WO2009140484A1 - Procédés de préparation d’une substance médicamenteuse amorphe - Google Patents

Procédés de préparation d’une substance médicamenteuse amorphe Download PDF

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Publication number
WO2009140484A1
WO2009140484A1 PCT/US2009/043936 US2009043936W WO2009140484A1 WO 2009140484 A1 WO2009140484 A1 WO 2009140484A1 US 2009043936 W US2009043936 W US 2009043936W WO 2009140484 A1 WO2009140484 A1 WO 2009140484A1
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Prior art keywords
dimethylpyrrolidine
dimethoxyphenyl
indol
methoxyphenyl
sulfonyl
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PCT/US2009/043936
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English (en)
Inventor
Olivier Monnier
Jean-Rene Authelin
Rim Daoussi
Nancy Midoux
Khawla Abdullah Abu-Izza
John D. Higgins
John Mcgurk
William L. Rocco
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Sanofi-Aventis
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Publication of WO2009140484A1 publication Critical patent/WO2009140484A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient

Definitions

  • the present invention relates to processes for preparing amorphous l-[5-chloro-l- [(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4- hydroxy-N,N-dimethylpyrrolidine-2-carboxamide, a pharmacological agent possessing affinity for the VIb receptors of arginine-vasopressin (AVP).
  • AVP arginine-vasopressin
  • (I) is a selective antagonist of Vu, receptors.
  • the preparation, physical properties and beneficial pharmacological properties of l-[5-chloro-l-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2- methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2- carboxamide are described in, for example, U.S. Patent No. 6,730,695.
  • Amorphous forms of drugs often have greater solubility and dissolution rates, and in some cases different bioavailability patterns, as compared to crystalline or semi-crystalline forms.
  • amorphous solid forms are usually less physically stable than crystalline or semi-crystalline forms. This increased instability is caused, at least in part, by a considerable increase in the amount of water that may be taken up by an amorphous form relative to that of a crystalline form of the same chemical entity (see e.g. Ahlneck et al, InternationalJournal of ' Pharmaceutics, 62 (1990) 87-95).
  • the amorphous form of the present invention is unexpectedly less hygroscopic than semi- crystalline 1 -[5-chloro- 1 -[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3- dihydro-lH-indol-3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide.
  • the present invention relates to processes for preparing amorphous 1 -[5-chloro- 1-
  • the spray drying process comprises: a) dissolving 1 -[5-chloro- 1 -[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3- dihydro-lH-indol-3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide in a suitable solvent to form a feed solution; b) pumping the feed solution through an atomizer; and c) removing the solvent to form the amorphous form.
  • the suitable solvent comprises one or more solvents selected from the group consisting of dichloromethane, chloroform, ethanol, methanol, 2-propanol, ethyl acetate, acetone, or mixtures thereof, and mixtures thereof with water.
  • the suitable solvent comprises a mixture of dichloromethane and ethanol.
  • Another aspect of the invention is a process of preparing an amorphous form of l-[5- chloro-l-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol- 3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide comprising drum drying a solution comprising 1 -[5-chloro- 1 -[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3- dihydro-lH-indol-3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide to form an amorphous form of 1 -[5-chloro- l-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxypheny
  • the drum drying process comprises: a) dissolving 1 -[5-chloro- 1 -[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3- dihydro-lH-indol-3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide in a suitable solvent to form a feed solution; b) pumping the feed solution on heated rotating cylinders; and c) removing the solvent to form the amorphous form.
  • the suitable solvent comprises a solvent selected from the group consisting of dichloromethane, methyl acetate, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran or mixtures thereof, and mixtures thereof with water.
  • a solvent selected from the group consisting of dichloromethane, methyl acetate, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran or mixtures thereof, and mixtures thereof with water.
  • Another aspect of the invention is a process of preparing an amorphous form of l-[5- chloro-l-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol- 3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide comprising: a) dissolving 1 -[5-chloro- 1 -[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3- dihydro-lH-indol-3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide in a suitable solvent to form a feed solution; b) mixing the feed solution at a rate between about 0.5 and about 1 ml/minute with a supercritical fluid at a rate between about 20 and about 30
  • the supercritical fluid is supercritical carbon dioxide.
  • the suitable solvent comprises a solvent selected from the group consisting of dichloromethane, 2-propanol, ethyl acetate, acetone, toluene, and mixtures thereof.
  • Another aspect of the invention is a process for preparing an amorphous form of l-[5- chloro-l-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol- 3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide comprising freeze drying a solution comprising 1 -[5-chloro- 1 -[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3- dihydro-lH-indol-3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide to form an amorphous form of 1 -[5-chloro- l-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxypheny
  • the freeze drying process comprises: a) dissolving 1 -[5-chloro- 1 -[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3- dihydro-lH-indol-3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide in a suitable solvent to form a solution; and b) removing the solvent from the solution via freeze-drying.
  • the suitable solvent comprises a solvent selected from the group consisting of ethanol, tert-butanol, acetonitrile, acetic acid, dimethyl sulfoxide, isopropanol, or mixtures thereof, and mixtures thereof with water.
  • the amorphous form of l-[5-chloro-l-[(2,4- dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4- hydroxy-N,N-dimethylpyrrolidine-2-carboxamide prepared according to the processes of the present invention contains less than about 10% by weight, preferably less than 5% by weight, and more preferably is essentially free of crystalline l-[5-chloro-l-[(2,4- dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4- hydroxy-N,N-dimethylpyrrolidine-2-carboxamide.
  • FIGURE 1 shows X-ray powder diffractograms of amorphous l-[5-chloro-l-[(2,4- dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4- hydroxy-N,N-dimethylpyrrolidine-2-carboxamide.
  • FIGURE 2 shows dissolution testing results comparing the solubility/dissolution rates of amorphous l-[5-chloro-l-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3- dihydro- lH-indol-3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide and semi- crystalline l-[5-chloro-l-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3- dihydro-lH-indol-3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide in aqueous 0.1% sodium lauryl sulfate.
  • FIGURE 3 shows averaged hygroscopicity testing results for samples of amorphous l-[5- chloro-l-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol- 3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide and semi-crystalline l-[5-chloro-l- [(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4- hydroxy-N,N-dimethylpyrrolidine-2-carboxamide.
  • FIGURES 4A and 4B show photomicrographs of amorphous solid l-[5-chloro-l-[(2,4- dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4- hydroxy-N,N-dimethylpyrrolidine-2-carboxamide under unstressed ( Figure 4A) and stressed ( Figure 4B) conditions.
  • FIGURE 5 shows an X-ray powder diffractogram of semi-crystalline l-[5-chloro-l-[(2,4- dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4- hydroxy-N,N-dimethylpyrrolidine-2-carboxamide.
  • drug substance refers to l-[5-chloro-l-[(2,4- dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4- hydroxy-N,N-dimethylpyrrolidine-2-carboxamide.
  • Amorphous means a solid that it is in a non-crystalline state. Amorphous solids generally possess crystal-like short range molecular arrangement, but no long range order of molecular packing as are found in crystalline solids.
  • the solid state form of a solid such as the amorphous form of l-[5-chloro-l-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)- 2-0X0-2, 3-dihydro-lH-indol-3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide, may be determined by Polarized Light Microscopy, X-Ray Powder Diffraction (XPRD), Differential Scanning Calorimetry (DSC), or other standard techniques known to those of skill in the art.
  • XPRD X-Ray Powder Diffraction
  • DSC Differential Scanning Calorimetry
  • the amorphous form of l-[5-chloro-l-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2- methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2- carboxamide prepared in accordance with the present invention preferably contains less than about 10% by weight of crystalline forms of the drug substance, and more preferably is essentially free of crystalline forms of the drug substance.
  • essentially free of crystalline forms of the drug substance it is meant that no crystalline forms of the drug substance can be detected within the limits of a conventional powder X-ray diffractometer, such as described herein.
  • the amorphous form of l-[5-chloro-l-[(2,4- dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4- hydroxy-N,N-dimethylpyrrolidine-2-carboxamide prepared according to the processes of the invention is substantially free of impurities.
  • substantially free it is meant that the amorphous form of the drug substance contains less than 10% by weight, preferably less than 5% by weight, and more preferably less than 2% by weight, of impurity or impurities.
  • micro-crystalline refers to a mixture of crystalline drug substance with amorphous drug substance and/or crystalline material that is a solvate or hydrate, wherein at least about 10% to less than 100% by weight of the drug substance is in crystalline form.
  • the amorphous form of l-[5-chloro-l-[(2,4- dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4- hydroxy-N,N-dimethylpyrrolidine-2-carboxamide is prepared by dissolving the drug substance in a suitable solvent to form a feed solution and then spray drying the feed solution to form an amorphous form of the drug substance.
  • a "suitable solvent,” as used herein, is a solvent or mixture of solvents in which the drug substance has adequate solubility, e.g.
  • solubility that is greater than about 1 mg/ml.
  • suitable solvents for spray drying include dichloromethane, chloroform, ethanol, methanol, 2-propanol, ethyl acetate, acetone, or mixtures thereof, which includes mixtures with water.
  • a particular solvent is a mixture of dichloromethane and ethanol.
  • Spray drying is a process well known to those skilled in the art.
  • the amorphous solid of the drug substance is formed by dispersing or dissolving the drug substance in a suitable solvent to form a feed solution, pumping the feed solution through an atomizer into a drying chamber, and removing the solvent to form the amorphous solid in the drying chamber.
  • a drying chamber uses hot gases, such as forced air, nitrogen, nitrogen-enriched air, or argon to dry particles.
  • the feed solution can be atomized by conventional means well known in the art, such as a two-fluid sonicating nozzle, a two-fluid non-sonicating nozzle, and the like.
  • the drug is dissolved or dispersed in the suitable solvent at a concentration between about 0.1% w/v to about 25% w/v.
  • the amorphous form of l-[5-chloro-l-[(2,4- dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4- hydroxy-N,N-dimethylpyrrolidine-2-carboxamide is prepared using conventional drum drying techniques.
  • the amorphous solid of the drug substance is formed by dispersing or dissolving the drug substance in a suitable solvent or a mixture of solvents to form a feed solution, pumping the feed solution on heated rotating cylinders, and removing the solvent to form the amorphous solid, such as in a drying chamber.
  • a suitable solvent or a mixture of solvents such as in a drying chamber.
  • the drying chamber is generally placed under vacuum.
  • suitable solvents for drum drying include dichloromethane, methyl acetate, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran or mixtures thereof, which includes mixtures with water.
  • Preferred solvent mixtures include acetone and water and methyl ethyl ketone with a small amount of water, e.g. less than about 10% water in methyl ethyl ketone (v/v).
  • the amorphous form of l-[5-chloro-l-[(2,4- dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4- hydroxy-N,N-dimethylpyrrolidine-2-carboxamide is prepared by crystallization using supercritical fluids.
  • the l-[5-chloro-l-[(2,4- dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4- hydroxy-N,N-dimethylpyrrolidine-2-carboxamide is prepared by dissolving the drug substance in a suitable solvent to form a feed solution and then mixing the feed solution with a supercritical fluid, for example supercritical carbon dioxide (CO 2 ) in a vessel at a temperature between about 60 and about 90 0 C and a pressure between about 80 and about 200 bars.
  • a supercritical fluid for example supercritical carbon dioxide (CO 2 ) in a vessel at a temperature between about 60 and about 90 0 C and a pressure between about 80 and about 200 bars.
  • the feeding rate of the supercritical CO 2 is between about 20 and about 30 ml/minute, whereas the feeding rate of the solution is between about 0.5 and about 1 ml/
  • the solvent is extracted with supercritical CO 2 to allow the formation of the amorphous form of l-[5-chloro-l-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2- oxo-2,3-dihydro-lH-indol-3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide.
  • the powder obtained is dried by passing supercritical CO 2 through the powder.
  • Examples of preferred suitable solvents for the supercritical fluid process include dichloromethane, 2-propanol, ethyl acetate, acetone, toluene, and the like.
  • a more preferred suitable solvent is dichloromethane.
  • the amorphous form of l-[5-chloro-l-[(2,4- dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4- hydroxy-N,N-dimethylpyrrolidine-2-carboxamide is prepared by conventional freeze drying methods.
  • a preferred freeze-drying process of the present invention involves dissolving the drug substance in a suitable solvent and then removing the solvent via freeze-drying.
  • Examples of preferred suitable solvents for the freeze-drying process include ethanol, tert- butanol, acetonitrile, acetic acid, dimethyl sulfoxide, isopropanol, or mixtures thereof, which includes mixtures with water.
  • Suitable l-[5-chloro-l-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2- oxo-2,3-dihydro-lH-indol-3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide starting material for the herein described procedures includes, but is not limited to, l-[5-chloro-l- [(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4- hydroxy-N,N-dimethylpyrrolidine-2-carboxamide prepared by the procedures described in
  • the amorphous drug substance was prepared according to the procedure described in Example 1, above. However, dichloromethane was used as the solvent instead of a mixture of dichloromethane and ethanol.
  • Drum drying preparation of amorphous drug substance 4.5 kg of the drug substance were dissolved in 4.5 kg of methyl acetate at room temperature.
  • the resulting clear feed solution was pumped over 2 contrarotating cylinders (rotation speed 5 rpm) of a vacuum bicylinder drum dryer at a mean feed rate of 16.8 kg of solution/hour.
  • the cylinder temperature was approximately 80 0 C and the pressure was approximately 60 mbar.
  • 4.6 kg of product containing about 5% of methyl acetate were obtained.
  • the residual solvent was further removed by vacuum drying to provide the desired amorphous solid.
  • Drum drying preparation of amorphous drug substance 5O g of the drug substance were dissolved in 50 g of methylene chloride at room temperature.
  • the resulting clear feed solution was pumped over 2 contrarotating cylinders (rotation speed 5 rpm) of a vacuum bicylinder drum dryer at a mean feed rate of 2.4 kg of solution/hour.
  • the cylinder temperature was approximately 82°C and the pressure was approximately 85 mbar. 40.5 g of product containing about 1% of solvent were obtained.
  • the residual solvent was further removed by vacuum drying to provide the desired amorphous solid.
  • Solutions of 4% of drug substance (weight/weight) were mixed with organic co- solvent (either 80%, 90%, or 100% tertbutylalcoho I/water) and placed in 3 ml, glass-tubing vials.
  • organic co- solvent either 80%, 90%, or 100% tertbutylalcoho I/water
  • the batch for freeze-drying runs contained 20 vials, each of them filled with 2 ml of solution corresponding to an initial product thickness of about 10 mm.
  • the vials were semi- stoppered and carefully deposited in rows on an aluminum tray in a freeze dryer.
  • the freeze-dryer used was a model SMH45 manufactured by Usifroid (France).
  • the freeze-drying chamber contained 3 shelves providing a total shelf area of 0.45m 2 .
  • the freeze- dryer-chamber had a volume equal to 120 L and the total pressure values were measured with a capacitance manometer MKS Baratron 622 (MKS instruments, USA).
  • MKS Baratron 622 MKS instruments, USA.
  • This sensor was connected to an acquisition system 2700 (Keithley instruments, USA) in order to record all necessary data.
  • a rapid closing pneumatic butterfly valve was used to isolate the condenser from the sublimation chamber.
  • the products obtained appeared to be 100% amorphous by X-Ray Power
  • the resulting clear feed solution was pumped into a crystallization vessel at a flow rate of 0.2 ml/min. Simultaneously, a liquid solution of CO 2 was pumped in the crystallization vessel at a flow rate of 10 ml/min.
  • the vessel was placed in temperature and pressure conditions so that the mixture of the two solutions was supercritical. The pressure was fixed at 120 bars, and the temperature of the vessel was fixed at 60 0 C.
  • the powder obtained was dried by passing supercritical CO 2 through the powder. 0.31 g of the desired product was obtained. The product appeared to be 100% amorphous by X-Ray Power Diffractometry.
  • XRPD patterns for Examples 1 and 2 and semi-crystalline drug substance are obtained with a Bruker D8 ® ADVANCE X-ray powder diffractometer using copper K-alpha radiation.
  • the instrument is equipped with parallel beam optics, and the tube voltage and amperage are set to 40 kV and 40 mA, respectively. Samples are scanned at a rate of 1.0 degree/minute from 2 to 40 degrees in angle 2-theta.
  • Example 2 (upper curve) demonstrates the amorphous nature of the material.
  • An X-ray powder diffraction pattern for semi-crystalline drug substance is shown in
  • Dissolution tests of Example 1 and semi-crystalline drug substance were conducted with a paddle-type drug dissolution testing bath (available from Distek Inc.) at 75 rpm and a HP 8453 UV brand spectrophotometer at a wavelength of 280 nm.
  • the following parameters were used: the drug substance concentration was 100 mg/L media, the dissolution media was 0.1% sodium lauryl sulfate in water, and the temperature was 37 0 C.
  • the percent dissolved was determined by UV absorbance from 0 to 60 minutes at 10 minute intervals.
  • Hygroscopicity tests were conducted on samples of amorphous drug substance and semi-crystalline drug substance. Hygroscopicity of these samples was measured with a VTI moisture sorption system. The samples were predried at 6O 0 C and run from 5 to 95% relative humidity at 25 0 C. Equilibrium criteria was 0.01 wt % in 5 minutes.
  • Figure 3 shows the resulting averaged hygroscopicity for two samples of amorphous drug substance versus three samples of semi-crystalline drug substance.
  • the data illustrate the lower moisture uptake for the amorphous material versus the higher moisture uptake for the semi-crystalline material.
  • Samples of the amorphous form of the drug substance were stored at 40°C/75% relative humidity in open glass vials to determine if polymorphic changes would be observed.
  • the chamber humidity was controlled via a saturated sodium chloride aqueous solution. Samples were analyzed at 2 months.

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Abstract

La présente invention concerne des procédés de préparation de 1-[5-chloro-1-[(2,4-diméthoxyphényl)sulfonyl]-3-(2-méthoxyphényl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-diméthylpyrrolidine-2-carboxamide amorphe.
PCT/US2009/043936 2008-05-15 2009-05-14 Procédés de préparation d’une substance médicamenteuse amorphe WO2009140484A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023187086A1 (fr) * 2022-03-31 2023-10-05 Sanofi Forme solide amorphe d'amcenestrant

Citations (1)

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Publication number Priority date Publication date Assignee Title
US6730695B2 (en) * 2000-01-25 2004-05-04 Sanofi-Synthelabo 1,3-dihydro-2h-indol-2-one derivatives and their use as ligands for V1b and V1a arginine-vasopressin receptors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6730695B2 (en) * 2000-01-25 2004-05-04 Sanofi-Synthelabo 1,3-dihydro-2h-indol-2-one derivatives and their use as ligands for V1b and V1a arginine-vasopressin receptors

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Title
YOSHIOKA S ET AL: "Correlations between Molecular Mobility and Chemical Stability During Storage of Amorphous Pharmaceuticals", JOURNAL OF PHARMACEUTICAL SCIENCE, AMERICAN PHARMACEUTICAL ASSOCIATION, WASHINGTON, US, vol. 96, no. 5, 1 May 2007 (2007-05-01), pages 960 - 981, XP003023875, ISSN: 0022-3549 *
YU L: "AMORPHOUS PHARMACEUTICAL SOLIDS: PREPARATION, CHARACTERIZATION AND STABILIZATION", ADVANCED DRUG DELIVERY REVIEWS, ELSEVIER BV, AMSTERDAM, NL, vol. 48, no. 1, 16 May 2001 (2001-05-16), pages 27 - 42, XP009065056, ISSN: 0169-409X *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023187086A1 (fr) * 2022-03-31 2023-10-05 Sanofi Forme solide amorphe d'amcenestrant

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