WO2014195977A2 - Novel polymorphs of vismodegib - Google Patents

Abstract

The present invention provides a novel crystalline Form of vismodegib, process for its preparation and pharmaceutical compositions comprising it. The present invention also provides a novel amorphous Form of vismodegib, process for its preparation and pharmaceutical compositions comprising it.

Description

NOVEL POLYMORPHS OF VISMODEGIB

This application claims the benefit of Indian patent Application No. 2449/CHE/2013, filed on June 05, 2013, which is incorporated herein by reference.

Filed of the Invention

The present invention provides a novel crystalline Form of vismodegib, process for its preparation and pharmaceutical compositions comprising it. The present invention also provides a novel amorphous Form of vismodegib, process for its preparation and pharmaceutical compositions comprising it.

Background of the Invention

Vismodegib is chemically, 2-Chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsu

Vismodegib is a drug for the treatment of basal-cell carcinoma (BCC). It is marketed by Genentech under the brand name ERIVEDGE^®.

Vismodegib and its process were disclosed in U.S. patent no. 7,888,364 ('364 patent).

Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is ί therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).

) Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.

Vismodegib can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.

> Process for the preparation of vismodegib was disclosed in the '364 patent.

According to the patent, crystalline solid of vismodegib was obtained by crystallizing vismodegib with acetone and ethyl acetate and recrystallized from hot slurry of isopropyl acetate. The crystalline vismodegib obtained by the process of the prior art is herein after designated as vismodegib crystalline Form I. The powdered x-ray diffractogram (PXRD)

) of vismodegib crystalline Form I is shown in figure 1. Crystalline Form I is characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 10.3, 14.0, 18.1, 19.9, 20.6 and 23.3 ± 0.2 degrees.

We have found a novel crystalline Form of vismodegib. The novel Form is stable, reproducible and so, suitable for pharmaceutical preparations.

5 We have also found a novel amorphous Form of vismodegib. The novel Form is stable, reproducible and so, suitable for pharmaceutical preparations.

Thus, one object of the present invention is to provide a novel crystalline Form of vismodegib, process for its preparation and pharmaceutical compositions comprising it.

Another object of the present invention is to provide a novel amorphous Form of

0 vismodegib, process for its preparation and pharmaceutical compositions comprising it. Summary of the Invention

In one aspect, the present invention provides a crystalline Form of vismodegib designated as Form II characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 6.5, 1 1.5, 15.5, 18.9, 19.6, 20.2, 21.2 and 22.7 ± 0.2 degrees.

In another aspect, the present invention provides a process for the preparation of vismodegib crystalline Form II, which comprises: .

a) dissolving vismodegib in an ester solvent; and

b) isolating vismodegib crystalline Form II.

In another aspect, the present invention provides a pharmaceutical composition comprising crystalline Form II of vismodegib and pharmaceutically acceptable excipients.

In another aspect, the present invention provides an amorphous Form of vismodegib.

In another aspect, the present invention provides a process for the preparation of vismodegib amorphous Form, which comprises:

a) dissolving vismodegib in an alcoholic solvent, a ketonic solvent^' or a mixture thereof; and

b) removing the solvent from the solution obtained in step (a) to obtain vismodegib amorphous Form.

Yet in another aspect, the present invention provides a pharmaceutical composition comprising amorphous Form of vismodegib and pharmaceutically acceptable excipients. Brief Description of the Drawings

Figure 1 is an X-ray powder diffraction spectrum of vismodegib crystalline Form

I.

Figure 2 is an X-ray powder diffraction spectrum of vismodegib crystalline Form

II.

Figure 3 is an X-ray powder diffraction spectrum of vismodegib amorphous

Form. X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X- ray powder diffractometer having a copper-Κα radiation. Approximately 500 gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two- theta, at 0.020 degrees two theta per step and a step time of 1 second. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.

Detailed Description of the Invention

The term "room temperature" refers to temperature at about 25 to 35°C.

According to one aspect of the present invention, there is provided a crystalline

Form of vismodegib designated as Form II characterized by peaks in the powder x-ray diffraction spectrum having 20 angle positions at about 6.5, 1 1.5, 15.5, 18.9, 19.6, 20.2, 21.2 and 22.7 ± 0,2 degrees. The powdered x-ray diffractogram (PXRD) of vismodegib crystalline Form II is shown in figure 2.

According to another aspect of the present invention, there is provided a process for the preparation of vismodegib crystalline Form II, which comprises:

a) dissolving vismodegib in an ester solvent; and

b) isolating vismodegib crystalline Form II.

Vismodegib used in step (a) may preferably be vismodegib obtained by the known process.

The ester solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate and ethyl₍ formate, and more preferably the ester solvent is ethyl acetate.

Isolation of vismodegib crystalline Form II in step (b) can be performed by conventional methods such as removal of solvents, concentrating the reaction mass, filtration, centrifugation or extraction with a solvent.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising crystalline Form II of vismodegib and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients. The crystalline Form II may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms. According to another aspect of the present invention, there is provided an amorphous Form of vismodegib. The powdered x-ray diffractogram (PXRD) of vismodegib amorphous Form is shown in figure 3.

According to another aspect of the present invention, there is provided a process for the preparation of vismodegib amorphous Form, which comprises:

a) dissolving vismodegib in an alcoholic solvent, a ketonic solvent or a mixture thereof; and

b) removing the solvent from the solution obtained in step (a) to obtain vismodegib amorphous Form.

Vismodegib used in step (a) may preferably be vismodegib obtained by the known process.

The ketonic solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from acetone, methyl ethyl ketone, diethyl ketone and methyl isobutyl ketone. More preferably the ketonic solvent is methyl ethyl ketone.

Preferably the alcoholic solvent used in step (a) may be a solvent or a mixture of solvents selected from methanol, ethanol, isopropyl alcohol and n-butanol, and more preferably the alcoholic solvent is ethanol.

The solvent may be removed from the solution in step (b) by known methods, for example, distillation.

The distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising amorphous Form of vismodegib and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients. The amorphous Form may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.

The invention will now be further described by the following examples, which are illustrative rather than limiting.

Reference examples

Reference example 1 : Preparation of vismodegib crystalline Form I

A solution of concentrated hydrochloric acid (146 gm) in water (2000 ml) was added to vismodegib (40 gm) and stirred for 10 minutes at room temperature. To the reaction mass was added a solution sodium hydroxide (48 gm) in water (1200 ml) and stirred for 1 hour. The reaction mass was filtered and then dried to obtain a solid. To the solid was added a mixture of acetone (480 ml) and ethyl acetate (120 ml) to obtain a clear solution. The resulting solution is subjected to carbon treatment and filtered through hi- flow bed. The filtrated thus obtained was then concentrated under high vacuum at 45 to 50°C and then cooled to 0 to 5°C. The contents were stirred for 1 hour at 0 to 5°C and filtered. The solid obtained was then dried to obtain a solid. To the solid was added isopropyl acetate (200 ml) and then heated to 60°C. The contents were maintained for 1 hour at 55 to 60°C and filtered. The solid was dried to obtain 20 gm of vismodegib crystalline Form I.

Examples

Example 1 :

Preparation of vismodegib crystalline Form II

Vismodegib (5 gm) was dissolved in ethyl acetate (500 ml) at room temperature and filtered through hi-flow bed. The resulting filtrate was subjected to spray drying to obtain 2 gm of vismodegib crystalline Form II.

Example 2:

Preparation of vismodegib crystalline Form II

Example 1 was repeated using isopropyl acetate solvent instead of ethyl acetate solvent to obtain vismodegib crystalline Form II.

Example 3:

Preparation of vismodegib amorphous Form

Vismodegib (5 gm) was dissolved in methyl ethyl ketone (200 ml) and filtered through hi-flow bed. The solvent was distilled off from the filtrate thus obtained under high vacuum at 45 to 50 C and maintained for 3 hours at 45 to 50 C to obtain 4.5 gm of vismodegib amorphous Form.

Example 4:

Preparation vismodegib amorphous Form

Example 3 was repeated using acetone solvent instead of methyl ethyl ketone solvent to obtain vismodegib amorphous Form.

Example 5:

Preparation of vismodegib amorphous Form

Vismodegib (5 gm) was dissolved in ethanol (500 ml) and filtered through hi-flow bed. The solvent was distilled off from the filtrate thus obtained under high vacuum at 45 to 50°C and maintained for 3 hours at 45 to 50°C to obtain 4.6 gm of vismodegib amorphous Form.

Example 6:

Preparation vismodegib amorphous Form

Example 5 was repeated using methanol solvent instead of ethanol solvent to obtain vismodegib amorphous Form.

Claims

We claim:

I. Vismodegib crystalline Form II, characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 6.5, 11.5, 15.5, 18.9, 19.6, 20.2, 21.2 and 22.7 ± 0.2 degrees.

2. Vismodegib crystalline Form II, characterized by an x-ray powder diffractogram as shown in figure 2.

3. A process for the preparation of vismodegib crystalline Form II as claimed in claim 1, which comprises:

a. dissolving vismodegib in an ester solvent; and

b. isolating vismodegib crystalline Form II.

4. The process as claimed in claim 3, wherein the ester solvent used in step (a) is a solvent or a mixture of solvents selected from ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate and ethyl formate.

5. The process as claimed in claim 4, wherein the ester solvent is ethyl acetate.

6. Vismodegib amorphous Form.

7. Vismodegib amorphous Form, characterized by an x-ray powder diffractogram as shown in figure 3.

8. A process for the preparation of vismodegib amorphous Form as claimed in claim 6, which comprises:

a. dissolving vismodegib in an alcoholic solvent, a ketonic solvent or a mixture thereof; and

b. removing the solvent from the solution obtained in step (a) to obtain vismodegib amorphous Form.

9. The process as claimed in claim 8, wherein the ketonic solvent used in step (a) is a solvent or a mixture of solvents selected from acetone, methyl ethyl ketone, diethyl ketone and methyl isobutyl ketone.

10. The process as claimed in claim 9, wherein the ketonic solvent is acetone.

I I. The process as claimed in claim 8, wherein the alcoholic solvent used in step (a) is a solvent or a mixture of solvents selected from methanol, ethanol, isopropyl alcohol and n-butanol.

12. The process as claimed in claim 11, wherein the alcoholic solvent is ethanol.

13. A pharmaceutical composition that comprises crystalline Form II of vismodegib and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.

14. A pharmaceutical composition that comprises amorphous Form of vismodegib and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.

15. The pharmaceutical composition as claimed in claims 13 and 14, wherein the crystalline Form and amorphous Form are formulated into tablets, capsules, suspensions, dispersions or injectables.