WO2008058992A1 - New crystalline form of entacapone and process for its preparation - Google Patents

New crystalline form of entacapone and process for its preparation Download PDF

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Publication number
WO2008058992A1
WO2008058992A1 PCT/EP2007/062331 EP2007062331W WO2008058992A1 WO 2008058992 A1 WO2008058992 A1 WO 2008058992A1 EP 2007062331 W EP2007062331 W EP 2007062331W WO 2008058992 A1 WO2008058992 A1 WO 2008058992A1
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Prior art keywords
entacapone
crystalline form
process according
solvent
organic solvent
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PCT/EP2007/062331
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French (fr)
Inventor
Francisco Eugenio Palomo Nicolau
Andrés Molina Ponce
Germán GARCIA RUIZ
Jordi Benet-Buchholz
Lluís SOLA CARANDELL
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Quimica Sintetica, S.A.
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Publication of WO2008058992A1 publication Critical patent/WO2008058992A1/en

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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
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the present invention relates to a novel stable crystalline form of Entacapone, herein denominated Form F.
  • the invention also relates to the process for preparing it and to pharmaceutical compositions containing it.
  • Entacapone is a COMT (Catechol-O-methyl-transfera -se) inhibitor indicated for Parkinson's disease, the E-isomer being used for therapeutic purposes. Its International non-propietary name is (2E) -2-cyano-3- (3, 4-dihydroxy-5-nitrophenyl) -N, N- diethyl-2-propenamide, and its structure is shown below:
  • Entacapone was disclosed for the first time in the US patent US 4,963,590 as a regioisomeric mixture of its geometric E/Z-isomers, though without specifying methods for separating them.
  • the process disclosed in the US patent 5,131,950 for preparing Form A of Entacapone comprises the crystallisation of the crude Entacapone (Z/E) in an aliphatic carboxylic acid with 1 or 2 atoms of carbon and contains a catalytic amount of HBr/HCl.
  • the Entacapone Form A thus obtained, as described in US patent 5,131,950, is a compound that contains a maximum of 3% of other polymorphic forms or of isomer Z .
  • the objective of the present invention is to provide a new stable and pure crystalline form of the compound
  • Entacapone that can be prepared simply and quickly, with a high yield, and is clearly characterisable and reproducible by crystallisation of Entacapone.
  • the object of the present invention is to provide a new polymorphic form of Entacapone (E-isomer) denominated Form F.
  • Another object of the present invention is to provide a method for obtaining said polymorphic form, Entacapone Form F .
  • Figure 1 shows the powder X-ray diffraction diagram for the new crystalline form object of the invention.
  • Figure 2 shows the infrared spectrum of the new crystalline form object of the invention, recorded by reflectance .
  • the authors thereof have, surprisingly, found a new stable and pure crystalline form of Entacapone suitable for use as an active ingredient in pharmaceutical compositions .
  • the new crystalline form of Entacapone, object of the invention is characterised by having the powder X-ray diffraction diagram of Figure 1, having peaks at the 2 ⁇ angles shown in Table 1.
  • a process for obtaining the new crystalline form of Entacapone which comprises the following steps: i) dissolving by heating the Entacapone product in an organic solvent or mixtures of organic solvents; ii) adding the solution obtained in step i) to a previously heated anti-solvent or mixtures of anti-solvents; iii) cooling the suspension obtained in step ii) ; and iv) isolating the precipitate obtained.
  • the Entacapone used as starting product is obtained by any process already described in the state of the art.
  • the Entacapone is dissolved in an organic solvent or a mixture of organic solvents, selected from tetrahydrofuran (THF) , dimethyl carbonate, toluene and chlorobenzene .
  • organic solvent selected from tetrahydrofuran (THF) , dimethyl carbonate, toluene and chlorobenzene .
  • THF tetrahydrofuran
  • dimethyl carbonate dimethyl carbonate
  • toluene toluene
  • chlorobenzene chlorobenzene
  • the solution is added to an anti-solvent or mixture of anti-solvents previously heated to a temperature above 50 0 C, selected from aliphatic hydrocarbons, e.g. heptane.
  • the suspension is cooled, firstly to room temperature, and then if desired down to 0 0 C.
  • the precipitate obtained is separated by vacuum filtration and dried in an oven with vacuum, preferably at 40-50 0 C, down to constant weight.
  • New crystalline Entacapone Form F is obtained in a stable form with a high yield and high purity. These features mean that the new polymorphic form is suitable for developing a pharmaceutical product.
  • the Entacapone Form F obtained according to the invention is E-entacapone essentially free from Z-entacapone, as determined by HPLC method.
  • the present invention is to provide a pharmaceutical composition that comprises the crystalline Form F of Entacapone according to the first object of the invention, together with one or more excipients or other auxiliary agents pharmaceutically acceptable.
  • Table 1 below shows the interplanar "d" spaces and the relative intensities that characterise the new crystalline form Entacapone Form F.
  • the infrared spectrum was obtained by grinding a mixture of the sample and KBr in an agate mortar, by means of reflectance, the sample content being 1%.
  • the characteristic peaks by IR that characterise the new crystalline form Entacapone Form F are:
  • IR (cm "1 ) 3143, 3076, 2984, 2940, 2209, 1632, 1615, 1597, 1537, 1459, 1441, 1418, 1386, 1366, 1313, 1283, 1255, 1213, 1158, 1099, 1088, 1072, 1026, 949, 577, 800, 775, 764, 746, 683, 644, 631, 612, 572.

Abstract

The invention relates to a new stable crystalline form of Entacapone, denominated Form F. It also relates to the process for preparing it and to the pharmaceutically acceptable composition that comprises it. The process comprises dissolving by heating the Entacapone product in an organic solvent; adding the solution obtained in the preceding step to a previously heated anti-solvent; cooling the suspension obtained; and isolating the precipitate so obtained by filtration, and then drying the product obtained until constant weight.

Description

NEW CRYSTALLINE FORM OF ENTACAPONE AND PROCESS FOR ITS PREPARATION
FIELD OF THE INVENTION
The present invention relates to a novel stable crystalline form of Entacapone, herein denominated Form F. The invention also relates to the process for preparing it and to pharmaceutical compositions containing it.
BACKGROUND OF THE INVENTION
Entacapone is a COMT (Catechol-O-methyl-transfera -se) inhibitor indicated for Parkinson's disease, the E-isomer being used for therapeutic purposes. Its International non-propietary name is (2E) -2-cyano-3- (3, 4-dihydroxy-5-nitrophenyl) -N, N- diethyl-2-propenamide, and its structure is shown below:
Figure imgf000003_0001
ENTACAPONE
Entacapone was disclosed for the first time in the US patent US 4,963,590 as a regioisomeric mixture of its geometric E/Z-isomers, though without specifying methods for separating them.
Later, US patent US 5,131,950 described a stable crystalline form denominated Entacapone Form A. According to this US patent, Entacapone is obtained as a mixture of its two geometric isomers E and Z in a proportion of 70-80% of isomer E and 30-20% of isomer Z. The authors of this patent likewise found that Entacapone (E-isomer) existed in two polymorphic Forms A and B, with the Z-isomer and the Form B being unstable.
The process disclosed in the US patent 5,131,950 for preparing Form A of Entacapone comprises the crystallisation of the crude Entacapone (Z/E) in an aliphatic carboxylic acid with 1 or 2 atoms of carbon and contains a catalytic amount of HBr/HCl. The Entacapone Form A thus obtained, as described in US patent 5,131,950, is a compound that contains a maximum of 3% of other polymorphic forms or of isomer Z .
We might also note that there are other patent applications that describe other crystalline forms of Entacapone, such as international applications WO 05/066117-A, WO 05/063695-A and WO 05/063696-A.
The objective of the present invention is to provide a new stable and pure crystalline form of the compound
Entacapone that can be prepared simply and quickly, with a high yield, and is clearly characterisable and reproducible by crystallisation of Entacapone.
BRIEF DESCRIPTION OF THE INVENTION
The object of the present invention is to provide a new polymorphic form of Entacapone (E-isomer) denominated Form F.
Another object of the present invention is to provide a method for obtaining said polymorphic form, Entacapone Form F .
It is also an object of the present invention to provide a pharmaceutical composition that includes the new polymorphic form object of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the powder X-ray diffraction diagram for the new crystalline form object of the invention.
Figure 2 shows the infrared spectrum of the new crystalline form object of the invention, recorded by reflectance .
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the first aspect of the present invention, the authors thereof have, surprisingly, found a new stable and pure crystalline form of Entacapone suitable for use as an active ingredient in pharmaceutical compositions .
The new crystalline form of Entacapone, object of the invention is characterised by having the powder X-ray diffraction diagram of Figure 1, having peaks at the 2Θ angles shown in Table 1.
The new crystalline form of Entacapone, object of the invention, presents the infrared spectrum of Figure 2.
In accordance with the second aspect of the invention, is provided a process for obtaining the new crystalline form of Entacapone, which comprises the following steps: i) dissolving by heating the Entacapone product in an organic solvent or mixtures of organic solvents; ii) adding the solution obtained in step i) to a previously heated anti-solvent or mixtures of anti-solvents; iii) cooling the suspension obtained in step ii) ; and iv) isolating the precipitate obtained.
The Entacapone used as starting product is obtained by any process already described in the state of the art.
The Entacapone is dissolved in an organic solvent or a mixture of organic solvents, selected from tetrahydrofuran (THF) , dimethyl carbonate, toluene and chlorobenzene . Preferably, it is dissolved in THF. The solution is heated at the reflux temperature of the solvent.
Once the Entacapone has been dissolved, the solution is added to an anti-solvent or mixture of anti-solvents previously heated to a temperature above 500C, selected from aliphatic hydrocarbons, e.g. heptane.
The suspension is cooled, firstly to room temperature, and then if desired down to 00C.
The precipitate obtained is separated by vacuum filtration and dried in an oven with vacuum, preferably at 40-500C, down to constant weight.
New crystalline Entacapone Form F is obtained in a stable form with a high yield and high purity. These features mean that the new polymorphic form is suitable for developing a pharmaceutical product.
Thus, the Entacapone Form F obtained according to the invention is E-entacapone essentially free from Z-entacapone, as determined by HPLC method. In still yet another aspect of the present invention is to provide a pharmaceutical composition that comprises the crystalline Form F of Entacapone according to the first object of the invention, together with one or more excipients or other auxiliary agents pharmaceutically acceptable.
The following diffractometer was used for recording the powder X-ray diffraction diagram:
XPERT PRO from PANALYTICAL
Copper Tube, at 40KV and 40 mA.
X CELERATOR Detector
Angular sweep of 2-45° Graphite monochromator . Automatic slit,
Table 1 below shows the interplanar "d" spaces and the relative intensities that characterise the new crystalline form Entacapone Form F.
Table 1 X-Ray diffraction peaks
Figure imgf000008_0001
The infrared spectrum was obtained by grinding a mixture of the sample and KBr in an agate mortar, by means of reflectance, the sample content being 1%. The characteristic peaks by IR that characterise the new crystalline form Entacapone Form F are:
IR (cm"1) : 3143, 3076, 2984, 2940, 2209, 1632, 1615, 1597, 1537, 1459, 1441, 1418, 1386, 1366, 1313, 1283, 1255, 1213, 1158, 1099, 1088, 1072, 1026, 949, 577, 800, 775, 764, 746, 683, 644, 631, 612, 572.
The purity of the new crystalline form of Entacapone object of the invention was determined by HPLC:
Column: Inertsil ODS-3V, 250 x 4.6 mm, 5 μm Wavelength: 304 nm. Flow: 1.0 ml/min. Temperature: 300C
Buffer: 0.1% aqueous solution of trifluoracetic acid. Mobile phase: gradient
Figure imgf000009_0001
Preparation of the samples: 0.2 mg/ml in mobile phase. Retention time: Isomer Z (13.4 min.); Isomer E (14.3 min.)
The following examples provide to illustrate one embodiment for obtaining the new crystalline Form F of Entacapone, though this does not limit the object defined in the attached claims.
EXAMPLES
Obtaining the new crystalline Entacapone Form F
Example 1. Entacapone (100 g) is added to THF (400 ml) and the mixture is heated to 60-65 0C. The solution obtained is added to heptane (4 litres) preheated to 60-70 0C, keeping the temperature within that range. The suspension obtained is cooled to r.t. and then to 0 0C. The precipitate obtained is isolated by vacuum filtration and dried in vacuum oven, providing 93.8 g (Yield = 93.8%).
Example 2. Entacapone (5 g) is added to dimethyl carbonate (45 ml) and the mixture is heated to 80-90 0C. The solution obtained is added to heptane (200 ml) preheated to 60-70 0C, keeping the temperature within that range. The suspension obtained is cooled to r.t. The precipitate obtained is isolated by vacuum filtration and dried in vacuum oven, providing 4.5 g (Yield = 90%).
Example 3. Entacapone (1 g) is added to Chlorobenzene (9 ml) and the mixture is heated to 120-130 0C. The solution obtained is slowly added to heptane (20 ml) preheated to 85-95 0C, keeping the temperature within that range. The suspension obtained is cooled to r.t. The precipitate obtained is isolated by vacuum filtration and dried in vacuum oven, providing 0.75 g (Yield = 75%).
Example 4. Entacapone (2 g) is added to toluene (88 ml) and the mixture is heated to 105-110 0C. The solution obtained is added to heptane (156 ml) preheated to 85-95 0C, keeping the temperature within that range. The suspension obtained is cooled to r.t. and then down to 0 0C. The precipitate obtained is isolated by vacuum filtration and dried in vacuum oven, providing 1.85 g (Yield = 92.5%).

Claims

C L A I M S
1. Crystalline form of Entacapone characterised by an X-ray diffraction diagram with the following characteristic peaks:
Figure imgf000011_0001
2. Crystalline form according to Claim 1, characterised in that it presents an X-ray diffraction diagram in accordance with Figure 1.
3. Crystalline form according to Claim 1, characterised by an infrared spectrum having the peaks: 3143, 3076, 2984, 2940, 2209, 1632, 1615, 1597, 1537, 1459, 1441, 1418, 1386, 1366, 1313, 1283, 1255, 1213, 1158, 1099, 1088, 1072, 1026, 949, 888, 877, 800, 775, 764, 746, 683, 644, 631, 612, 572 cm"1.
4. Crystalline form according to Claim 3, characterised in that it presents an infrared spectrum in accordance with Figure 2.
5. Process for preparing the crystalline form of
Entacapone according to any of claims 1 to 4, which comprises: i) dissolving by heating the Entacapone product in an organic solvent, or mixture of organic solvents; ii) adding the solution obtained in step i) to a previous heated anti-solvent or mixtures of anti-solvents; iii) cooling the suspension obtained in step ii) ; and iv) isolating the precipitate obtained.
6. Process according to Claim 5, wherein in said step i) the Entacapone is dissolved in at least one organic solvent selected from tetrahydrofuran (THF) , dimethyl carbonate, toluene and chlorobenzene, at the reflux temperature of said solvent.
7. Process according to Claim 6, wherein said organic solvent is THF.
8. Process according to Claim 5, wherein the antisolvent is selected from at least one aliphatic hydrocarbon .
9. Process according to Claim 8, wherein said antisolvent is heptane.
10. Process according to Claim 5, wherein said step ii) is carried out at a temperature above 500C.
11. Process according to Claim 5, wherein in said step iii) the suspension is cooled to room temperature.
12. Process according to Claim 5, wherein in said step iv) the precipitate is isolated by vacuum filtration, and then dried at 40-500C until constant weight.
13. Pharmaceutical composition characterised in that it comprises a therapeutically effective amount of the crystalline Entacapone Form F according to any of claims 1 to 4, in association with at least an inert diluent pharmaceutically acceptable.
PCT/EP2007/062331 2006-11-15 2007-11-14 New crystalline form of entacapone and process for its preparation WO2008058992A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5135950A (en) * 1989-11-03 1992-08-04 Orion-Yhtyma Oy Stable polymorphic form of (e)-n,n-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide and the process for its preparation
WO2005063696A2 (en) * 2003-12-31 2005-07-14 Cilag Ag Novel crystalline forms of entacapone and production thereof
WO2005063695A1 (en) * 2003-12-31 2005-07-14 Cilag Ag Novel crystalline forms of entacapone, and production thereof
WO2005066117A1 (en) * 2003-12-29 2005-07-21 Wockhardt Limited Stable polymorphs of (e)-n,n-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5135950A (en) * 1989-11-03 1992-08-04 Orion-Yhtyma Oy Stable polymorphic form of (e)-n,n-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide and the process for its preparation
WO2005066117A1 (en) * 2003-12-29 2005-07-21 Wockhardt Limited Stable polymorphs of (e)-n,n-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide
WO2005063696A2 (en) * 2003-12-31 2005-07-14 Cilag Ag Novel crystalline forms of entacapone and production thereof
WO2005063695A1 (en) * 2003-12-31 2005-07-14 Cilag Ag Novel crystalline forms of entacapone, and production thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CAIRA M R: "CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS", TOPICS IN CURRENT CHEMISTRY, SPRINGER, BERLIN, DE, vol. 198, 1998, pages 163 - 208, XP001156954, ISSN: 0340-1022 *

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