WO2008081475A2

WO2008081475A2 - Novel crystalline forms of zolmitriptan

Info

Publication number: WO2008081475A2
Application number: PCT/IN2007/000620
Authority: WO
Inventors: Purna Chandra Ray; Amit Rohatgi; Jetti Ramakoteswara Rao; Om Dutt Tyagi
Original assignee: Matrix Laboratories Ltd
Priority date: 2007-01-04
Filing date: 2007-12-31
Publication date: 2008-07-10
Also published as: WO2008081475A3

Abstract

The present invention provides novel crystalline polymorphic forms of zolmitriptan characterized by.different solid state techniques. The novel processes for their preparation are also disclosed. Further, the present invention is also directed to novel processes for the preparation of zolmitriptan crystalline form A.

Description

Title: Novel Crystalline forms of Zolmitriptan

Field of the Invention

The invention in general relates to novel polymorphs of zolmitriptan. More particularly, the present invention is directed to novel crystalline solvates of zolmitriptan which is designated as Form I and Form II and the process for preparing the same. Further, the present invention is also directed to novel processes for the preparation of zolmitriptan crystalline form A.

Background of the Invention

Zolmitriptan is chemically known as (S)-iV,7V-dimethyl-2-[5-(2-oxo-l₅3-oxazolidm-4- ylmethyl)-lH-indole-3-yl]ethylamine and is represented by the following structural formula.

Zolmitriptan

Zolmitriptan is a selective 5-hydroxytryptamine IB/ID receptor agonist. This receptor mediates vasoconstriction and thus modifies blood flow to the carotid vascular bed. Agonists of the 5-HT IB/ ID receptor are therefore beneficial in the treatment (including prophylaxis) of disease conditions include migraine, cluster headache and headache associated with vascular disorders referred to collectively as "migraine". Due to its agonist effect at the 5-HT receptor, zolmitriptan has been developed for the acute treatment of migraine.

The synthesis of zolmitriptan is first disclosed in US 5,466,699. Example 2 and 3 of US'699 discloses the preparation of zolmitriptan as a solvate i.e. 0.9 isopropanolate hemihydrate. A number of crystalline forms and solvates of zolmitriptan are known from WO 2005075467 and WO 2006055964. WO 2005075467 discloses the novel crystalline polymorphic forms of zolmitriptan i.e. Form-A, Form-B (1-butanol solvate), Form-C (Anisole solvate), Form-D (IPA solvate), Form-E (Ethyl methyl ketone solvate), Form-F (Tetrahydrofuran solvate) and Form-G (1,4-dioxane solvate) and process for preparing the same whereas WO 2006055964 discloses the solvated forms zolmitriptan Form B (DMF solvate), Form C (ethanol solvate), Form D (2-butanol or 1,3-dioxane solvate), Form E (1-butanol solvate), Form F (isobutanol solvate), Form G (THF solvate), Form H (cyclohexanone solvate), Form I (1,4-dioxane solvate), Form J (piperidine solvate), Form K (solvate of Methanol or ethanol or DMF or acetonitrile), Form L (acetonitrile solvate), Form M (cyclopentanone solvate), Form N (methyl ethyl ketone), Form O (piperidine solvate), Form P (pyridine solvate), Form Q (DEA solvate), Form R (MDC solvate), Form S (solvate of butyl acetate of n-butanol), Form T (ethyl acetate solvate) and amorphous form.

Polymorphism, is a property of a molecule, and a 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 polymorphic form may give rise to thermal behavior different from that of another polymorphic form. Thermal behavior can be measured by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC"), which have been used to distinguish polymorphic forms.

The difference in the physical properties of different polymorphic forms results from the orientation and inlermolecular 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 crystalline forms of the same compound or complex. Furthermore, the solubility of polymorphic forms in aqueous solutions, in particular in the gastric juices, can also be significantly different. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.

The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. There is a need in the art for polymorphic forms of zolmitriptan.

During our recent studies on polymorphic screening of zolmitriptan inventors found two novel polymorphic forms as well as their processes. Inventors also found the novel process for the preparation of pure zolmitriptan prior art Form A.

Summary of the Invention

It is the principal aspect of the present invention to provide novel crystalline forms of zolmitriptan referred to as Form I and Form II characterized by Infrared absorption spectrum, X-ray powder diffraction pattern, thermo gravimetric analysis (TGA), differential scanning calorimetry (DSC), moisture content and/or melting point.

Furthermore, the present invention is also directed to the process for the preparation of novel crystalline polymorphs of the zolmitriptan by using different solvent systems and conditions.

In accordance with one preferred embodiment of the present invention, there is provided a crystalline zolmitriptan Form I as a chloroform solvate with a chloroform content of 14- 30 % supported by thermo gravimetric analysis (TGA) and moisture content of 0.2-0.3% (By KF method).

In accordance with another preferred embodiment of the present invention, there is provided a crystalline Zolmitriptan Form II as a n-butanol/diethylether solvate with the LOD (loss on drying) content of about 8-15% supported by thermo gravimetric analysis (TGA) and moisture content of 0.2% (By ICF method).

In accordance with yet another preferred embodiment of the present invention there is provided a process for the preparation of novel crystalline Form I and Form II.

Another embodiment provides a novel process for the preparation of zolmitriptan Form A

Brief Description of the Drawings Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures, wherein:

Figure 1 is the X-ray powder diffraction pattern of chloroform solvate (Form I) of

Zolmitriptan

Figure 2 is the Thermo gravimetric Analysis (TGA) of Form I

Figure 3 is the Differential scanning calorimetric (DSC) curve of Form I

Figure 4 is the X-ray powder, diffraction pattern of chloroform solvate (Form I) of Zolmitriptan after drying.

Figure 5 is the X-ray powder diffraction pattern of Form A of Zolmitriptan crystallized from nitromethane

Figure 6 is the Thermo gravimetric Analysis (TGA) of Form A crystallized from nitromethane Figure 7 is the Differential scanning calorimetric (DSC) curve of Form A of Zolmitriptan crystallized from nitromethane Figure 8 is the X-ray powder diffraction pattern of Form II of Zolmitriptan crystallized from n-BuOH/Diethylether

Figure 9 is the Thermo gravimetric Analysis (TGA) of Form II Figure 10 is the Differential scanning calorimetric (DSC) curve of Form II

Detailed Description of the Invention

The present invention describes the crystalline zolmitriptan Form I and Form II, which exists in solvate forms and are intended to be encompassed with in the scope of the present invention. The said forms are differ from each other in their physical properties, spectral data and method of preparation and characterized by their X-ray powder diffraction patterns, thermo gravimetric analysis (TGA) and/or by infra red absorption spectrum (IR).

Powder X-ray Diffraction (PXRD) The said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern. Thus, the, X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of θ/θ configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 4OkV and 3OmA. The experiments were conducted over the 2Θ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

Diffrential Scanning Calorime try (DSC)

The DSC measurements were carried out on Mettler Toledo 822 star⁶ and TA QlOOO of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with three pin holes were used.

Thermo gravimetric Analysis (TGA)

TGA was recorded on out using the instrument Mettler Toledo TGA/SDTA 85 l^e and TGA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 25ml/min.

Karl-Fisher Water content was determined on Metrohra Karl-Fisher titrator (Model: 794 Basic Titrino) using pyridine. free single solution (Merck, Mumbai) with sample mass between 450mg to 550mg.

Crystalline Zolmitriptan Form I is characterized by powder X-ray diffraction pattern as shown in Figure 1 with peaks at 8.06, 11.79, 12.93, 14.37, 14.72, 15.60, 16.24, 17.07, 17.40, 17.61, 18.14, 18.41, 18.96, 19.67, 21.09, 21.77, 22.10, 22.44, 22.90, 23.17, 23.44, 23.85, 24.80, 25.06, 25.89, 26.26, 26.49, 26.70, 27.17, 27.59, 28.20, 29.39, 30.19, 30.72, 31.55, 31.75, 32.30, 33.77, 34.78, 35.32, 37.33, 39.08, 42.00, 42.38, 47.47 and 48.31 ± 0.2 θvalues

Crystalline Zolmitriptan Form I is further characterized by DSC with two endothermic peaks as shown in Figure 3; first endotherm is at about 89°C attributed to the loss of the solvent and second at 97⁰C indicates the melting of the product. (The water content determined by the Karl-Fisher method is 0.2 to 0.3%)

Crystalline zolmitriptan Form I, is a chloroform solvate having between about 14-30 weight percent and more specifically about 26 percent of chloroform content, which is analyzed by its TGA data shown in Figure 2. The calculated first derivative curves shows two weight loss steps during heating by TGA.

The present invention also provides the process for the preparation of crystalline zolmitriptan Form I, which comprises contacting zolmitriptan in a solvent, such as chloroform, from about ambient temperature to reflux temperature. The obtained solid is filtered under suction followed by vacuum drying. Zolmitriptan used herein selected from the group consisting of but not limited to anhydrous or solvate form. Crystalline Zolmitriptan Form II is characterized by powder X-ray diffraction pattern as shown in Figure 4 with peaks at 8.22, 8.80, 11.20, 11.72, 12.90, 13.87, 14.55, 15.63, 16.46, 17.13, 17.64, 18.20, 18.51, 19.20, 19.75, 21.88, 22.48, 22.70, 23.58, 24.01, 25.19, 25.68, 26.14, 26.56, 27.10, 27.46, 28.33, 29.58, 30.00, 30.31, 30.68, 31.69, 33.19, 33.74, 35.00, 35.89, 36.98, 37.74, 39.35, 40.71, 41.92, 42.69, 43.84 and 49.02 ± 0.2 θvalues

Crystalline Zolmitriptan Form II is further characterized by DSC with a broad melting endotherm at 88⁰C and 138⁰C attributed to desolvation followed by melting of the product as shown in Figure 10.

Crystalline zolmitriptan Form II is an n-butanol/diethylether solvate having between about 8-about 15 % of n-butanql/diethylether content, which is analyzed by as weight loss due to desolvation in its TGA data as depicted in Figure 9.

The present invention also provides the process for the preparation of crystalline zolmitriptan Form II, which comprises contacting the zolmitriptan in solvent, such as n- butanol, from about room temperature to reflux temperature and adding an anti-solvent such as diethylether drop-wise to cause the precipitation and recovering the crystalline zolmitriptan Form II. Zolmitriptan used herein selected from the group consisting of but not limited to anhydrous or solvate form.

The present invention also provides a process for the preparation of crystalline zolmitriptan Form A, which comprises heating any of the crystalline form of zolmitriptan selected from the group consisting of Form I or Form IL Crystalline zolmitriptan Form A may also be prepared by slurrying Form I in a solvent selected from the group consisting of but not limited to isopropanol, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), water and mixtures thereof.

The following non-limiting examples illustrate specific embodiments of the present invention. They are, not intended to be limiting the scope of present invention in any way. Experimental Section

Example 1: Preparation of crystalline zolmitriptan Form I.

A sample of zolmitriptan (25 g) was placed in a glass flask containing chloroform (250ml) and heated to obtain a clear solution. The solution was filtered and the filtrate was kept overnight for slow crystallization at room temperature. The slurry was filtered to obtain the crystals.

Example 2: Preparation of zolmitriptan Form II A sample of zolmitriptan (5g) was placed in a glass flask containing n-butanol (65ml) and heated to obtain a clear solution. Diethyl ether (10 ml) was added and the solution was allowed to stand at room temperature overnight. The crystalline material was filtered and dried at 60 - 7O⁰C under vacuum for 12 hrs.

Example 3: Preparation of zolmitriptan Form A.

The dried sample (3.5g, example -1) was taken in isopropyl alcohol (35ml) and heated to 6O⁰C to obtain a clear solution. Isopropyl alcohol was distilled under vacuum at 60⁰C up to maximum extent. Residue was slurred with a solution of 20% Isopropyl alcohol - water mixture (7ml) for 4hrs, filtered and washed with a solution of 20% isopropyl alcohol - water (3.5ml). The wet solid was dried at 60 - 65°C under vacuum for 15hrs.

Example 4: Preparation of zolmitriptan Form A.

The dried sample (3.5g, example -1) was taken in acetone (35ml) and heated to 60⁰C to obtain a clear solution. Acetone was distilled under vacuum at 60⁰C up to maximum extent. Residue was slurred with a solution of 20% acetone - water mixture (7ml) for 4hrs, filtered and washed with a solution of 20% acetone - water (3.5ml). The wet solid was dried at 60 - 65⁰C under vacuum for 15hrs.

Example 5: Preparation of zolmitriptan Form A. The dried sample (3.5g, example -1) was taken in methyl ethyl ketone (35ml) and heated to 60⁰C to obtain a clear solution. Methyl ethyl ketone was distilled under vacuum at 6O⁰C up to maximum extent. Residue was slurred with a solution of 20% methyl ethyl ketone - water mixture (7ml) for 4hrs, filtered and washed with a solution of 20% methyl ethyl ketone - water (3.5ml). The wet solid was dried at 60 - 65°C under vacuum for 15hrs.

Example 6: Preparation of zolmitriptan Form A.

The dried sample (3.5g, example -1) was taken in methyl isobutyl ketone (35ml) and heated to 6O⁰C to obtain a clear solution. Methyl isobutyl ketone was distilled under vacuum at 60°C up to maximum extent. Residue was slurred with a solution of 20% methyl isobutyl ketone - water mixture (7ml) for 4hrs, filtered and washed with a solution of 20% methyl isobutyl ketone - water (3.5ml). The wet solid was dried at 60 - 65⁰C under vacuum for 15hrs.

Example 7: Preparation of zolmitriptan Form A. The dried sample (3.5g, example -1) was taken in water (35ml) and heated to 6O⁰C. Water was distilled under vacuum at 6O⁰C up to maximum extent. Residue was slurred with water (7ml) for 4hrs, filtered and washed with water (3.5ml). The wet solid was dried at 60 - 65°C under vacuum for 15hrs.

Example 8: Preparation of zolmitriptan Form A.

A sample of zolmitriptan (5g) was placed in a glass flask containing chloroform (50ml) and heated to reflux for 10 min to obtain a clear solution. The solution was cooled to room temperature and maintained for 15min. The slurry was filtered and the material unloaded. The wet solid was suspended in isopropyl alcohol (50ml) and heated to 6O⁰C to make a clear solution. Isopropyl alcohol was then distilled under reduced pressure up to maximum extent. Residue was then taken in 20% isopropyl alcohol - water (10ml) and stirred for 4hrs, filtered and washed with 20% isopropyl alcohol - water (5ml). The wet solid was dried at 60 - 65°C under reduced pressure for 15hrs. Example 9: Preparation of zolmitriptan Form A.

A sample of zolmitriptan (5g) was placed in a glass flask containing chloroform (50ml) and heated to reflux for 10 min to obtain a clear solution. The solution was cooled to room temperature and maintained for 15min. The slurry was filtered and the material unloaded. The wet solid was suspended in acetone (50ml) and heated to 60°C to make a clear solution. Acetone was then distilled under reduced pressure up to maximum extent. Residue was then taken in 20% acetone - water (10ml) and stirred for 4hrs, filtered and washed with 20% acetone - water (5ml). The wet solid was dried at 60 - 65⁰C under reduced pressure for 15hrs.

Example 10: Preparation of zolmitriptan Form A.

A sample of zolmitriptan (5g) was placed in a glass flask containing chloroform (50ml) and heated to reflux for 10 min to obtain a clear solution. The solution was cooled to room temperature and maintained for 15min. The slurry was filtered and the material unloaded. The wet solid was suspended in methyl ethyl ketone (50ml) and heated to 6O⁰C to make a clear solution. Methyl ethyl ketone was then distilled under reduced pressure up to maximum extent. Residue was then taken in 20% methyl ethyl ketone — water (10ml) and stirred for 4hrs, filtered and washed with 20% methyl ethyl ketone - water (5ml). The wet solid was dried at 60 - 65⁰C under reduced pressure for 15hrs.

Example 11: Preparation of zolmitriptan Form A.

A sample of zolmitriptan (5g) was placed in a glass flask containing chloroform (50ml) and heated to reflux for 10 min to obtain a clear solution. The solution was cooled to room temperature and maintained for 15min. The slurry was filtered and the material unloaded. The wet solid was suspended in methyl isόbutyl ketone (50ml) and heated to 60⁰C to make a clear solution. Methyl isobutyl ketone was then distilled under reduced pressure up to maximum extent. Residue was then taken in a mixture of methyl isobutyl ketone (2ml) and water (8ml), stirred for 4hrs, filtered. The wet cake was washed with methyl isobutyl ketone (ImI) and water (4ml). The wet solid was dried at 60 - 65°C under reduced pressure for 15hrs. Example 12: Preparation of zolmitriptan Form A.

A sample of zolmitriptan (5g) was placed in a glass flask containing chloroform (50ml) and heated to reflux for 10 min to obtain a clear solution. The solution was cooled to room temperature and maintained for 15min. The slurry was filtered and the material unloaded. The wet solid was suspended in water (50ml) and heated to 60⁰C to make a clear solution. Water was then distilled under reduced pressure at 60°C up to maximum extent and residue taken in water (10ml) and stirred for 4hrs, filtered and washed with water (5ml). The wet solid was dried at 60 - 65°C under reduced pressure for 15hrs.

Example 13: Preparation of zolmitriptan Form A.

The dried sample (3.5g, example -1) was taken in 20% isopropyl alcohol - water (7ml) and stirred for 4hrs, filtered and washed with a solution of 20% isopropyl alcohol - water (3.5ml). The wet solid was dried at 40 - 45°C under vacuum for 8 hrs.

Example 14: Preparation of zolmitriptan Form A from Form I

2g of zolmitriptan Form I obtained as described above was kept in a static dryer and heated at 40-45⁰C under vacuum. The resulting solid was identified as Form A.

Example 15: Preparation of zolmitriptan Form A from Form I The dried sample (3.5g, example -1) was taken in isopropyl alcohol (35ml) and heated to 6O⁰C to obtain a clear solution. Isopropyl alcohol was distilled under vacuum at 6O⁰C up to maximum extent. Residue was slurred with a solution of 20% Isopropyl alcohol - water mixture (7ml) for 4hrs, filtered and washed with a solution of 20% isopropyl alcohol - water (3.5ml). The wet solid was dried at 60 - 65⁰C under vacuum for 8 hrs.

Example 16: Preparation of zolmitriptan Form A using nitromethane A sample of zolmitriptan (5g) was placed in a glass flask containing nitromethane (50 ml) and heated to obtain a clear solution. The solution was filtered and the filtrate was allowed to stand at room temperature for overnight. The crystalline material obtained was filtered and dried at 40 - 45°C under vacuum for 4 hrs. Example 17: Preparation of zolmitriptan Form A from Form II by heating

2g of zolmitriptan Form II obtained as described above was kept in a static dryer and heated at 60-65°C under vacuum. The resulting solid was identified as Form A.

Claims

We Claim:

1. Crystalline zolmitriptan Form I.

2. Crystalline zolmitriptan Form I according to claim 1 having an X-ray powder diffraction pattern characterized by peaks at 14.3, 16.2, 17.0, 18.1 and 23.8 ± 0.2

2 θ values.

3. Crystalline zolmitriptan Form I according to claim 2 having an X-ray powder diffraction pattern characterized by peaks at 8.06, 11.79, 12.93, 14.37, 14.72, 15.60, 16.24, 17.07, 17.40, 17.61, 18.14, 18.41, 18.96, 19.67, 21.09, 21.77, 22.10,

22.44, 22.90, 23.17, 23.44, 23.85, 24.80, 25.06, 25.89, 26.26, 26.49, 26.70, 27.17, 27.59, 28.20, 29.39, 30.19, 30.72, 31.55, 31.75, 32.30, 33.77, 34.78, 35.32, 37.33, 39.08, 42.00, 42.38, 47.47 and 48.31 ± 0.2 θvalues.

4. Crystalline zolmitriptan Form I according to claim 3 having a substantially similar

X-ray powder diffraction pattern as depicted in Figure 1.

5. Crystalline zolmitriptan Form I according to claim 1 characterized by DSC as depicted in Figure 3 and TGA as depicted in Figure 2.

6. Crystalline zolmitriptan Form I according to claim 1, wherein said polymorphic Form I is a solvate containing 14-30 % of chloroform.

7. A process for the preparation of crystalline zolmitriptan Form I, which comprises: (a) contacting zolmitriptan in a solvent such as chloroform;

(b) isolating the solid obtained and dried.

8. The process according to claim 7, wherein zolmitriptan used is anhydrous or solvate form.

9. The process according to claim 7, wherein contacting is done at about ambient temperature to reflux temperature.

10. Crystalline zolmitriptan Form II. ■ 5

11. Crystalline zolmitriptan Form II according to claim 10 having an X-ray powder diffraction pattern characterized by peaks at 8.2, 11.7, 13.8, 18.2, 21.8 and 23.5 ± 0.2 2θvalues. 0 12. Crystalline zolmitriptan Form II according to claim 11 having an X-ray powder diffraction pattern characterized by peaks at 8.22, 8.80, 11.20, 11.72,

12.90,

13.87, 14.55, 15.63, 16.46, 17.13, 17.64, 18.20, 18.51, 19.20, 19.75, 21.88, 22.48,

22.70, 23.58, 24.01, 25.19, 25.68, 26.14, 26.56, 27.10, 27.46, 28.33, 29.58, 30.00,

- 30.31, 30.68, 31.69, 33.19, 33.74, 35.00, 35.89, 36.98, 37.74, 39.35, 40.71, 41.92,5 42.69, 43.84 and 49.02 ± 0.2 θvalues.

13. Crystalline zolmitriptan Form II according to claim 12 having a substantially similar X-ray powder diffraction pattern as depicted in Figure 8. 0

14. Crystalline zolmitriptan Form II according to claim 10 characterized by DSC as depicted in Figure 10 and TGA as depicted in Figure 9.

15. A process for the preparation of crystalline zolmitriptan Form II, which comprises: 5 (a) contacting zolmitriptan in a solvent such as n-butanol;

(b) adding an antisolvent such as diethylether; and

(c) isolating the solid obtained and dried.

16. The process according to claim 15, wherein zolmitriptan used is anhydrous or0 solvate form.

17. The process according to claim 15, wherein contacting is done at about room temperature to reflux temperature.

18. A process for the preparation of crystalline zolmitriptan Form A, which comprises the heating of crystalline Form I and Form II.

19. A process for the preparation of crystalline zolmitriptan Form A₅ which comprises

(a) slurrying Form I in a solvent;

(b) isolating the solid and dried.

20. The process according to claim 19, wherein solvent used is selected from the group consisting of isopropanol, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), water and mixtures thereof.