Novel Polymorph of Eletriptan Hydrobromide and

Process for the Preparation Thereof

Field of the invention

The present invention relates to a novel polymorphic form of Eletriptan Hydrobromide, designated as Form D. The invention also covers process for the preparation of the said polymorph.

Background of the invention

Eletriptan is an anti-migraine drug marketed as Relpax and is currently marketed in over 50 countries worldwide. It belongs to the triptan class of drugs that also includes sumatriptan, naratriptan, rizatriptan, almotriptan, zolmitriptan and frovatriptan. Eletriptan Hydrobromide has the following structure.

STATE OF THE ART

A few patents have been filed on the polymorphs of Eletriptan and its hydrated forms.

WO9606842A1/US6110940 describes α -form and β -form of Eletriptan Hydrobromide and their process for preparation.

WOOO/32589 describes a process for the preparation of Eletriptan Hydrobromide Monohydrate.

US2005/0245591 describes another process for the preparation of α -form of Eletriptan Hydrobromide.

US2008/0287519A1 describes a process for the preparation of amorphous form of Eletriptan Hydrobromide.

SUMMARY OF THE INVENTION

One object of the invention was to develop a stable form of Eletriptan Hydrobromide which is not hygroscopic and is crystalline in nature, hereinafter designated as Form D .
Another object of the invention is to provide a process for the preparation of polymorphic Form D of Eletriptan Hydrobromide.

Another object of the invention is to provide a process for the preparation of polymorphic Form D of Eletriptan Hydrobromide from the alpha or beta form.

In yet another aspect of the present invention it has been found that hydrated or anhydrous form of Eletriptan hydrobromide, or mixtures thereof can be converted to Form-D under the conditions mentions above.

The process of the invention is illustrated by the following examples to obtain Eletriptan.

Detailed description of the invention

Eletriptan Hydrobromide is known to exist in polymorphic forms known in the art as α form and β form. The inventors of the present invention found a novel polymorphic form of Eletriptan Hydrobromide Form D.

Form D is found to be possessing properties that make it suitable and promote easy handling in the manufacture of solid dosage forms. These properties like crystallinity, chemical stability and the non hygroscopic nature make it a suitable form for manufacturing solid dosage form.

The present invention provides a novel polymorphic Form D of Eletriptan Hydrobromide with the X-ray diffraction (PXRD) patterns as shown in Figure 1. Form D is characterized by the following two theta values: 13.2, 15.2. 16.9, 18.8, 19.8. 20.5, 22.6, 23.2, 23.7, 24.2. The XRD spectrum is obtained using using copper radiation filtered with a graphite monochromator (λ =0.15405 nm).

Form-D is further characterized by its differential scanning calorimetry (DSC) trace run at a scan rate of 5ºC/min which is shown in Figure 2.

The IR spectrum of the sample is shown in Fig 3.

Physico chemical stability of Form D

Form D is also found to have good chemical stability as evidenced by only a nominal increase in impurities when stored at 25˚ C and 40%RH

As is evident from the following data the impurities A, B and C were below the detectable limit initially and on storage.

Table-1

Form D is also found to be non hygroscopic. The sample when stored at 25 °C and 40%RH showed no moisture uptake when analyzed by the TGA. At 0 Day it was 2.9% and after 6 months it was 2.6%

Process for making Form D

Form-D of Eletriptan Hydrobromide can be made using solvent mixtures; from alpha or beta forms of Eletriptan Hydrobromide or from hydrated and non hydrated forms of
Eletriptan Hydrobromide.

In one aspect of the invention, Form D is made by treating Eletriptan in water or in a suitable organic solvent such as acetone, ethanol, THF, isobutylacetate or a combination thereof with sufficient amount of water to facilitate the formation of the hydrobromide salt with hydrogen bromide or a suitable source thereof. The preparation can be carried out in acetonitrile, toluene, DMF, DMAc, acetone, THF, ethyl acetate, isobutyl acetate or alcohols (methanol, ethanol, propanol, IPA and n-butanol) or a suitable mixture of these solvents. More preferably organic solvent selected can be combination of acetone and ethanol.

The hydrogen bromide source can be a gaseous hydrogen bromide or dissolved in water, acetic acid, or a suitable organic solvent mentioned above.
In the second aspect of the present invention, it has been surprisingly found that the Form-D can be made from the alpha or beta forms using the following process:

(i) Dissolving the alpha or beta form or a mixture of Eletriptan Hydrobromide in water, and water miscible solvents,

(ii) Cooling to temperatures to the range of 10 to -80˚C and

(iii) Stirring for sufficient amount of time for the crystals to form.

The stirring may be done for 1 hour to 24 hours. In some instances, this may also need stirring at 25-30 ˚C for 2-24 h.

In third aspect of the present invention it has been found that hydrated or anhydrous form of Eletriptan hydrobromide, or mixtures thereof can be converted to Form-D under the conditions mentions above.

The process of the invention is illustrated by the following examples to obtain Eletriptan.

Example 1

Preparation of Form-D Eletriptan Hydrobromide

A solution of 48% HBr in water (3.16 ml) dissolved in acetone 30 ml was charged to a solution of Eletriptan (10.0 g) in acetone 100 ml cooled to 10-15 X. The solution was allowed to stir at 10-15 X for 10 minutes and the solution was cooled to -35 to -45 ˚C. Heavy precipitation occurred during cooling and the suspension was allowed to stir for 2-6 h. The suspension was then allowed to stir at 25-30 ˚C for 3-5 h. The precipitate was filtered and washed with fresh acetone and dried under vacuum until constant weight. 85-90% yield

Example 2

Preparation of Form-D Eletriptan Hydrobromide

A solution of 48% HBr in water (3.16 ml) dissolved in THF 30 ml was charged to a solution of Eletriptan (10.0 g) in THF 100 ml cooled to 10-15 X. The solution was allowed to stir at 10-15 X for 30 minutes and the solution was cooled to -35 to -45 X. Heavy precipitation occurred during cooling and the suspension was allowed to stir for 2-6 h. The precipitate was filtered and washed with fresh acetone and dried under vacuum until constant weight. 80% yield

Example 3

Preparation of Form-D Eletriptan Hydrobromide

A suspension of Eletriptan Hydrobromide (10 g) in acetone 130 ml and water 2.5 ml was allowed to stir at 25-40 ˚C for 2-4 h. The suspension was cooled to -35 to -45 ˚C was allowed to stir for 2-6 h. To the suspension was charged ethanol (20 ml) and the suspension was then allowed to stir at 25-30 X for 3-5 h. The precipitate was filtered and washed with fresh acetone and dried under vacuum until constant weight. 70% yield

Example 4

Preparation of Form-D Eletriptan Hydrobromide

A solution of 48% HBr in water (3.16 ml) dissolved in acetone 30 ml was charged to a solution of Eletriptan (10.0 g) in acetone 100 ml and ethanol 50 ml cooled to 10-15 °C. The solution was allowed to stir at 0-15 ˚C for 30 minutes and the solution was cooled to 0 to 10 X. Heavy precipitation occurred during cooling and the suspension was allowed to stir for 2-6 h. The precipitate was filtered and washed with fresh acetone and dried under vacuum until constant weight. 85-90% yield

claim:-

1. A crystalline polymorphic Form D of Eletriptan Hydrobromide characterised by an XRD pattern with two theta values at 18.8, 20.5, 23.7, 24.2.

2. The polymorphic form D of claim 1 which has additional two theta values at 13.2, 15.2, 16.9, 18.8, 19.8, 20.5, 22.6, 23.2, 23.7, 24.2.

3. The polymorphic form D of claim 1 which is further characterised by a DSC heating trace as shown in Figure 2.

4. The polymorphic form D of claim 1 which is further characterised by a TGA heating trace as shown in Figure 4.

5. A process for making Form D comprising treating Eletriptan in water or in a suitable organic solvent with hydrogen bromide and cooling to temperatures to the range of 10°C to sub -zero temperatures.

6. The process of claim 4 wherein the organic solvent is selected from acetone, ethanol, THF, isobutylacetate or a combination thereof.

7. The process of claim 4 wherein the organic solvent is a combination of acetone and ethanol

8. The process of claim 4 which further comprises the preparation to be carried out in acetonitrile, toluene, DMF, DMAc, acetone, THF, ethyl acetate, isobutyl acetate or alcohols or a suitable mixture of these solvents.

9. A process for making Form D of Eletriptan Hydrobromide wherein the input active is either the alpha or beta form.

10. The process of claim 7 which further involves dissolving the alpha or beta form or a mixture of Eletriptan Hydrobromide in water, and water miscible solvents and cooling to temperatures in the range of 10 to -80 ˚C.

11. A crystalline polymorphic substantially as herein described with reference to the foregoing description, table, examples and the accompanying drawings.