WO2010079498A2 - Novel polymorph of sorafenib tosylate - Google Patents
Novel polymorph of sorafenib tosylate Download PDFInfo
- Publication number
- WO2010079498A2 WO2010079498A2 PCT/IN2009/000039 IN2009000039W WO2010079498A2 WO 2010079498 A2 WO2010079498 A2 WO 2010079498A2 IN 2009000039 W IN2009000039 W IN 2009000039W WO 2010079498 A2 WO2010079498 A2 WO 2010079498A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- sorafenib tosylate
- polymorph iii
- sorafenib
- polymorph
- iii
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
Definitions
- the present invention provides a novel polymorph of sorafenib tosylate, process for its preparation and to pharmaceutical composition containing it.
- Sorafenib and its salts are antineoplastic agents and were disclosed in WO Patent Publication No. 00/41698 and U.S. Patent Application No. 2003/139605.
- Sorafenib is known by the chemical name 4-[4-[[[[4-chloro-3-(tri- fluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarbox- amide. Sorafenib is represented by the following structure.
- 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.
- polymorphs are different crystalline forms 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.
- 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 a crystalline form over the other.
- XRD X-ray diffraction
- DSC Differential Scanning Calorimetry
- IR Infrared spectrometry
- Sorafenib tosylate can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
- WO Patent Publication No. 2007/053574 disclosed two polymorphs, polymorph I and polymorph Il of sorafenib tosylate.
- sorafenib tosylate polymorph Il was obtained by stirring a suspension of the sorafenib with p-toluenesulfonic acid in ethanol and sorafenib tosylate polymorph I was obtained by heating of sorafenib tosylate polymorph II.
- One object of the present invention is to provide a novel polymorph of sorafenib tosylate and a process for preparing it. According to another object of the present invention is to provide pharmaceutical compositions containing the novel polymorph of sorafenib tosylate.
- sorafenib tosylate polymorph III characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 9.7, 11.2, 13.1, 17.7, 18.4, 21.4, 22.7 and 24.6 ⁇ 0.2 degrees.
- the powdered x-ray diffractogram (PXRD) of sorafenib tosylate polymorph III is shown in figure 1.
- Sorafenib tosylate polymorph III of present invention is further characterized by a Differential Scanning Calorimetry (DSC) thermogram as shown in figure 2.
- DSC Differential Scanning Calorimetry
- sorafenib tosylate polymorph III which comprises stirring sorafenib tosylate with water and isolating sorafenib tosylate polymorph III.
- Sorafenib tosylate used in the process of the invention may be in any polymorph. Sorafenib tosylate may be stirred with water until conversion into sorafenib tosylate polymorph III occurs. The temperature is not critical during stirring. According to process of present invention, sorafenib tosylate polymorph III can be obtained in almost quantitative yield, simply by stirring with water.
- a pharmaceutical composition comprising sorafenib tosylate polymorph III and a pharmaceutically acceptable excipient.
- Preferable pharmaceutical composition of sorafenib tosylate polymorph III is a solid oral dosage form, comprising sorafenib tosylate polymorph III.
- Figure 1 is X-ray powder diffraction spectrum of sorafenib tosylate polymorph III.
- Figure 2 is Differential scanning calorimetry (DSC) thermogram of sorafenib tosylate polymorph III.
- DSC Differential scanning calorimetry
- Sorafenib tosylate (3 gm) was added to water (50 ml) at room temperature. The contents were stirred for 24 hours at room temperature and filtered. The solid obtained was washed with water (10 ml) and dried at room temperature for 48 hours to obtain 2.9 gm of sorafenib tosylate polymorph III.
- sorafenib tosylate 10 gm
- water 160 ml
- the solid obtained was washed with water (30 ml) and dried at room temperature for 48 hours to obtain 9.5 gm of sorafenib tosylate polymorph III.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention provides a novel polymorph of sorafenib tosylate, process for its preparation and to pharmaceutical composition containing it. Thus, for example, sorafenib tosylate was added to water, the contents were stirred at room temperature, the solid obtained was collected by filtration and dried to give sorafenib tosylate polymorph III.
Description
NOVEL POLYMORPH OF SORAFENIB TOSYLATE
FIELD OF THE INVENTION
The present invention provides a novel polymorph of sorafenib tosylate, process for its preparation and to pharmaceutical composition containing it.
BACKGROUND OF THE INVENTION
Sorafenib and its salts are antineoplastic agents and were disclosed in WO Patent Publication No. 00/41698 and U.S. Patent Application No. 2003/139605. Sorafenib is known by the chemical name 4-[4-[[[[4-chloro-3-(tri- fluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarbox- amide. Sorafenib is represented by the following structure.
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 forms 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 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 a crystalline form over the other.
Sorafenib tosylate can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
WO Patent Publication No. 2007/053574 disclosed two polymorphs, polymorph I and polymorph Il of sorafenib tosylate. According to WO Patent Publication No. 2007/053574, sorafenib tosylate polymorph Il was obtained by stirring a suspension of the sorafenib with p-toluenesulfonic acid in ethanol and sorafenib tosylate polymorph I was obtained by heating of sorafenib tosylate polymorph II.
We have discovered a stable novel polymorph of sorafenib tosylate.
One object of the present invention is to provide a novel polymorph of sorafenib tosylate and a process for preparing it. According to another object of the present invention is to provide pharmaceutical compositions containing the novel polymorph of sorafenib tosylate.
DETAILED DESCRIPTION OF THE INVENTION In accordance with one aspect of the present invention, there is provided a novel polymorph of sorafenib tosylate designated as polymorph III characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 9.7, 11.2, 13.1, 17.7, 18.4, 21.4, 22.7 and 24.6 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of sorafenib tosylate polymorph III is shown in figure 1.
Sorafenib tosylate polymorph III of present invention is further characterized by a Differential Scanning Calorimetry (DSC) thermogram as shown in figure 2.
In accordance with another aspect of the present invention, there is provided a process for preparing sorafenib tosylate polymorph III, which comprises stirring sorafenib tosylate with water and isolating sorafenib tosylate polymorph III.
Sorafenib tosylate used in the process of the invention may be in any polymorph. Sorafenib tosylate may be stirred with water until conversion into
sorafenib tosylate polymorph III occurs. The temperature is not critical during stirring. According to process of present invention, sorafenib tosylate polymorph III can be obtained in almost quantitative yield, simply by stirring with water.
In accordance with another aspect of the present invention, there is provided a pharmaceutical composition comprising sorafenib tosylate polymorph III and a pharmaceutically acceptable excipient.
Preferable pharmaceutical composition of sorafenib tosylate polymorph III is a solid oral dosage form, comprising sorafenib tosylate polymorph III.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is X-ray powder diffraction spectrum of sorafenib tosylate polymorph III.
Figure 2 is Differential scanning calorimetry (DSC) thermogram of sorafenib tosylate polymorph III. X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper-Kα radiation. Approximately 1gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.03 degrees to theta per step and a step of 0.5 seconds. 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.
DSC (Differential Scanning Calorimetry) measurements were performed with a DSC Q10 (TA Instruments, Inc.). About 3 mg of the powder was placed in an open aluminum pan and it was crimped with an aluminum lid. The crimped sample was then placed in the DSC cell opposite to empty aluminum pan (as reference) and the sample was scanned at 10 deg C/min from 50 deg C to 250 deg C.
The invention will now be further described by the following examples, which are illustrative rather than limiting.
Examples Example 1
Sorafenib tosylate (3 gm) was added to water (50 ml) at room temperature. The contents were stirred for 24 hours at room temperature and filtered. The solid obtained was washed with water (10 ml) and dried at room temperature for 48 hours to obtain 2.9 gm of sorafenib tosylate polymorph III.
Example 2
The mixture of sorafenib tosylate (10 gm) and water (160 ml) was stirred for 24 hours at room temperature and filtered. The solid obtained was washed with water (30 ml) and dried at room temperature for 48 hours to obtain 9.5 gm of sorafenib tosylate polymorph III.
Claims
We claim:
1. A sorafenib tosylate polymorph III, characterized by an X-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 9.7,
11.2, 13.1, 17.7, 18.4, 21.4, 22.7 and 24.6 ± 0.2 degrees. 2. The sorafenib tosylate polymorph III as claimed in claim 1, wherein the sorafenib tosylate polymorph III is further characterized by a differential scanning calorimetry thermogram as shown in figure 2. 3. A sorafenib tosylate polymorph III, characterized by an x-ray powder diffractogram as shown in figure 1. 4. A process for the preparation of sorafenib tosylate polymorph III as defined in claim 1, which comprises stirring sorafenib tosylate with water and isolating sorafenib polymorph III. 5. A pharmaceutical composition comprising sorafenib tosylate polymorph III of claim 1 and a pharmaceutically acceptable excipient. 6. The pharmaceutical composition as claimed in claim 5, wherein the pharmaceutical composition of sorafenib tosylate polymorph III is a solid oral dosage form.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2009/000039 WO2010079498A2 (en) | 2009-01-12 | 2009-01-12 | Novel polymorph of sorafenib tosylate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2009/000039 WO2010079498A2 (en) | 2009-01-12 | 2009-01-12 | Novel polymorph of sorafenib tosylate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2010079498A2 true WO2010079498A2 (en) | 2010-07-15 |
| WO2010079498A3 WO2010079498A3 (en) | 2011-11-17 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2009/000039 WO2010079498A2 (en) | 2009-01-12 | 2009-01-12 | Novel polymorph of sorafenib tosylate |
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| Country | Link |
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| WO (1) | WO2010079498A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013175483A1 (en) * | 2012-05-23 | 2013-11-28 | Shilpa Medicare Limited | Process for preparing crystalline sorafenib tosylate |
| JP2015522591A (en) * | 2012-07-18 | 2015-08-06 | ▲蘇▼州▲澤▼▲ジン▼生物制▲薬▼有限公司 | Deuterated ω-dimethylurea or polymorph of its salt |
| EP2806860B1 (en) * | 2012-01-23 | 2023-04-19 | Sandoz AG | Pharmaceutical composition containing crystalline sorafenib tosylate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006034797A1 (en) * | 2004-09-29 | 2006-04-06 | Bayer Healthcare Ag | Thermodynamically stable form of bay 43-9006 tosylate |
-
2009
- 2009-01-12 WO PCT/IN2009/000039 patent/WO2010079498A2/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006034797A1 (en) * | 2004-09-29 | 2006-04-06 | Bayer Healthcare Ag | Thermodynamically stable form of bay 43-9006 tosylate |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2806860B1 (en) * | 2012-01-23 | 2023-04-19 | Sandoz AG | Pharmaceutical composition containing crystalline sorafenib tosylate |
| WO2013175483A1 (en) * | 2012-05-23 | 2013-11-28 | Shilpa Medicare Limited | Process for preparing crystalline sorafenib tosylate |
| JP2015522591A (en) * | 2012-07-18 | 2015-08-06 | ▲蘇▼州▲澤▼▲ジン▼生物制▲薬▼有限公司 | Deuterated ω-dimethylurea or polymorph of its salt |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2010079498A3 (en) | 2011-11-17 |
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