HK1017893B - Mesylate trihydrate salt 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

Description

Mesylate trihydrate of 5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazine) ethyl) -6-chloro-1, 3-dihydro-2 (1H) -indol-2-one (ZIPRASIDONE), its preparation and its use as dopamine D2Use of antagonists

Mesylate salt of dihydro-2 (1H) -indol-2-one (ZIPRASIDONE)

Hydrates, their preparation and their use as dopamine D2 antagonists

Background

The present invention relates to the mesylate trihydrate of 5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazine) ethyl) -6-chloro-1, 3-dihydro-2H-indol-2-one (hereinafter referred to as ziprasidone mesylate trihydrate), pharmaceutical compositions containing ziprasidone mesylate trihydrate and methods of using ziprasidone mesylate trihydrate for the treatment of psychotic disorders. ziprasidone is a potent antipsychotic drug and is therefore effective in the treatment of a variety of disorders including schizophrenia, migraine and anxiety. U.S. patent No. 5,312,925 relates to ziprasidone hydrochloride monohydrate and indicates that ziprasidone hydrochloride monohydrate has sufficient hygroscopic stability to alleviate the potential problem of weight change of the active ingredient during the manufacture of capsules or tablets. U.S. Pat. No. 5,312,925 is incorporated herein by reference in its entirety. However, ziprasidone hydrochloride monohydrate is poorly water soluble and is therefore more suitable for formulation into capsules or tablets rather than injectable dosage forms.

The ziprasidone mesylate trihydrate is also hygroscopic stable. The ziprasidone mesylate trihydrate also has the additional advantage that it has significantly enhanced water solubility over ziprasidone hydrochloride monohydrate, which makes it more suitable for dosage forms using injections than ziprasidone hydrochloride monohydrate. Also, of the four crystalline forms of ziprasidone mesylate, the ziprasidone mesylate trihydrate is the most thermodynamically stable in aqueous media at room temperature. This makes ziprasidone mesylate trihydrate more suitable for the preparation of stable and precise doses of medicaments containing aqueous media.

Summary of The Invention

The present invention relates to 5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazine) ethyl) -6-chloro-1, 3-dihydro-2H-indol-2-one mesylate trihydrate.

The invention also relates to a pharmaceutical composition for treating psychotic disorders such as schizophrenia, migraine or anxiety, which comprises an amount of 5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazine) ethyl) -6-chloro-1, 3-dihydro-2H-indol-2-one mesylate trihydrate effective in treating said disorders and a pharmaceutically acceptable carrier.

The invention also relates to a method of treating a psychotic disorder such as schizophrenia, migraine or anxiety in a mammal, including a human, which comprises administering to the mammal an amount of 5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazine) ethyl) -6-chloro-1, 3-dihydro-2H-indol-2-one mesylate trihydrate that is effective in treating said disorder.

Description of the figures

FIG. 1 is an X-ray powder diffraction spectrum of ziprasidone mesylate trihydrate expressed in intensity (Cps) versus diffraction angle (2 θ).

FIG. 2 the structure of ziprasidone mesylate trihydrate determined by single crystal X-ray crystal geometry analysis.

FIG. 3 is a photomicrograph of ziprasidone mesylate trihydrate (column).

Table 1 is a selection of peaks in the spectrum of fig. 1 determined by diffraction angle (2 θ), d-spacing (d-spacing), maximum intensity (max.int.) and relative intensity (rel.int.).

TABLE 1 ziprasidone mesylate trihydrate

X-ray powder diffraction data

2-theta (degree)	D-space (degree)	Maximum intensity (counts/sec)	Relative Strength (%)
				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

2-theta (degree)	D-space (degree)	Maximum intensity (counts/sec)	Relative Strength (%)
				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

Detailed description of the invention

ziprasidone mesylate exists in four different lattice forms: anhydrous ziprasidone mesylate (platelets), ziprasidone mesylate dihydrate (needles) and ziprasidone mesylate trihydrate (columns). Each lattice form has different characteristics such as different X-ray powder diffraction patterns, different single crystal X-ray diffraction patterns, and different crystal shapes observable from micrographs. The platelets, needles and anhydrous ziprasidone mesylate dihydrate were relatively long and thin compared to the columnar crystals of ziprasidone mesylate trihydrate (fig. 3). The anhydrous ziprasidone mesylate salt, although similar in shape to the ziprasidone mesylate dihydrate platelets, is in fact different. The micrograph of FIG. 3 was taken with an Olympus polarizing microscope (model BH-2) equipped with a halogen lamp, a binocular eye piece, a polarizing filter, and a Sony 3ccd camera with a Sony color printer.

FIG. 1 is a characteristic spectrum of X-ray powder diffraction of ziprasidone mesylate trihydrate. FIG. 2 is a graph of the structure of ziprasidone mesylate trihydrate as determined by single crystal X-ray crystal geometry. The X-ray powder diffraction spectrum of FIG. 1 and the single crystal X-ray of FIG. 2 were measured using a Siemens R3RA/v diffractometer. The ziprasidone mesylate trihydrate is additionally characterised by its water content, which is a Karl Fischer (KF) value of 9.6 ± 1.0. ziprasidone mesylate dihydrate (platelet and needle) is the subject of copending (co-pending) U.S. provisional application (Pfizer catalog No. PC 9573), entitled "5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazine) ethyl) -6-chloro-1, 3-dihydro-2H-indol-2-one mesylate dihydrate," filed concurrently herewith. The entire contents of the aforementioned co-pending U.S. provisional application are hereby incorporated by reference.

The ziprasidone mesylate trihydrate is the most thermodynamically stable form of the four ziprasidone mesylate forms in an aqueous medium at atmospheric temperature. Thus, ziprasidone mesylate trihydrate is the mesylate salt form of the preferred aqueous formulation. It is particularly noted that the mesylate trihydrate is particularly suitable for use in aqueous formulations for parenteral administration. The anhydrous methanesulfonate salt is hygroscopic when exposed to air (moisture). This makes it difficult to prepare a formulation because the weight of the active ingredient changes during the preparation of the formulation. The relative thermodynamic stability of the three ziprasidone mesylate hydrate crystals can be determined using a series of bridging experiments to equilibrate mixtures of different crystal forms. In this bridging experiment, 200mg of sample was equilibrated at atmospheric temperature (22-25 ℃) in water (4 ml). Two samples (column vs. dihydrate (platelet), column vs. dihydrate (needle), dihydrate (needle) vs. dihydrate (platelet)) each containing a mixture of two different polymorphs of ziprasidone mesylate salt, 90/10(w/w) and 10/90(w/w), were determined. After equilibration (12-13 days), the solid was assayed for polymorphic transition and the supernatant was checked by HPLC to determine its solubility. The stability of the interconversion of the crystalline form was determined to follow the trend observed for the solubility of the crystalline form, as shown in table 2 below. ziprasidone mesylate trihydrate is more thermodynamically favored than ziprasidone mesylate dihydrate.

Each of the four crystalline forms of ziprasidone mesylate has better solubility than the ziprasidone hydrochloride monohydrate, which has a solubility of 0.08mg/ml at atmospheric temperature. The solubilities of the four ziprasidone mesylate crystal forms are listed in table 2.

TABLE 2

Water solubility of ziprasidone mesylate polymorphs

Polymorphic substance	Water solubility
		Trihydrate	0.73mg/ml
Dihydrate (lamella crystal)	1.11mg/ml
		Monohydrate (needle crystal)	1.10mg/ml
Anhydrous compound	1.27mg/ml

Ziprasidone mesylate trihydrate may be prepared from the free base (ziprasidone) described in the aforementioned U.S. patent No. 5,312,925, column 4, lines 22-43, the disclosure of which is incorporated herein by reference in its entirety. When the preparation is to be used in the form of injection, it is preferable to prepare the preparation under pyrogen-free and particle-free conditions. 0.45 mu m Millipore can be used^Filtering the nylon filter layer to obtain the solvent and the reagent without particles.

The free base (ziprasidone) is mixed with a mixture of water and an organic solvent, preferably tetrahydrofuran, at an organic solvent/water ratio (v/v) of about 3: 7 to 27: 3, at a temperature ranging from 10 ℃ to 30 ℃, preferably at atmospheric temperature (about 22-25 ℃). Preference is given to using a THF/water ratio of 4: 7.5(v/v per unit of free base). The mixture was heated to about 50 ℃ with stirring. A diluted solution of methanesulfonic acid (1: 4w/w acid/water) is then prepared to provide 1.2 equivalents of acid, which is added slowly, preferably over 30 to 60 minutes, to the free base-containing compound. The reaction mixture was heated to reflux (about 65 ℃) for 30 minutes with exclusion of light. After the mixture was heated, it was slowly cooled to atmospheric temperature again. During cooling, the ziprasidone mesylate trihydrate will begin to crystallize from the mixture. Once the mixture was cooled to atmospheric temperature, it was stirred for at least one hour to ensure complete crystallization. This trihydrate crystal appears as a large, yellowish, hexagonal prismatic crystal. The trihydrate crystals were filtered from the mixture using a multi-layer filter cloth and then washed successively with appropriate amounts of THF/water (65/35, v/v) solution and water. After drying at atmospheric temperature, the crystals had a water content Karl Fischer value in the range of 8.9-10.1% KF (theoretical KF value of the trihydrate of 9.6%).

The ziprasidone mesylate trihydrate may be administered orally or parenterally, including intravenously or intramuscularly. For parenteral administration requiring the use of water, Sterile Water for Injection (SWI) is preferably used. Administration by intramuscular injection is preferred. Compositions for intramuscular injection are preferably ziprasidone mesylate trihydrate combined with a butylsulfoxylate beta cyclodextrin carrier, preferably the composition is prepared with the trihydrate and carrier in a 1: 10 ratio. Compositions containing ziprasidone mesylate trihydrate and butylsulfoxylate beta cyclodextrin were prepared according to methods described in pending U.S. provisional applications entitled "method for preparation of Inclusion Compound" (Pfizer docket number PC 9563) and "Inclusion Compound" (Pfizer docket number PC8838) filed concurrently herewith. Both co-pending U.S. provisional applications are incorporated herein by reference in their entirety.

The effective dosage of ziprasidone mesylate trihydrate depends on the intended route of administration, the condition to be treated and other factors such as age, weight, etc. of the patient. In the dosage ranges below, "mgA" refers to the number of milligrams of the free base (ziprasidone). The recommended range of the oral dosage is to take it once or in divided portions at a dosage of 5 to 300 mgA/day, preferably 40 to 200 mgA/day, particularly preferably 40 to 80 mgA/day. Parenteral administration, e.g. injection, is recommended in a dosage range of 2.5 mgA/day to 160 mgA/day, preferably 5-80 mgA/day.

The invention is illustrated by the following examples, which are not intended to be limited to the details of the examples. Unless otherwise indicated, the preparations in the following examples were carried out in a particle-free, pyrogen-free condition. In the following examples, tetrahydrofuran is represented by THF and sterile water for injection is represented by SWI.

Example 1

Decontamination of 5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazine) ethyl) -6-chloro-1, 3-dihydro-2H-indol-2-one

To a clean dry enamel jar was added 46.8kg of 5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazine) ethyl) -6-chloro-1, 3-dihydro-2H-indol-2-one and 2816.4L of THF. The mixture slurry was heated to reflux and held for 45 minutes to form a cloudy solution. The solution was filtered through a 33-inch sparkler precoated with filter aid and passed through a Fulfo filter (Parker Hannifin corp., Indiana, Lebanon) back into a clean, dry enamel jar located low. The filtrate was concentrated by vacuum distillation, cooled to 5 ℃ and stirred for 2 hours. The product was collected on a filter on a centrifuge and washed with cold (0-5 ℃) THF. The product was collected and dried under vacuum at 45 ℃ to yield 40.5kg of product. The product was determined to have a purity of 101.5% by HPLC measurement (within a typical range of 100 ± 2% compared to the standard).

Example 2

5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazine) ethyl) -6-chloro-1, 3-dihydro-2H-indol-2-one mesylate trihydrate

1000g of 5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazine) ethyl) -6-chloro-1, 3-dihydro-2H-indol-2-one, 7500ml of SWI and 4000ml of THF were added to a 22 liter three-necked round bottom flask equipped with a heating mantle, an overhead mechanical stirrer, a condenser and a temperature probe to give a slurry reaction. The contents of the flask were protected from light by an aluminum foil cover. The slurry reaction was heated to 50 ℃ with stirring. 188ml of methanesulfonic acid were mixed with 812ml of SWI to give diluted methanesulfonic acid, which was slowly added to the reaction mixture through a dropping funnel. The reaction was heated to reflux (about 65 ℃) to give a dark red solution. Under the reflux stateThe reaction mixture was stirred for about 30 minutes. After 30 minutes the heating mantle was turned off and the reaction was allowed to cool slowly with stirring. The reaction mixture was cooled overnight (about 18 hours) with stirring. During cooling, the product crystallized into large yellowish hexagonal prismatic crystals. The mixture was stirred under atmospheric conditions for 1 hour. The product was isolated using a Buchner funnel with multi-layer cloth filtration and washed successively with 1500mL of LTHF/SWI (65/35, V/V) and 1000mL of SWI. The crystals were spread in a glass dish and dried under atmospheric conditions to a Karl Fischer value of about 9.6%. The product was crushed using a micro-sample crusher (Mikro-Samplill) equipped with a 0.027H disk^) (by the trade Machinery Division of Mikropul Corp., New Jersey, Summit,) was pulverized at 14000rpm to give 945g of product.

The product structure is 5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazine) ethyl) -6-chloro-1, 3-dihydro-2H-indol-2-one mesylate trihydrate by nuclear magnetic assay.¹³CNMR(DMSO-d₆)：

¹³C NMR(DMSO-d₆)：δ177.1(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)，362(2)，27.9(2).¹H NMR(DMSO-d₆)：δ10.5(s，1H)；9.8(br.s，1H)；8.2(d，J＝8.2Hz，1H)；8.1(d，J＝8.2Hz，1H)；7.6(m，1H)，7.5(m，1H)；7.3(s1H)，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).

HPLC analysis of the product showed a peak with a retention time corresponding to the standard value. The HPLC conditions are listed in Table 3 below.

TABLE 3

HPLC State
		Chromatographic column	Waters-Pureseil C-1815 cm long by 4.6mm diameter (Catalog number (Catalog No.) WATO44345)
Mobile phase	0.05M Potassium dihydrogen phosphate pH3.0 methanol (60: 40v/v)
		Flow rate of flow	2.0 mL/min
Detector	UV，229nm
		Column temperature	Ambient temperature
Sample volume	10μL

Example 3

5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazine) ethyl) -6-chloro-1, 3-dihydro-2H-indol-2-one anhydrous methanesulfonate

350g of 5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazine) ethyl) -6-chloro-1, 3-dihydro-2H-indol-2-one, 7000ml of isopropanol are added to a 12 l three-necked round-bottomed flask equipped with a heating mantle, an overhead mechanical stirrer, a condenser and a temperature probe to give a slurry reaction. The slurry reaction was heated to 50 ℃ with stirring. 65.9ml of methanesulfonic acid were slowly added to the reaction mixture at 50 ℃ via a dropping funnel. As the slurry became thicker and lighter in color, a slight temperature rise was observed to bring the temperature of the reaction to 55 ℃. The reaction was distilled under atmospheric conditions to remove 25% of the volume (1750 ml). It was cooled to atmospheric temperature and stirred overnight. The product was isolated on a sintered glass funnel and washed with fresh isopropanol. The crystals were spread in a glass dish and dried under atmospheric conditions to a Karl Fischer value of about 0.5%. 420.3g of product are obtained. HPLC detection of the product showed a peak corresponding to the standard retention time. The purity of the product, determined by HPLC (conditions shown in Table 3), was 99.8%.

Example 4

5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazine) ethyl) -6-chloro-1, 3-dihydro-2H-indol-2-one methanesulfonate dihydrate (Crystal)

5g of 5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazine) ethyl) -6-chloro-1, 3-dihydro-2H-indol-2-one, 37.5mL of water and 20mL of THF were added to a 150mL three-necked round bottom flask equipped with a heating mantle, an overhead mechanical stirrer, a condenser and a temperature probe to give a slurry reaction. The contents of the flask were protected from light by an aluminum foil cover. The slurry reaction was heated to 65 ℃ with stirring. 1ml of methanesulfonic acid was mixed with 4ml of SWI to give diluted methanesulfonic acid, which was slowly added to the reaction mixture through a dropping funnel. The reaction was heated to reflux (about 65 ℃) to give a dark red solution. The reaction mixture was stirred under reflux for about 30 minutes. After 30 minutes, seed crystals of needle-shaped polymorph were added to the reaction solution. After crystallization began, the reaction was slowly cooled with stirring without further warming. During cooling to 50 ℃, a thick, fine red powder slurry of the reactant was observed in the flask. Water (20ml) was added to the flask to dilute the slurry. It was stirred at ambient conditions for 1 hour. The product was isolated using a Buchner funnel with paper filtration and the resulting solid was dried at ambient conditions to a Karl Fischer value of about 6.6%. 6.03g of the product was obtained. The purity of the product was 99.8% by HPLC (conditions shown in Table 3).

Example 5

5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazine) ethyl) -6-chloro-1, 3-dihydro-2H-indol-2-one methanesulfonate dihydrate (platelet)

25g of 5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazine) ethyl) -6-chloro-1, 3-dihydro-2H-indol-2-one, 375ml of water were added to a 500ml three-necked round-bottom flask equipped with a heating mantle, an overhead mechanical stirrer, a condenser and a temperature probe to give a slurry reaction. The contents of the flask were protected from light by an aluminum foil cover. The slurry was heated to 50-55 ℃ with stirring. 5ml of methanesulfonic acid were slowly added to the reaction mixture via a dropping funnel. The slurry reaction was observed to be thicker and lighter in color. The reaction was heated to reflux (about 100 ℃) and stirred for about 1 hour. The heating was then stopped and the reaction was allowed to cool with stirring. The reaction solution was stirred at ambient conditions for 1 hour. The product was isolated using a Buchner funnel with paper filtration and the resulting solid was dried at ambient conditions to a karl fischer value of about 6.2%. 32.11g of product was obtained. The purity of the product was determined to be 98.7% by HPLC (conditions shown in Table 3).

Claims (8)

1. 5- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazine) ethyl) -6-chloro-1, 3-dihydro-2H-indol-2-one mesylate trihydrate.

2. The compound of claim 1 which is the mesylate trihydrate salt having the following X-ray powder diffraction data.

ziprasidone mesylate trihydrate

X-ray powder diffraction data 2-theta (degree) D-space (degree) Maximum intensity (counts/sec) Relative Strength (%) 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 2-theta (degree) D-space (degree) Maximum intensity (counts/sec) Relative Strength (%) 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

3. A pharmaceutical composition for treating a psychotic disorder comprising an amount of a compound of claim 1 or 2 effective in treating said psychotic disorder and a pharmaceutically acceptable carrier.

4. Use of a compound of claim 1 or 2 for the preparation of a pharmaceutical composition for the treatment of psychotic disorders in a mammal.

5. The use of claim 4, wherein the psychotic disorder is schizophrenia, migraine or anxiety.

6. The use of claim 5, wherein the psychotic disorder is schizophrenia.

7. The use of claim 4, wherein said pharmaceutical composition is suitable for parenteral administration.

8. The use of claim 4, wherein said pharmaceutical composition is adapted for intramuscular injection.