The present invention relates to a process for the preparation of crystalline Form I of Dolasetron mesylate monohydrate.
Dolasetron mesylate is an antinauseant and antiemetic agent. It is chemically (2α,6α,8α,9aß)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl-IH-indole-3-carboxylate monomethanesulfonate of Formula I.
(Formula Removed)
FORMULA I
Dolasetron mesylate is presently in the market as a monohydrate. EP 0,339,669 A1 provides a process for the crystallization of dolasetron mesylate, wherein dolasetron mesylate is dissolved in hot aqueous isopropanol, followed by the addition of ether at ambient temperature to obtain crystalline solid. The crystalline dolasetron mesylate obtained by this process is referred as Form I of dolasetron mesylate monohydrate in WO 07/072506. The crystalline form prepared by using the same method and using the same solvents is referred as Form II of dolasetron mesylate monohydrate in WO 07/081909. However, above mentioned Form I and Form II have different XRPD patterns.
WO 07/072506 provides processes for preparing crystalline Forms II, III, IV, V, VI, VII, VIII and XI of dolasetron mesylate, as well as amorphous dolasetron mesylate, using various solvent such as methanol, ethanol, n-propanol, chloroform, dichloromethane, dimethylformamide, 1,4-dioxane, ether and ethyl methyl ketone. WO '506 application also provides processes for preparing Form I, wherein dolasetron mesylate is dissolved in hot isopropanol and cooled to room temperature to obtain Form I. WO '506 application also provides similar processes for preparing Form I using acetonitrile, acetone and ethyl acetate as solvents. WO '506 application further provides processes for preparing Form I using dimethylformamide, dimethylsulfoxide or N,N-

dimethylacetamide as a solvent and tetrahydrofuran, toluene or isopropanol as an antisolvent.
WO 07/081909 provides processes for preparing crystalline Forms I, II, III, IV, V, VI, VIII, IX, X, XI, XII, XIII, XIV, XV and XVI, as well as amorphous dolasetron mesylate, using solvents such as acetone, tert-butyl methyl ether, water, methanol, ethanol, dimethylcarbonate, nitromethane, 1,4-dioxane, ethyl acetate and toluene. WO 07/003522 provides a process for preparing crystalline Form I of dolasetron mesylate monohydrate by recrystallizing from isopropanol-water (95:5 by weight).
US 4,906,755 mentions that dolasetron mesylate is recrystallized from water. US 755 patent further mentions that dolasetron mesylate so obtained has a melting point of 278°C. WO 06/026927 also provides a recrystallization of dolasetron mesylate from water. According to the process provided in WO '927 application, dolasetron mesylate ethylene glycol condensate is dissolved in water, heated to 85°C for 5 h and concentrated under reduced pressure to obtain dolasetron mesylate monohydrate. The dolasetron mesylate monohydrate so obtained has a melting point of 161° to 164°C and a characteristic XRPD pattern, which is different from that of Form I.
The present inventors have developed a process for the preparation of crystalline Form I of dolasetron mesylate monohydrate using water alone as a solvent. The present invention consistently provides Form I of dolasetron mesylate monohydrate as a stable crystalline form. By employing present invention, dolasetron mesylate existing in any solid form can be converted into crystalline Form I. Further, the present process avoids the use of organic solvents. Thus, the present invention is simple, efficient and economic to obtain dolasetron mesylate monohydrate as crystalline Form I.
A first aspect of the present invention provides a process for the preparation of crystalline Form I of dolasetron mesylate monohydrate, wherein the process comprises,
a) dissolving dolasetron mesylate in water,
b) cooling the solution obtained in step a) to a temperature of about 15°C or below, and
c) isolating crystalline Form I of dolasetron mesylate monohydrate from the mixture
thereof.

Dolasetron mesylate existing in any solid form known to the person skilled in the art can be used as a starting material. The dolasetron mesylate is dissolved in water preferably by heating to a temperature of about 40°C or above, more preferably by heating to a temperature of about 40°C to about 50°C. Water is used in a volume of about 5 times or above to the weight of the starting substrate dolasetron mesylate. The solution so obtained is cooled to a temperature of about 15°C or below to effect crystallization. The solution is preferably cooled to a temperature of about 2°C to about 5°C. Crystallization process may be accompanied by stirring. Stirring may be carried out for about 10 minutes to about 100 h, preferably for about 1 hour to about 3 hours. The crystalline Form I of dolasetron mesylate monohydrate is isolated from the mixture by filtration. The crystalline Form I of dolasetron mesylate monohydrate is optionally washed with water and dried. Drying can be carried out at about 50° to about 65°C. The crystalline Form I of dolasetron mesylate monohydrate so obtained has an XRPD pattern as depicted in Figure 1. The crystalline Form I of dolasetron mesylate monohydrate so obtained has a melting point of about 160°C to about 165°C when determined by DSC.
Figure 1 depicts the XRPD of crystalline Form I of dolasetron mesylate monohydrate
obtained by reference example 1.
Figure 2 depicts the XRPD of crystalline Form I of dolasetron mesylate monohydrate
obtained by reference example 2.
Figure 3 depicts the XRPD of crystalline Form I of dolasetron mesylate monohydrate
obtained by example 1.
X-Ray powder diffraction of the samples were determined by using X-Ray Difractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

REFERENCE EXAMPLE 1
PREPARATION OF CRYSTALLINE FORM I OF DOLASETRON MESYLATE MONOHYDRATE:
Aqueous isopropanol (80 ml; prepared by mixing 4 ml of water with 76 ml of isopropanol) was added to dolasetron mesylate (8 g) at 25° to 30°C. The mixture was heated to reflux temperature to obtain a homogeneous solution. Activated carbon (8 g) was added to the solution and stirred for 1 h at reflux temperature. The mixture was filtered through Celite bed and washed with aqueous isopropanol (8 ml; prepared by mixing 4 ml of water with 76 ml of isopropanol). The filtrate was cooled to 20° to 25°C in 2 to 3 h. The crystallization was observed at 20° to 25°C after 1 h. The mixture was stirred for 2 to 3 h at 20° to 25°C and filtered at 20° to 25°C. The solid was washed with isopropanol (2X10 ml) at 20° to 25°C and dried under vacuum for 12 to 14 h at 45° to 50°C to obtain the title compound having an XRPD pattern as depicted in Figure 1.
Yield: 4.04 g
REFERENCE EXAMPLE 2
PREPARATION OF CRYSTALLINE FORM I OF DOLASETRON MESYLATE MONOHYDRATE:
Aqueous isopropanol (30 ml; prepared by mixing 1.5 ml of water with 28.5 ml of isopropanol) was added to dolasetron mesylate (3 g) at 25° to 30°C. The mixture was heated to reflux temperature to obtain a homogeneous solution. Activated carbon (0.3 g) was added to the solution and stirred for 1 h at reflux temperature. The mixture was filtered through Celite bed and washed with aqueous isopropanol (3 ml; prepared by mixing 1.5 ml of water with 28.5 ml of isopropanol). Diethyl ether (8 ml) was added to the filtrate (40° to 45°C) till turbidity appeared. The resultant mixture was cooled to 20° to 25°C in 2 to 3 h and stirred for further 2 to 3 h at 20° to 25°C. The mixture was filtered at 20° to 25°C and washed with a mixture of diethyl ether and isopropanol (2X3 ml; 1:9). The solid obtained was dried under vacuum for 12 to 14 h at 45° to 50°C to obtain the title compound having an XRPD pattern as depicted in Figure 2.
Yield: 1.65g

EXAMPLE 1
PREPARATION OF CRYSTALLINE FORM I OF DOLASETRON MESYLATE MONOHYDRATE:
Dolasetron mesylate (1g) was dissolved in water (5 ml) at 40° to 45°C. The solution so obtained was cooled to 2° to 5°C and stirred at 2° to 5°C for 2 h. The mixture was filtered at 2° to 5°C and washed with water (1 ml; please provide the temperature of water). The solid obtained was dried for 12 to 14 h at 55° to 60°C to obtain the title compound having an XRPD pattern as depicted in Figure 3.
Yield: 0.38 g

WE CLAIM:
1. A process for the preparation of crystalline Form I of dolasetron mesylate
monohydrate, wherein the process comprises,
a) dissolving dolasetron mesylate in water,
b) cooling the solution obtained in step a) to a temperature of about 15°C or
below, and
c) isolating crystalline Form I of dolasetron mesylate monohydrate from the
mixture thereof.

2. A process according to claim 1, wherein dolasetron mesylate is dissolved in
water by heating to a temperature of about 40°C or above.
3. A process according to claim 2, wherein dolasetron mesylate is dissolved in
water by heating to a temperature of about 40°C to about 50°C.
4. A process according to claim 1, wherein water is used in a volume of about 5
times or above to the weight of dolasetron mesylate.
5. A process according to claim 1, wherein the solution is cooled to a temperature
of about 2°C to about 5°C.
6. A process according to claim 1, wherein step b) further comprises stirring.
7. A process according to claim 1, wherein the crystalline Form I of dolasetron
mesylate monohydrate is isolated by filtration.
8. A process according to claim 1, wherein the crystalline Form I of dolasetron
mesylate monohydrate has an XRPD pattern as depicted in Figure 1.

9. A process according to claim 1, wherein the crystalline Form I of dolasetron mesylate monohydrate has a melting point of about 160°C to about 165°C.