WO2007135406A2 - Nouvelles formes d'un principe actif pharmaceutique - Google Patents

Nouvelles formes d'un principe actif pharmaceutique Download PDF

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Publication number
WO2007135406A2
WO2007135406A2 PCT/GB2007/001870 GB2007001870W WO2007135406A2 WO 2007135406 A2 WO2007135406 A2 WO 2007135406A2 GB 2007001870 W GB2007001870 W GB 2007001870W WO 2007135406 A2 WO2007135406 A2 WO 2007135406A2
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Prior art keywords
entacapone
polymorphic form
same
pattern
ray powder
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PCT/GB2007/001870
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English (en)
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WO2007135406A3 (fr
Inventor
Dijana Skalec Semec
Marina Marinkovic
Zvonimir Siljkovic
Michaela Horvat
Original Assignee
Pliva Hrvatska D.O.O.
Mcleish, Nicholas, Alistair, Maxwell
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Application filed by Pliva Hrvatska D.O.O., Mcleish, Nicholas, Alistair, Maxwell filed Critical Pliva Hrvatska D.O.O.
Publication of WO2007135406A2 publication Critical patent/WO2007135406A2/fr
Publication of WO2007135406A3 publication Critical patent/WO2007135406A3/fr

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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
    • 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 is concerned with new polymorphic forms of entacapone, in particular new polymorphic forms ⁇ , ⁇ , ⁇ , ⁇ , ⁇ , ⁇ and the amorphous form of entacapone, processes of preparing the forms, pharmaceutical compositions containing the same, therapeutic uses thereof and methods of treatment employing the same.
  • Polymorphic forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapour pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture a drug substance and a drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, polymorphism can affect the quality, safety, and efficacy of a drug product.
  • Polymorphic forms as referred to herein can include crystalline and amorphous forms as well as solvate and hydrate forms, which can be further characterised as follows.
  • Crystalline forms have different arrangements and/or conformations of the molecules in the crystal lattice.
  • Amorphous forms consist of disordered arrangements of molecules that do not possess a distinguishable crystal lattice.
  • Solvates are crystal forms containing either stoichiometric or non-stoichiometric amounts of a solvent. If the incorporated solvent is water, the solvate is commonly known as a hydrate.
  • Dynamic vapour sorption is a further method for characterising a polymorphic form.
  • DVS is a measure of the water vapour or moisture sorption of a material under varying conditions of humidity and it can be used as a measure of the hygroscopicity of a given material.
  • the water vapour or moisture sorption properties of pharmaceutical ingredients are recognised in the art as critical factors in determining the storage, stability, processing and application performance thereof. Moisture sorption properties are thus routinely determined for pharmaceutical materials and have traditionally been evaluated by storing samples over saturated salt solutions of established relative humidities and then regularly weighing until equilibrium is reached.
  • Drug substance polymorphic forms can exhibit different chemical, physical and mechanical properties as referred to above, including aqueous solubility and dissolution rate, hygroscopicity, particle shape, density, flowability, and compactibility, which in turn may affect processing of the drug substance and/or manufacturing of the drug product.
  • Polymorphs can also exhibit different stabilities. The most stable polymorphic form of a drug substance is often chosen during drug development based on the minimal potential for conversion to another polymorphic form and on its greater chemical stability. However, a meta-stable form can alternatively be chosen for various reasons, including bioavailability enhancement.
  • Entacapone cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N 3 N-diethyl-2-propenamide, can be represented by the following structural formula
  • Entacapone acts by increasing the bioavailability of levodopa and carvidopa, by facilitating the passage of these drugs across the blood-brain barrier. Entacapone is, therefore, employed in the treatment of Parkinson' s disease.
  • Entacapone can exist as a mixture of two geometrical isomers E and Z, as described in US5135950, which part is incorporated herein by reference.
  • Isomer E can exist as two distinct polymorphs Form A and B. It has been found that Form B is unstable and converts to Form A, even at room temperature. In addition it has been found that isomer Z is also relatively unstable and will, under certain conditions, convert to isomer E.
  • Polymorphically pure forms of entacapone form A, and processes for preparing them are described in US5135950.
  • WO2005/066117 discloses polymorphic Form C and Form D of entacapone and process for preparing them.
  • WO2005/063696 and WO2005/063695 discloses polymorphic Form C 5 Form D and Form E of entacapone and process for preparing them.
  • polymorphic forms of entacapone polymorphic form ⁇ , polymorphic form ⁇ , polymorphic form ⁇ , polymorphic form ⁇ , polymorphic form ⁇ , polymorphic form ⁇ and the amorphous form
  • the invention includes mixtures of the polymorphic forms which include at least 10% of one or more of the polymorphs described herein.
  • a polymorphic form ⁇ of entacapone characterised as having x-ray diffraction peaks (2 ⁇ ) ⁇ 0.2° of one or more (preferably 2, 3, 4 or 5) of the following: 6.7°, 12.5°, 13.1°, 13.6° and 18.4°.
  • the polymorphic form ⁇ may be further characterised as having one or more (preferably 2, 3, 4 or 5) additional x-ray diffraction peaks (2 ⁇ ) ⁇ 0.2°, selected from: 13.8°, 15.7°, 18.0°, 24.7°, and 26.1°.
  • a polymorphic form ⁇ of entacapone characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 1.
  • DSC differential scanning calorimetry
  • a polymorphic form ⁇ of entacapone characterised as having a phase transition in a temperature range of from 146 to 158 0 C. Melting onset occurs at a temperature of about 164°C ("about" being in particular +0.5 0 C).
  • a polymorphic form ⁇ of entacapone characterised as having x-ray diffraction peaks (2 ⁇ ) ⁇ 0.2° of one or more (preferably 2, 3, 4 or 5) of the following: 6.5°, 12.9°, 19.5°, 21.9° and 27.5°.
  • the polymorphic form ⁇ of entacapone may be further characterised as having one or more (preferably 2, 3, 4 or 5) additional x-ray diffraction peaks (2 ⁇ ) ⁇ 0.2°, selected from: 15.8°, 16.6°, 17.2°, 20.1°, and 24.0°.
  • a polymorphic form ⁇ of entacapone characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 4.
  • a polymorphic form ⁇ of entacapone characterised as having a thermo gravimetric analysis (TGA) thermogram, or substantially the same TGA thermogram, as Figure 6.
  • TGA thermo gravimetric analysis
  • a polymorphic form ⁇ of entacapone characterised as having a broad endothermic peak corresponding to solvent loss in a temperature range of from 58 to 88°C.
  • a phase transition occurs at a temperature range of from 157 to 159 °C.
  • Melting onset occurs at a temperature of about 163°C ("about” being in particular +0.5 0 C).
  • a polymorphic form ⁇ of entacapone characterised as having x-ray diffraction peaks (2 ⁇ ) ⁇ 0.2° of one or more (preferably 2, 3, 4 or 5) of the following: 6.2°, 10.2°, 12.5°, 16.4° and 19.4°.
  • the polymorphic form ⁇ of entacapone may be further characterised as having one or more (preferably 2, 3, 4 or 5) additional x-ray diffraction peaks (2 ⁇ ) +0.2° selected from: 12.2°, 16.9°, 21.3°, 21.7° and 23.4°.
  • a polymorphic form ⁇ of entacapone characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 8.
  • a polymorphic form ⁇ of entacapone characterised as having a thermo gravimetric analysis (TGA) thermogram, or substantially the same TGA thermogram, as Figure 10.
  • TGA thermo gravimetric analysis
  • a polymorphic form ⁇ of entacapone characterised as having a broad endothermic peak corresponding to solvent loss at a temperature range of from 90 to 135°C.
  • a phase transition occurs at a temperature range of from 150 to 161 0 C.
  • Melting onset occurs at a temperature of about 164°C ("about" being in particular +0.5 0 C).
  • a polymorphic form ⁇ of entacapone characterised as having x-ray diffraction peaks (2 ⁇ ) ⁇ 0.2° of one or more (preferably 2, 3, 4 or 5) of the following: 5.9°, 15.0°, 17.8°, 18.2° and 20.3°.
  • the polymorphic form ⁇ of entacapone may be further characterised as having one or more (preferably 2, 3, 4 or 5) additional x-ray diffraction peaks (2 ⁇ ) ⁇ 0.2°, selected from: 13.5°, 13.8°, 14.1°, 14.7° and 21.5°.
  • a polymorphic form ⁇ of entacapone characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 12.
  • a polymorphic form ⁇ of entacapone characterised by a vapour sorption of about 0.09 % at 70% relative humidity (RH).
  • DVS dynamic vapour sorption curve
  • a polymorphic form ⁇ of entacapone characterised as having a phase transition at a temperature range of from 148 to 15O 0 C. Melting onset occurs at a temperature of about 163 0 C ("about" being in particular +0.5°C).
  • a polymorphic form ⁇ of entacapone characterised by following single crystal parameters measured by single crystal X-ray diffraction at room temperature (293(2) K) using a Bruker Nonius FR591/Kappa CCD diffractometer with CuKa radiation and atomic coordinates and equivalent isotropic displacement parameters (Table 1) at room temperature (293(2) K).
  • U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
  • a polymorphic form ⁇ of entacapone characterised by following single crystal parameters measured by single crystal X-ray diffraction at temperature of 100 K using a Bruker Nonius FR591/Kappa CCD diffractometer with CuKa radiation and atomic coordinates and equivalent isotropic displacement parameters (Table 2) at temperature of 100 K.
  • U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
  • a polymorphic form ⁇ of entacapone characterised as having x-ray diffraction peaks (20) ⁇ 0.2° of one or more (preferably 2, 3, 4 or 5) of the following: 10.5°, 14.2°, 14.4°, 19.2° and
  • the polymorphic form ⁇ of entacapone may be further characterised as having one or more (preferably 2, 3, 4 or 5) additional x-ray diffraction peaks (2 ⁇ )+0.2°, selected from: 16.5°, 20.4°, 21.0°, 23.3° and 26.5°.
  • a polymorphic form ⁇ of entacapone characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 16.
  • a polymorphic form ⁇ of entacapone characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 17.
  • Amorphous entacapone may be further characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 18.
  • the process can comprise dissolving entacapone in any suitable solvent and precipitating the entacapone from solution with a suitable anti-solvent.
  • suitable solvents include lower alcohols (preferably ethanol, propanol or isopropanol), alkyl and cycloalkyl ketones (acetone or cyclohexanone), cyclic ethers (preferably dioxane, tetrahydrofuran
  • Suitable antisolvents include alkanes, cycloalkanes and water.
  • the interconversion comprises drying of a polymorphic form in vacuo over a prolonged period of time to yield a different polymorphic form.
  • the ⁇ form may be dried in vacuo over a prolonged period of time to yield the ⁇ form.
  • the present invention further provides, therefore, a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of a polymorphic form of entacapone as described herein, together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
  • Excipients are chosen according to the pharmaceutical form and the desired mode of administration.
  • terapéuticaally effective amount means an amount of a polymorphic form of entacapone according to the invention, which is capable of preventing, ameliorating or eliminating a disease state for which administration of entacapone, such as Parkinson's disease, is indicated.
  • pharmaceutically acceptable it is meant that the carrier, diluent or excipient is compatible with entacapone according to the invention, and not deleterious to a recipient thereof.
  • the present invention also provides:
  • a method of treating Parkinson's disease comprising the administration of a pharmaceutically effective amount of a polymorphic form of entacapone as described herein to a patient in need thereof.
  • treatment of Parkinson's disease also includes the prevention of the disease by administering the polymorphic form of entacapone according to the invention to patients at risk of developing Parkinson's disease.
  • compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration a polymorphic form of entacapone as described herein (or a mixture thereof) may be administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases.
  • the appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration.
  • the polymorphic form of entacapone as described herein can be used in creams, ointments or lotions.
  • the dose of the polymorphic form of entacapone as described herein can vary from 0.01 to 50 mg per kg of body weight per day.
  • Each unit dose can contain from 0.1 to 1000 mg, preferably 1 to 500 mg, of the polymorphic form of entacapone described herein in combination with a pharmaceutical carrier.
  • This unit dose can be administered 1, 2, 3, 4 or 5 times a day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg.
  • the polymorphic form of entacapone as described herein is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • the tablets can be coated with sucrose, a cellulose derivative or other appropriate substances, or else they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously.
  • a preparation in the form of gelatin capsules can be obtained by mixing a polymorphic form of entacapone as described herein with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
  • a preparation in the form of a syrup or elixir or for administration in the form of drops can contain a polymorphic form of entacapone as described herein typically in conjunction with a sweetener, which is preferably calorie-free, optionally antiseptics such as methylparaben and propylparaben, as well as a flavoring and an appropriate colour.
  • a sweetener which is preferably calorie-free, optionally antiseptics such as methylparaben and propylparaben, as well as a flavoring and an appropriate colour.
  • Water-dispersible granules or powders can contain a polymorphic form of entacapone as described herein mixed with dispersants or wetting agents, or suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.
  • Rectal administration is effected using suppositories prepared with binders which melt at the rectal temperature, for example polyethylene glycols.
  • Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.
  • pharmacologically compatible dispersants and/or wetting agents for example propylene glycol or butylene glycol.
  • a polymorphic form of entacapone substantially as hereinbefore described for use in therapy.
  • the present invention further provides a polymorphic form of entacapone substantially as hereinbefore described, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of entacapone, such as Parkinson's disease.
  • the present invention provides a polymorphic form of entacapone substantially as hereinbefore described, for use in the manufacture of a medicament for the treatment of Parkinson's disease.
  • XRPD X-ray powder diffraction
  • Figure 2 is a differential scanning calorimetry (DSC) thermogram of form ⁇ obtained by using a DSC Pyris 1 manufactured by Perkin-Elmer.
  • Figure 3 is a Fourier transform infrared (FTIR) spectrum of form ⁇ . obtained by using a KBr pelett and Spectrum GX manufactured by Perkin-Elmer.
  • FTIR Fourier transform infrared
  • Figure 5 is a DSC thermogram of form ⁇ obtained by using a DSC Pyris 1 manufactured by
  • FIG. 6 is a thermogravimetric analysis (TGA) thermogram of form ⁇ obtained by using a
  • FIG. 7 is a FTIR spectrum of form ⁇ obtained by using a KBr pelett and Spectrum GX manufactured by Perkin-Elmer
  • Figure 9 is a DSC thermogram of form ⁇ obtained by using a DSC Pyris 1 manufactured by Perkin-Elmer.
  • Figure 10 is a TGA thermogram of form ⁇ obtained by using a TGA 7 manufactured by Perkin-Elmer,
  • Figure 11 is a FTIR spectrum of form ⁇ obtained by using a KBr pelett and Spectrum GX manufactured by Perkin-EImer
  • Figure 13 is a DSC thermogram of form ⁇ obtained by using a DSC Pyris 1 manufactured by Perkin-Elmer.
  • Figure 14 is a FTIR spectrum of form ⁇ obtained by using a KBr pelett and Spectrum GX manufactured by Perkin-Elmer
  • Figure 15 is a dynamic vapour sorption (DVS) curve of form ⁇
  • the DVS data as described herein was obtained using the Dynamic Vapour Sorption (DVS) methodology developed by Surface Measurement Systems (SMS) Ltd. for the rapid quantitative analysis of the water sorption properties of solids including pharmaceutical materials.
  • the Surface Measurement Systems DVS instrument rapidly measures uptake and loss of moisture by flowing a carrier gas at a specified relative humidity (RH) over a sample (1 mg - 1.5 g) suspended from the weighing mechanism of a Cahn D-200 ultra sensitive recording microbalance.
  • This particular microbalance is used because it is capable of measuring changes in sample mass lower than 1 part in 10 million and provides the long-term stability as required for the accurate measurement of vapour sorption phenomena, which may take from minutes to days to complete depending upon the sample size and material.
  • a major factor in determining the water sorption behaviour of materials is the need to establish rapid water sorption equilibrium, therefore the DVS instrument allows sorption behaviour to be accurately determined on very small sample sizes (typically 10 mg), thus minimising the equilibration time required.
  • entacapone 1 g was dissolved in 3.8 ml of THF while heating. To the warm solution of entacapone 26.2 ml of cold n-hexane was added. The resulting suspension was filtered under vacuum yielding 920 mg of entacapone form ⁇ . Product was dried at 50 0 C for 15 hours.
  • EXAMPLE 7 1 g of entacapone was dissolved in 19 ml of an acetone/water mixture (ratio 12.5:1) and solution was heated to 60 0 C. The warm solution was added to 46 ml of water/acetone mixture (ratio 24.5) seeded with 11 mg of entacapone form D. The resulting suspension was dried under negative pressure and crystals were stirred in 47.5 ml of water for 10 min. Crystals were filtered and washed with water. 702 mg of entacapone form ⁇ was obtained.
  • EXAMPLE S 1 g of entacapone was dissolved in 5 ml of DMF. The solution was added dropwise to 40 ml of strongly stirred cold water. The obtained suspension was stirred for 2 hours while maintaining temperature at 5-8 0 C. Crystals were filtered and washed with 10 ml of cold water and 10 ml of diisopropyl ether, yielding 977 mg of entacapone form ⁇ .
  • entacapone 1 g was dissolved in 5 ml of DMA. The solution was added dropwise to 40 ml of cold water. The resulting suspension was stirred for 2 hours at 5-10 0 C. Crystals were filtered and washed with 10 ml of cold water and with 10 ml of diisopropyl ether yielding 963 mg of entacapone form ⁇ .
  • entacapone 1 g was dissolved in 5 ml of DMSO. Solution was added dropwise to 40 ml of cold water. Obtained suspension was stirred for 2 hours at 5-10 0 C. Crystals were filtered off and washed with 10 ml of cold water and with 10 ml of diisopropyl ether yielding 981 mg of entacapone form ⁇ .
  • entacapone 1 g was dissolved in 3.2 ml of THF while heating. The resulting solution was added dropwise to 25 ml of cold water. The suspension was stirred for 20 min and dried under negative pressure. 937 mg of entacapone form ⁇ was obtained.
  • EXAMPLE 15 2 g of entacapone was dissolved in 24 ml of cyclohexanone while heating. The solution was cooled to room temperature, filtered and added dropwise to 46 ml of 77-heptane seeded with 1 % of form ⁇ . A suspension of crystals was obtained and stirred for 1 hour at room temperature. The crystals were filtered, washed with 3-4 ml of 77-heptane and dried, yielding 1.508 g of entacapone form ⁇ .
  • EXAMPLE 20 The amorphous form of entacapone was obtained by cooling a melt of entacapone.

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Abstract

La présente invention concerne de nouvelles formes polymorphiques de l'entacapone, en particulier de nouvelles formes polymorphiques α, β, γ, δ, ε, τ et la forme amorphe de l'entacapone, ainsi que des procédés de synthèse desdites formes, des compositions pharmaceutiques les contenant, leurs applications thérapeutiques et des méthodes de traitement les utilisant.
PCT/GB2007/001870 2006-05-23 2007-05-21 Nouvelles formes d'un principe actif pharmaceutique WO2007135406A2 (fr)

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GBGB0610207.3A GB0610207D0 (en) 2006-05-23 2006-05-23 New forms of active pharmaceutical ingredient
GB0610207.3 2006-05-23

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1935873A1 (fr) * 2006-12-19 2008-06-25 Dipharma Francis S.r.l. Procédé de préparation d'entacapone

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
US5446194A (en) * 1986-11-28 1995-08-29 Orion-Yhtyma Oy Pharmacologically active catechol derivatives
WO2005063696A2 (fr) * 2003-12-31 2005-07-14 Cilag Ag Nouvelles formes cristallines d'entacapone et fabrication
WO2005066117A1 (fr) * 2003-12-29 2005-07-21 Wockhardt Limited Polymorphes stables de (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
US5446194A (en) * 1986-11-28 1995-08-29 Orion-Yhtyma Oy Pharmacologically active catechol derivatives
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 (fr) * 2003-12-29 2005-07-21 Wockhardt Limited Polymorphes stables de (e)-n,n-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide
WO2005063696A2 (fr) * 2003-12-31 2005-07-14 Cilag Ag Nouvelles formes cristallines d'entacapone et fabrication

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1935873A1 (fr) * 2006-12-19 2008-06-25 Dipharma Francis S.r.l. Procédé de préparation d'entacapone
US7750177B2 (en) 2006-12-19 2010-07-06 Dipharma Francis S.R.L. Process for the preparation of entacapone

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