OA10909A - Mesylate dihydrate salts of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-ethyl)-6-chloro-1,3-dihydro-2(1H)-indol-2-one (=ziprasidone) its preparation and its use as dopamine d2 antagonist - Google Patents

Mesylate dihydrate salts of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-ethyl)-6-chloro-1,3-dihydro-2(1H)-indol-2-one (=ziprasidone) its preparation and its use as dopamine d2 antagonist Download PDF

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OA10909A
OA10909A OA9800206A OA9800206A OA10909A OA 10909 A OA10909 A OA 10909A OA 9800206 A OA9800206 A OA 9800206A OA 9800206 A OA9800206 A OA 9800206A OA 10909 A OA10909 A OA 10909A
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ziprasidone
indol
dihydro
benzisothiazol
piperazinyl
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Frank Robert Busch
Carol Anne Rose
Russell James Shine
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Pfizer
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    • 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
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/18Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/22Anxiolytics

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Description

-Ι- ΟΙ Ü 9 G 9
MESYLATE DIHYDRATE SALTS OF 5-<2-<4-(L2-BENZlSOTHIAZOL-3-YL>-l-PIPERAZTNYL>-ETHYLV-6-CHLORO-l,3-DIHYDRO-2(IH>-TNDOL-2-ONE (-ZIPRASIDONE). ITS PREPARATIONAND ITS USE AS DOPAMINE D2 ANTAGONIST
Backqround of the Invention
The invention is directed to the mesylate dihydrate salts of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1 -piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one (hereafter 10 “ziprasidone mesylate dihydrates"), pharmaceutical compositions containing one orboth of the ziprasidone mesylate dihydrates, and methods of administering the ziprasidonemesylate dihydrates to treat psychotic diseases. Ziprasidone is a potent antipsychoticagent and is therefore useful for treating various disorders including schizophrénie,anxiety and migraine pain. United States Patent 5,312,925 refers to ziprasidone 15 hydrochlonde monohydrate, and States that ziprasidone hydrochloride monohydrate issubstantially hygroscopically stable, which alleviates potential problems associated withweight changes of the active ingrédient during the manufacture of capsules or tablets.United States Patent 5,312.925 is herein incorporated by reference in its entirey.Ziprasidone hydrochloride monohydrate, however, has low aqueous solubility and, as 20 a resuit, is more appropriate for capsule ortablet formulation than for injectable dosageforms.
The ziprasidone mesylate dihydrates also possess hygroscopic stability. Theziprasidone mesylate dihydrates hâve the added advantage of having significantlygreater aqueous solubility than the hydrochloride monohydrate, which makes the 25 mesylate dihydrates more suitable for injectable dosage forms than the hydrochloridemonohydrate.
Summary of the Invention
The présent invention reiates to the mesylate dihydrate salts of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one. 33 This invention also relates to a pharmaceutical composition for the treatment of a psychotic disorder, such as schizophrenia, anxiety or migraine pain, comprising anamount of the mesylate dihydrate satts of 5-(2-(4-( 1,2-benzisothiazol-3-yl}-1-piperazinyl)ethyl)-5-chloro-1,3-dihydro-2H-indol-2-one that is effective in treating saidpsychotic disorder, and a pharmaceuticaliy acceptable carrier. 35 This invention also relates to a method of treating a psychotic disorder, such as schizophrenia. anxiety or migraine pain, in amammal, including a human, compnsing aaministenng to said mammal an amount of the mesylate dihydrate salts of 5-(2-(4-(1,2- -2- Ü 1 U 9 ü 9 benzisothiazo!-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dibydro-2H-indol-2-one thaï iseffective in treating said disorder.
Description of the Drawinqs
Fig. 1 depicts the X-ray powder diffraction spectrum of ziprasidone mesylate5 dihydrate (lath crystal) expressed as intensity (Cps) versus diffraction angle (two-theta degrees).
Fig. 2 depicts the X-ray powder diffraction spectrum of ziprasidone mesylatedihvdrate (needle crystal) expressed as intensity (Cps) versus diffraction angle (two-theta degrees). 10 Fig. 3 depicts the X-ray powder diffraction spectrum of ziprasidone mesylate anhydrous (iath crystal) expressed as intensity (Cps) versus diffraction angle (two-thetadegrees).
Fig. 4 shows a photomicrograph of ziprasidone mesylate dihydrate (lathcrystals). 15 Fig. 5 shows a photomicrograph of ziprasidone mesylate dihydrate (needle crystals),
Fig 6 shows a photomicrograph of ziprasidone mesylate anhydrous (lathcrystals). -3- 010909
Tables 1-3 below identify selected peaks from the spectra of Figures 1-3,respectively, by diffraction angle (two-theta), d-spacing, maximum intensity (max. int.),and relative intensity (rel. int.).
Table 1
X-RAY POWDER DIFFRACTION DATA FOR ZIPRASIDONE MESYLATE DIHYDRATE (LATH CRYSTALS)
Two-Theta (deqrees) D-spacing (deqrees) Max. Int.(counts/sec) Rel. int. (%) 3.080 28.6618 245.00 4.19 3.684 23.9618 210.00 3.60 7.208 12.2538 626.00 10.71 7.931 11.1377 493.00 8.44 i 8.429 10.4810 100.00 1.71 9.968 8.8664 386.00 6.61 ! 12.022 7.3558 1947.00 33.33 I 12.721 6.9527 620.00 10.61 I 13.394 6.6049 548.00 9.38 I 13.886 6.3720 331.00 5.67 | 14.481 6.1116 390.00 6.68 15.152 5.8426 194.00 3.32 15.949 5.5523 2462.00 42.15 17.048 5.1967 5841.00 100.00 18.111 4.8941 493.00 8.44 18.592 4.7684 3227.00 55.25 19.520 4.5438 740.00 12.67 19.862 4.4663 1512.00 25.89 ΐ 20.517 4.3253 733.00 12.55 | 20.883 4.2503 872.00 14.93 21.372 4.1541 412.00 7.05 21.814 4.0709 1848.00 31.64 -4- 010909
Two-Theta (deqrees) D-spacing (deqrees) Max. Int.(counts/sec) Rel. Int (%) 22.711 3.9121 571.00 9.78 23.078 3.8507 920.00 15.75 24.263 3.6652 2218.00 37.97 24.798 3.5874 1982.00 33.93 25.665 3.4581 1778.00 30.44 26.640 3.3434 204.00 3.49 27.162 3.2803 1232.00 21.09 28.728 3.1049 347.00 5.94 29.202 3.0556 209.00 3.58 30.004 2.9758 225.00 3.85 30.721 2.9079 366.00 6.27 j 31.610 2.8281 407.00 6.97 32.267 2.7720 522.00 8.94 32.800 2.7282 252.00 4.31 33.202 2.6960 743.00 12.72 34.549 2.5940 373.00 6.39 34.549 2.5940 373.00 6.39 35.144 2.5514 245.00 4.19 36.738 2.4443 220.00 3.77 38.910 2.3127 124.00 2.12 39.751 2.2657 204.00 3.49 ώί ,>rr Û10909 •5-
Table 2
X-RAY PQWDER DIFFRACTION DATA FOR 5 ZIPRASIDONE MESYLATE DIHYDRATE (NEEDLE CRYSTALS)
Two-Theta (deqrees) D-spacing (deqrees) Max. Int.(counts/sec) Rel. Int. (%) 7.823 11.2913 33.00 1.78 10.049 8.7946 504.00 27.20 11.502 7.6872 1095.00 59.09 12.660 6.9866 148.00 7.99 13.440 6.5826 87.00 4.70 14.080 6.2848 83.00 4.48 14.958 5.9178 791.00 42.69 15.762 5.6179 446.00 24.07 16.313 5.4293 398.00 21.48 16.760 5.2854 140.00 7.56 17.261 5.1330 71.00 3.83 17.696 5.0078 125.00 6.75 18.640 4.7563 631.00 3405 19.002 4.6665 1853.00 100.00 19.976 4.4411 294.00 15.87 ! 20.726 4.2820 115.00 6.21 ! 22.348 3.9748 470.00 25.36 i 22.790 3.8987 1440.00 77.71 ? I 24.377 3.6484 884.00 47.71 j 25.368 3.5080 192.00 10.36 ; ! 25.861 3.4423 457.00 24.66 ; 26.640 3.3434 150.00 8.09 ' 27.212 3.2743 329.00 17.75 28.349 3.1456 309.00 16.68 28.930 3.0837 180.00 9.71 ’ 010909
Two-Theta (deqrees) D-spacing (deqrees) Max. Int.(counts/sec) Rel. Int. (%) 29.644 3.0111 231.00 12.47 30.130 2.9636 175.00 9.44 30.601 2.9190 236.00 12.74 31.704 2.8200 95.00 5.13 32.198 2.7778 63.00 4.48 33.887 2.6431 98.00 5.29 34.830 2.5737 124.00 6.69 35.519 2.5253 106.00 5.72 36.901 2.4339 63.00 3.40 37.716 2.3831 110.00 5.94 38.331 2.3463 113.00 6.10 38.732 2.3229 146.00 7.88 39.751 2.2657 105.00 5.67 15 Table 3
X-RAY PDWDER DIFFRACTION DATA EOR ZIPRASIDONE MESYLATE ANHYDROUS (LATH CRYSTALS) i Two-Theta ! (deqrees) D-spacing (deqrees) Max. Int,(counts/sec) Rel. Int, (%) i 3.065 28.8018 120.00 9.16 6.521 13.5424 63.00 4.81 : 8.737 10.1124 72.00 5.50 11.860 7.4557 38.00 2 '! 12.776 6.9231 528.00 4C ] 13.992 6.3241 386.00 29,- ' j 16.307 5.4311 653.00 49.85 | 16.847 5.2582 448.00 34.20 ; 17.538 5.0527 608.00 46.41 -7- Ù10909
Two-Theta fdeqrees) D-spacing fdeqrees) Max. Int.(counts/sec) Rel. Int. (%) 18.385 4.8217 369.00 28.17 18.800 4.7162 169.00 12.90 19.712 4.5001 1310.00 100.00 20.722 4.2829 208.00 15.88 21.424 4.1441 932.00 71.15 22.600 3.9311 509.00 38.85 22.918 3.8772 658.00 50.23 23.690 3.7526 502.00 38.32 24.558 3.6219 743.00 56.72 25.792 3.4513 175.00 13.36 26.399 3.3734 612.00 46.72 28.185 3.1636 109.00 8.32 28.706 3.1073 82.00 6.26 29.652 3.0103 135.00 10.31 30.680 2.9117 104.00 7.94 31.034 2.8793 171.00 13.05 31.365 2.8497 152.00 11.60 32.983 2.7135 98.00 7.48 33.737 2.6545 101.00 7.71 35.533 2.5244 63.00 4.81 ί 38.737 2.3226 92.00 7.02 i 39.608 2.2735 73.00 5.57 -8- 01 0 9 0 9
Detailed Description of the Invention
Ziprasidone mesyiate exists in four distinct crystalline forms; ziprasidonemesylate anhydrous (lath crystal), ziprasidone mesyiate dihydrate (lath crystal),ziprasidone mesylate dihydrate (needle crystal), and ziprasidone mesylate trihydrate. 5 Each crystal form has distinct characteristics, such as a distinct powder X-ray diffractionpattern and a distinct crystal shape that can be observed by photomicrograph. Theziprasidone mesylate dihydrate lath (Figure 4) and needle (Figure 5) crystals arerelatively long and thin in contrast to the prism crystals of ziprasidone mesylatetrihydrate. Ziprasidone mesylate anhydrous crystals (Figure 6) are distinct, though 10 similar in shape to the dihydrate lath crystals. The photomicrographs of Figures 4-6were obtained using an Olympus polarizing microscope (model BH-2) equiped with ahalogen lamp, binocular eye piece, polarizing filter and Sony 3ccd video caméra withSony color pnnter.
The characteristic X-ray powder diffraction spectra of the ziprasidone mesylate 15 dihydrates are depicted in Figures 1 and 2. While the ziprasidone mesylate anhydrouscrystals (Figure 6) may be similar to the dihydrate lath crystals (Figure 4) in shape, theX-ray powder diffraction spectrum of ziprasidone mesylate anhydrous (Figure 3) isclearly distinct from the X-ray powder diffraction spectra of the ziprasidone mesylatedihydrates (Figures 1 and 2). The X-ray powder diffraction spectra of Figures 1-3 were 20 taken on a Siemens R3RA/v diffractometer. The ziprasidone mesylate dihydrates arefurther characterized by their water content which is indicated by their Karl Fischer (KF)value of 6.4 ± 1.0. Ziprasidone mesylate trihydrate is the subject of co-pending UnrtedStates provisional application entitled “Mesylate T rihydrate of 5-(2-(4-(1,2-Benzisothiazol- 3-yl)-1-pipera2inyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one‘' (Pfizer docket number 25 PC9277), filed concurrent^ herewith. The foregoing co-pending United States provisional application is incorporated herein by reference in rts entirety.
The ziprasidone mesylate dihydrates are significantly more soluble in anaqueous medium than ziprasidone hydrocnioride monohydrate which has a solubiviyof 0.08 mg/ml in water at ambient température. The aqueous soiubility of tne four 30 ziprasidone mesylate forms is indicated in Table 4 below. -9- 010909
Table 4
Aqueous Solubility Of Ziprasidone Mesylate Polymorphs
POLYMORPH SOLUBIUTY IN WATER trihydrate 0.73 mg/mL dihydrate (lath) 1.11 mg/mL dihydrate (needle) 1.10 mg/mL anhydrous 1.27 mg/mL
The ziprasidone mesylate dihydrates may be prepared from the free base W (ziprasidone) which is prepared as described in column 4, lines 22-43 of United StatesPatent 5,312,925, referred to above. The free base can also be prepared as describedin United States Patent 5,338,845, the disclosure of which is herein incorporated byreference in its entirety. When the intended use is as an injectable formulation, it ispreferred to conduct the préparation under pyrogen-free and speck-free conditions. 15 Speck-free solvents and reagents can be prepared by filtering them through a 0.45 μπ}Millipore* nylon fitter.
Ziprasidone mesylate dihydrate needle crystals are prepared by mixing the freebase with a mixture of water and organic solvent, adding dilute methanesulfonic acid,and heating to reflux as described above for the préparation of the trihydrate. The 20 dihydrate needle crystals are prepared by adding a seed crystal of the needle shaoedDolymorph to the reaction solution after the solution has been stirred under refluxconditons for about thirty minutes. A thick -pinkish" slurry indicating crystal formationwill begin to form. The reaction solution is then allowed to cool slowly with stimng.During cooling at about 50°C, water can be added to the solution to thin the slurry. 25 The needie crystals can be filtered from the composition through a poly-cloth fitter, andtnen washea consecutively with appropriate volumes of a THF/water (65/35, v/v)solution and water. When allowed to dry at ambient température, the water content ofthe needle crystals has a Karl Fischer value ranging from 5.0-6.8% KF (theoretical KFfor the trihydrate is 6.4 %). 30 Ziprasidone dihydrate lath crystals are prepared by mixing the free base with water and warming the resulting slurry to 50°C to 55°C. Concentrated methanesulfonic acid is then added and the mixture is heated to reflux. After about i -10- to 6 hours, preterably 2 hours, at reflux, îhe solution is cooled to provide the dihydratelath crystals. The resulting slurry is stirred for about 2 hours at ambient températureand the crystals are then filtered from the composition and washed as described abovefor the needle crystals. When allowed to dry at ambient température, the water content 5 of the lath crystals has a Karl Fischer value ranging from 6.0% to 6.8 % (theoretical KFfor the dihydrate is 6.4%).
The ziprasidone mesylate dihydrates may be administered as a psychotic agentas described in United States Patents 5,312,925, referred to above. Administration ofziprasidone mesylate dihydrate is preterably done in combination with pharmaceutically 10 acceptable carriers or diluents in a pharmaceutical composition, in accordance withstandard pharmaceutical practice and as described in United States Patent 5,312,925,referred to above. Suitable pharmaceutical carriers include solid diluents or filiers, andsteriie aqueous solutions, various organic solvents and excipients known to thoseskilled in the art. 15 The ziprasidone mesylate dihydrates may be administered orally or parenterally, including intravenously or intramuscularly. For parentéral administration, it is preferred,where the use of water is called for, to use stérile water for injection (SWI).Administration through intramuscular injection is preferred. A preferred composition forintramuscular injection is ziprasidone mesylate dihydrate (needle or lath, or both) in 20 combination with sulfoxybutyl /?-cyclodextnn as carrier, preterably prepared at a ratioof 1:10 (w/w) dihydrate to carrier. Compositions containing ziprasidone mesylatedihydrate (needle or lath) in combination with sulfoxy ^-cyclodextrin can be preparedas described in co-pending United States provisional applications entitled "Method OfMaking Inclusion Complexes* (Pfizer docket number PC 9563), filed concurrently 25 herewith, and 'Inclusion Complexes Of Aryl-Heterocyclic Compounds* (Pfizer docketnumber PC 8838), filed concurrently herewith. Both of the foregoing co-pending UnitedStates provisional applications are incorporated herein by reference in their entirety.
The effective dosage for the ziprasidone mesylate dihydrates dépends on tneintended route of administration, the indication to be treated, and other factors sucn as 30 âge and weight of the subject. In the following dosage ranges, the term ‘mgA* refersmilligrams of the free base (ziprasidone). A recommended range for oral dosing is 5-300 mgA/day, preterably 40-200 mgA/day, more preterably 40-80 mgA/day, in single or —« r — - -11- Ü1 0909 divided doses. A recommended range for parentéral adiministration, such as injectionis 2.5 mgA/day to 160 mgA/day, and preferabiy 5-80 mgA/day.
The présent invention is illustrated by the foliowing examples, but it is not limitedto the details thereof. Unless otherwise indicated, the préparations described in the 5 foliowing examples were conducted under speck-free and pyrogen-free conditions. Asused in the foliowing examples, THF means tetrahydrofuran and SWI means stérilewater for injection.
Example 1
Purification of 5-(2-(4-(1,2-benzisothiazol-3-yl}-1-piperazinvl]ethvi]-6~chlorc>-10 1,3-dihydro-2H-lndol-2-one
To a ciean and dry glass-lined tank, 46.8 kg of 5-(2-(4-(1,2-benzisothiazol-3-yl}-1 -piperazinyl}ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one and 2816.4 L of THF werecharged. The slurry was heated to reflux and held for forty-five minutes to form a hazysolution. The solution was filtered through a 33-inch sparkler precoated with filter aid 15 and backed with a Fulflo® filter (manufactured by Parker Hannifin Corp., Lebanon,Indiana) to a clean, dry glass-lined tank on a lower level. The filtered solution wasconcentrated by vacuum distillation, cooled to 5°C, and allowed to stir for two hours.The product was collected by filtration on a centrifuge and washed with cold (0-5°C)THF. The product was collected and dried under vacuum at 45°C, to yield 40.5 kg of 20 product. The product had a purity of 101.5% (within the typical range of 100 x 2% vs.the standard) as determined by an HPLC assay.
Example 2 5-(2-(4-(1-benzisothiazot-3-yl)-1-pipe razinvnethyH-6-chloro-1,3- dihydro-2H-indol-2-one methanesulfonate trihydrate 25 A slurry was produced by charging 1000 g of 5-(2-(4-(1,2-benzisothiazo!-3-yl)-i-
piperazinyl)ethyl}-6-chloro-1,3-dihydro-2H-indol-2-one, 7500 mL of SWI, and 4000 mLof THF to a 22-liter, three-neck, round-bottom flask equipped with a neating mantle, anoverhead mechanical stirrer, a condenser, and a température probe. The flask contentswere protected from light with an aluminum foil cover. The slurry was heated to 50 °C 30 while stirring. Dilute methanesutfonic acid was prepared by combining 188 mL ofmethanesulfonic acid with 812 mL SWI. The dilute methanesulfonic acid was addedslowly through a dropping tunnel to the reaction mixture. The reaction was heated toreflux (about 65°C), and a dark red solution formed as the reaction mixture was heated. -12- Ü10909
The réaction mixture was allowed to stir under reflux conditions for approximateiy thirtyminutes. After the thirty minute time period, the heating mantle was shut off to aiiowsiow cooiing of the reaction mixture with stirring. The reaction mixture was allowed tocool with stirring overnight (about 18 hours). As the reaction mixture cooied, the 5 product crystallized out as large 'yellowish' hexagonal prismatic crystais. The mixturewas aliowed to stir under ambient conditions for one hour. The product was isolatedon a Buchner tunnel with a poly cloth filter and was washed consecutively with 1500mL of THF/SWI (65/35, v/v) and 1000 mL of SWl. The crystais were spread over glasstrays and allowed to dry under ambient conditions to a Karl Fischer value of about 10 9.6%. The product was milled through a Mikro-Samplmifl* (manufactured by the
Pulverizing Machinery Division of Mikropul Corp., Summit, New Jersey) equipped witha 0.027 H plate at a speed of 14,000 rpm. The yield was 945 g of product.
The product's structure was confirmed as 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one methanesulfonate trihydrate by 15 NMR. ’3C NMR (DMSO-de): δ 177.1(0), 163.0(0), 153.0(0), 145.0(0), 132.4(0), 129.0(1),127.8(0), 127.7(1), 127.1(0), 126.5(0), 125.6(1), 124.9 91), 122.1(1), 110.6(1), 55.9(2),51.7(2), 47.5(2), 40.7(3), 36.2(2), 27.9(2). Ή NMR (DMSO-d6): δ 10.5 (s, 1H); 9.8 (br.s, 1H); 8.2 (d, J=8.2 Hz, 1H); 8.1 (d, J=8,2 Hz, 1H); 7.6 (m, 1H), 7.5 (m, 1H); 7.3 (s,1H). 6.9 (s, 1H); 4.2 (m, 2H); 3.7 (m, 2H); 3.5 (m, 2H), 3.4 (m, 2H); 3.1 (m, 2H); 2.4 (s, 20 3H).
Evaluation of the product by HPLC showed a peak with a rétention timecorresponding to that of a standard. The HPLC conditions are summarized in Table5 below.
Table 5
HPLC Conditions: Column: Waters - Puresil C-18 15 cm length x 4.6 mm I.D. (Catalog No. WAT044345) Mobile pnase: 0.05 M KH,PO« pH 3.0:methanol (60:40. v/v) Flow rate: 2.0 mUminute | Détection: UV. 229 nm I Column température: ambient Sample volume: 10 pL -13- ÜiU9Ü9
Example 3 5-(2-(4-(1,2-benzisothiazol-3-vl)-1-piperazinyf1ethvn-6-chloro-1.3-dihydro-2H- indol-2-one methanesulfonate anhydrousA slurry was produced by charging 350 g of 5-(2-(4-(1,2-benziosothiazol-3-yl)-1 - 5 piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one and 7000 mL of isopropanol toa 12-liter three-neck, round-bottom fiask equipped with a heating mantle, an overheadmechanical stirrer, a condenser, and a température probe. The slurry was heated to50°C while stirring. 65.9 mL of methanesulfonic acid was added slowly through adropping funnel to the 50°C reaction mixture. A siight exotherm to 55°C along with 10 thickening of the slurry and lightening of the slurry color were observed. The reactionwas atmospherically distilled to remove 25% of the volume (1750 mL). The slurry wascooled to ambient température and allowed to stir ovemight. The product was isolatedon a sintered glass funnel and washed with fresh isopropanol. The solids were spreadover glass trays and aliowed to dry under ambient conditions to a Karl Fischer value 15 of 0.5%. The yield was 420.3 g of product. Evaluation of the product by HPLC showeda peak with a rétention time corresponding to that of a standard. The purity of theproduct, as determined by HPLC (conditions in Table 5), was 99.8%.
Example 4 5-(244-(1-benzisothiazol-3-vl)-1-piperazinyllethvB-6-chloro-1,3- 20 dihydro-2H-indol-2-one methanesulfonate dihydrate (needle crystals) A slurry was produced by charging 5 g of 5-(2-(4-(1,2-benzisothiazo!-3-yl)-i- piperazinyl]etnyl]-6-chloro-1,3-dihydro-2H-indol-2-one, 37.5 mL of water, and 20 mL ofTHF to a 150 mL, three-neck, round-bottom fiask equipped with a neating mantle, anoverhead mechanical stirrer, a condenser, and a température probe. The fiask contents 25 were protected from light with an aluminum foi! cover. The slurry was heated to 65 °Cwith stirring. Dilute methanesuifonic acid was prepared by combining 1 mL ofmethanesulfonic acid with 4 mL SWI. The dilute methanesulfonic acid was addedslowly through a dropping funnel to the reaction mixture. The reaction was heated toreflux (about 65 °C) and a dark red solution formed. The reaction mixture was allowed 30 to stir under reflux conditions for approximately thirty minutes. After the thirty minuteperiod, a seed crystal of the needle shaped polymorph was added to the reactionsolution. Crystal formation started, and the heat was removed to allow slow cooiing ofthe reaction with stirring. During cooiing at 50°C, athick "pinkish" slurry was observed -14- in the fiask. Water (20 mL) was added to the fiask to thin the slurry. The product wasallowed to stir under ambient conditions for one hour. The product was isolated on aBuchner funnel with a paper filter and the solids were allowed to dry under ambientconditions to a Karl Fischer value of about 6.6%. The yield was 6.03 g of product. The 5 purity of the product, as determined by HPLC (conditions in Table 5), was 99.8%.Example 5 5-(2-14-(1-benzisothiazol-3-vl)-1-piperazinvllethyl)-6-chloro-1,3- dihydro-2H-indol-2-one methanesulfonate dihydrate Qath crystals) A slurry was produced by charging 25 g of 5-[2-[4-(1,2-benzisothiazol-3-yl)-1- 10 piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one and 375 mL of water to a 500 mL,three-neck, round-bottom fiask equipped with a heating mantle, an overheadmechanical stirrer, a condenser, and a température probe. The fiask contents wereprotected from light with an aluminum foil cover. The slurry was heated to 50-55 °Cwhile stirring. Methanesulfonic acid (5 mL) was added slowly through a dropping funnel 15 to the reaction mixture. Thickening of the slurry and lightening of the slurry color wereobserved. The reaction was heated to reflux (about 100°C) and allowed to stir forabout one hour. The heat was removed to allow slow cooling of the reaction withstirring. The reaction solution was allowed to stir under ambient conditions for aboutone hour. The product was isolated on a Buchner funnel with a paper filter and the 20 solids were allowed to dry under ambient conditions to a Karl Fischer value of aoout6.2%. The yield was 32.11 g of product. The purity of the product, as determined byHPLC (conditions in Table 5), was 98.7%.

Claims (8)

  1. -15- 01 0 90 9 CLAIMS We daim:
    1. A mesylate dihydrate sait of 5-(2-(4-(1,2-benzisothiazo!-3-yl)-1 piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one.
  2. 2. The compound of daim 1 in the form of iath crystals.
  3. 3. The compound of daim 1 in the form of needle crystals.
  4. 4. A pharmaceutical composition for the treatment of a psychotic disordercomprising an amount of the compound of daim 1 that is effective in the treatment ofsaid psychotic disorder and a pharmaceutically acceptable carrier. 10 5. A method of treating a psychotic disorder in a mammal comprising administenng to said mammal an amount of the compound of daim 1 that is effectivein the treatment of said psychotic disorder.
  5. 6. The method of daim 5 wherein said disorder is schizophrenia, anxietyor migraine pain.
  6. 7. The method of daim 5 wherein said disorder is schizophrenia.
  7. 8. The method of daim 5 wherein said administration is parentéraladministration.
  8. 9. The method of daim 8 wherein said parentéral administration isintramuscular injection. 20
OA9800206A 1996-05-07 1998-10-30 Mesylate dihydrate salts of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-ethyl)-6-chloro-1,3-dihydro-2(1H)-indol-2-one (=ziprasidone) its preparation and its use as dopamine d2 antagonist OA10909A (en)

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UY27668A1 (es) * 2002-02-20 2003-10-31 Pfizer Prod Inc Composición de ziprasidona y controles sintéticos
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MXPA05012317A (es) 2003-05-16 2006-01-30 Pfizer Prod Inc Combinaciones terapeuticas de agentes antipsicoticos atipicos con agentes moduladores del gaba anticonvulsivos o benzodiazepinas.
CA2528100A1 (fr) 2003-06-03 2005-04-21 Teva Pharmaceutical Industries Ltd Formes polymorphes de ziprasidone chlorhydrate et procedes pour leur elaboration
US7667037B2 (en) 2003-10-24 2010-02-23 Teva Pharmaceutical Industries Ltd. Processes for preparation of ziprasidone
MXPA06013163A (es) * 2004-05-11 2007-02-13 Pfizer Prod Inc Combinacion de antipsicoticos atipicos y antagonistas del receptor 5-ht1b.
CA2467538C (fr) 2004-05-14 2010-08-24 Apotex Pharmachem Inc. Nouveau chlorhydrate de ziprasidone amorphe (chlorhydrate de 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydr o-2h-indol-2-one) et procedes pour sa production
CA2471219A1 (fr) 2004-06-14 2005-12-14 Apotex Pharmachem Inc. Preparation amelioree d'une forme anhydre du chlorhydrate de 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2h-indol-2-one (chlorhydrate de ziprasidone)
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KR20130030305A (ko) * 2004-11-16 2013-03-26 엘란 파마 인터내셔널 리미티드 주사가능한 나노입자형 올란자핀 제형
EP1863806A1 (fr) * 2005-02-11 2007-12-12 Teva Pharmaceutical Industries Ltd Ziprasidone mesylate amorphe
US20060258679A1 (en) * 2005-02-11 2006-11-16 Alex Mainfeld Process of preparing ziprasidone mesylate
EP1855651A4 (fr) * 2005-03-03 2011-06-15 Elan Pharma Int Ltd Compositions nanoparticulaires de derives d'amide heterocyclique
ITMI20050346A1 (it) 2005-03-07 2006-09-08 Dipharma Spa Forma solida di ziprasidone cloridrato
CA2500667C (fr) 2005-03-11 2013-01-15 Apotex Pharmachem Inc. Synthese de sels d'addition acide de ziprasidone et de produits intermediaires connexes au moyen de reactions solide-gaz
EP1858892A1 (fr) * 2005-03-14 2007-11-28 Teva Pharmaceutical Industries Ltd Mesylate de ziprasidone anhydre et son procede de preparation
US20060270684A1 (en) * 2005-03-14 2006-11-30 Judith Aronhime Crystalline forms of ziprasidone mesylate
ITMI20052216A1 (it) * 2005-11-18 2007-05-19 Dipharma Spa Procedimento per la preparazione di ziprasidone
MX2009011681A (es) * 2007-05-18 2009-11-10 Scidose Llc Formulaciones de ziprasidona.
CA2727573A1 (fr) * 2008-06-25 2009-12-30 Pfizer Inc. Composes diaryle et leurs utilisations
JP5893616B2 (ja) * 2010-10-18 2016-03-23 大日本住友製薬株式会社 注射用徐放性製剤
SI23610A (sl) 2011-01-13 2012-07-31 Diagen@d@o@o Nove adicijske soli ziprasidona postopek za njihovo pripravo in njihova uporaba v terapiji
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