Cross-Reference to Related Applications
This application is a patent of addition to Indian Patent Application No. 131/CHE/2010 filed on January 19, 2010, which is incorporated herein by reference for its teachings related to the invention disclosed herein.
Field of the Invention
The present invention provides a novel crystalline form of Eletriptan hydrobromide monohydrate. The present invention also relates to a process for the preparation of novel crystalline form of Eletriptan hydro bromide monohydrate
Background of the Invention
Eletriptan hydro bromide is a selective 5-hydroxytryptamine IB/ID (5-HT1B/1D) receptor agonist and is chemically designated as (R)-3-[(l-methyl-2-pyrrolidinyl)methyl]-5-[2-(phenylsulfonyl)ethyl]-lH-indole mono hydro bromide. The empirical formula is C22H26N2C>2S.HBr, representing a molecular weight of 463.40 and it has the following chemical structure:
Eletritpan hydro bromide is marketed under the trade name RELPAX® for the treatment of migraine headaches with or without aura in adults.
Eletriptan was first described and claimed in U.S. Pat. No. 5,545,644. This patent discloses the preparation of Eletriptan by the catalytic reduction of 3-(((R)-l-methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl)vinyl)-lH-indole of formula II, which is prepared by reaction of 3-(R)-5-bromo-(N-methylpyrrolidin-2-ylmethyl)-lH-indole with phenyl vinyl sulphone in the presence of a palladium catalyst, triarylphosphine and triethylamine.

U.S. Pat. No. 7 ,238,723 B2 discloses crystalline Eletriptan hydro bromide monohydrate and the preparation thereof. The process comprises treatment of a solution of Eletriptan in water, or in an organic solvent containing at least 4% by volume of water based on the total volume of water and solvent to facilitate formation of the required monohydrate, with hydrogen bromide.
U.S. Appl. No. 2008/0287519 Al discloses the process for the preparation of Eletriptan hydro bromide monohydrate from amorphous Eletriptan hydro bromide by maintaining wet amorphous Eletriptan hyro bromide at a temperature of about room temperature to about 60°C.
PCT. Appl. No. WO 2010/116386 Al discloses a crystalline polymorphic Form D of Eletriptan Hydro bromide characterised by an XRD pattern with two theta values at 18.8, 20.5, 23.7, 24.2 degrees. The process for making Form D comprises treating Eletriptan (a or p form) in water or in a suitable organic solvent with hydrogen bromide and cooling to temperatures to the range of 10°C to -zero temperatures.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One polymorph may give rise to thermal behaviour different from that of another polymorph. Thermal behaviour can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC"), which have been used to distinguish polymorphic forms.
The differences in the physical properties of different polymorphs results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other polymorphs of the same composition or complex. Hence there remains a need for polymorphic forms which have properties suitable for pharmaceutical processing on a commercial scale. The inventors of the present invention during their continuous efforts developed a high melting stable novel crystalline form of Eletriptan hydrobromide monohydrate.

Objective of the Invention
The main objective of the present invention is to provide novel crystalline Form of Eletriptan hydro bromide monohydrate of formula III.
Another objective of the present invention is to provide process for the preparation novel crystalline Form of Eletriptan hydro bromide monohydrate.
Summary of the Invention
Accordingly, the present invention provides a novel high melting crystalline Form (S) of Eletriptan hydro bromide monohydrate having a characteristic endothermic peak between 122-125°C in DSC thermo gram spectrum and a melting point of 118-119°C.
In another embodiment, the present invention provides a process for the preparation of novel crystalline Form (S) of Eletriptan hydro bromide monohydrate, which comprises the steps of: i. dissolving Eletriptan hydro bromide monohydrate in a solvent, ii. optionally filtering the reaction mass and, iii. isolating pure Eletriptan hydro bromide monohydrate from the filtrate obtained in step (ii).
Brief Description of Drawings
Figure 1: Represents DSC thermo gram of crystalline Form (S) of Eletriptan hydro bromide
monohydrate.
Figure 2: Represents X-ray powder diffraction pattern of crystalline Form (S) of Eletriptan
hydro bromide monohydrate.
Figure 3: Represents TGA thermo gram of crystalline Form (S) of Eletriptan hydro bromide monohydrate.

Detailed Description of the Invention
The present invention provides a novel high melting crystalline Form (S) of Eletriptan hydro bromide monohydrate of the formula III having a DSC thermo gram spectrum, showing endothermic peak at about 122-125°C as depicted in Figure 1.
In another embodiment, the present invention provides a novel high melting crystalline Form (S) of Eletriptan hydro bromide monohydrate of the formula III melting in the range of 118-119°C.
In another embodiment, the present invention provides a novel high melting crystalline Form (S) of Eletriptan hydro bromide monohydrate characterized by X-ray powder diffraction pattern with peaks at 13.22, 19.72, 23.09,23.61 and 24.15 ± 0.2° 29 values.
In yet another embodiment, the present invention provides novel crystalline Form (S) of Eletriptan hydro bromide monohydrate further characterized by X-ray powder diffraction pattern having additional peaks at 15.14,18.86,20.00,21.88,27.33, 28.39 and 29.71 ± 0.2° 29 values as depicted in Figure 2.
In yet another embodiment, the present invention provides novel crystalline Form (S) of Eletriptan hydro bromide monohydrate further characterized by TGA with a mass loss of about 8.9% as depicted in Figure 3.
In yet another embodiment, the present invention provides a process for the preparation of novel crystalline Form (S) of Eletriptan hydro bromide monohydrate of formula III which comprises:
i. dissolving Eletriptan hydro bromide monohydrate in a solvent, ii. optionally filtering the reaction mass and,
iii. isolating pure crystalline Form (S) of Eletriptan hydro bromide monohydrate from the filtrate obtained in step (ii).
The isolation of pure Eletriptan hydro bromide monohydrate of formula III according to the present invention is carried out using conventional methods used for isolation of compounds known in the field.

Suitable solvents used for dissolution are selected from methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, acetonitrile, water or mixtures thereof.
In yet another embodiment, the present invention provides a process for the preparation of Eletritpan hydro bromide monohydrate of formula III comprising:
i. reducing (((R)-l-methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl)-vinyl)-lH-indole of formula II in presence of a metal catalyst and hydrogen in an organic solvent,
ii. converting the compound obtained in step (i) to Eletriptan hydrobromide, iii. isolating the Eletriptan hydro bromide monohydrate (formula-Ill).
Eletriptan hydro bromide monohydrate used as the starting material can also be prepared by any of the processes reported in the literature.
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. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.

Example 1
Preparation of Eletriptan hydro bromide monohydrate 3-(((R)-1 -Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl)vinyl)-1 H-indole (which was prepared according to the procedure described in WO 1992/06973) 2 kg and methanol (20 L) charged into hydrogenate. Raney Nickel (0.5kg) was added carefully under vacuum and evacuated. The reactor was applied with a hydrogen pressure of 10-15psi. The reaction was maintained till the hydrogen consumption ceases (usually 4-5 hours). The reaction mixture was filtered and filtrate concentrated under reduced pressure. The remaining residue dissolved in ethyl acetate (10 L) and 48% aqueous hydrobromic acid (1.1 kg) added. The mixture was stirred for 30 minutes and filtered. The obtained product was dried at 45-50°C under reduced pressure for 4-5 hours to give 2.41 kg of Eletriptan hydro bromide monohydrate with a melting point of 118-119°C and purity by HPLC 99.5%.

Example-2
Preparation of Eletriptan hydro bromide a-form Eletriptan hydro bromide monohydrate (1.0 kg) which was prepared in Example-1 was charged into toluene (10 L) and refluxed for 2 hours. The reaction mass was distilled till the volumes reduced to 3 L and cooled to 25-30°C. Stirred for 30 minutes and filtered off. The wet material was dried at 50-55°C to give 0.9 kg of Eletriptan hydro bromide with a melting point of 169-171 °C and purity by HPLC 99.8%. PXRD data in Fig-I shows a-polymorph.

Example-3
Preparation of Eletriptan hydro bromide a-form Eletriptan hydro bromide monohydrate (1.0 kg) which was prepared in Example-1 was charged into isospropylalcohol (8 L) and refluxed for 2 hours. The reaction mass was distilled till the volumes reduced to 2 L and cooled to 25-30°C. Stirred for 30 minutes and filtered off. The wet material was dried at 45-50°C to give 0.93 kg of Eletriptan hydro bromide with a melting point of 168-170°C and purity by HPLC 99.7%. PXRD data in Fig-II shows