WO2012110911A1 - Novel polymorphic form of teriflunomide - Google Patents
Novel polymorphic form of teriflunomide Download PDFInfo
- Publication number
- WO2012110911A1 WO2012110911A1 PCT/IB2012/050538 IB2012050538W WO2012110911A1 WO 2012110911 A1 WO2012110911 A1 WO 2012110911A1 IB 2012050538 W IB2012050538 W IB 2012050538W WO 2012110911 A1 WO2012110911 A1 WO 2012110911A1
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- WO
- WIPO (PCT)
- Prior art keywords
- teriflunomide
- preparation
- acetonitrile
- crystalline form
- solution
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/23—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same unsaturated acyclic carbon skeleton
Definitions
- the present invention relates to novel polymorphic form of Teriflunomide and preparation thereof. Specifically present invention relates to polymorphic form of Teriflunomide especially Form I.
- Teriflunomide 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide and formula is C 12 H 9 F 3 N 2 O 2 and molecular weight is 270.207.
- Teriflunomide is used as Immunosupressant. It acts as tyrosine kinase inhibitor. It is used in treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis.
- Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
- a single molecule may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum, thermogravimetric analysis ('TGA'), and differential scanning calorimetry ('DSC') which have been used to distinguish polymorphic forms.
- polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
- One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient.
- a drug that is unstable to conditions in the patient's stomach or intestine it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment.
- Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubility.
- Pharmaceutical compounds having different crystalline forms or polymorphs have different dissolution property. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
- composition is affected by the rate of delivery or the bioavailability of the pharmaceutically active substance is the crystalline forms or polymorphs. This relationship between crystalline forms or polymorphs and bioavailability is well known in the pharmaceutical industry and across a range of pharmaceutical products.
- Another object of the present invention is to provide a process for preparation of new crystalline Form I of Teriflunomide.
- Another object of the present invention is to provide a process for preparation of pure Teriflunomide.
- a new crystalline polymorphic Form I of Teriflunomide characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at 2 ⁇ at about 7.9, 10.1, 15.7, 15.9, 19.5, 20.0, 20.3, 24.7, 26.9, 27.9, 31.7 + 0.2 degrees 2 ⁇ .
- XRD X-ray powder diffraction
- Fig. 1 The XRD of crystalline polymorphic Form I of Teriflunomide is depicted in Fig. 1.
- Fig. 1 shows the X-ray powder diffraction pattern of new polymorph Form I of Teriflunomide.
- the present invention provides a polymorphic crystalline Form I of Teriflunomide characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at 2 ⁇ at about 7.9, 10.1, 15.7, 15.9, 19.5, 20.0, 20.3, 24.7, 26.9, 27.9, 31.7 + 0.2 degrees 2 ⁇ .
- XRD X-ray powder diffraction
- the present invention provides a process for preparation of a crystalline Form I of Teriflunomide comprising steps of:
- 'crystallizing means crystallizing compounds using methods known in the art. For example either reducing the volume of the solvent with respect to solute or decreasing the temperature of the solution or using both so as to crystallize the compound.
- Teriflunomide is dissolved or suspended in acetonitrile at about reflux temperature.
- the acetonitrile is taken 2 to 50 times the quantity of Teriflunomide.
- the solution is filtered through know filtration methods.
- the filtrate was kept at room temperature for crystallization.
- the precipitate were filtered and dried to give crystalline Form I of Teriflunomide.
- the present invention provides a process for preparation of pure Teriflunomide comprising steps of:
- 'treating' refers to suspending, dissolving or mixing and contacting or reacting of Teriflunomide with solvent or reagents followed by isolating Teriflunomide by removal of reagents and solvents.
- 'triturating' refers to suspending Teriflunomide in solvent and stirring for period of time sufficient for surface contact of solid with solvent and then filtering the compound from the mixture.
Abstract
The present invention provides a new polymorph Form I of Teriflunomide and a process for preparation thereof. The present invention provides a process for preparation of pure Teriflunomide.
Description
The present invention relates to novel
polymorphic form of Teriflunomide and preparation thereof.
Specifically present invention relates to polymorphic form
of Teriflunomide especially Form I.
The chemical name of Teriflunomide is
2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide
and formula is
C12H9F3N2O2
and molecular weight is 270.207.
Teriflunomide is used as Immunosupressant.
It acts as tyrosine kinase inhibitor. It is used in
treatment of rheumatoid arthritis, autoimmune disease and
multiple sclerosis.
Teriflunomide was first disclosed and
claimed in US patent no. 5,679,709 but this patent does
not mention any polymorphic form or process of preparation
for polymorphic form.
US 5,494,911, US 5,990,141 disclose various
processes for preparing Teriflunomide. These patents do
not disclose process for preparation Teriflunomide
polymorphic form or mention any its polymorphic form.
Polymorphism, the occurrence of different
crystal forms, is a property of some molecules and
molecular complexes. A single molecule, may give rise to a
variety of crystalline forms having distinct crystal
structures and physical properties like melting point, X-ray
diffraction pattern, infrared absorption fingerprint, and
solid state NMR spectrum, thermogravimetric analysis
('TGA'), and differential scanning calorimetry
('DSC') which have been used to distinguish
polymorphic forms.
The difference in the physical properties
of different crystalline forms results from the
orientation and intermolecular interactions of adjacent
molecules or complexes in the bulk solid. Accordingly,
polymorphs are distinct solids sharing the same molecular
formula yet having distinct advantageous physical
properties compared to other crystalline forms of the same
compound or complex.
One of the most important physical
properties of pharmaceutical compounds is their solubility
in aqueous solution, particularly their solubility in the
gastric juices of a patient. For example, where absorption
through the gastrointestinal tract is slow, it is often
desirable for a drug that is unstable to conditions in the
patient's stomach or intestine to dissolve slowly so
that it does not accumulate in a deleterious environment.
Different crystalline forms or polymorphs of the same
pharmaceutical compounds can and reportedly do have
different aqueous solubility. Pharmaceutical compounds
having different crystalline forms or polymorphs have
different dissolution property. It enlarges the repertoire
of materials that a formulation scientist has available
for designing, for example, a pharmaceutical dosage form
of a drug with a targeted release profile or other desired characteristic.
Pharmaceutical formulation is affected by
the rate of delivery or the bioavailability of the
pharmaceutically active substance is the crystalline forms
or polymorphs. This relationship between crystalline forms
or polymorphs and bioavailability is well known in the
pharmaceutical industry and across a range of
pharmaceutical products.
It is therefore, a need to develop novel
polymorphs of Teriflunomide so that it can be useful for formulation.
Present inventors have directed their
research work towards developing a process for the
preparation of Teriflunomide novel polymorphic forms thereof.
Present inventors have also directed their
research work towards developing a process for the
preparation of pure Teriflunomide.
It is therefore an object of the present
invention to provide new crystalline Form I of Teriflunomide.
Another object of the present invention is
to provide a process for preparation of new crystalline
Form I of Teriflunomide.
Another object of the present invention is
to provide a process for preparation of pure Teriflunomide.
According to one aspect of the present
invention, there is provided a new crystalline polymorphic
Form I of Teriflunomide characterized by an X-ray powder
diffraction (XRD) pattern having peaks expressed at 2θ at
about 7.9, 10.1, 15.7, 15.9, 19.5, 20.0, 20.3, 24.7, 26.9,
27.9, 31.7 +0.2 degrees 2θ.
The XRD of crystalline polymorphic Form I
of Teriflunomide is depicted in Fig. 1.
According to second aspect of the present
invention, there is provided a process for preparation of
a crystalline polymorphic Form I of Teriflunomide
comprising steps of:
- providing a solution or suspension of Teriflunomide in acetonitrile;
- crystallizing the product from the said solution;
- isolating crystalline Form I of Teriflunomide.
According to third aspect of the present
invention, there is provided a process for preparation of
pure Teriflunomide comprising steps of:
- treating Teriflunomide in acetonitrile;
- isolating Teriflunomide form the solution or suspension;
- triturating the Teriflunomide solid with acetonitrile.
Fig. 1 shows the X-ray powder diffraction
pattern of new polymorph Form I of Teriflunomide.
The present invention provides a
polymorphic crystalline Form I of Teriflunomide
characterized by an X-ray powder diffraction (XRD) pattern
having peaks expressed at 2θ at about 7.9, 10.1, 15.7,
15.9, 19.5, 20.0, 20.3, 24.7, 26.9, 27.9, 31.7 +0.2
degrees 2θ.
The XRD of polymorphic crystalline Form I
of Teriflunomide is depicted in Fig. 1.
The present invention provides a process
for preparation of a crystalline Form I of Teriflunomide
comprising steps of:
- providing a solution or suspension of Teriflunomide in acetonitrile;
- crystallizing the product from the said solution;
- isolating crystalline Form I of Teriflunomide.
Here the term 'crystallizing'
means crystallizing compounds using methods known in the
art. For example either reducing the volume of the solvent
with respect to solute or decreasing the temperature of
the solution or using both so as to crystallize the compound.
Teriflunomide is dissolved or suspended in
acetonitrile at about reflux temperature. The acetonitrile
is taken 2 to 50 times the quantity of Teriflunomide. The
solution is filtered through know filtration methods. The
filtrate was kept at room temperature for crystallization.
The precipitate were filtered and dried to give crystalline
Form I of Teriflunomide.
Analysis of this solid gives XRD which is
as shown in Fig. 1, XRD is recorded by X-pert-PRO RDAD-1044.
The present invention provides a process
for preparation of pure Teriflunomide comprising steps
of:
- treating Teriflunomide in acetonitrile;
- isolating Teriflunomide form the solution or suspension;
- triturating the Teriflunomide solid with acetonitrile.
The term 'treating' as used
hereinabove refers to suspending, dissolving or mixing and
contacting or reacting of Teriflunomide with solvent or
reagents followed by isolating Teriflunomide by removal of
reagents and solvents.
The term 'triturating' as used
hereinabove refers to suspending Teriflunomide in solvent
and stirring for period of time sufficient for surface
contact of solid with solvent and then filtering the
compound from the mixture.
The following examples illustrate the
invention further. It should be understood, however, that
the invention is not confined to the specific limitations
set forth in the individual examples but rather to the
scope of the appended claims.
Example-1
Preparation of polymorphic form I of Teriflunomide
Teriflunomide (5.0g) was dissolved in
acetonitrile (125ml). The mixture was stirred at reflux
temperature. The solution is filtered through celite bed.
The filtrate was kept overnight at room temperature for crystallization.
XRD of the compound is as shown in Fig. 1
Claims (5)
- A crystalline form of Teriflunomide.
- A polymorphic crystalline Form I of Teriflunomide characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at about 7.9, 10.1, 15.7, 15.9, 19.5, 20.0, 20.3, 24.7, 26.9, 27.9, 31.7 +0.2 degrees 2θ.
- A polymorphic crystalline Form I of Teriflunomide of claim 2, further characterized by an X-ray powder diffraction pattern as in Fig. 1.
- A process of preparation of a crystalline Form I of Teriflunomide as comprising steps of:(i) providing a solution or suspension of Teriflunomide in acetonitrile;(ii) crystallizing the product from the said solution;(iii) isolating crystalline Form I of Teriflunomide
- A process for preparation of pure Teriflunomide comprising steps of:(i) treating Teriflunomide in acetonitrile;(ii) isolating Teriflunomide form the solution or suspension;(iii) triturating the Teriflunomide solid with acetonitrile .
Applications Claiming Priority (2)
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IN459/MUM/2011 | 2011-02-18 | ||
IN459MU2011 | 2011-02-18 |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015029063A3 (en) * | 2013-08-30 | 2015-04-23 | Msn Laboratories Private Limited | Novel polymorph of (z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)-amide and process for the preparation thereof |
CN105272882A (en) * | 2014-07-23 | 2016-01-27 | 欣凯医药化工中间体(上海)有限公司 | Environmental-protection simple preparation method of teriflunomide |
WO2016203410A1 (en) * | 2015-06-17 | 2016-12-22 | Biocon Limited | A novel process for the preparation of teriflunomide |
WO2022128156A1 (en) | 2020-12-15 | 2022-06-23 | Pharmathen S.A. | Immediate release solid dosage form comprising teriflunomide and method of preparation thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5494911A (en) | 1990-05-18 | 1996-02-27 | Hoechst Aktiengesellschaft | Isoxazole-4-carboxamides and hydroxyalkylidenecyanoacetamides, pharmaceuticals containing these compounds and their use |
US5679709A (en) | 1985-09-27 | 1997-10-21 | Hoechst Aktiengesellschaft | Medicaments to combat autoimmune diseases |
US5990141A (en) | 1994-01-07 | 1999-11-23 | Sugen Inc. | Treatment of platelet derived growth factor related disorders such as cancers |
WO2009147624A2 (en) * | 2008-06-05 | 2009-12-10 | Alembic Limited | A process for preparing teriflunomide |
WO2011004282A2 (en) * | 2009-07-09 | 2011-01-13 | Alembic Limited | Novel polymorphic form of teriflunomide salts |
-
2012
- 2012-02-07 WO PCT/IB2012/050538 patent/WO2012110911A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5679709A (en) | 1985-09-27 | 1997-10-21 | Hoechst Aktiengesellschaft | Medicaments to combat autoimmune diseases |
US5494911A (en) | 1990-05-18 | 1996-02-27 | Hoechst Aktiengesellschaft | Isoxazole-4-carboxamides and hydroxyalkylidenecyanoacetamides, pharmaceuticals containing these compounds and their use |
US5990141A (en) | 1994-01-07 | 1999-11-23 | Sugen Inc. | Treatment of platelet derived growth factor related disorders such as cancers |
WO2009147624A2 (en) * | 2008-06-05 | 2009-12-10 | Alembic Limited | A process for preparing teriflunomide |
WO2011004282A2 (en) * | 2009-07-09 | 2011-01-13 | Alembic Limited | Novel polymorphic form of teriflunomide salts |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015029063A3 (en) * | 2013-08-30 | 2015-04-23 | Msn Laboratories Private Limited | Novel polymorph of (z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)-amide and process for the preparation thereof |
CN105272882A (en) * | 2014-07-23 | 2016-01-27 | 欣凯医药化工中间体(上海)有限公司 | Environmental-protection simple preparation method of teriflunomide |
CN105272882B (en) * | 2014-07-23 | 2019-05-31 | 欣凯医药化工中间体(上海)有限公司 | A kind of easy method for preparing Tai Rui meter Te of environmental protection |
WO2016203410A1 (en) * | 2015-06-17 | 2016-12-22 | Biocon Limited | A novel process for the preparation of teriflunomide |
EP3310755A4 (en) * | 2015-06-17 | 2019-02-27 | Biocon Limited | A novel process for the preparation of teriflunomide |
US10526279B2 (en) | 2015-06-17 | 2020-01-07 | Biocon Limited | Process for the preparation of teriflunomide |
RU2722316C2 (en) * | 2015-06-17 | 2020-05-29 | Биокон Лимитед | New method of producing teriflunomide |
WO2022128156A1 (en) | 2020-12-15 | 2022-06-23 | Pharmathen S.A. | Immediate release solid dosage form comprising teriflunomide and method of preparation thereof |
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