WO2005074387A2

WO2005074387A2 - Novel crystal forms of 4-[2-di-n-propylamino)ethyl]-2 (3h)- indolone hydrochloride

Info

Publication number: WO2005074387A2
Application number: PCT/IN2004/000439
Authority: WO
Inventors: Hetalkumar Virendrabhai Patel; Jitendra Gopaldas Dipchandani; Raja Jyotir Jani; Rajamannar Thennati
Original assignee: Sun Pharmaceutical Industries Ltd
Current assignee: Sun Pharmaceutical Industries Ltd
Priority date: 2003-12-30
Filing date: 2004-12-30
Publication date: 2005-08-18
Anticipated expiration: 2006-06-30
Also published as: WO2005074387A3

Abstract

Crystal forms I and II of 4-[2-(di-n-propylamino)ethyl]2(3H)-indolone hydrochloride and the process for their preparation.

Description

NOVEL CRYSTAL FORMS OF -[2-(DI-N-PROPYLAMINO)ETHYL]-2(3H)- INDOLONE HYDROCHLORIDE

FIELD OF THE INVENTION

The present invention relates to novel crystal forms of 4-[2-(di-n-propylamino)ethyl] 2(3 H)- indolone hydrochloride, compound of formula I, commonly known as ropinirole hydrochloride (INN Name) used for the treatment of Parkinson's disease.

^■ HCI

Formula I

BACKGROUND OF THE INVENTION

United States patent number 4,452,808 (Assigned to SmithKline Beecham Company, referred to herein as '808) discloses compound of formula I and the process of its preparation. Subsequently other patents viz. United States patent number 4,950,765; United States patent number 4,997,954, United States patent number 5,336,781 (referred to herein as '781) and PCT publication number 94/15918 (All Assigned to SmithKline) describe various synthetic routes tor preparing compound of formula I. These patents/publications do not disclose any crystalline forms of 4-[2-(di-n-propylamino)ethyl] 2(3H)-indolone hydrochloride. We have now found novel crystal forms of 4-[2-(di-n-propylamino)ethyl] 2(3H)-indolone hydrochloride, compound of formula I.

OBJECT OF THE INVENTION

The object of the present invention is to provide novel crystal forms of 4-[2-(di-n- propylamino)ethyl] 2(3H)-indolone hydrochloride, compound of formula I.

Yet another object is to provide process for the preparation of novel crystal forms of 4-[2-(di-n- propylamino)ethyl] 2(3H)-indolone hydrochloride, compound of formula I. The present invention provides a simple and viable process for the preparation of new crystal forms of Ropinirole hydrochloride, 4-[2-(di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride, compound of formula I.

SUMMARY OF THE INVENTION

Crystal forms I and II of 4-[2-( di-n-propyIamino)ethyl] 2(3H)-indolone hydrochloride and the process for their preparation.

DETAILED DESCRIPTION OF THE INVENTION

In our endeavour for simple process for the preparation of 4-[2-(di-n-propylamino)ethyl] 2(3H)- indolone hydrochloride we have surprisingly found novel crystal forms of 4-[2-(di-n- propylamino)ethyl] 2(3H)-indolone hydrochloride. Prior art process '781 teaches extraction of 4-[2-(di-n-propylamino)ethyl]-2(3H)-indolone in methylene chloride followed by addition of isopropanol and concentrated hydrochloric acid. The presence of water with IPA makes the product precipitation less efficient, thereby reducing yield of the product as the resultant hydrochloride is freely soluble in water. On the other hand, to recover maximum yield of product by removal of solvents yields product with impurities. Also, we have found that 4-[2-(di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride, compound of formula I, is susceptible to degradation at higher temperatures, hence removal of solvents at higher temperature for longer periods furnishes impure product, requiring multiple purifications which results in the formation of product crystals which are not uniform batch to batch.

We have found that 4-[2-(di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride exhibits two crystal forms, viz. Form - 1 and Form - II which is the reproducible form.

The novel crystal forms I and II are characterized by x-ray powder diffractograms as represented in figs 1 & 2.

The novel crystal form I exhibits an x-ray powder diffraction pattern having characteristic peaks expressed in d spacing values at about 12.33, 11.98, 8.88, 7.73, 6.59, 6.01, 5.76, 5.38, 5.08, 4.83, 4.61, 4.37, 4.18, 3.99, 3.96, 3.93, 3.90, 3.75, 3.61, 3.54, 3.43, 3.39, 3.32, 3.29, 3.22, 3.12, 2.96, 2.90, 2.83, 2.81, 2.70, 2.64, 2.53, 2.48, 2.42, 2.37, 2.35, 2.30 ± 0.2 A.

The novel crystal form I exhibits an x-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 theta at about 7.16, 7.36, 9.94, 11.43,13.42, 14.70, 15.36, 16.44, 17.43, 18.33,19.22, 20.27, 21.19, 22.21, 22.41, 22.59, 22.75, 23.66, 24.58, 25.13, 25.93, 26.26, 26.75, 27.03, 27.61, 28.49, 30.06, 30.76, 31.48, 31.80, 33.10, 33.82, 35.33, 36.11, 37.04, 37.93, 38.26, 38.98 ± 0.2. The novel crystal form II exhibits an x-ray powder diffraction pattern having characteristic peaks expressed in d spacing values at about 11.81, 8.70, 7.65, 6.53, 5.96, 5.70, 5.35, 5.04, 4.78, 4.58, 4.34, 4.15, 3.98, 3.90, 3.73, 3.58, 3.51, 3.41, 3.31,3.28, 3.21, 3.09, 3.01, 2.99, 2.95, 2.92, 2.88, 2.80, 2.69, 2.52, 2.46, 2.44, 2.41, 2.34, 2.30 ± 0.2 A.

The novel crystal form II exhibits an x-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 theta at about 7.47, 10.14,11.54,13.53, 14.83, 15.52, 16.54, 17.55, 18.53, 19.35, 20.42, 21.32, 22.31, 22.74, 23.82, 24.82, 25.31, 26.04, 26.87, 27.14, 27.72, 28.81, 29.55, 29.85, 30.22, 30.55, 31.02, 31.91, 33.21, 35.48, 36.39, 36.70, 37.22, 38.33, 39.06 ± 0.2 .

Further, the novel crystal forms have also been characterized by crystal parameters such as particle size, aspect ratio.

Crystal form II of 4-[2-(di-n-propylamino)ethyl] 2(3H)-indolone hydrochloride particle size with volume mean diameter equal to or less than 40 microns.

The novel crystal forms of 4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride, compound of formula I, may be prepared by different methods such as A. Process comprising a. dissolving 4-[2-(di-n-propylamino)ethyl] 2(3H)-indolone hydrochloride in solvent; b. cooling followed by optional partial or complete removal of said solvent.

B. Process comprising a. dissolving 4-[2-(di-n-propylamino)ethyl] 2(3H)-indolone in solvent; b. adding ammonia; c. optionally extracting with anti-solvent; and d. adding alkartolic hydrochloric acid for crystallizing.

For instance, 4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride may be dissolved in solvent(s) followed by crystallizing 4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride from the solvent(s). Crystallization may be achieved by dissolving 4-[2-(Di-n- propylamino)ethyl]-2(3H)-indolone hydrochloride in a solvent followed by cooling or by addition of anti-solvent or by distilling off the solvent in the presence or absence of vacuum.

The solvent(s) for crystallization may be selected from the group consisting of aliphatic or aromatic or cyclic hydrocarbon such as n-pentane, n-hexane, n-octane, cyclohexane, toluene and the like; halogenated aliphatic or aromatic hydrocarbons such as dichloromethane, chlorobenzene and the like; alkanols such as methanol, ethanol, t-butanol, isopropanol, cyclohexanol and the like; ethers such as diethylether, tetrahydrofuran, dioxane and the like; ketones such as acetone, methylethylketone, cyclohexanone and the like; nitriles such as acetonitrile and the like; amides such as dimethylformamide, dimethylacetamide and the like; esters such as ethylacetate, butylacetate and the like ; sulfoxides such as dimethylsulfoxide and the like; water and mixtures thereof. The dissolution of 4-[2-(dι-n-propylamino)ethyl]-2(3H)-indolone hydrochloride in solvent(s) may be carried out at ambient or at elevated temperatures.

Alternatively, the 4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride may be taken in water or water admixed with water miscible organic solvent. The aqueous phase may be treated with a base, followed by extraction with water immiscible organic solvent or mixture of water immiscible organic solvent with polar solvent(s), to get 4-[2-(di-n-propylamino)ethyl]-2(3H)- indolone as a free base in solvent. The hydrochloride salt formation may be carried out by adding hydrochloric acid which is dissolved in organic solvent or by passing HC1 gas to precipitate 4-[2- (Di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride .

The base may be selected from organic base such as ammonia, primary, secondary or tertiary amine bases and the like or inorganic base such as salts of alkali metal and alkaline earth metal hydroxides, carbonates and bicarbonates and the like. The base may be used as such or as a solution in water or water miscible solvent The addition of base may be carried at a temperature ranging from about 0 to 120°C. Preferably, the base is ammonia. Ammonia may be used in gaseous form or as an aqueous solution.

Extraction of the 4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone free base may be carried out with water immiscible organic solvents like aliphatic or aromatic hydrocarbons such as n- pentane, n-hexane, n-octane, cyclohexane, toluene and the like; ethers such as diethylether, tetrahydrofuran, dioxane and the like; esters such as ethylacetate, butylacetate and the like; or mixture of these solvents with alkanol like methanol, ethanol, isopropanol and the like, preferably with hydrocarbons .

The hydrochloride salt formation may be carried out with hydrochloric acid dissolved in alcoholic solvent like methanol, ethanol, isopropanol, n-propanol, n-butanol, t-butanol, isobutanol or by passing HC1 gas at a temperature ranging from about -10 to 100°C to get 4-[2-(Di-n- propylamino)ethyl]-2(3H)-indolone hydrochloride.

In a preferred embodiment the process for the preparation of crystal form II of 4-[2-(di-n- propylamino)ethyl]-2(3H)-indolone hydrochloride as given in method B wherein solvent is water, base is ammonia and anti-solvent is hydrocarbon.

Crystallization of 4-[2-(di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride obtained by any of these methods may be carried out at ambient or lower temperatures. The process of crystallization may be carried out with or without the presence of seed crystals. Crystallization may be allowed to occur by chilling or seeding or scratching the glass of the reaction vessel or cooling and other such common techniques. Isolation of the novel crystal forms may be achieved by using standard techniques known to those skilled in the art such as filtration/centrifugation and drying. Filtration may be carried out in the presence or absence of vacuum. Drying may be carried out at ambient or elevated temperature in the presence or absence of vacuum. The product may be dried using different techniques of drying like fluid bed drying, tray drying, spray freeze drying and rotatory drying techniques with or without application of vacuum and / or under inert conditions.

The invention is further illustrated but not restricted by the description in the following examples.

EXAMPLES Preparation of form-I of 4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride Technical grade 4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride (1.53 Kg) was taken into Methanol (7.66 L) at room temperature and heated to 65-67°C temperature to get clear solution. To the clear solution activated charcoal (75.0 Gm) was added and stirred for 30 minutes at 65-67°C temperature. Filtered the solution through a bed of hyflo and washed twice with methanol (100.0 ml each) and combined washings with main mother liquor. The filtered solution was cooled to 50-51°C temperature and methanol (about 4.5 L) was distilled out under vacuum. The reaction mixture was cooled to room temperature within 1.0 hour and further to 5-10°C temperature within 1.0 hour. The precipitated solid was stirred for 1.0 more hour at 5-10°C temperature and filtered, washed twice with chilled methanol (100.0 ml each. 5-10°C temperature). Suck dried the material followed by further drying in oven at 50-55°C temperature under vacuum to give 4-[2-(Di-n- propylamino)ethyl]-2(3H)-indolone hydrochloride of form-I. The x-ray powder diffraction pattern of the novel crystal Form I having characteristic peaks expressed in d-spacing values & degrees 2 theta as listed in Table 1 Table 1

The product exhibited DSC (Diffraction scanning calorimetry) of 246.68°C. Example 2 Preparation of crystal form II of 4-[2-(Di-n-propylamino)ethyI]-2(3H)-indoIone hydrochloride To the solution 4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride (7.0 gm) in water (42.0 ml), was added at 22 to 25° C temperature, 25 % aqueous Ammonia solution (4.0 ml) and stirred for 30 minutes. Add to the aqueous layer Toluene (28.0 ml) and extract base in Toluene. Separate organic layer containing product and extract aqueous layer again with toluene (7.0 ml) and combined toluene extract with main organic layer. Combined organic layer was washed with water (14.0 ml), dried over anhydrous sodium sulfate (0.5 gm) and filtered. To the solution of 4-[2-(Di-n- propylamino)ethyl]-2(3H)-indolone base in Toluene, was added BPA.HC1 (4.0 ml) at 15-20°C temperature. The precipitated solid was stirred at 18-20°C temperature for 1.0 hour, filtered and dried in vacuum oven at 50-55°C temperature to get crystal form-II of 4-[2-(Di-n- propylamino)ethyl]-2(3H)-indolone hydrochloride.

The x-ray powder diffraction pattern of the novel crystal Form II having characteristic peaks expressed in d-spacing values & degrees 2 theta as listed in Table 2 Table 2

The product exhibited DSC (Diffraction scanning calorimetry) of 246.39°C.

The product exhibited DSC (Diffraction scanning calorimetry) of 247.30°C. Example 3

Form II is analysed for particle size and aspect ratio and found to be as follows:

Claims

1. Crystal form I of 4-[2-(di-n-propylamino)ethyl] 2(3H)-indolone hydrochloride.

2. Crystal form II of 4-[2-(di-n-propylamino)ethyl] 2(3H)-indolone hydrochloride.

3. Crystal form II of 4-[2~(di-n-propylamino)ethyl] 2(3 H)-indolone hydrochloride particle size with volume mean diameter less than 40 microns.

4. A process for the preparation of crystal fonn I of 4-[2-(di-n-propylamino)ethyl] 2(3 H)- indolone hydrochloride said process comprising a. dissolving 4-[2-(di-n-propylamino)ethyl] 2(3H)-indolone hydrochloride in solvent; and b. cooling followed by optional partial or complete removal of said solvent.

5. A process as claimed in claim 9 wherein solvent is methanol and the selected temperature is about 50 to 55°C.

6. A process for the preparation of crystal form II of 4-[2-(di-n-propylamino)ethyl] 2(3 H)- indolone hydrochloride said process comprising a. dissolving 4-[2-(di-n-propylamino)ethyl] 2(3H)-indolone in solvent; b. adding base; c. optionally extracting with anti-solvent; and d. adding alkanolic hydrochloric acid for crystallizing.

A process as claimed in claim 11 wherein solvent is water, base is ammonia and anti- solvent is hydrocarbon.

4-[2-(Di-n-propylamino)ethyl] 2(3H)-indolone hydrochloride, compound of formula las claimed in claims 1 to 7 substantially as herein described and illustrated by examples 1 and 2.