WO2008075376A1 - Polymorphic forms of bortezomib and process for their preparation - Google Patents
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- WO2008075376A1 WO2008075376A1 PCT/IN2007/000561 IN2007000561W WO2008075376A1 WO 2008075376 A1 WO2008075376 A1 WO 2008075376A1 IN 2007000561 W IN2007000561 W IN 2007000561W WO 2008075376 A1 WO2008075376 A1 WO 2008075376A1
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- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 title claims abstract description 60
- 229960001467 bortezomib Drugs 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title claims abstract description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 239000013078 crystal Substances 0.000 claims description 8
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- 238000000862 absorption spectrum Methods 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims 3
- 239000000047 product Substances 0.000 claims 3
- 239000003937 drug carrier Substances 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 239000012265 solid product Substances 0.000 claims 1
- 208000034578 Multiple myelomas Diseases 0.000 abstract description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 abstract description 4
- 229940034982 antineoplastic agent Drugs 0.000 abstract description 2
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000000113 differential scanning calorimetry Methods 0.000 description 6
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 108010022579 ATP dependent 26S protease Proteins 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- -1 Pyrazinyl carbonyl Chemical group 0.000 description 2
- 150000001642 boronic acid derivatives Chemical class 0.000 description 2
- 125000005620 boronic acid group Chemical class 0.000 description 2
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 108091005508 Acid proteases Proteins 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 102100027612 Kallikrein-11 Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 101710152431 Trypsin-like protease Proteins 0.000 description 1
- 108010005705 Ubiquitinated Proteins Proteins 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000037012 chymotrypsin-like activity Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 230000009097 homeostatic mechanism Effects 0.000 description 1
- 238000013415 human tumor xenograft model Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000013037 reversible inhibitor Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000006663 ubiquitin-proteasome pathway Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Definitions
- 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.
- 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.
- 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.
- 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.
- the main objective of the present invention is to provide polymorphic Forms of bortezomib designated by us as Form I and Form II.
- 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)
- DSC Differential scanning calorimetry data
- Polymorphic Form-I is characterized by the following data.
- Peaks in the powder X-ray diffraction pattern are as given below.
- 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 25-30 0 C, 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.
- solvents selected from ketones such as acetone or halogenated solvents such as methylene chloride, chloroform or nitriles such as acetonitrile at 25-30 0 C
- anti solvents such as diisoprpyl ether or tert-butylmethl ether or n-hexane or
- Peaks in the powder X-ray diffraction pattern are as given below.
- 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 70 0 C, cooling of the resultant solution to 25-30°c°C, and filtering of the crystals.
- solvents selected from esters such as ethyl acetate, isopropyl acetate at 70 0 C
- cooling of the resultant solution to 25-30°c°C
- filtering of the crystals The novel forms of bortezomib may be formulated in a form suitable for oral administration or injection.
- 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-k ⁇ radiation (1.5406a).
- 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.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 823e
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
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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2348/CHE/2006 | 2006-12-18 | ||
| IN2348CH2006 | 2006-12-18 |
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| WO2008075376A1 true WO2008075376A1 (en) | 2008-06-26 |
| WO2008075376A8 WO2008075376A8 (en) | 2010-04-15 |
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Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010539183A (en) * | 2007-09-12 | 2010-12-16 | ドクター・レディーズ・ラボラトリーズ・リミテッド | Bortezomib and process for its production |
| WO2011099018A1 (en) * | 2010-02-15 | 2011-08-18 | Hetero Research Foundation | Polymorphs of bortezomib |
| WO2011107912A1 (en) | 2010-03-04 | 2011-09-09 | Ranbaxy Laboratories Limited | Polymorphic forms of bortezomib |
| US8263578B2 (en) | 2010-03-18 | 2012-09-11 | Innopharma, Inc. | Stable bortezomib formulations |
| US8497374B2 (en) | 2011-05-12 | 2013-07-30 | Scinopharm Taiwan, Ltd. | Process for preparing and purifying bortezomib |
| EP2644189A1 (en) | 2012-03-27 | 2013-10-02 | Innopharma, Inc. | Stable bortezomib formulations |
| WO2014076713A2 (en) | 2012-11-16 | 2014-05-22 | Shilpa Medicare Limited | Crystalline bortezomib process |
| WO2014097306A1 (en) | 2012-12-21 | 2014-06-26 | Natco Pharma Limited | Stable and pure polymorphic form of bortezomib |
| US8962572B2 (en) | 2010-10-05 | 2015-02-24 | Fresenius Kabi Usa, Llc | Bortezomib formulations |
| US9061037B2 (en) | 2010-03-18 | 2015-06-23 | Innopharma, Inc. | Stable bortezomib formulations |
| WO2015122702A1 (en) * | 2014-02-14 | 2015-08-20 | Kyongbo Pharm. Co., Ltd. | Novel crystalline form of bortezomib and preparation method thereof |
| WO2016085943A1 (en) | 2014-11-25 | 2016-06-02 | Rastelli, Luca | Use of ubiquitin-proteasome system inhibitors for treatment of tumors associated with neurofibromatosis type-2 |
| EP3031811A1 (en) | 2014-12-09 | 2016-06-15 | Teva Pharmaceuticals Ltd. | Malic acid esters of bortezomib |
| US10023611B2 (en) * | 2013-04-16 | 2018-07-17 | Cipla Limited | Process for the preparation of bortezomib mannitol ester |
| WO2019151133A1 (en) * | 2018-02-01 | 2019-08-08 | 日本化薬株式会社 | Manufacturing method for bortezomib crystals |
| CN110642881A (en) * | 2019-10-18 | 2020-01-03 | 扬子江药业集团上海海尼药业有限公司 | Bortezomib crystal form M and preparation method and application thereof |
| AU2018221670B2 (en) * | 2017-02-17 | 2021-02-04 | Fresenius Kabi Oncology Ltd. | An improved process for the preparation of boronic acid esters |
| US11964993B2 (en) | 2021-07-03 | 2024-04-23 | Shilpa Pharma Lifesciences Limited | Crystalline bortezomib process |
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| CN110642881A (en) * | 2019-10-18 | 2020-01-03 | 扬子江药业集团上海海尼药业有限公司 | Bortezomib crystal form M and preparation method and application thereof |
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