WO2008075376A1

WO2008075376A1 - Polymorphic forms of bortezomib and process for their preparation

Info

Publication number: WO2008075376A1
Application number: PCT/IN2007/000561
Authority: WO
Inventors: Janaki Rama Rao Ravi; Muddasani Pulla Reddy; Bhujanga Rao Adibatla Kali Satya; Nannapaneni Benkaiah Chowdary
Original assignee: Natco Pharma Limited
Priority date: 2006-12-18
Filing date: 2007-12-03
Publication date: 2008-06-26
Also published as: WO2008075376A8

Abstract

The present invention relates to two novel and stable polymorphic forms, namely Form I and Form II of bortezomib (1) and processes for the preparation of these forms. Bortezomib is an anti-neoplastic agent used in the treatment of multiple myeloma.

Description

POLYMORPHIC FORMS OF BORTEZOMIB AND PROCESS FOR THEIR

PREPARATION

FIELD OF THE INVENTION The present invention relates to the polymorphic Form-I and Form-II of bortezomib (1) and processes for preparation of the above said forms. Bortezomib is an anti-neoplastic agent used in the treatment of multiple myeloma.

1 The chemical name of bortezomib is [(lR)-3-methyl-l-[[(2S)-l-oxp-3-phenyl-2- [(Pyrazinyl carbonyl)amino]propyl]-amino]butyl] boronic acid.

Bortezomib is introduced by Millennium Pharmaceuticals Inc., a U.S. based company.

BACKGROUD OF THE INVENTION

Boronic acid and ester compounds display a variety of pharmaceutically useful biological activities. Shenvi, et al., US pat No 4,499,082 (1985), discloses that peptide boronic acids are inhibitors of certain proteolytic enzymes. Kettner and SHENVI, US Pat. No. 5,187157 (1993), US Pat. No. 5,242,904 (1993), and US. Pat. No. 5,250,720 (1993), describe a class of peptide boronic acids that inhibit trypsin like proteases. Kinder, et al., US Pat. No.5, 106,948 (1992), discloses that certain tripeptide boronic acid compounds inhibit the growth of cancer cells. Studies of boronic acid protease inhibitors have been greatly advanced by the preparation of functionalized boronic acid compounds, particularly alpha-halo and alpha-amino boronic acids.

Bortezomib (1) is a modified dipeptidyl boronic acid, and is a reversible inhibitor of the Chymotrypsin like activity of the 26s proteasome in mammalian cells. Bortezomib shows significant antitumor activity in human tumor xenograft models and is undergoing clinical evaluation. The 26s proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homestasis within cells.

Inhibition of the 26s proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death.

Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in non-clinical tumor models, including multiple myeloma.

SUMMARY OF THE INVENTION

As result of our studies on solid state properties of bortezomib, two polymorphic forms of bortezomib are generated, which can be easily prepared with reproducible results.

The main objective of the present invention is to provide polymorphic Forms of bortezomib designated by us as Form I and Form II.

DESCRIPTION OF THE INVENTION

Present invention relates to the preparation of two polymorphic Forms I and II of bortezomib. The polymorphs being characterized by: (1) The peaks appearing in powder X-ray diffraction pattern (XRD)

(2) Infrared absorption bands in the IR spectra in potassium bromide and

(3) Differential scanning calorimetry data (DSC).

Polymorphic Form-I is characterized by the following data.

a) Absorption bands in the IR spectrum (KBr): 444, 516, 556, 620, 703, 759, 878, 929, 976, 1022, 1048, 1080, 1114, 1151, 1203, 1250, 1274, 1325, 1365, 1395, 1456, 1466, 1521,1582, 1628, 1656, 1690, 2867, 2926, 2953, 3064, 3292, 3364, and 3403 cm-¹ b) Differential scanning calorimetry data (°C)

A. onset 62.23⁰C B. onset 175.33°C peak 84.51⁰C peak 177.20⁰C endset 94.54°C endset 179.86°C c) Peaks in the powder X-ray diffraction pattern are as given below.

According to another aspect of the present invention there is provided a process for the preparation of Form I crystals of bortezomib of the Formula 1 having the characteristics given above which comprises dissolving bortezomib in solvents selected from ketones such as acetone or halogenated solvents such as methylene chloride, chloroform or nitriles such as acetonitrile at 25-30⁰C, adding anti solvents such as diisoprpyl ether or tert-butylmethl ether or n-hexane or n-heptane stirring of the resultant solution atlO-3O°C, and filtering of the crystals by conventional techniques. Polymorphic Form-II is characterized by the following data. a) Absorption bands in the IR spectrum (KBr):

448, 516, 617, 702, 752, 775, 868, 923, 1021, 1048, 1080, 1114, 1154, 1201, 1238, 1260, 1325, 1401, 1456, 1466, 1521,1582, 1655, 1676, 2868, 2928, 2954, 3030, 3064 and 3385cm^"1 b) Differential scanning calorimetry data (°C)

A. onset 140.40°C B. onset 175.94°C peak 146.19⁰C peak 178.54°C endset 151.64⁰C endset 180.15⁰C c) Peaks in the powder X-ray diffraction pattern are as given below.

According to another aspect of the present invention there is provided a process for the preparation of Form II of bortezomib of the formula 1 having the characteristics given above which comprises dissolving bortezomib in solvents selected from esters such as ethyl acetate, isopropyl acetate at 70⁰C, cooling of the resultant solution to 25-30°c°C, and filtering of the crystals. The novel forms of bortezomib may be formulated in a form suitable for oral administration or injection. BRIEF DESCRIPTION OF DRAWINGS:

FIG.l : Powder X-ray diffraction pattern of Form-I bortezomib FIG.2: Infrared absorption spectrum of Form-I bortezomib FIG.3: DSC thermogram of Form-I bortezomib FIG.4: Powder X-ray diffraction pattern of Form-II bortezomib FIG.5: Infrared absorption spectrum of Form-II bortezomib FIG.6: DSC thermogram of Form-II bortezomib

X-ray powder diffraction spectra were measured on a Siemens d5000 x-ray powder diffracto-meter having a copper-kα radiation (1.5406a).

IR spectra were recorded on Perkin Elmer; Model: FTIR Paragon 1000

DSC data was collected from Mettler Toledo; Model: DSC 823^e

The details of the process of the invention are provided in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Example 1 Preparation of bortezomib polymorphic Form-I

Into a IL, three-necked RB flask was charged 67g of crude bortezomib, prepared according to the process disclosed in US Pat. No. 2005/0240047A1 and 280ml of acetone. After stirring for 5-10 min at 25-3O⁰C, reaction mass became a clear solution.

After maintaining at 25-3O⁰C for about 30min crystallization began. After stirring for another lOmin, 70ml of acetone was added to the reaction mass to facilitate the stirring. The reaction mass was stirred for another 1.5 to 2.Oh at 25-3O⁰C. The reaction mass was filtered under suction and washed the wet solid with 150 ml of chilled acetone (5-1O⁰C) to get white crystalline bortezomib. Product is dried under vacuum (20mm Hg) at 25- 3O⁰C for 45-50 h to get 4Og of Form I crystals of bortezomib.

Example 2

Preparation of bortezomib polymorphic Form-I

Into a 100ml, three-necked RB flask was charged 0.50 g of bortezomib polymorphic Form-II and 5 ml of chloroform. After stirring for 5min at 25-30⁰C reaction mass became a clear solution. To this solution was charged 5.0 ml of diisopropyl ether. After stirring at 25-3O⁰C for about 5min crystallization began. The resulting suspension was stirred for 1 hour at 25-30⁰C. The reaction mass was filtered under suction and washed with 5.0 ml diisopropyl ether to get white crystalline bortezomib. Product is dried under vacuum (20mm/Hg) at 25-30°C for 45-50 hours to get 0.45 g of Form-I crystals of bortezomib.

Example 3

Preparation of bortezomib polymorphic Form-I

Into a 100ml, three-necked RB flask was charged 0.5g of bortezomib polymorphic Form- II and 17 ml of acetonitrile. After 5min stirring at 25-30⁰C, reaction mass became a clear solution. To the above clear solution was charged 42ml of diisopropyl ether. After stirring at 25-30⁰C for about 24h crystallization began. The resulting suspension was stirred for another 24h at 25-30⁰C. The reaction mass was filtered under suction and washed with 10 ml of diisopropyl ether to get white crystalline bortezomib. Product is dried under vacuum (20mm/Hg) at 25-3O⁰C for 45-50 hours to get 0.25 g of Form-I crystals of bortezomib.

Example 4

Preparation of bortezomib polymorphic Form-II Into a IL, three necked RB flask was charged 47g of bortezomib polymorphic Form-I and 750ml of ethyl acetate. The reaction mass was heated to 7O⁰C, and stirred for 5 min to get clear solution. The above clear solution is cooled to 25-30°C and allowed to stand for 18-2Oh to precipitate the white colored solid. The resulting suspension was stirred for 2 h at 25-3O⁰C, and filtered under suction, washed with chilled ethyl acetate (5-10⁰C) to get white crystalline bortezomib. Product is dried under reduced pressure (20mm Hg) at 25-30⁰C for 45-50 h to get 26 g of Form-II crystals of bortezomib

Advantages of present invention:

1. Present invention discloses two novel crystalline forms of bortezomib designated by us as Form-I and Form-II which are stable, reproducible, and useful for the treatment of multiple myeloma.

2. Processes for the preparation of the novel crystalline forms, namely Form-I and Form-II of bortezomib are simple and easy to adopt on a commercial scale.

Claims

WE CLAIM:

1. A novel, stable, and crystalline Form I of bortezomib of formula I₉

1 characterized by powder X-ray diffraction pattern with peaks at 5.643, 9.785, 11.435, 12.952, 15.275, 20.467, 20.762, 21.486, 22.079, 23.632, 26.264 ± 0.2° 2Θ; bands in the infra red (IR) absorption spectrum (KBr) with peaks at 444, 516, 556, 620, 703, 759, 878, 929, 976, 1022, 1048, 108O₅ 1114, 1151, 1203, 1250, 1274, 1325, 1365, 1395, 1456, 1466, 1521,1582, 1628, 1656, 1690, 2867, 2926, 2953, 3064, 3292, 3364, and 3403 cm^"1; and Differential Scanning Calorimetric peak from 160.44 to 180.75°C (onset 175.09°C).

2. A novel, stable, and crystalline Form II of bortezomib of formula I₅

1 characterized by powder X-ray diffraction pattern with peaks at 4.532, 6.066, 8.497, 9.374, 11.869, 12.270, 14.539, 16.355, 22.585, 23.420 ± 0.2° 2Θ; bands in the infra red (IR) absorption spectrum (KBr) with peaks at 448, 516, 617, 702, 752, 775, 868, 923, 1021, 1048, 1080, 1114, 1154, 1201, 1238, 1260, 1325, 1401, 1456, 1466, 1521,1582, 1655, 1676, 2868, 2928, 2954, 3030, 3064 and 3385cm^'1; and Differential Scanning Calorimetric peaks from 137.50 to 153.57°C (onset 140.41⁰C) and from 172.32 to 182.14°C (onset 177.08°C).

3. A process for producing the polymorphic Form I of bortezomib as defined claim 1, which comprises dissolving bortezomib in acetone and allowing to crystallize at 25-30°C, stirring the resulting crystallized material for 1.5-2.Oh₅ filtering the product, drying under reduced pressure (25-3O⁰C) for 40-5Oh period.

4. Another process for producing the polymorphic Form I of bortezomib as defined in claim 1, which comprises 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 25-3O⁰C to precipitate the product, filtering, and drying under reduced pressure (10-20mm Kg) at 25-30⁰C for 40-50 h period.

5. A process for producing the polymorphic Form II of bortezomib as defined in claim 5, which comprises dissolving bortezomib solid in ethyl acetate while hot, allowing to crystallize at 25-3Q°C for 15-20 h, stirring for another 2 h at 25-3O⁰C, filtering the resulting solid product, and drying the product under reduced pressure (10-20 rnmHg) at 25-30⁰C for 40-50 h period.

6. Processes for the preparation of polymorphic crystal forms, namely Form I and Form II of bortezomib essentially as claimed in claims 1-5.

7. A pharmaceutical composition comprising the crystalline Form I of bortezomib as defined in claim 1 and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition comprising the crystalline Form II of bortezomib as defined in claim 5 and a pharmaceutically acceptable carrier.