WO2010062333A1 - Polymorphes de vorinostat et sel de potassium de vorinostat et procédé pour la préparation de ceux-ci - Google Patents

Polymorphes de vorinostat et sel de potassium de vorinostat et procédé pour la préparation de ceux-ci Download PDF

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Publication number
WO2010062333A1
WO2010062333A1 PCT/US2009/005837 US2009005837W WO2010062333A1 WO 2010062333 A1 WO2010062333 A1 WO 2010062333A1 US 2009005837 W US2009005837 W US 2009005837W WO 2010062333 A1 WO2010062333 A1 WO 2010062333A1
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WO
WIPO (PCT)
Prior art keywords
vorinostat
potassium salt
theta
degrees
pattern
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Application number
PCT/US2009/005837
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English (en)
Inventor
Nidia-Paulina Villalva-Servin
Angel-Alfredo Rodriguez-Hernandez
Pavel Vraspir
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Plus Chemicals Sa
Teva Pharmaceuticals Usa, Inc.
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Application filed by Plus Chemicals Sa, Teva Pharmaceuticals Usa, Inc. filed Critical Plus Chemicals Sa
Publication of WO2010062333A1 publication Critical patent/WO2010062333A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms

Definitions

  • the present invention relates to polymorphs of Vorinostat and Vorinostat potassium salts.
  • SAHA suberoylanilide hydroxamic acid
  • Vorinostat which is marketed under the trade name Zolinza® by Merck, is a histone deacetylase inhibitor ("HDI") used for the treatment of cutaneous T cell lymphoma and Sezary's lymphoma.
  • HDI histone deacetylase inhibitor
  • Vorinostat is disclosed in US patent No. 5,369,108 as a member of a family of compounds that selectively induce terminal differentiataion of neoplastic cells. It can be prepared by the process described by the following scheme: C-OIf
  • the present invention discloses new polymorph of Vorinostat and of Vorinostat potassium salt.
  • 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.
  • One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (“TGA”), and differential scanning calorimetry (“DSC”) as well as by content of solvent in the crystalline form, which have been used to distinguish polymorphic forms.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • 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.
  • aqueous solutions particularly their solubility in the gastric juices of a patient.
  • 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 solubilities.
  • the present invention encompasses a crystalline Vorinostat potassium salt characterized by data selected from the group consisting of: a powder XRD pattern having peaks at about 4.9 and 7.4 ⁇ 0.2 degrees 2-theta and any 3 peaks selected from the list consisting of: 12.3, 19.8, 20.9, 22.1, 22.8, 28.7 and 29.5 ⁇ 0.2 degrees 2-theta; a powder XRD pattern having peaks at about 4.9, 7.4, 12.3, 20.9 and 22.8 ⁇ 0.2 degrees 2- theta; the PXRD pattern depicted in Figure 1, and combinations thereof.
  • the present invention encompasses a process for preparing Vorinostat comprising preparing the above described polymorph of Vorinostat potassium salt according to the process of the present invention, and converting it to Vorinostat.
  • the present invention provide the use of the above described polymorph of Vorinostat potassium salt to prepare Vorinostat.
  • the present invention encompasses crystalline Vorinostat characterized by data selected from the group consisting of: a powder XRD pattern having peaks at about 14.3, 14.8, 17.6, 21.4 and 23.1 ⁇ 0.2 degrees 2-theta; the PXRD pattern depicted in Figure 4, and the combination thereof.
  • Figure 1 illustrates a powder X-ray diffraction pattern of crystalline Vorinostat potassium salt designated form A.
  • FIG. 2 illustrates TGA results obtained for pure crystalline Vorinostat potassium salt designated form A.
  • Figure 3 illustrates a DSC pattern of polymorphically pure crystalline Vorinostat potassium salt designated form A.
  • Figure 4 illustrates a powder X-ray diffraction pattern of crystalline Vorinostat designated form VI.
  • FIG. 5 illustrates TGA results obtained for crystalline Vorinostat designated form VI.
  • Figure 6 illustrates a DSC pattern of crystalline Vorinostat designated form VI.
  • Figure 7 illustrates a powder X-ray diffraction pattern of crystalline Vorinostat designated form I.
  • Figure 8 illustrates a powder X-ray diffraction pattern of crystalline Vorinostat designated form HI.
  • the present invention relates to polymorphs of Vorinostat and Vorinostat potassium salts.
  • Vorinostat form I refers to crystalline Vorinostat characterized by data selected from a group consisting of: an X-ray powder diffraction pattern having peaks at about 9.1, 10.8, 12.3, 17.2, 19.2, 19.8, 23.7, 25.7, 26.8 and 27.7 ⁇ 0.2 degrees two-theta; a powder XRD pattern as depicted in figure 7; and the combination thereof.
  • Vorinostat form III refers to crystalline Vorinostat characterized by data selected from a group consisting of: an X-ray powder diffraction pattern having peaks at about 11.9, 17.5, 18.4, 18.7 and 24.4 ⁇ 0.2 degrees rwo-theta; a powder XRD pattern as depicted in figure 8; and the combination thereof.
  • the present invention encompasses a crystalline Vorinostat potassium salt characterized by data selected from the group consisting of: a powder XRD pattern having peaks at about 4.9 and 7.4 ⁇ 0.2 degrees 2-theta and any 3 peaks selected from the list consisting of: 12.3, 19.8, 20.9, 22.1, 22.8, 28.7 and 29.5 ⁇ 0.2 degrees 2-theta; a powder XRD pattern having peaks at about 4.9, 7.4, 12.3, 20.9 and 22.8 ⁇ 0.2 degrees 2- theta; the PXRD pattern depicted in Figure 1, and combinations thereof.
  • the above-described polymorph of potassium salt of Vorinostat can be designated form A.
  • Vorinostat potassium salt can be further characterized by data selected from a group consisting of: a powder XRD pattern having peaks at about 19.8, 22.1, 28.7 and 29.5 ⁇ 0.2 degrees 2-theta; a weight loss of less than about 0.5% by weight as measured by TGA; a TGA pattern depicted in Figure 2; a DSC pattern having an exothermic peak at about 195 0 C ⁇ 0.5 0 C; a DSC pattern depicted in Figure 3, and combinations thereof.
  • the above form A of Vorinostat potassium salt is polymorphically pure.
  • Vorinostat potassium salt form A relates to Vorinostat potassium salt containing less than about 10% by weight of crystalline Vorinostat form I; preferably less than about 5%, more preferably less than 1% by weight crystalline Vorinostat form I.
  • the amount of Vorinostat form I in the crystalline Vorinostat potassium salt form A of the present invention is measured by PXRD using any peak from the following list of peaks at about: 9.1, 10.8, 19.2, 24.1 and 26.8 ⁇ 0.2 degrees two theta.
  • the above polymorphically pure Vorinostat potassium salt form A is a composition which comprises about 0% to about 10% Vorinostat form I and about 100% to about 90% Vorinostat potassium salt form A, based on the combined weight of Vorinostat form I and Vorinostat potassium salt form A. More preferably, the composition comprises about 0% to about 5% Vorinostat form I and about 100% to about 95% Vorinostat potassium salt form A. Most preferably, the composition comprises about 0% to about 1% Vorinostat form I and about 100% to about 99% Vorinostat potassium salt form A.
  • the polymorphically pure Vorinostat potassium salt form is a composition which contains essentially Vorinostat form I and Vorinostat potassium salt form A in the above described amounts.
  • Vorinoatat potassium salt can be prepared by a process comprising reacting Suberanilic acid methyl ester ("SAME") of the following formula:
  • SAME is reacted with hydroxylamine in other alcohols such as ethanol, propanol, isopropanol, 1-butanol, 2-butanol, or 3-butanol, or combinations thereof, or combinations of the other alcohols with methanol.
  • a solution of hydroxylamine in methanol is reacted with a solution of SAME in methanol.
  • the above solution of hydroxylamine in methanol can be prepared by reacting hydroxylamine hydrochloride with a base in methanol, to obtain a suspension comprising free hydroxylamine, and filtering the suspension to obtain the said solution.
  • the said base is inorganic base, more preferably an alkali base, most preferably the base is potassium hydroxide.
  • the reaction between hydroxylamine hydrochloride and the base is performed at a temperature of about O 0 C to about 5 0 C.
  • the reaction can proceed at 18-22 0 C.
  • the said suspension is preferably maintained, prior to the filtration.
  • maintaining is with stirring.
  • Preferably maintaining is performed at a temperature of about O 0 C to about 5 0 C.
  • Preferably maintaining is for a period of about 15 minutes to about 60 minutes; more preferably about 15 minutes to about 30 minutes.
  • the solution comprising hydroxylamine obtained after the filtration is then used to produce Vorinostat potassium salt crystalline form A by reacting the said solution with a solution of SAME in methanol at a pH of at least about 13.
  • Obtaining a pH of at least about 13 can be done by reacting SAME and hydroxylamine in the presense of a base.
  • the base is an inorganig base, more preferably an alkali base, most preferably the base is potassium hydroxide, hi certain embodiments, the base is sodium hydroxide or tetrabutylammoniurn hydroxide.
  • the said reaction is done by adding SAME to the solution of hydroxylamine in methanol.
  • SAME is added as a solid to the hydroxylamine solution.
  • the SAME container can then be rinsed with methanol and the rinsings added to the SAME/hydroxylamine solution. Then a solution of potassium hydroxide in methanol can be added.
  • the above reaction is done at a temperature of about 0 0 C to about 5 0 C.
  • the process for preparing crystalline form A of Vorinostat potassium salt may further comprise recovering the said crystalline form.
  • the recovery may be done, for example, by filtering the suspension, washing and drying.
  • washing is done with water.
  • drying is done under vacuum.
  • drying is performed for a period of about 1 hour to about 12 hours, more preferably drying is for a period of about 1 hour.
  • the present invention encompasses crystalline Vorinostat characterized by data selected from the group consisting of: a powder XRD pattern having peaks at about 14.3, 14.8, 17.6, 21.4 and 23.1 ⁇ 0.2 degrees 2-theta; the PXRD pattern depicted in Figure 4, and the combination thereof.
  • This crystalline form of Vorinostat can be designated form VI.
  • Vorinostat can be further characterized by data selected from a group consisting of: a powder XRD pattern having peaks at about 9.1, 10.5, 19.8 and 28.3 ⁇ 0.2 degrees 2-theta; a double diffraction peak at about 14.3 and 14.8 ⁇ 0.2 degrees 2-theta; a weight loss of less than about 0.2% by weight at a temperature of about 30° to about 140 0 C as measured by TGA; a TGA pattern depicted in Figure 5; a DSC pattern having an endothermic melting peak at about 159 0 C ⁇ 2 0 C; a DSC pattern depicted in Figure 6; and combinations thereof.
  • a powder XRD pattern having peaks at about 9.1, 10.5, 19.8 and 28.3 ⁇ 0.2 degrees 2-theta
  • a double diffraction peak at about 14.3 and 14.8 ⁇ 0.2 degrees 2-theta
  • Vorinostat is an anhydrous form.
  • anhydrous form in relation to Vorinostat form VI refers to a substance containing water and/or any other solvent in an amount of less than 0.2 % (w/w)as measured by TGA.
  • the above described crystalline Vorinostat form VI can be prepared by a process comprising heating crystalline Vorinostat form III to a temperature of about 133°C to about 137 0 C, preferably to a temperature of about 135 0 C.
  • the present invention encompasses a process for preparing Vorinostat comprising preparing the above described polymorph of Vorinostat potassium salt according to the process of the present invention, and converting it to Vorinostat.
  • Li another embodiment the present invention provide the use of the above described polymorph of Vorinostat potassium salt to prepare Vorinostat.
  • Step size 0.0167 °
  • Sample holder stainless steel sample holder with zero-background silicon plate.
  • the samples Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder.
  • the sample might be mixed with n-dodecane in order to avoid the environment contamination by airborne particles coming from the powder.
  • the ground sample or its suspension with n-dodecane was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.
  • Parameters temperature range at least 25 0 C - 250°C, heating rate 10°C/min, nitrogen flow 50 ml/min.
  • Alumina crucibles 70 ⁇ l were used for sample preparation. Usual weight of sample was 7 - 13 mg.
  • Suberanilic acid methyl ester (5 g, 0.019 mol, 1.0 eq.) was added to the filtrate followed by a solution of Potassium hydroxide (2.5 g, 0.045 mol, 2.35 eq.) in methanol (15 mL, 3 vol.), maintaining the temperature at 0°C-5°C while the measured pH was 12.8.
  • the flask was rinsed with methanol (5 mL, 1 vol.) and maintained at 0°C-5°C until completion.
  • the suspension was filtered at 0°C-5°C.
  • the solid was washed with water (5 mL, 1 vol.) and was allowed to drain under vacuum for 1 hour.
  • Vorinostat form III was heated at 135 ⁇ 2 °C for 1 hour in a drying oven.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne la forme cristalline A de sel de potassium de vorinostat caractérisée par un profil de diffraction X ayant des pics à environ 4,9 et 7,4 ± 0,2 degrés 2-thêta et 3 pics quelconques choisi dans la liste constituée de : 12,3, 19,8, 20,9, 22,1, 22,8, 28,7 et 29,5 ± 0,2 degrés 2-thêta. La forme cristalline A de sel de potassium de vorinostat peut être pure sur le plan polymorphe. La présente invention concerne en outre des procédés pour préparer la forme cristalline A de sel de potassium de vorinostat. La présente invention concerne en outre la forme cristalline VI de vorinostat caractérisée par un profil de diffraction X ayant des pics à environ 14,3, 14,8, 17,6, 21,4 et 23,1 ± 0,2 degrés 2-thêta ainsi que des procédés pour préparer la forme cristalline VI de vorinostat.
PCT/US2009/005837 2008-10-27 2009-10-26 Polymorphes de vorinostat et sel de potassium de vorinostat et procédé pour la préparation de ceux-ci WO2010062333A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US19749308P 2008-10-27 2008-10-27
US61/197,493 2008-10-27
US19932408P 2008-11-13 2008-11-13
US61/199,324 2008-11-13
US21089009P 2009-03-23 2009-03-23
US61/210,890 2009-03-23
US16740809P 2009-04-07 2009-04-07
US61/167,408 2009-04-07

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008039421A2 (fr) * 2006-09-28 2008-04-03 Merck & Co., Inc. Compositions pharmaceutiques d'inhibiteurs hdac et composés métalliques chélatables, et complexes métalliques chélatés d'inhibiteurs hdac

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008039421A2 (fr) * 2006-09-28 2008-04-03 Merck & Co., Inc. Compositions pharmaceutiques d'inhibiteurs hdac et composés métalliques chélatables, et complexes métalliques chélatés d'inhibiteurs hdac

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GEDIYA LALJI K ET AL: "A New Simple and High-Yield Synthesis of Suberoylanilide Hydroxamic Acid and Its Inhibitory Effect Alone or in Combination with Retinoids on Proliferation of Human Prostate Cancer Cells", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US, vol. 48, no. 15, 1 January 2005 (2005-01-01), pages 5047 - 5051, XP009126904, ISSN: 0022-2623 *

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