stirred at 70 ° C to dissolve. It is hot filtered and cooled overnight to + 5 ° C to crystallize. 2.80 g (89.9%) of reddish crystals are obtained, mp 184-186 ° C.

Elemental analysis corresponds to the formula C24H28CIN5O4S2. H ₂ O and is as follows:

calculated: C: 50.75% H: 5.32% N: 12.33% found: C: 51.26% H: 5.16% N: 12.37%

The water content determined by the K. Fischer method is 3.4% (theory: 3.2%), which corresponds to the monohydrate.

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

MS TOF ES ': 136.0 (Mi - H)', acid.

^{The 1} H-NMR spectrum corresponds to this structure and is shown in Fig. Fig.4. X-ray powder diffraction pattern:

No. Position [2 theta / ⁰ ] Distance [d / A] Relat. intensity 1 4,1220 21.41892 26,92 2 8.2590 10,69697 26.05 3 16,5511 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 11 25,9876 3,42590 17.92 12 26,4147 3,37146 12.36 13 27.088 3,28966 14,41 14 29,1733 3,05864 92.09 15 31,4309 2,84390 12.58

[%]

35.4323 2.53137 9.37

EXAMPLE 7 Ziprasidone N-tert-butylsulfaminate monohydrate

a. Synthesis of N-tert. butylsulfamic acid.

N-tert.butylsulfamic acid was prepared according to the procedure described in Example 4.a. Acetone crystals melt at 169-171 ° C. The synthesis yield is 52%.

b. Ziprasidone N-tert.butylsulfaminate - monohydrate.

Ziprasidone base (2.5 g, 6.054 mmol) and N-tert.butylsulfamic acid (0.93 g, 6.054 mmol) were suspended in acetone / ethanol / water = 100/801150 and stirred at 80 ° C to dissolve everything. . Cool and crystallize at -15 ° C overnight. 2.98 g (84.2%) of the crystals are obtained, m.p. 169-171 ° C.

Elemental analysis corresponds to the formula C25H32CIN5O4S2. H ₂ O and is as follows:

calculated: C: 51.40% H: 5.86% N: 11.99% found: C: 51.60% H: 5.65% N: 11.89%

The water content is 3.23% (theory 3.1%) and corresponds to the monohydrate.

Mass spectrum: MS TOF ES ⁺ : 413.2 and 415.1 (MH) ⁺ , base,

MS TOT ES ': 152.0 (Mi-H)', acid. ^{The 1} H-NMR spectrum corresponds to this structure, Fig. 5. X-ray powder diffraction pattern:

No. Position [2 theta / ⁰ ] Distance [d / A] Rel. 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. Preparation of Spray Granules.

The reaction solution of ziprasidone base and sulfamic acid in a mixture of 5700 ml of ethanol and 2000 ml of water containing 255 g of ziprasidone sulfaminate is finely sprayed onto a mixture of inert fillers consisting of 1940 g of dibasic calcium phosphate dihydrate and 2160 g of corn starch. During intensive vortexing, the fillers are dried in a hot air flow at 50 ° C. The granulate is then sieved through a 1 mm sieve and mixed homogeneously with 80 g of magnesium stearate and tableted. Composition of tablets:

Ingredient: Amount mg / tablet: Ziprasidone sulfaminate hydrate 25,5 * Dibasic calcium phosphate dihydrate 194,0 Corn starch 22.5 Magnesium stearate 8.0

Weight of the tablet 250 mg

EXAMPLE 9. Capsule composition.

Ingredient: Amount of mg / capsule:

Ziprasidone N-n-propylsulfaminate dihydrate 28.5 *

Lactose monohydrate 69.0

Starch 1500 pregelatinized 10.0

Polyvinylpyrrolidone 1.5

Magnesium stearate_1,0

110 mg

*) corresponds to 20 mg ziprasidone base.

Claims (14)

Patent claims 1. Ziprasidone sulfaminates and their hydrates of general formula I: I. wherein R represents a hydrogen, alkyl or cycloalkyl group of 1 to 6 carbon atoms, and n represents 0 to 2. 2. Ziprasidone sulfaminates according to claim 1 in amorphous form. 3. Ziprasidone sulfaminates according to claim 1 in crystalline form. Ziprasidone sulfaminate monohydrate according to claim 1, followed by an x-ray Powder diffraction pattern: No .: Position [2 theta / °] Distance [d / Α] 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 5,11191 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 5. Ziprasidone N-cyclohexylsulfaminate dihydrate according to claim 1 with the following X-ray diffractogram: No. Position [2 theta / ⁰ ] Distance [d / A] Rel. 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 11 31,9312 2,80048 5,27 12 32,7476 2,73250 5.44 13 34,9873 2,56254 3.13 Ziprasidone N-n-propylsulfaminate according to claim 1 with the following X-ray diffractogramon; No. Position [2 theta / ⁰ ] Distance [d / A] Rel. 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 7. Ziprasidone N-n-propylsulfaminate dihydrate according to claim 1 with the following X-ray powder diffraction pattern: No. Position [2 theta / ⁰ ] Distance [d / A] Relat. intensity [%] 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 280894 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 8. Ziprasidone N-cyclopropylsulfaminate monohydrate according to claim 1 with the following X-ray powder diffraction pattern: No. Position [2 theta / ⁰ ] Distance [d / A] Relat. intensity [% 1 4,1220 21.41892 26,92 2 8.2590 10,69697 26.05 3 16,5511 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 11 25,9876 3,42590 17.92 12 26,4147 3,37146 12.36 13 27.088 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.butylsulfaminate monohydrate according to claim 1 with the following X-ray powder diffraction pattern: 1 Position [2 theta / ⁰ ] 7.6370 Distance [d / A] 11.56674 Rel. intensity [% 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 10. A process for the preparation of ziprasidone sulfaminates and their hydrates in amorphous and crystalline form of the general formula I: wherein R is a hydrogen, alkyl or cycloalkyl group of 1 to 6 carbon atoms, and n is 0 to 2, characterized in that ziprasidone is a base of formula II .; II. is reacted with sulfamic acids of the general formula: R-NH-SO ₃ H, wherein R is a hydrogen, alkyl or cycloalkyl group of 1 to 6 carbon atoms, in a 1: 1 molar ratio, in a polar solvent at a temperature of from 50 to 90 ° C. , preferably at 70 to 80 ° C, and the resulting salt is isolated in solid form by drying, crystallization, transformation or lyophilization. Process according to claim 10, characterized in that a lower aliphatic alcohol of 1 to 4 carbon atoms, acetonitrile, acetone, dioxane, tetrahydrofuran, 1,3-dixolane, Ν, Ν-dimethylformamide or N-methylpyrrolidone is taken as the solvent. A process according to claims 10 and 11, characterized in that to accelerate crystallization or to precipitate a second solvent is taken in which the ziprasidone salt is very poorly soluble, for example aliphatic ethers having 4 to 6 carbon atoms. 13. A process for the preparation of a tabletting or encapsulating granulate comprising a finely divided ziprasidone salt, characterized in that the aqueous / alcoholic solution of the ziprasidone salt according to claim 1 is sprayed onto inert components and fillers for the preparation of the granulate and simultaneously dried in hot air with temperature between 30 and 80 ° C. Use of ziprasidone sulfaminates and their hydrates according to claims 1 to 9 for the preparation of a solid pharmaceutical form for the treatment and prevention of psychotic conditions such as schizophrenia, bipolar disorders, psychotic depression and anxiety conditions.