AP838A - Mesylate trihydrate salts of 5-(2-(4-(1,2-benzisothiazol-3-y1)-1-piperaziny1)-ethy1) -6-chloro-1,3-dihydro-2h-indol-2-one. - Google Patents

Mesylate trihydrate salts of 5-(2-(4-(1,2-benzisothiazol-3-y1)-1-piperaziny1)-ethy1) -6-chloro-1,3-dihydro-2h-indol-2-one. Download PDF

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AP838A
AP838A APAP/P/1997/000978A AP9700978A AP838A AP 838 A AP838 A AP 838A AP 9700978 A AP9700978 A AP 9700978A AP 838 A AP838 A AP 838A
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Prior art keywords
chloro
indol
mesylate trihydrate
benzisothiazol
ziprasidone
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APAP/P/1997/000978A
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AP9700978A0 (en
Inventor
Frank Robert Busch
Carol Anne Rose
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Pfizer
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic 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
    • C07D417/02—Heterocyclic 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
    • C07D417/12—Heterocyclic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics

Abstract

The invention relates to the mesylate trihydrate salt of 5-(2-{4-(1,2-benzisothiazol-3-yl)-1 -piperazinyi)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one, pharmaceutical compositions containing said mesylate trihydrate salt, and methods of using said mesylate trihydrate salt to treat psychotic disorders.

Description

5 MESYLATE TRIHYDRATE OF 5-(2-(4-(1,2-BENZISOTH IAZOL-3YL)-1-PIPERAZINYL)-ETHYL)-6-CHLORO-1.3-DIHYDRQ-2H-INDOL-2-ONE
Background of the Invention
The invention is directed to the mesylate trihydrate salt of 5-(2-(4-(1,2benzisothiazol-3-yl)-1 -piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one (hereafter ziprasidone mesylate trihydrate), pharmaceutical compositions containing ziprasidone mesylate trihydrate, and methods of administering ziprasidone mesylate trihydrate to treat psychotic diseases. Ziprasidone is a potent psychotic agent and is therefore useful for treating various disorders including schizophrenia, migraine pain and anxiety. United States Patent 5,312,925 refers to ziprasidone hydrochloride monohydrate, and states that ziprasidone hydrochloride monohydrate is substantially hygroscopically stable, which alleviates potential problems associated with weight changes of the active ingredient 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 a result, is more appropriate for capsule or tablet formulation than for injectable dosage forms.
Ziprasidone mesylate trihydrate also possesses hygroscopic stability.
Ziprasidone mesylate trihydrate has the added advantage of having significantly greater aqueous solubility than the hydrochloride monohydrate, which makes the mesylate trihydrate more suitable for injectable dosage forms than the hydrochloride
.../ 25 monohydrate. Further, of the tour crystalline forms of ziprasidone mesylate, the
Ό mesylate trihydrate is the most thermodynamically stable in an aqueous medium at ambient conditions. This makes ziprasidone mesylate trihydrate advantageously suited for the preparation of consistent and precise dosage forms involving an aqueous medium.
Summary of the Invention
The present invention relates to the mesylate trihydrate salt of 5-(2-(4-(1,2benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one.
This invention also relates to a pharmaceutical composition for the treatment of a psychotic disorder, such as schizophrenia, migraine pain or anxiety, comprising an 35 amount of the mesylate trihydrate salt of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one that is effective in treating said disorder, and a pharmaceutically acceptable carrier.
AP/P/ 97 / 0 0 9 78
AP Ο Ο Ο 8 3 8
-2This invention also relates to a method of treating a psychotic disorder, such as schizophrenia, migraine pain or anxiety, in a mammal, including a human, comprising administering to said mammal an amount of the mesylate trihydrate salt of 5-(2-(4-(1,2benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one that is effective in treating said disorder.
Description of the Drawings
Fig. 1 depicts the X-ray powder diffraction spectrum of ziprasidone mesylate trihydrate expressed as intensity (Cps) versus diffraction angle (two-theta degrees).
Fig. 2 depicts the structure of ziprasidone mesylate trihydrate as determined by 10 single crystal X-ray crystallographic analysis.
Fig. 3 shows a photomicrograph of ziprasidone mesylate trihydrate (prism crystals).
Table 1 below identifies selected peaks from the spectra of Figure 1 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 TRIHYDRATE
Two-Theta (deqrees) D-spacing (deqrees) Max. Int. (counts/sec) Rel. int.(%)
7.680 11.5025 84.00 8.54
9.657 9.1515 216.00 21.95
10.827 8.1650 48.00 4.88
12.205 7.2455 216.00 21.95
13.203 6.7002 803.00 81.61
13.564 6.5227 329.00 33.43
15.240 5.8089 191.00 19.41
15.507 5.7095 388.00 39.43
15.923 5.5612 836.00 84.96
16.680 5.3106 100.00 10.16
17.000 5.2112 103.00 10.47
17.946 4.9386 428.00 43.50
AP/P/ 97 / 0 0 9 78 •Wi?
AP 0 0 0 8 3 8
Two-Theta (deorees) D-spacing (deqrees) Max. int. (counts/sec) Rel. Int.(%)
18.794 4.7178 383.00 38.92
19.881 4.4622 195.00 19.82
20.491 4.3306 93.00 9.45
21.585 4.1136 603.00 61.28
22.179 4.0047 984.00 100.00
23.472 3.7870 282.00 28.66
24.359 3.6511 240.00 24.39
24.918 3.5705 429.00 43.60
25.280 3.5201 159.00 16.16
26.034 3.4198 221.00 22.46
26.832 3.3199 196.00 19.92
27.594 3.2300 132.00 13.41
28.299 3.1511 261.00 26.52
29.151 3.0608 86.00 8.74
29.819 2.9938 197.00 20.02
30.361 2.9415 138.00 14.02
30.792 2.9014 112.00 11.38
32.448 2.7570 102.00 10.37
33.559 2.6682 73.00 7.42
34.264 2.6149 159.00 16.16
35.069 2.5567 165.00 16.77
35.742 2.5100 84.00 8.54
38.182 2.3551 158.00 16.06
AP/P/ 97/00978
Detailed Description of the Invention
Ziprasidone mesylate exists in four distinct crystalline forms: ziprasidone mesylate anhydrous (lath crystal), ziprasidone mesylate dihydrate (lath crystal), ziprasidone mesylate dihydrate (needle crystal), and ziprasidone mesylate trihydrate (prism crystal). Each crystal form has distinct characteristics, such as a distinct powder
ΑΡ ϋ υ Ο 8 3 8
-4i
Α.~$
X-ray diffraction pattern, a distinct single crystal X-ray, and a distinct crystal shape that can be observed by photomicrograph. The lath and needle crystals of ziprasidone mesylate dihydrate and the lath crystals of ziprasidone anhydrous are relatively tong and thin in contrast to the prism crystals of ziprasidone mesylate trihydrate (Figure 3).
Ziprasidone mesylate anhydrous crystals are distinct, though similar in shape to the ziprasidone dihydrate lath crystals. The photomicrograph of Figure 3 was obtained using an Olympus polarizing microscope (model BH-2) equiped with a halogen lamp, binocular eye piece, polarizing filter and Sony 3ccd video camera with Sony color printer.
The characteristic X-ray powder diffraction spectra of ziprasidone mesylate trihydrate is depicted in Figure 1. The structure of ziprasidone mesylate trihydrate as determined by single crystal X-ray crystallographic analysis is depicted in Figure 2. The X-ray powder diffraction spectra of Figure 1 and the single crystal X-ray for Figure 2 were taken on a Siemens R3RA/v diffractometer. Ziprasidone mesylate trihydrate is further characterized by its water content which is indicated by its Karl Fischer (KF) value of 9.6 ± 1.0. The ziprasidone mesylate dihydrates (lath and needle) are the subject of co-pending United States provisional application entitled Mesylate Dihydrate Salts of 5-(2-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)ethyl}-6-chloro-1, 3-d i hydro-2 Hindol-2-one (Pfizer docket number PC 9573), filed concurrently herewith. The foregoing co-pending United States provisional application is incorporated herein by reference in its entirety.
In an aqueous medium at ambient temperature, ziprasidone mesylate trihydrate is the most thermodynamically stable form of the four ziprasidone mesylate forms. As a result, the mesylate trihydrate is the preferred mesylate form for dosage forms involving an aqueous medium. In particular, the mesylate trihydrate is particularly suited for aqueous dosage forms for parenteral administration. The anhydrous mesylate form was found to be hygroscopic when exposed to air (humidity). This makes formulation of dosages difficult because the active ingredient changes in weight during the process of preparing the dosages. The relative thermodynamic stability of the three ziprasidone mesylate hydrated crystal forms was determined in a series of bridging experiments where mixtures of the crystal forms were allowed to equilibrate.
For the bridging experiments, 200 mg samples were allowed to equilibrate in water (4 mL) at ambient temperature (22-25°C). Two samples each of 90/10 (w/w) and 10/90
AP/P/ 9 7 / 0 0 9 78
.Htfj
V. J1
AP ύ u u8 3 8
-5(w/w) mixtures of the two different identified polymorphs of ziprasidone mesylate (prism vs. dihydrate (lath), prism vs. dihydrate (needle), dihydrate (needle) vs. dihydrate (lath)) were evaluated. After equilibration (12-13 days), the solids were evaluated for polymorph changes and the supernatants were assayed by HPLC to determine solubility. It was found that the stability of the crystal forms to interconversion follows the trend observed for the solubility of the crystal forms, as shown in Table 2 below. Ziprasidone mesylate trihydrate was thermodynamically favored over the dihydrate forms.
Each of the four ziprasidone mesylate forms is significantly more soluble than ziprasidone hydrochloride monohydrate which has a solubility of 0.08 mg/ml in water at ambient temperature. The solubility of the four ziprasidone mesylate forms is indicated below in Table 2.
Table 2
Aqueous Solubility Of Ziprasidone Mesylate Polymorphs
POLYMORPH SOLUBILITY IN WATER
trihydrate dihydrate (lath) dihydrate (needle) anhydrous 0.73 mg/mL 1.11 mg/mL 1.10 mg/mL 1.27 mg/mL
AP/P/ 97 / 0 0 9 78
Ziprasidone mesylate trihydrate may be prepared from the free base (ziprasidone) which is prepared as described in column 4, lines 22-43 of United States Patent 5,312,925, referred to above. The free base can also be prepared as described in United States Patent 5,338,846, the disclosure of which is herein incorporated by reference in its entirety. When the intended use is as an injectable formulation, it is preferred to conduct the preparation under pyrogen-free and speck-free conditions. Speck-free solvents and reagents can be prepared by filtering them through a 0.45 μτη Millipore® nylon filter.
Ziprasidone mesylate trihydrate is prepared by mixing the free base with a mixture of water and organic solvent, preferably tetrahydrofuran, at an organic solvent/water ratio (v/v) of about 3:7 to about 27:3 at a temperature ranging from 10°C to 30°C, preferably ambient temperature (about 22-25°C). Preferably, a THF/water
APOy0838
-6ratio of 4:7.5 (v/v per unit of free base) is used. The mixture is then heated to a temperature of about 50°C while stirring. A dilute solution of methanesulfonic acid is then prepared (1:4 w/w acid/water) to provide 1.2 equivalents acid, which is then added slowly, preferably over a 30 to 60 minute period, to the composition that includes the free base. The reaction mixture is then heated to reflux (about 65°C) for about 30 minutes while protected from light. After the mixture has been heated, it is allowed to cool slowly to ambient temperature. While the mixture is cooling, ziprasidone mesylate trihydrate will begin to crystallize out of the mixture. Once the mixture has cooled to ambient temperature, it should be allowed to stir for at least another hour to ensure full crystallization. The trihydrate crystals will appear as large “yellowish hexagonal prismatic crystals. The trihydrate crystals can be filtered from the composition through a poly-cloth filter, and then washed consecutively with appropriate volumes of a THF/water (65/35, v/v) solution and water. When allowed to dry at ambient temperature, the water content of the crystals has a Karl Fischer value ranging from 8.915 10.1% KF (theoretical KF for the trihydrate is 9.6%).
Ziprasidone mesylate trihydrate may be administered orally or parenterally, including intravenously or intramuscularly. For parenteral administration, it is preferred, where the use of water is called for, to use sterile water for injection (SWI). Administration through intramuscular injection is preferred. A preferred composition for intramuscular injection is ziprasidone mesylate trihydrate in combination with sulfoxybutyl /?-cyclodextrin as carrier, preferably prepared at a ratio of 1:10 (w/w) trihydrate to carrier. Compositions containing ziprasidone mesylate trihydrate in combination with sulfoxy /?-cyclodextrin can be prepared as described in co-pending United States provisional applications entitled Method Of Making Inclusion Complexes (Pfizer docket number PC 9563), filed concurrently herewith, and 'Inclusion Complexes Of Aryl-Heterocyclic Compounds (Pfizer docket number PC 8838), filed concurrently herewith. Both of the foregoing co-pending United States provisional applications are incorporated herein by reference in their entirety.
The effective dosage for ziprasidone mesylate trihydrate depends on the intended route of administration, the indication to be treated, and other factors such as age and weight of the subject. In the following dosage ranges, the term mgA refers milligrams of the free base (ziprasidone). A recommended range for oral dosing is 5300 mgA/day, preferably 40-200 mgA/day, more preferably 40-80 mgA/day, in single or
AP/P/ 97/00978
APB 0 0838
-7divided doses. A recommended range for parenteral adiministration, such as injection, is 2.5 mgA/day to 160 mgA/day, and preferably 5-80 mgA/day.
The present invention is illustrated by the following examples, but it is not limited to the details thereof. Unless otherwise indicated, the preparations described in the following examples were conducted under speck-free and pyrogen-free conditions. As used in the following examples, THF means tetrahydrofuran and SWI means sterile water for injection.
Example 1
Purification of 5-f2-f4-(1.2-benzisothiazol-3-yl)-1-Piperazinvl1ethvn-6-chloro10 1,3-dihydro-2H-indol-2-one
To a clean 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 were charged. The slurry was heated to reflux and held for forty-five minutes to form a hazy solution. The solution was filtered through a 33-inch sparkler precoated with filter aid and backed with a Fuiflo® filter (manufactured by Parker Hannifin Corp., Lebanon, Indiana) to a clean, dry glass-lined tank on a lower level. The filtered solution was concentrated 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 product. The product had a purity of 101.5% (within the typical range of 100 ± 2% vs. the standard) as determined by an HPLC assay.
Example 2
5-r2-r4“(1-benzisothiazol-3-y 1)-1-pipe raziny 11 ethy ll-6-chloro-1.3dihydro-2H-indol-2-one methanesulfonate trihydrate
A slurry was produced by charging 1000 g of 5-[2-[4-(1,2-benzisothiazol-3-yl)-1 piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, 7500 mL of SWI, and 4000 mL of THF to a 22-lrter, three-neck, round-bottom flask equipped with a heating mantle, an overhead mechanical stirrer, a condenser, and a temperature probe. The flask contents were protected from light with an aluminum foil cover. The slurry was heated to 50°C while stirring. Dilute methanesulfonic acid was prepared by combining 188 mL of methanesulfonic acid with 812 mL SWI. The dilute methanesulfonic acid was added slowly through a dropping funnel to the reaction mixture. The reaction was heated to reflux (about 65°C), and a dark red solution formed as the reaction mixture was heated.
AP/P/ 97/00978
APO00838
-8The reaction mixture was allowed to stir under reflux conditions for approximately thirty minutes. After the thirty minute time period, the heating mantle was shut off to allow slow cooling of the reaction mixture with stirring. The reaction mixture was allowed to cool with stirring overnight (about 18 hours). As the reaction mixture cooled, the product crystallized out as large ‘yellowish* hexagonal prismatic crystals. The mixture was allowed to stir under ambient conditions for one hour. The product was isolated on a Buchner funnel with a poly cloth filter and was washed consecutively with 1500 mL of THF/SWI (65/35, v/v) and 1000 mL of SWl. The crystals were spread over glass trays and allowed to dry under ambient conditions to a Karl Fischer value of about
9.6%. The product was milled through a Mikro-Samplmill® (manufactured by the
Pulverizing Machinery Division of Mikropul Corp., Summit, New Jersey) equipped with a 0.027 H plate at a speed of 14,000 rpm. The yield was 945 g of product.
The products 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
NMR. 13C NMR (DMSO-ds): 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,
3H).
Evaluation of the product by HPLC showed a peak with a retention time corresponding to that of a standard. The HPLC conditions are summarized in Tabie 3 below.
AP/P/ 97/00978
Table 3
HPLC Conditions:
Column: Waters - Puresil C-18 15 cm length x 4.6 mm I.D. (Catalog No. WAT044345)
Mobile phase: 0.05 M KH2PO4 pH 3.0:methanol (60:40. v/v)
Flow rate: 2.0 mL/minute
Detection: UV, 229 nm
Column temperature; ambient
Sample volume: 10pL
-9Example 3
5-f2-[4-(1,2-benzisothiazol-3-vl)-1 -piperazinvUethvll-S-chloro-l ,3-dihydro-2Hindol-2-one methanesuifonate anhydrous
A 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 to a 12-liter three-neck, round-bottom flask equipped with a heating mantle, an overhead mechanical stirrer, a condenser, and a temperature probe. The slurry was heated to 50°C while stirring. 65.9 mL of methanesulfonic acid was added slowly through a dropping funnel to the 50°C reaction mixture. A slight exotherm to 55°C along with 10 thickening of the slurry and lightening of the slurry color were observed. The reaction was atmospherically distilled to remove 25% of the volume (1750 mL). The slurry was cooled to ambient temperature and allowed to stir overnight. The product was isolated on a sintered glass funnel and washed with fresh isopropanol. The solids were spread over glass trays and allowed 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 showed
I a peak with a retention time corresponding to that of a standard. The purity of the product, as determined by HPLC (conditions in Table 3), was 99.8%.
Example 4
542-(4-(1 -benzisothiazol-3-yl)-1 -piperazinvnethyl1-6-chloro-1.320 dihydro-2H-indol-2-one methanesuifonate dihydrate (needle crystals)
A slurry was produced by charging 5 g of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1Q piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, 37.5 mL of water, and 20 mL of
THF to a 150 mL, three-neck, round-bottom flask equipped with a heating mantle, an overhead mechanical stirrer, a condenser, and a temperature probe. The flask contents were protected from light with an aluminum foil cover. The slurry was heated to 65°C with stirring. Dilute methanesulfonic acid was prepared by combining 1 mL of methanesulfonic acid with 4 mL SWI. The dilute methanesulfonic acid was added slowly through a dropping funnel to the reaction mixture. The reaction was heated to reflux (about 65°C) and a dark red solution formed. The reaction mixture was allowed to stir under reflux conditions for approximately thirty minutes. After the thirty minute period, a seed crystal of the needle shaped polymorph was added to the reaction solution. Crystal formation started, and the heat was removed to allow slow cooling of the reaction with stirring. During cooling at 50°C, a thick pinkish slurry was observed
AP/P/ 9 7 / 0 0 9 78 ΑΡθ00838
-10in the flask. Water (20 mL) was added to the flask to thin the slurry. The product was allowed to stir under ambient conditions for one hour. The product was isolated on a Buchner funnel with a paper filter and the solids were allowed to dry under ambient conditions to a Karl Fischer value of about 6.6%. The yield was 6.03 g of product. The purity of the product, as determined by HPLC (conditions in Table 3), was 99.8%. Example 5
5-f2-f4-(1-benzisothiazol-3-vl)-1-piperazinvnethvn-€-chloro-1,3dihydro-2H-indol-2-one methanesulfonate dihydrate (lath crystals)
A slurry was produced by charging 25 g of 5-[2-[4-(1,2-benzisothiazol-3-yl)-110 piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one and 375 mL of water to a 500 mL, three-neck, round-bottom flask equipped with a heating mantle, an overhead mechanical stirrer, a condenser, and a temperature probe. The flask contents were protected from light with an aluminum foil cover. The slurry was heated to 50-55°C while stirring. Methanesulfonic acid (5 mL) was added slowly through a dropping funnel to the reaction mixture. Thickening of the slurry and lightening of the slurry color were observed. The reaction was heated to reflux (about 100°C) and allowed to stir for about one hour. The heat was removed to allow slow cooling of the reaction with stirring. The reaction solution was allowed to stir under ambient conditions for about one hour. The product was isolated on a Buchner funnel with a paper filter and the solids were allowed to dry under ambient conditions to a Karl Fischer value of about 6.2%. The yield was 32.11 g of product. The purity of the product, as determined by HPLC (conditions in Table 3), was 98.7%.

Claims (7)

1. 5-(
2-(4-(1,2-benzisothiazol-3-yl)-1 -piperazinyl)ethyl)-6-chloro-1,3-dihydro2H-indol-2-one mesylate trihydrate.
5 2. A pharmaceutical composition for the treatment of a psychotic disorder comprising an amount of the compound of claim 1 that is effective in the treatment of said psychotic disorder and a pharmaceutically acceptable carrier.
3. A method of treating a psychotic disorder in a mammal comprising administering to said mammal an amount of the compound of claim 1 that is effective
10 in the treatment of said psychotic disorder.
4. The method of claim 3 wherein said psychotic disorder is schizophrenia, migraine pain or anxiety.
5. The method of claim 3 wherein said pyschotic disorder is schizophrenia.
6. The method of claim 3 wherein said administration is parenteral
15 administration.
7. The method of claim 6 wherein said parenteral administration is intramuscular injection.
APAP/P/1997/000978A 1996-05-07 1997-04-30 Mesylate trihydrate salts of 5-(2-(4-(1,2-benzisothiazol-3-y1)-1-piperaziny1)-ethy1) -6-chloro-1,3-dihydro-2h-indol-2-one. AP838A (en)

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Families Citing this family (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HN1996000101A (en) * 1996-02-28 1997-06-26 Inc Pfizer COMBINED THERAPY FOR OSTEOPOROSIS
UA57734C2 (en) 1996-05-07 2003-07-15 Пфайзер Інк. Arylheterocyclic inclusion complexes
TW491847B (en) 1996-05-07 2002-06-21 Pfizer Mesylate dihydrate salts of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-ethyl)-6-chloro-1,3-dihydro-2h-indol-2-one
IL127497A (en) * 1997-12-18 2002-07-25 Pfizer Prod Inc Pharmaceutical compositions containing piperazinyl-heterocyclic compounds for treating psychiatric disorders
EP0985414B1 (en) * 1998-05-26 2003-08-27 Pfizer Products Inc. Medicament for the treatment of glaucoma and ischemic retinopathy
US20080113025A1 (en) * 1998-11-02 2008-05-15 Elan Pharma International Limited Compositions comprising nanoparticulate naproxen and controlled release hydrocodone
JP2003518485A (en) * 1999-12-23 2003-06-10 ファイザー・プロダクツ・インク Pharmaceutical composition giving improved drug concentration
CN1431901A (en) * 2000-06-02 2003-07-23 辉瑞产品公司 S-methyl-dihydro-zipprasidone for treatment of psychiatric and ocular disorders
AR032641A1 (en) * 2001-01-29 2003-11-19 Otsuka Pharma Co Ltd RECEIVER SUBTIPE AGONIST 5-HT 1A.
US7053092B2 (en) 2001-01-29 2006-05-30 Otsuka Pharmaceutical Co., Ltd. 5-HT1a receptor subtype agonist
US8703772B2 (en) 2001-09-25 2014-04-22 Otsuka Pharmaceutical Co., Ltd. Low hygroscopic aripiprazole drug substance and processes for the preparation thereof
AR033485A1 (en) 2001-09-25 2003-12-26 Otsuka Pharma Co Ltd MEDICINAL SUBSTANCE OF ARIPIPRAZOL OF LOW HYGROSCOPICITY AND PROCESS FOR THE PREPARATION OF THE SAME
UY27668A1 (en) * 2002-02-20 2003-10-31 Pfizer Prod Inc ZIPRASIDONE COMPOSITION AND SYNTHETIC CONTROLS
US20040048876A1 (en) * 2002-02-20 2004-03-11 Pfizer Inc. Ziprasidone composition and synthetic controls
WO2004050655A1 (en) * 2002-12-04 2004-06-17 Dr. Reddy's Laboratories Limited Polymorphic forms of ziprasidone and its hydrochloride
US7488729B2 (en) 2002-12-04 2009-02-10 Dr. Reddy's Laboratories Limited Polymorphic forms of ziprasidone and its hydrochloride salt and process for preparation thereof
JP2006528236A (en) * 2003-05-16 2006-12-14 ファイザー・プロダクツ・インク How to enhance cognition with ziprasidone
MXPA05012391A (en) * 2003-05-16 2006-02-02 Pfizer Prod Inc Treatment of psychotic and depressive disorders.
EP1633361A1 (en) * 2003-05-16 2006-03-15 Pfizer Products Inc. Anxiety treatments with ziprasidone
WO2005016325A2 (en) * 2003-06-03 2005-02-24 Teva Pharmaceutical Industries Ltd. CRISTALLINE ZIPRASIDONE HCl AND PROCESSES FOR PREPARATION THEREOF
BRPI0414082A (en) * 2003-09-02 2006-10-24 Pfizer Prod Inc Sustained-release dosage forms of ziprasidone
EP1628973A2 (en) * 2003-10-24 2006-03-01 Teva Pharmaceutical Industries Ltd. Processes for preparation of ziprasidone
JP2007514001A (en) 2003-12-18 2007-05-31 テバ ファーマシューティカル インダストリーズ リミティド Ziprasidone base polymorphic form B2
CA2552126A1 (en) * 2003-12-31 2005-07-21 Actavis Group Hf Ziprasidone formulations
ES2334800T3 (en) * 2004-02-27 2010-03-16 Ranbaxy Laboratories Limited PROCESS FOR PREPARATION OF ZIPRASIDONA.
US9044503B2 (en) * 2004-08-27 2015-06-02 University Of Kentucky Research Foundation Amyloid peptide inactivating enzyme to treat alzheimer's disease peripherally
ES2250001B1 (en) * 2004-09-29 2007-06-01 Medichem, S.A. PROCESS FOR THE PURIFICATION OF ZIPRASIDONA.
US7777037B2 (en) * 2004-10-27 2010-08-17 Dr. Reddy's Laboratories Limited Ziprasidone process
EA200701065A1 (en) * 2004-11-16 2007-12-28 Элан Фарма Интернэшнл Лтд. INJECTABLE COMPOSITIONS CONTAINING NANODISPERS Olanzapine
CA2593497A1 (en) * 2005-02-11 2006-08-17 Judith Aronhime Amorphous ziprasidone mesylate
US20080254114A1 (en) * 2005-03-03 2008-10-16 Elan Corporation Plc Controlled Release Compositions Comprising Heterocyclic Amide Derivative Nanoparticles
ITMI20050346A1 (en) 2005-03-07 2006-09-08 Dipharma Spa SOLID FORM OF CHLORIDATED ZIPRASIDONE
WO2006099452A1 (en) * 2005-03-14 2006-09-21 Teva Pharmaceutical Industries Ltd. Anhydrous ziprasidone mesylate and a process for its preparation
CA2599391A1 (en) * 2005-03-14 2006-09-21 Teva Pharmaceutical Industries Ltd. Crystalline forms of ziprasidone mesylate
MX2009011681A (en) * 2007-05-18 2009-11-10 Scidose Llc Ziprasidone formulations.
KR100948126B1 (en) * 2007-12-10 2010-03-18 씨제이제일제당 (주) Crystalline sulfonic acid salt of ziprasidone, a process for the preparation thereof, and a pharmaceutical composition comprising the same
CN102234273B (en) * 2010-04-21 2015-08-05 上海医药工业研究院 Ziprasidone mesylate semihydrate and preparation method thereof
SI23610A (en) 2011-01-13 2012-07-31 Diagen@d@o@o New addition salts of ziprasidone, process for their preparation and their use in therapy
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0281309A1 (en) * 1987-03-02 1988-09-07 Pfizer Inc. Piperazinyl-heterocyclic compounds
EP0584903A1 (en) * 1992-08-26 1994-03-02 Pfizer Inc. Process for preparing aryl piperazinyl-heterocyclic compounds
EP0586191A1 (en) * 1992-09-01 1994-03-09 Pfizer Inc. Monohydrate of 5-(2-(4-(1,2 Benzisothiazol-3-YL)-1-Piperazinyl)-Ethyl)-6-Chloro-1,3-Dihydro-2H-indol-2-one Hydrochloride

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5359068A (en) * 1993-06-28 1994-10-25 Pfizer Inc. Processes and intermediates for the preparation of 5-[2-(4-(benzoisothiazol-3-yl)-piperazin-1-yl)ethyl]-6-chloro-1,3-dihydro-indol-2-one

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0281309A1 (en) * 1987-03-02 1988-09-07 Pfizer Inc. Piperazinyl-heterocyclic compounds
EP0584903A1 (en) * 1992-08-26 1994-03-02 Pfizer Inc. Process for preparing aryl piperazinyl-heterocyclic compounds
EP0586191A1 (en) * 1992-09-01 1994-03-09 Pfizer Inc. Monohydrate of 5-(2-(4-(1,2 Benzisothiazol-3-YL)-1-Piperazinyl)-Ethyl)-6-Chloro-1,3-Dihydro-2H-indol-2-one Hydrochloride

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