POLYMORPHIC FORM OF BORTEZOMIB AND PROCESS FOR PREPARATION
THEIR OF

Field of invention:

The present invention relates to the polymorphic Form of Bortezomib in Form I, From II, amorphous form and process for the preparation their of

The chemical name of Bortezomib (lR)-3-methyl-l-[[(2S)-l-oxo-3-phenyl-2-[(pyrazinylcarbonyl) ainino]propyl]amino]butyl] boronic acid.

Bortezomib is an anti-neoplastic agent used in the treatment of multiple myeloma.

Bortezomib is used to treat multiple myeloma and mantle cell lymphoma for the people who have already been treated with at least one other medication. It is in a class of medications called antineoplastic agents that works by killing cancer cells.

BACKGROUND OF THE INVENTION:

Polymorphism is defined as the ability of the substance to exist as two or more crystalline phases that have different arrangement or conformations of the molecules in the crystal lattice.

The physical properties such as melting points and X-ray diffraction values will differ for different polymorphs.

WO 2008/075376 discloses a process for the preparation of Form I and From II of Boretzomib, involving dissolving bortezomib in acetone and allowing to crystallize at 25-30°C, stirring the resulting crystallized material for about 2hrs to obtain Form I and dissolving polymorphic Form II of bortezomib in halogenated solvents such as chloroform, methylene chloride or nitriles such as acetonitrile at 25-30°C, adding diluents such as diisopropyl ether, tert-butylmethyl ether, n-hexane and n-heptane etc allowing to stir at 25-30°C to precipitate the product to obtain Form I.

International patent application number, WO 2009/036281 discloses the process for the preparation of Form A & B. According to this patent. Form A is prepared by dissolving compound in methanol and diluted with water. Form B is prepared by crystallizing
Bortezomib in a mixture of dichloromethane and toluene.

WO 2011/099018 described a novel preparation of Bortezomib amorphous form and also Form HI. Amorphous form is prepared by dissolving Bortezomib in ethyl acetate and diluting with aliphatic hydrocarbons like n-Heptane, Cyclohexane and Hexane and also by recrystallization using DMF- water mixture. Form HI is prepared by crystallization from acetonitrile.

WO 2011/1079I2 relates the preparation of Form AI and A2 of Bortezomib. Form AI is prepared by stirring bortezomib with acetonitrile. Form A2 is prepared by crystallization from 1, 4-Dioxane water mixture.

Summary of the invention:

In accordance with the present invention, processes for the preparation of two polymeric Forms i.e., Form I and II and amorphous powder of Bortezomib are disclosed.

According to one aspect of the present invention, a process for the preparation of Form I comprise of;

a) Dissolving Bortezomib in a mixture of solvents.

b) Isolating Bortezomib as Form I

According to another aspect of the present invention, a process for the preparation of Form II comprises of;

a) Dissolving Bortezomib in hot aliphatic esters

b) Precipitation of Bortezomib with less polar solvents.

c) Isolating Bortezomib in Form II

According to another aspect of the present invention, a process for the preparation of amorphous comprises of;

a) Dissolving Bortezomib in hot aliphatic esters or halogenated solvents

b) Precipitation of Bortezomib with less polar solvents or aliphatic hydrocarbons.

c) Isolating Bortezomib in amorphous Form.

According to another aspect of the present invention, a process for the preparation of Form I from amorphous comprises of;

a) Dissolving Bortezomib in amorphous Form in acetone or mixture of acetone and aliphatic ethers

b) Crystallization and Isolation of Bortezomib as Form I.

According to another aspect of the present invention polymorphic Form I of Bortezomib as characterized by X-ray diffraction analysis as shown in the Figure 1

A novel process for the preparation of Form II is disclosed and the X-ray diffraction pattern as shown in the Figure 2, proves the polymeric Form II.

Another aspect of the present invention is to provide a novel process for the preparation of amorphous Form, as shown in the Figure 3.

Brief description of the drawings

Fig 1: Powder XRD of Bortezomib polymorphic Form I

Fig 2: Powder XRD of Bortezomib polymorphic Form II

Fig 3: Powder XRD of Bortezomib Amorphous Form

Fig 4: DSC Spectra of Bortezomib polymorphic Form I

Fig 5: DSC Spectra of Bortezomib polymorphic Form II

Fig 6: DSC Spectra of Bortezomib Amorphous Form

Fig 7: IR Spectra of Bortezomib polymorphic Form I

Fig 8: IR Spectra of Bortezomib polymorphic Form II

Fig 9: IR Spectra of Bortezomib Amorphous Form Detailed description of the process:

According to the another aspect of the present invention, Preparation of Form II which comprises;

a) dissolving Bortezomib in aliphatic esters under hot condition where aliphatic ester is preferably methyl acetate, more preferably ethyl acetate;

b) precipitating the solution into aliphatic ether, preferably methyl tertiary butyl ether, more preferably diethyl ether.

c) isolating of Bortezomib in Form II.

According to the another aspect of the present invention, preparation of Form I comprises of;

a) dissolving Bortezomib in a solvent mixture acetone with diethyl ether or diisopropyl ether or methyl tertiary butyl ether (MTBE)

b) isolating crystalline form of Bortezomib in Form I.

Solvent mixture is acetone : diethyl ether, acetone : diisopropyl ether, acetone : methyl tertiary butyl ether, most preferably acetone : methyl tertiary butyl ether.

The proportion of MTBE in acetone is, preferably 30% MTBE in acetone, most preferably 40% MTBE in acetone. The proportion of MTBE to acetone in the solvent mixture is between 10:90 and 90:10.

According to the another aspect of the present invention, preparation of Amorphous Form comprises of;

a) dissolving Bortezomib in halogenated solvents dichloromethane, 1,2-dichloroethane and chloroform, most preferably chloroform;

b) precipitating the solution into aliphatic hydrocarbons, such as n-heptane, n-hexane, n-pentane, isopentane, methyl cyclohexane, most preferably n-pentane and n-heptane

c) Isolating of Bortezomib in amorphous Form.

According to the another aspect of the present invention, preparation of Form I from Amorphous Form comprises of;

a) dissolving Bortezomib in amorphous Form in acetone

b) Filtering and isolating crystallized Bortezomib Form I.

According to the another aspect of the present invention, preparation of Form I from Amorphous Form which comprises;

a) dissolving amorphous form of Bortezomib in 40% MTBE in acetone

b) Filtering and isolating crystallized Bortezomib Form I.

Example I: Preparation of Bortezomib Form I:

In a 1 lit 3N Round bottom flask, 100 gm of crude Bortezomib (lOOgm) was dissolved in 400 ml of 40% MTBE in acetone at 25-30°C. After addition, the mixture was stirred for 2 hrs at 25-30°C.The crystallized material was filtered and washed with acetone and dried to yield 70 gm of Bortezomib as Form I having purity greater than 99.5%

Example II: Preparation of Bortezomib Form I from Amorphous Form:

In a 2 lit 3N Round bottom flask, 100 gm Bortezomib (Amorplious Form) was dissolved in I lit of acetone at 25-30°C.The solution was stirred at the same temperature for 2 hrs during which Bortezomib Form I. The crystallized was filtered, washed with acetone and dried to yield 70 gm of Bortezomib Form I having purity greater than 99.5%.

Example III: Preparation of Bortezomib Form I from Amorphous Form:

In a 2 lit 3N Round bottom flask, 100 gm of Bortezomib Amorphous Form was dissolved in a mixture of 1.5 lit 40% MTBE in acetone at 25-30°C and left for 2 hrs at 25-30°C.The crystallized material was filtered, washed with acetone and dried to yield 70 gm of Bortezomib Form I having purity greater than 99.5%.

Example IV: Preparation of Bortezomib Amorphous Form from Form I or Form II:

In a 2 lit 3N Round bottom flask, 100 gm of Bortezomib as Form I or Form II was dissolved in Hit of chloroform at 25-30°C.The solution was added stirring into 10 lit of n-Pentane at 10-15° for 30 minutes. The solid formed was filtered and washed with n-Pentane and dried to yield 80 gm of Bortezomib in amorphous form.

Example V: Preparation of Bortezomib Form II from Form I or Amorphous Form:

In a 2 lit 3N Round bottom flask, 100 gm of Bortezomib as Form I or Amorphous Form was dissolved in ethyl acetate (0.751it) at 70-75°C. The solution was cooled to 30-35°C and added with stirring into 5.25 lit of diethyl ether at 25-30° for 30 minutes. The solid formed was filtered, washed with diethyl ether and dried to yield of Bortezomib as Form II(70gm) having purity greater than 99.5%.

Table 1: Powder XRD value for Bortezomib Form I & II

Table 2: FT-IR spectra(KBR pellets): comparison of characteristic bands for the Form-I, Form-II and amorphous form of the bortezomib

Table 3: DSC: comparison of the melting points and melting enthalpies of the Form-I and Form-II of the Bortezomib.

We claim:

1. A novel process for the preparation of Form I of Bortezomib characterized by powder X-ray diffraction pattern with peaks at 5.684, 9.818, 11.412, 12.721, 15.187, 20.431, 20.84, 21.542, 22.182, 23.729, 26.555 ± 0.2° 29 the process comprising;

a. dissolving Bortezomib in a solvent mixture acetone and ether at 25-30°C;

b. stirring the mixture for 2 hrs at 25-30°C

c. isolating crystalline form of Bortezomib in Form I.

2. The process as claimed in claim 1, wherein ether is selected from diethyl ether, diisopropyl ether and methyl tertiary butyl ether (MTBE); more preferably methyl tertiary butyl ether.

3. The process as claimed in claim 1, where in ratio of ether to acetone in the solvent mixture is between 10:90 and 90:10.

4. A novel process for the preparation of Form II of Bortezomib characterized by powder X-ray diffraction pattern with peaks at 4.555, 6.103, 8.484, 9.386, 11.802, 12.272, 14.511, 16.351,22.523,23.403± 0.2° 28 the said process comprising;

a. dissolving Bortezomib in aliphatic ester at 70-75°C;

b. cooling the solution into 30-35 and mixing with aliphatic ether to crystallize the
compound;

c. Isolatingof Bortezomib in Form II.

5. The process as claimed in claim 4, where aliphatic ester is preferably methyl acetate, ethyl acetate, more preferably ethyl acetate and ether selected from diethyl ether,
diisopropyl ether and methyl tertiary butyl ether (MTBE), more preferably diethyl ether.

6. A process for the preparation of Amorphous Form which comprises;

a. dissolving Bortezomib in halogenated solvents at 25-30°C;

b. precipitating the solution into aliphatic hydrocarbons,

c. isolating of Bortezomib in amorphous Form.

7. The process as claimed in claim 6, wherein halogenated solvents slected from dichloromethane, 1,2-dichloroethane and chloroform, most preferably chloroform; aliphatic hydrocarbons selected from n-heptane, n-hexane, n-pentane, isopentane, methyl cyclohexane, most preferably n-pentane and n-heptane

8. A process for the preparation of Form I from Amorphous Form which comprises;

a. dissolving Bortezomib in Amorphous Form in acetone

b. filtering and isolating crystallized Bortezomib Form I.

9. The process as claimed in any preceding claim, wherein purity of Form I, Form II and Amorphous Form is more than 99.5%.

10. Bortezomib Form I, Form II and Amorphous Form is prepared according to claims 1-9.

11. Crystalline Form I of Bortezomib characterized by powder X-ray diffraction pattern with peaks at 5.684, 9.818,11.412, 12.721, 15.187,20.431,20.84,21.542,22.182,23.729, 26.555 ± 0.2° 20 wherein the process comprising;

a. dissolving Bortezomib in a solvent mixture acetone and ether at 25-30°C;

b. stirring the mixture for 2 hrs at 25-30°C;

c. isolating crystalline form of Bortezomib in Form I.

12. Crystalline Form II of Bortezomib characterized by powder X-ray diffraction pattern with peaks at 4.555, 6.103, 8.484,9.386, 11.802, 12.272, 14.511, 16.351,22.523, 23.403± 0.2° 26 wherein process comprising;

d. dissolving Bortezomib in aliphatic ester at 70-75°C;

e. cooling the solution into 30-35 and mixing with aliphatic ether to crystalize the
compound;

f. isolating of Bortezomib in Form II.