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

New addition salts of ziprasidone, process for their preparation and their use in therapy Download PDF

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SI23610A
SI23610A SI201100014A SI201100014A SI23610A SI 23610 A SI23610 A SI 23610A SI 201100014 A SI201100014 A SI 201100014A SI 201100014 A SI201100014 A SI 201100014A SI 23610 A SI23610 A SI 23610A
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ziprasidone
according
distance
intensity
preparation
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SI201100014A
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Sinhala (si)
Slovenian (sl)
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Rudolf@RuÄŤman
Pavel@Zupet
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Diagen@d@o@o
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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 their preparation and their use in therapy.

Field of technique.

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

I. wherein R represents hydrogen, an alkyl or cycloalkyl group having 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 in 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.

Technical problem.

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

Therefore, there is a need for new addition salts with improved solubility in water, which would allow better resorption and higher bioavailability. 2 • ·

State of the art.

Ziprasidone is a heterocyclic compound of the formula II:

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

Ziprasidone is used to treat psychiatric disorders such as schizophrenia and intramuscular injections in acute schizophrenia and mania and in 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 probably acts as an antagonist. It seems to inhibit the susceptibility of seroprotein for serotonin and norepinephrine, although the clinical relevance for this can not be explained. The mechanism of action of ziprasidone is unknown. It is believed that the cause of antipsychotic activity is primary antagonism on dopamine receptors, specifically D2. Serotonin antagonism plays a role in the effect of ziprasidone, the significance of the 5-HT2A antagonism is unexplained. Probably the most selective affinity for 5-ΗΪ2Α receptors relative to D2 and 5-HT2c receptors, as with all neuroleptics. Antagonism to histamine and alpha-adrenergic receptors can also explain its side effects, such as sedation and orthostasis. Ziprasidone hydrochloride is used in the oral pharmaceutical formulation, and the mesylate salt in the form of trihydrate is more suitable for intramuscular use.

The synthesis of ziprasidone was investigated by Pfizer and reported patents US 4 831 031 and EP 0281309, wherein a full range of various addition salts is indicated, of which only ziprasidone hydrochloride is documented in detail. Synthesis is carried out by the reaction of the ziprasidone base with gaseous chloride. Depending on the solvent used, hydrochloride may be formed in amorphous or crystalline form. In the reaction in organic solvents in the presence of some water, hydrates are also produced, as published in US Pat. No. 5 312 925. Amorphous ziprasidone 3

hydrochloride is formed by reacting the ziprasidone base suspended in n-hexane or n-heptane if dry, gaseous chloride is introduced.

European patent EP 0584903 and EP 1 029 861 deal with the preparation of addition salts of ziprasidone by the reaction of the ziprasidone base suspension with one equivalent of a pharmaceutically acceptable acid, for example, chloride or methanesulfonic acid.

EP 0 918 772 and EP 0 904 273 protect mesylates in the form of dihydrates and trihydrates for which they indicate some better solubility in water.

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

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

Patent EP 0 965 343 B1 lists the pharmaceutical formulations of ziprasidone hydrochloride dihydrate with various large particles, in particular less than 85 pm, and with the addition of surfactants to improve solubility.

Pfizer in EP 0 900 088 protects inclusion complexes with cyclodextrins containing ziprasidone hydrochloride. This should increase the solubility and ability to be used in the form of intramuscular injections.

Various polymorphic crystalline forms of ziprasidone hydrochloride also refer to other patents and patent applications such as: WO 2004/050655 A1 (Dr. Reddy Labs), WO 2004/089948 A1 (Hetero Drugs) and WO 2005/01 5325 A2 (TEVA).

Patent Application US 2005/0059680 A deals with the polymorphic crystalline form of ziprasidone hydrochloride having a specific particle size of more than 4 m2 / g.

According to the description in Canadian patent 2 245 269, a pharmaceutical granulate containing ziprasidone base is prepared by spraying a ziprasidone base suspension in a solution of hydroxypropylcellulose acetate and succinate and drying in a warm air stream.

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 sulphate and their hydrates. A pharmaceutical formulation is also provided in the form of a capsule containing ziprasidone hydrogensulfate dihydrate. In view of the known data and efforts to improve the solubility of ziprasidone salt, • 9 4 there is still a need to prepare new addition salts with better physico-chemical properties and increased bioavailability.

Description of the solution of the technical problem.

The problem of high hydrophobicity and poor solubility of the active substance in water and, consequently, low bioavailability can be solved by the introduction of a new addition salt, with another crystalline form, by reducing the particle size, also by converting the salt into an amorphous form or even by adding a surfactant. According to the invention, new addition salts of ziprasidone with sulfamic acid and N-substituted sulfamic acids are synthesized. The salts were prepared in crystalline form, in the form of hydrates and in the amorphous state. Ziprasidone salts with sulfamic acids work very hard to crystallize. In some of the above, in the above mentioned procedures, a solubilization reaction (hydrochloride) is carried out in such a way that the solid ziprasidone base is suspended in the solvent by reacting with gaseous chloride. Since crystallization does not result in a mother liquor, the resulting crystals are less pure (since impurities are not removed).

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

After completion of the reaction, the ziprasidone salt is crystallized from the reaction mixture unless desired in amorphous form. The amorphous material is obtained by removing the salt solution after the reaction fine-grained (to keep the particles that would be the core for crystallization), cool rapidly to freeze the solution and then lyophilize. The solubility of amorphous salts is usually much better than crystalline.

Some N-substituted sulfamic acids are commercially unavailable. Therefore, we have also developed procedures for their synthesis. They are obtained by reaction of the chlorosulfonic acid with the corresponding amine dissolved in 1,2-dichloroethane at a temperature of -20 ° C, then the solvent is evaporated, the solid is dissolved in water and passed through a column with an ion exchanger. The evolution in vacuo was dried by evaporation, and the solid was then crystallized from acetone. 5

The composition and structure of the new salts was demonstrated by elemental analysis, mass and 1H-NMR spectra. Melting points were determined using the Kofler method. The crystal structure was determined by X-ray powder diffraction with X 'Pert PRO diffractometer with alpha configuration, CuKa radiation, in the range of 3-35 degrees 2 theta. The 1H-NMR spectra were recorded with the Bruker Advance DPX 300 MHz NMR spectrometer in DMSO. Mass spectra were recorded with the AutoSpec Q spectrometer. Elemental analyzes were made using the Perkin Elmer type 240, and the crystal water content by the Karl Fischer method by titration. According to the invention, ziprasidone sulfate salts have surprisingly better solubility in water, especially if they are in amorphous form. The solubility of amorphous ziprasidone sulfamate at 20 ° C is 100 mg / 100 ml of water and ziprasidone N-propyl sulfamate is 75 mg / 100 ml.

On the other hand, the particle size can be significantly affected by crystallization conditions: concentration, crystallization rate, mixing or type of solvent. The already obtained crystals can also be mechanically milled up to 20 to 10 pm. Particularly suitable is wet grinding in an inert, heavy volatile organic solvent (for example in octane or dean), followed by filtration, washing with a volatile inert solvent and drying. Thus, solubility can also increase at the same time.

Ziprasidone sulfamate obtained by the procedure described is used to prevent and treat psychotic conditions, for example, schizophrenia, bipolar disorder, psychotic depression and anxiety states. The usual doses in the treatment of these diseases range from 20 to 80 mg (calculated on the ziprasidon base).

The pharmaceutical formulations are in various solid forms such as tablets, capsules, powders or granules. They are prepared in accordance with conventional, well-known procedures. In this case, pharmaceutically acceptable fillers such as lactose, microcrystalline cellulose, dibasic calcium phosphate, various sugars and mixtures thereof are used. Massage substances such as polyvinylpyrrolidone, carboxymethylcellulose, gelatin and others must also be present. Sodium croscarmellose, crospovidone, starch and derivatives thereof are added as disintegrants. As lubricating agents or Magnesium agate, stearic acid, talc, polyethylene glycols and silicon dioxide (aerosil) are better scroll.

The granulate for the preparation of tablets or capsules may also be manufactured in such a way that the water / alcohol solution of the ziprasidone sulfamate or N-alkylsulfamate is sprayed onto the granular inert ingredients and dried at the same time as a hot air countercurrent. In this way, the ziprasidone in the form of salt is very finely distributed on the carrier. Very small particles are much easier to dissolve in therapeutic applications. 6

Short description of images.

Fig. 1.1H.NMR spectrum of ziprasidone sulfamate.

Fig. 2.1H-NMR spectrum of ziprasidone N-cyclohexylsulfamine.

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

Fig. 4.1H-NMR spectrum of ziprasidone N-cyclopropylsulfamine.

Fig. 5.1H-NMR spectrum of ziprasidone N-tert. butilsulfaminata.

The invention is explained by the following embodiments which are intended to clarify the procedures and in no case restrict the invention. EXAMPLE 1 Ziprasidone sulfamate 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, heated to 80 ° C and intensively stirred to dissolve everything. The solution was filtered and 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 with a melting point of 244 DEG C. (with decomposition) are obtained.

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

XRPD: No.: Position [2 theta / °] Distance [d / Α] Relative intensity [%] 1 7.3133 12.07701 8.50 2 , 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 24.0434 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 7 15 27.3383 3.25963 20.46 16 31.0822 2.87501 4.27 17 31.7111 2.891941 6.71 18 32.7022 2.73618 11.57 EXAMPLE 2. Ziprasidone sulfamate - amorphous.

Ziprasidone sulfamate monohydrate (0.65 g) is dissolved in 47 ml of dioxane and 32 ml of water at 80 ° C. The solution is still warmly filtered through a filter with pores of 0.22 pm to remove the potential crystallization cores. The clear solution was quickly frozen and lyophilized.

Finally, it is dried in a high vacuum. 0.62 g (99.7%) of amorphous material with a melting point of 180 [deg.] C. (decomposition) are obtained.

Elemental analysis corresponds to 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 is also responsible for the 1H-NMR spectrum (Fig. Fig.1), and X-ray powder diffractogram does not show any sharp reflexes, which is characteristic of amorphous substances. EXAMPLE 3 Ziprasidone N-cyclohexylsulfamine 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 it to dissolve everything. Filtrate, cool and crystallize overnight at -15 ° C. 7.03 g (95.2%) of reddish crystals with a melting point of 209-215 ° C are obtained.

The elemental analysis corresponds to the composition of C27H34CIN5O4S2. 2 H2O 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 of K. Fischer is 5.70% (theoretical 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-FT), acid. The 1H-NMR spectrum corresponds to said structure (Fig. Fig. 2).

X-ray powder diffractogram:

No. Position [2 theta / 0] Distance [d / A] Rel. intensity [% 1 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 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. ZIPRASIDON Nn-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. Then, chlorosulfonic acid (2.2 ml, 0.033 mol) is slowly added dropwise while stirring, the solvent is evaporated in vacuo to crystallize the solid residue. The crystalline mass is dissolved in water and this solution is passed through a column of diameter 4 cm, length 10 cm, filled with a cation exchanger in H + form (Amberlyt IR-120, ®). The acidic eluate was collected and evaporated in vacuo to a solid residue. It is heated in hot acetone and crystallized. 3.23 g (45.8%) of N-n-propylsulfamic acid are obtained with a melting point of 189-193 ° C. 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 DEG C. in a mixture of 50 ml of acetone and 25 ml of water. The hot filtrate (5 pm filter) and cool to crystallize. 3.03 g (89%) of reddish crystals with a melting point of 128-130 ° C are obtained.

Elemental analysis corresponds to the formula C24H30CIN5O4S2.2H2O and is: Calculated: C: 49.09% H: 5.78% N: 11.82% Found: C: 49.02% H: 5.81% N: 11.90 %

Analysis by K. Fischer gives 5.31% water, which corresponds to dihydrate.

Mass spectrum: MS TOF ES +: 413.1.415.1 (MH) +, base, MS TOF ES ': 138.0 (M1-H)', 277.1 (2M1-H) ', acid. The 1H-NMR spectrum corresponds to the structure and is shown in Figure 3.

X-ray powder diffractogram:

No. Position [2 theta / 0] Distance [d / A] Relative. intenzil 1 10.077 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 4.99909 14.76 7 18.2241 4.86405 85.29 8 19.5437 4.53851 32.47 9 22.2301 3.99576 17.95 9 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 Nn-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 N, N-dimethylformamide at a temperature of 70 ° C. To this solution slowly, while stirring, a total of 20 ml of methyl tert-butyl ether is added, cooled and crystallized overnight. Filter and wash the crystals thoroughly 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: MS TOF ES +: 413.1, 415.1 (MH) +, base, MS TOF ES ': 138.0 (MH)', 277.1 (MH) ', acid.

X-ray powder diffractogram:

No. Position [2 theta / 0] Distance [d / A] Rel. intenzil 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 22.9525 3.87167 23.49 13 23.4233 3.79482 72.96 14 23.6162 3.76427 26.57 10 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. Synthesis of N-cyclopropylsulfamine xylene. N-Cyclopropylsulfamic acid is prepared according to the procedure described in Example 4.a. The yield is 32.6%. The acid is melted at 166-168 [deg.] C. b. Ziprasidone N-cyclopropylsulfamate-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. Hot filter and cool overnight at + 5 ° C to crystallize. 2.80 g (89.9%) of reddish crystals with a melting point of 184-186 ° C are obtained.

The elemental analysis corresponds to the formula C24H28CIN5O4S2. H20 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 is determined by K. Fischerje 3.4% (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 1H-NMR spectrum corresponds to this structure and is shown in Figure 4.

X-ray powder diffractogram:

No. Position [2 theta / 0] Distance [d / A] Relative. 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 4.08816 15.41 10 24.2023 3.67443 14 , 01 11 25.9876 3.42590 17.92 12 26.4147 3.37146 12.36 13 27.0840 3.28966 14.41 14 29.1733 3.055864 92.09 15 31.4309 2.84390 12 , 58 • · · · 11 16 35.4323 2.53137 9.37 EXAMPLE 7. Ziprasidone N-tert-butylsulfamate monohydrate a. Synthesis of N-tert. butylsulfamoyl acid. N-tert-butylsulfamic acid is prepared according to the procedure described in Example 4.a. The crystals from acetone are melted at 169-171 ° C. The yield of the synthesis is 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) are suspended in an acetone / ethanol / water mixture = 100/801150 and stirred at 80 DEG C. to dissolve . Cool and crystallize at -15 ° C overnight. 2.98 g (84.2%) of crystals with a melting point of 169-171 [deg.] C are obtained.

The elemental analysis corresponds to the formula C25H32CIN5O4S2. H2O and the following: 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% (theoretical 3.1%) and corresponds to the monohydrate.

Mass spectrum: MS TOF ES +: 413.2 and 415.1 (MH) +, base, MS TOT ES ': 152.0 (M1-H)', acid. The 1H-NMR spectrum corresponds to this structure, Fig. 5.

X-ray powder diffractogram:

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 3.033701 10.00 15 29.7182 3.00379 14, 97 16 31.5594 2.83261 6.52 12 EXAMPLE 8 Preparation of spray granules.

The solution after the reaction of ziprasidone base and sulfamic acid in a mixture of 5700 ml of ethanol and 2000 ml of water containing 255 g of ziprasidone sulfamate 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 the intense vortexing of the fillers, dry in a warm air countercurrent with a temperature of 50 ° C. The granulate is then sieved through a sieve with apertures of 1 mm and homogenously mixed with 80 g of magnesium stearate and tableted. Tablet Composition:

Ingredient: Quantity mg / tablet:

Ziprasidone sulfamate hydrate 25,5 *

Dibasic calcium phosphate dihydrate 194.0

Maize starch 22.5

Magnesium stearate_8.0

Weight of tablet 250 mg EXAMPLE 9. Capsule composition.

Ingredients: Quantity mg / capsule:

Ziprasidone N-n-propylsulfamine dihydrate 28.5 *

Lactose monohydrate 69.0 Starch 1500 pregelatinized 10.0

Polyvinylpyrrolidone 1.5

Magnesium stearate_1J) 110 mg *) corresponds to 20 mg ziprasidone base.

Claims (12)

13 • Patent claims 1. Ziprasidone sulfamines and their hydrates of the general formula I:
wherein R represents hydrogen, an alkyl or cycloalkyl group having 1 to 6 carbon atoms, and n is 0 to 2.
Ziprasidone sulfamines according to claim 1 in an amorphous form.
Ziprasidone sulfamines according to claim 1 in crystalline form.
Ziprasidone sulfamate monohydrate according to claim 1 with the following X-ray powder diffraction pattern: No.: Position [2 t 1 7,3133 2 12,8124 3 14,6293 4 16,2193 5 17,3335 6 18,7029 7 19,9887 8 20,2788 9 21,2019 10 21,9870 11 24,0433 12 24,4496 13 25,1488 14 25,7515 15 27,3383 16 31,0822 17 31,7111 18 32,7022 / °] Distance [d / Α] 12.07701 6.90380 6.05017 5.46049 5.11191 4.74058 4.43846 4.37562 4.18713 4.03938 3.69836 3.63781 3.53823 3.45677 3.25963 2.87501 2,81941 2,73618 Relative intensity 8,50 3,98 3,30 71,43 49,02 9,80 11,59 6,39 14,64 100,00 6,53 9,87 25,32 19,53 20,46 4 , 27 6.71 11.57 [%] 14
Ziprasidone N-cyclohexylsulfamine dihydrate according to claim 1 with the following X-ray 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 Ziprasidone N-propylsulfamate according to claim 1 with the following X-ray diffractogram: 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 22.9525 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 15 15 • · • »
Ziprasidone N-n-propylsulfamine dihydrate according to claim 1 with the following X-ray powder diffraction pattern: No. Position [2 theta / 0] Distance [d / A] Relative. intensity [° / 1 10.077 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 4.99909 14.76 7 18.2241 4.86405 85.29 8 19.5437 4.53851 32.47 g 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 Ziprasidone N-cyclopropylsulfamate monohydrate according to claim 1 with the following X-ray powder diffraction pattern: No. Position [2 theta / 0] Distance [d / A] Relative. 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 4.08816 15.41 10 24.2023 3.67443 14.01 11 25.9876 3.42590 17.92 12 26.4147 3.37146 12.36 13 27.0840 3.28966 14.41 14 29.1733 3.055864 92.09 15 31.4309 2.84390 12.58 16 35.4323 2.53137 9.37 16
Ziprasidone N-tert-butylsulfamine monohydrate according to claim 1, with the following 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 3.033701 10.00 15 29.7182 3, 00379 14.97 16 31.5594 2.83261 6.52
A process for the preparation of ziprasidone sulfamines and their hydrates in amorphous and crystalline form of the general formula I: V = o
wherein R represents hydrogen, an alkyl or cycloalkyl group having 1 to 6 carbon atoms and n represents 0 to 2, characterized in that the ziprasidone base of formula II is:
II. 17 is reacted with sulfamic acids of general formula: R-NH-SO3H, wherein R represents hydrogen, alkyl or cycloalkyl of 1 to 6 carbon atoms in a molar ratio of 1: 1 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, precipitation or lyophilization.
A process according to claim 10, characterized in that a lower aliphatic alcohol having 1 to 4 carbon atoms, acetonitrile, acetone, dioxane, tetrahydrofuran, 1,3-dixolane, N, N-dimethylformamide or N-methylpyrrolidone are used as the solvent.
A process according to claims 10 and 11, characterized in that for the acceleration of crystallization or for precipitation, a second solvent is used in which the ziprasidone salt is very poorly soluble, for example, aliphatic ethers with 4 to 6 carbon atoms.
A process for preparing a tabletting or capsule granulate containing a ziprasidone finely distributed salt, characterized in that the aqueous / alcoholic solution of the ziprasidone salt of claim 1 is sprayed onto inert components and granules for the preparation of the granulate, and simultaneously dried in a hot air counter temperature between 30 and 80 ° C.
Use of ziprasidone sulfamines 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 disorder, psychotic depression and anxiety states.
SI201100014A 2011-01-13 2011-01-13 New addition salts of ziprasidone, process for their preparation and their use in therapy SI23610A (en)

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