WO2011107912A1 - Polymorphic forms of bortezomib - Google Patents
Polymorphic forms of bortezomib Download PDFInfo
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- WO2011107912A1 WO2011107912A1 PCT/IB2011/050795 IB2011050795W WO2011107912A1 WO 2011107912 A1 WO2011107912 A1 WO 2011107912A1 IB 2011050795 W IB2011050795 W IB 2011050795W WO 2011107912 A1 WO2011107912 A1 WO 2011107912A1
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- WIPO (PCT)
- Prior art keywords
- bortezomib
- polymorphic form
- depicted
- dsc thermogram
- same
- Prior art date
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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 81
- 229960001467 bortezomib Drugs 0.000 title claims abstract description 79
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims description 19
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 claims description 10
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 150000002825 nitriles Chemical class 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 230000008018 melting Effects 0.000 claims description 6
- 238000002844 melting Methods 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000007787 solid Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- 0 CC1C(CC=*)*CC1 Chemical compound CC1C(CC=*)*CC1 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000126 substance Substances 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 polymorphic forms of bortezomib.
- the polymorphic forms of the present invention are designated as Form Al and Form A2 of bortezomib.
- the present invention also relates to processes for the preparation of polymorphic Form Al and Form A2 of bortezomib.
- bortezomib the monomeric boronic acid
- the chemical name for bortezomib is [(lR)-3- methyl-l-[[(2S)-l-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid of Formula I.
- Bortezomib is available in the market for the treatment of patients with multiple myeloma and patients with mantle cell lymphoma.
- WO 2008/075376 discloses a process for preparing crystalline Form I and Form II of bortezomib.
- Form I of bortezomib is prepared by dissolving bortezomib in acetone and allowing it to crystallize at 25°C to 30°C.
- Form I is also prepared by dissolving crystalline Form II in chloroform at 25°C to 30°C, adding diisopropylether and allowing it to stir at 25°C to 30°C to obtain Form I.
- Form II is prepared by dissolving solid bortezomib in ethyl acetate while hot, allowing it to crystallize at 25 °C to 30°C to obtain Form II.
- WO 2009/036281 discloses Form A and Form B of bortezomib.
- WO '281 application describes that Form A is obtained from a solvent system of methanol and water and Form B is obtained by using a solvent system of one of either ethyl acetate or dichloromethane mixed with toluene.
- the present invention provides for polymorphic Form Al of bortezomib, which includes substantially the same XRPD pattern as depicted in Figure 1.
- the present invention provides for polymorphic Form Al of bortezomib, which includes an XRPD pattern wherein characteristic d-spacing values are obtained substantially at 12.37, 10.39, 8.72, 7.25, 6.69, 6.08, 5.59, 5.31, 4.83, 4.69, 4.55, 4.16 and 3.52.
- Embodiments of this aspect may include one or more of the following features.
- the polymorphic Form Al of bortezomib may further include substantially the same DSC thermogram as depicted in Figure 2, substantially the same FTIR as depicted in Figure 3, and/or a DSC thermogram wherein the DSC thermogram exhibits one melting endotherm between about 195°C and 205°C.
- the present invention provides for polymorphic Form A2 of bortezomib, which includes substantially the same XRPD pattern as depicted in Figure 4.
- the present invention provides for polymorphic Form A2 of bortezomib, which includes an XRPD pattern wherein characteristic d-spacing values are obtained substantially at 12.86, 12.27, 10.38, 8.79, 8.30, 7.26, 6.67, 6.05, 5.54, 5.36, 4.84, 4.66, 4.54, 4.15, 3.50 and 3.37.
- Embodiments of this aspect may include one or more of the following features.
- the polymorphic Form A2 of bortezomib may further include substantially the same DSC thermogram as depicted in Figure 5, a DSC thermogram wherein the DSC thermogram exhibits two melting endotherms between about 170°C and 185°C and about 195°C and 210°C, and /or substantially the same FTIR as depicted in Figure 6.
- the present invention provides for a process for the preparation of polymorphic Form Al of bortezomib.
- the process includes: a) treating bortezomib with a nitrile solvent; and
- Embodiments of the process may include one or more of the following features.
- the nitrile solvent may be acetonitrile or benzonitrile.
- the present invention provides for a process for the preparation of Form A2 of bortezomib.
- the process includes:
- Embodiments of the process may include one or more of the following features.
- the water-miscible ether solvent may be 1,4-dioxane or tetrahydrofuran.
- the water-miscible solvent may be a mixture with water.
- the present invention provides polymorphic Form Al of bortezomib.
- Form Al of bortezomib has substantially the same XRPD pattern as depicted in Figure 1.
- the XRPD of polymorphic Form Al of bortezomib shows characteristic d-spacing values
- Form Al of bortezomib has substantially the same DSC thermogram as depicted in Figure 2.
- the DSC thermogram of polymorphic Form Al of bortezomib exhibits one melting endotherm between about 195°C and 205°C.
- Form Al of bortezomib has substantially the same FTIR as depicted in Figure 3.
- the present invention also provides polymorphic Form A2 of bortezomib.
- Form A2 of bortezomib has substantially the same XRPD pattern as depicted in Figure 4.
- the XRPD of polymorphic Form A2 of bortezomib shows characteristic d-spacing values substantially at 12.86, 12.27, 10.38, 8.79, 8.30, 7.26, 6.67, 6.05, 5.54, 5.36, 4.84, 4.66, 4.54, 4.15, 3.50 and 3.37.
- Form A2 of bortezomib has substantially the same DSC thermogram as depicted in Figure 5.
- the DSC thermogram of polymorphic Form A2 of bortezomib exhibits two melting endotherms between about 170°C and 185°C and about 195°C and 210°C.
- Form A2 of bortezomib has substantially the same FTIR as depicted in Figure 6.
- the present invention also provides a process for the preparation of polymorphic Form Al of bortezomib, wherein the process includes:
- Bortezomib existing in any solid form for example, that prepared according to WO 2009/036281 and U.S. Publication No. 2005/0240047, can be used as a starting material.
- Bortezomib is treated with a nitrile solvent.
- the nitrile solvent may be acetonitrile or benzonitrile.
- the formation of polymorphic Form Al of bortezomib may be effected by stirring.
- the stirring may be carried out at a temperature of about 10°C to about 40°C, for example, at 15°C to about 30°C.
- the stirring may be carried out for about 30 minutes to about 50 hours, for example, for about 1 hour to about 5 hours.
- Polymorphic form Al of bortezomib may be isolated by filtration, decantation, solvent evaporation, or a combination thereof.
- the present invention also provides a process for the preparation of polymorphic Form A2 of bortezomib.
- the process includes:
- Bortezomib existing in any solid form can be used as a starting material.
- Bortezomib is treated with a water miscible ether solvent.
- the water-miscible ether solvent may be a cyclic ether, for example, 1,4-dioxane or tetrahydrofuran.
- the water-miscible ether solvent may also be a mixture with water.
- the formation of polymorphic Form A2 of bortezomib may be effected by stirring. The stirring may be carried out at a temperature of about 10°C to about 40°C, for example, at 15°C to about 30°C.
- Polymorphic Form A2 of bortezomib may be isolated by filtration, decantation, solvent evaporation, or a combination thereof.
- Powder XRD of the samples were determined using X-Ray diffractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Power: 40 KV, 100 Ma, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A.
- Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of polymorphic Form
- Figure 1A depicts the table of values for X-Ray Powder Diffractogram (XRPD) of Figure 1.
- Figure 2 depicts the Differential Scanning Calorimetry (DSC) thermogram of polymorphic Form Al of bortezomib.
- Figure 3 depicts the Fourier- TransForm Infra-red (FTIR) spectrum of polymorphic Form Al of bortezomib.
- FTIR Fourier- TransForm Infra-red
- Figure 4 depicts the X-Ray Powder Diffractogram (XRPD) of polymorphic Form A2 of bortezomib.
- Figure 4A depicts the table of values for X-Ray Powder Diffractogram (XRPD) of
- Figure 5 depicts the Differential Scanning Calorimetry (DSC) thermogram of polymorphic Form A2 of bortezomib.
- Figure 6 depicts the Fourier-TransForm Infra-red (FTIR) spectrum of polymorphic Form A2 of bortezomib.
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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 polymorphic forms of bortezomib. The polymorphic forms of the present invention are designated as Form A1 and Form A2 of bortezomib. The present invention also relates to processes for the preparation of the polymorphic Form A1 and Form A2 of bortezomib.
Description
POLYMORPHIC FORMS OF BORTEZOMIB
Field of Invention
The present invention relates to polymorphic forms of bortezomib. The polymorphic forms of the present invention are designated as Form Al and Form A2 of bortezomib. The present invention also relates to processes for the preparation of polymorphic Form Al and Form A2 of bortezomib.
Background of the Invention
The chemical name for bortezomib, the monomeric boronic acid, is [(lR)-3- methyl-l-[[(2S)-l-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid of Formula I.
Formula I
Bortezomib is available in the market for the treatment of patients with multiple myeloma and patients with mantle cell lymphoma.
WO 2008/075376 discloses a process for preparing crystalline Form I and Form II of bortezomib. Form I of bortezomib is prepared by dissolving bortezomib in acetone and allowing it to crystallize at 25°C to 30°C. Form I is also prepared by dissolving crystalline Form II in chloroform at 25°C to 30°C, adding diisopropylether and allowing it to stir at 25°C to 30°C to obtain Form I. Form II is prepared by dissolving solid bortezomib in ethyl acetate while hot, allowing it to crystallize at 25 °C to 30°C to obtain Form II. The crystalline Form I and Form II are characterized in WO '376 application by their XRPD, IR patterns, and DSC thermograms.
WO 2009/036281 discloses Form A and Form B of bortezomib. WO '281 application describes that Form A is obtained from a solvent system of methanol and water and Form B is obtained by using a solvent system of one of either ethyl acetate or dichloromethane mixed with toluene.
Summary of the Invention
In one general aspect, the present invention provides for polymorphic Form Al of bortezomib, which includes substantially the same XRPD pattern as depicted in Figure 1.
In another general aspect, the present invention provides for polymorphic Form Al of bortezomib, which includes an XRPD pattern wherein characteristic d-spacing values are obtained substantially at 12.37, 10.39, 8.72, 7.25, 6.69, 6.08, 5.59, 5.31, 4.83, 4.69, 4.55, 4.16 and 3.52.
Embodiments of this aspect may include one or more of the following features. For example, the polymorphic Form Al of bortezomib may further include substantially the same DSC thermogram as depicted in Figure 2, substantially the same FTIR as depicted in Figure 3, and/or a DSC thermogram wherein the DSC thermogram exhibits one melting endotherm between about 195°C and 205°C.
In another general aspect, the present invention provides for polymorphic Form A2 of bortezomib, which includes substantially the same XRPD pattern as depicted in Figure 4.
In another general aspect, the present invention provides for polymorphic Form A2 of bortezomib, which includes an XRPD pattern wherein characteristic d-spacing values are obtained substantially at 12.86, 12.27, 10.38, 8.79, 8.30, 7.26, 6.67, 6.05, 5.54, 5.36, 4.84, 4.66, 4.54, 4.15, 3.50 and 3.37.
Embodiments of this aspect may include one or more of the following features. For example, the polymorphic Form A2 of bortezomib may further include substantially the same DSC thermogram as depicted in Figure 5, a DSC thermogram wherein the DSC thermogram exhibits two melting endotherms between about 170°C and 185°C and about 195°C and 210°C, and /or substantially the same FTIR as depicted in Figure 6.
In another general aspect, the present invention provides for a process for the preparation of polymorphic Form Al of bortezomib. The process includes:
a) treating bortezomib with a nitrile solvent; and
b) isolating polymorphic Form Al of bortezomib from the mixture thereof.
Embodiments of the process may include one or more of the following features. For example, the nitrile solvent may be acetonitrile or benzonitrile.
In yet another general aspect, the present invention provides for a process for the preparation of Form A2 of bortezomib. The process includes:
a) treating bortezomib with a water-miscible ether solvent; and
b) isolating Form A2 of bortezomib from the mixture thereof.
Embodiments of the process may include one or more of the following features. For example, the water-miscible ether solvent may be 1,4-dioxane or tetrahydrofuran. The water-miscible solvent may be a mixture with water.
Detailed Description of the Invention
The present invention provides polymorphic Form Al of bortezomib. Form Al of bortezomib has substantially the same XRPD pattern as depicted in Figure 1. The XRPD of polymorphic Form Al of bortezomib shows characteristic d-spacing values
substantially at 12.37, 10.39, 8.72, 7.25, 6.69, 6.08, 5.59, 5.31, 4.83, 4.69, 4.55, 4.16 and 3.52. Form Al of bortezomib has substantially the same DSC thermogram as depicted in Figure 2. The DSC thermogram of polymorphic Form Al of bortezomib exhibits one melting endotherm between about 195°C and 205°C. Form Al of bortezomib has substantially the same FTIR as depicted in Figure 3.
The present invention also provides polymorphic Form A2 of bortezomib. Form A2 of bortezomib has substantially the same XRPD pattern as depicted in Figure 4. The XRPD of polymorphic Form A2 of bortezomib shows characteristic d-spacing values substantially at 12.86, 12.27, 10.38, 8.79, 8.30, 7.26, 6.67, 6.05, 5.54, 5.36, 4.84, 4.66, 4.54, 4.15, 3.50 and 3.37. Form A2 of bortezomib has substantially the same DSC thermogram as depicted in Figure 5. The DSC thermogram of polymorphic Form A2 of bortezomib exhibits two melting endotherms between about 170°C and 185°C and about 195°C and 210°C. Form A2 of bortezomib has substantially the same FTIR as depicted in Figure 6.
The present invention also provides a process for the preparation of polymorphic Form Al of bortezomib, wherein the process includes:
a) treating bortezomib with a nitrile solvent; and
b) isolating polymorphic Form Al of bortezomib from the mixture thereof.
Bortezomib existing in any solid form, for example, that prepared according to WO 2009/036281 and U.S. Publication No. 2005/0240047, can be used as a starting material. Bortezomib is treated with a nitrile solvent. The nitrile solvent may be acetonitrile or benzonitrile. The formation of polymorphic Form Al of bortezomib may be effected by stirring. The stirring may be carried out at a temperature of about 10°C to about 40°C, for example, at 15°C to about 30°C. The stirring may be carried out for about 30 minutes to about 50 hours, for example, for about 1 hour to about 5 hours.
Polymorphic form Al of bortezomib may be isolated by filtration, decantation, solvent evaporation, or a combination thereof.
The present invention also provides a process for the preparation of polymorphic Form A2 of bortezomib. The process includes:
a) treating bortezomib with a water-miscible ether solvent; and
b) isolating polymorphic Form A2 of bortezomib from the mixture thereof.
Bortezomib existing in any solid form, for example, that prepared according to WO 2009/036281 and U.S. Publication No. 2005/0240047, can be used as a starting material. Bortezomib is treated with a water miscible ether solvent. The water-miscible ether solvent may be a cyclic ether, for example, 1,4-dioxane or tetrahydrofuran. The water-miscible ether solvent may also be a mixture with water. The formation of polymorphic Form A2 of bortezomib may be effected by stirring. The stirring may be carried out at a temperature of about 10°C to about 40°C, for example, at 15°C to about 30°C. The stirring may be carried out for about 30 minutes to about 50 hours, for example, for about 1 hour to about 5 hours. Polymorphic Form A2 of bortezomib may be isolated by filtration, decantation, solvent evaporation, or a combination thereof.
Brief Description of the Drawings
Powder XRD of the samples were determined using X-Ray diffractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Power: 40 KV, 100 Ma, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A.
FTIR spectra of the samples were recorded on a Perkin-Elmer 16 PC instrument, as potassium bromide pellets.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of polymorphic Form
Al of bortezomib.
Figure 1A depicts the table of values for X-Ray Powder Diffractogram (XRPD) of Figure 1.
Figure 2 depicts the Differential Scanning Calorimetry (DSC) thermogram of polymorphic Form Al of bortezomib.
Figure 3 depicts the Fourier- TransForm Infra-red (FTIR) spectrum of polymorphic Form Al of bortezomib.
Figure 4 depicts the X-Ray Powder Diffractogram (XRPD) of polymorphic Form A2 of bortezomib.
Figure 4A depicts the table of values for X-Ray Powder Diffractogram (XRPD) of
Figure 4.
Figure 5 depicts the Differential Scanning Calorimetry (DSC) thermogram of polymorphic Form A2 of bortezomib.
Figure 6 depicts the Fourier-TransForm Infra-red (FTIR) spectrum of polymorphic Form A2 of bortezomib.
EXAMPLES
Example 1: Preparation of Polymorphic Form Al of Bortezomib
Bortezomib (1 g) was added to acetonitrile (10 ml) at 25 °C to 30°C to form a solution. The solution was stirred at 25°C to 30°C for 2 hours to obtain a solid, then filtered and washed with acetonitrile (5 ml). The filtered solid was vacuum dried at 40°C to 50°C for 3 hours to obtain the title product.
Yield : 0.70 g
Example 2: Preparation of Polymorphic Form A2 of Bortezomib
Bortezomib (1 g) was added to 1,4-dioxane (4 ml) and water (7 ml) at 25°C to
30°C to form a solution. The solution was stirred at 25°C to 30°C for 2.5 hours to obtain a solid, filtered and washed with water (2 ml). The filtered solid was vacuum dried at 40°C to 50°C to obtain the title product.
Yield : 0.66 g
Claims
1. A polymorphic Form Al of bortezomib comprising substantially the same XRPD pattern as depicted in Figure 1.
2. A polymorphic Form Al of bortezomib comprising an XRPD pattern wherein characteristic d-spacing values are obtained substantially at 12.37, 10.39, 8.72, 7.25, 6.69, 6.08, 5.59, 5.31, 4.83, 4.69, 4.55, 4.16 and 3.52.
3. A polymorphic Form Al of bortezomib according to claim 2, further comprising substantially the same DSC thermogram as depicted in Figure 2.
4. A polymorphic Form Al of bortezomib according to claim 2, further comprising substantially the same FTIR as depicted in Figure 3.
5. A polymorphic Form Al of bortezomib according to claim 2, further comprising a DSC thermogram wherein the DSC thermogram exhibits one melting endotherm between about 195°C and 205°C.
6. A polymorphic Form A2 of bortezomib comprising substantially the same XRPD pattern as depicted in Figure 4.
7. A polymorphic Form A2 of bortezomib comprising an XRPD pattern wherein characteristic d-spacing values are obtained substantially at 12.86, 12.27, 10.38, 8.79, 8.30, 7.26, 6.67, 6.05, 5.54, 5.36, 4.84, 4.66, 4.54, 4.15, 3.50 and 3.37.
8. A polymorphic Form A2 of bortezomib according to claim 7, further comprising substantially the same DSC thermogram as depicted in Figure 5.
9. A polymorphic Form A2 of bortezomib according to claim 7, further comprising a DSC thermogram wherein the DSC thermogram exhibits two melting endotherms between about 170°C and 185°C and about 195°C and 210°C.
10. A polymorphic Form A2 of bortezomib according to claim 7, further comprising substantially the same FTIR as depicted in Figure 6.
11. A process for the preparation of polymorphic Form Al of bortezomib, wherein the process comprises:
a) treating bortezomib with a nitrile solvent; and b) isolating polymorphic Form Al of bortezomib from the mixture thereof.
12. A process according to claim 11, wherein the nitrile solvent comprises acetonitrile or benzonitrile.
13. A process for the preparation of Form A2 of bortezomib, wherein the process comprises:
a) treating bortezomib with a water-miscible ether solvent; and
b) isolating Form A2 of bortezomib from the mixture thereof.
14. A process according to claim 13, wherein the water-miscible ether solvent comprises 1,4-dioxane or tetrahydrofuran.
15. A process according to claim 13, wherein the water-miscible solvent comprises a mixture with water.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN494DE2010 | 2010-03-04 | ||
| IN494/DEL/2010 | 2010-03-04 |
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| Publication Number | Publication Date |
|---|---|
| WO2011107912A1 true WO2011107912A1 (en) | 2011-09-09 |
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ID=43902631
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2011/050795 WO2011107912A1 (en) | 2010-03-04 | 2011-02-24 | Polymorphic forms of bortezomib |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012131707A2 (en) * | 2011-03-28 | 2012-10-04 | Laurus Labs Private Limited | Novel crystalline form of bortezomib, process for the preparation and pharmaceutical composition thereof |
| WO2014097306A1 (en) | 2012-12-21 | 2014-06-26 | Natco Pharma Limited | Stable and pure polymorphic form of bortezomib |
| AU2018221670B2 (en) * | 2017-02-17 | 2021-02-04 | Fresenius Kabi Oncology Ltd. | An improved process for the preparation of boronic acid esters |
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| US20050240047A1 (en) | 2004-03-30 | 2005-10-27 | Millennium Pharmaceuticals, Inc. | Synthesis of boronic ester and acid compounds |
| WO2008075376A1 (en) | 2006-12-18 | 2008-06-26 | Natco Pharma Limited | Polymorphic forms of bortezomib and process for their preparation |
| WO2009036281A2 (en) | 2007-09-12 | 2009-03-19 | Dr. Reddy's Laboratories Ltd. | Bortezomib and process for producing same |
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| WO2012131707A2 (en) * | 2011-03-28 | 2012-10-04 | Laurus Labs Private Limited | Novel crystalline form of bortezomib, process for the preparation and pharmaceutical composition thereof |
| WO2012131707A3 (en) * | 2011-03-28 | 2012-11-29 | Laurus Labs Private Limited | Crystalline form of bortezomib, preparation method and pharmaceutical composition there f |
| WO2014097306A1 (en) | 2012-12-21 | 2014-06-26 | Natco Pharma Limited | Stable and pure polymorphic form of bortezomib |
| AU2018221670B2 (en) * | 2017-02-17 | 2021-02-04 | Fresenius Kabi Oncology Ltd. | An improved process for the preparation of boronic acid esters |
| US11667654B2 (en) | 2017-02-17 | 2023-06-06 | Fresenius Kabi Oncology Ltd. | Process for the preparation of boronic acid esters |
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