WO2017221163A1 - Nouveaux sels et formes polymorphes de panobinostat - Google Patents

Nouveaux sels et formes polymorphes de panobinostat Download PDF

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Publication number
WO2017221163A1
WO2017221163A1 PCT/IB2017/053685 IB2017053685W WO2017221163A1 WO 2017221163 A1 WO2017221163 A1 WO 2017221163A1 IB 2017053685 W IB2017053685 W IB 2017053685W WO 2017221163 A1 WO2017221163 A1 WO 2017221163A1
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panobinostat
acid
lactate
crystalline form
amorphous
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PCT/IB2017/053685
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English (en)
Inventor
Mahender Rao Siripragada
Irfan Vohra
Chirag Parikh
Mayur BUDDH
Akash Joshi
Ananda Babu Thirunavakarasu
Pinky PARIKH
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Alembic Pharmaceuticals Limited
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Publication of WO2017221163A1 publication Critical patent/WO2017221163A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane

Definitions

  • the present invention provides novel crystalline polymorphic form of DL-lactate salt of Panobinostat of Formula-I. This invention also provides process for preparation of crystalline forms of Panobinostat DL-lactate. Further, the present invention relates to a novel pharmaceutically acceptable salts and solid forms of Panobinostat.
  • Panobinostat which is chemically known as 2-(E)-N-hydroxy-3-[4[[[2-(2-methyl-lH- indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide, has the following structural formula:
  • Panobinostat is formulated in the form of its DL-lactate salt and marketed under the name FARYDAK.
  • FARYDAK is a histone deacetylase inhibitor, in combination with bortezomib and dexamethasone, indicated treatment of patients with multiple myeloma who have received at least 2 prior regimens, including Bortezomib and an immunomodulatory agent.
  • Panobinostat, its salts, their preparation and solid state forms thereof are described in WO2002022577, WO2007146715, WO2007146716, WO2007146717 and WO2007146718.
  • WO2007146716 describes Panobinostat DL-lactate salt polymorphic form A, form HA and form SA.
  • the different physical properties exhibited by salts and polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e.g., tablets crumble on storage as a kinetically favoured crystalline form converts to thermodynamically more stable crystalline form) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity).
  • chemical reactivity e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph
  • mechanical changes e.g., tablets crumble on storage as a kinetically favoured crystalline form converts to thermodynamically more stable crystalline form
  • both e.g., tablets of one polymorph are more susceptible
  • the present invention relates to novel polymorphic forms of Panobinostat DL-lactate form Al-1 and form Al-2.
  • the present invention relates to benzyl alcohol solvate of Panobinostat DL-lactate, referred herein as form Al- 1 and monohydrate of Panobinostat DL-lactate, referred herein as form Al-2.
  • the present invention also relates to preparation of Panobinostat DL-lactate form Al-1 and form Al-2.
  • the present invention relates to a novel pharmaceutically acceptable salts and solid forms of Panobinostat.
  • the salts according to the present invention are adipate, benzenesulfonate, mandelate, benzoate, tartrate, hydrobromide, hydrochloride, edetate, esylate, fumarate, gluceptate, glucinate, glutamate, hydrocynapthoate, lactobionate, mandelate, methylnitrate, mucate, napsylate, nitrate, pantothenate, stearate, tannate, teoclate, alginate, amiosahcylate, citrate, aspartate, camphorate, diglyconate, disuccinate, hydroiodide, methylenebis(salicylate), pectinate, persulfate, picrate, propionate, thiocyanate, phosphate, hippurate, isoethanoate, ascorbate, stearate, xinofoate, napsylate, formate, pyruv
  • the present invention relates to Panobinostat Adipate; more specifically, its amorphous form and crystalline form and preparation thereof.
  • the present invention relates to Panobinostat formate; more specifically, its amorphous form, and crystalline form and preparation thereof.
  • the present invention relates to Panobinostat S-(+)-mandelate, its amorphous form and preparation thereof.
  • the present invention is also directed to a method of treating disease which responds to an inhibition of histone deacetylase activity comprising the step of administrating Panobinostat DL-lactate salt of present invention.
  • compositions comprising:
  • Fig 1 shows the X-ray powder diffraction ("PXRD") pattern of crystalline Panobinostat DL- lactate form Al-1
  • Fig 2 shows the Differential Scanning Calorimetry (DSC) of Panobinostat DL-lactate form Al- 1
  • Fig 3 shows the X-ray powder diffraction ("PXRD") pattern of Panobinostat DL-lactate form Al- 2.
  • Fig 4 shows the Differential Scanning Calorimetry (DSC) of Panobinostat DL-lactate form Al-2
  • Fig 5 shows the Thermo gravimetric analyses (TGA) of Panobinostat DL-lactate form Al-1
  • Fig 6 shows the X-ray powder diffraction ("PXRD") pattern of amorphous Panobinostat DL- lactate
  • Fig 7 shows the X-ray powder diffraction ("PXRD") crystalline form of Panobinostat adipate
  • Fig 8 shows the X-ray powder diffraction ("PXRD") amorphous form of Panobinostat adipate
  • Fig 9 shows the X-ray powder diffraction ("PXRD") crystalline form of Panobinostat formate
  • Fig 10 shows the X-ray powder diffraction ("PXRD”) amorphous form of Panobinostat formate
  • Fig 11 shows the X-ray powder diffraction ("PXRD”) amorphous form of Panobinostat S(+)mandelate
  • invention relates to a novel pharmaceutically acceptable salts and solid forms of Panobinostat.
  • the solid form can be amorphous or crystalline form.
  • the present invention relates to benzyl alcohol solvate of Panobinostat DL-lactate form Al- 1.
  • Benzyl alcohol solvate of Panobinostat DL-lactate polymorph form Al-1 characterized with an XRPD pattern showing at least one characteristic peak (2theta ⁇ 0.2) at 9.78, 10.73 and 22.65; and further characterized by having XRPD peaks (2theta ⁇ 0.2) at 7.86, 9.78, 10.73, 13.54, 13.99, 14.29, 15.61, 15.80, 16.11, 16.88, 18.62, 18.73, 19.12, 19.65, 19.92, 20.83, 21.42, 21.96, 22.65, 23.18, 24.27, 24.55, 25.02, 26.28, 26.85, 27.31, 28.07, 28.70, 29.08, 29.89, 31.08, 31.54, 32.36, 34.73 and 36.11.
  • Benzyl alcohol solvate of Panobinostat DL-lactate form Al- 1 can alternatively characterized by an XPRD pattern having 2 theta values as shown in fig-
  • the present invention relates to a crystalline benzyl alcohol solvate of Panobinostat DL-lactate, wherein the molar ratio of Panobinostat DL-lactate to benzyl alcohol is approximately 1 :0.3-1: 1.1; more specifically, crystalline Panobinostat DL-lactate benzyl alcohol solvate 1:0.5.
  • the crystalline solvates of the present invention may have advantages relative to other known forms of Panobinostat DL-lactate including chemical stability, polymorphic stability and/or varying solubility.
  • crystalline form Al-1 of Panobinostat DL-lactate benzyl alcohol solvate may be characterized by thermal analysis.
  • a representative DSC plot for crystalline form Al-1 of Panobinostat DL-lactate benzyl alcohol solvate is shown in fig. 2.
  • crystalline form Al-1 of Panobinostat DL-lactate benzyl alcohol solvate is characterized by a DSC plot comprising an endothermic event with an onset temperature of about 168.78° C.
  • crystalline form Al-1 of Panobinostat DL-lactate benzyl alcohol solvate may be characterized by TGA shown in Fig 5.
  • the invention provides a process for preparation of benzyl alcohol solvate of Panobinostat DL-lactate form Al-1 comprises;
  • Providing a solution of Panobinostat DL-lactate in benzyl alcohol solvent means the solution of Panobinostat DL-lactate may be obtained by dissolving Panobinostat DL-lactate in benzyl alcohol solvent, or such a solution may be obtained directly from a chemical synthesis mixture in which Panobinostat DL-lactate is formed.
  • Providing a solution of Panobinostat DL- lactate in benzyl alcohol optionally involves use of other suitable solvents capable of dissolving Panobinostat DL-lactate.
  • suitable solvent is selected from water, methanol, ethanol, isopropanol, 2- propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, acetonitrile, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran (THF), 1,4- dioxane, 2-
  • crystalline form Al-1 may be characterized by its stability profile.
  • form Al-1 material is stable, e.g., its XRPD pattern remains substantially unchanged, upon exposure to elevated temperature, upon exposure to elevated humidity, upon exposure to one or more solvents, and/or upon compression.
  • Form Al-1 is substantially nonhygroscopic.
  • form Al-1 is stable with respect to humidity. Certain embodiments herein provide form Al-1 of Panobinostat DL-lactate which is substantially pure.
  • the present invention relates to monohydrate of Panobinostat DL- lactate form Al-2.
  • Panobinostat DL-lactate monohydrate polymorph form Al-2 characterized with an XRPD pattern showing at least one characteristic peak (2theta ⁇ 0.2) at 6.57, 7.85 and 23.90, and further characterized by having XRPD peaks (2theta ⁇ 0.2) at 3.28, 6.17, 6.58, 7.84, 8.65, 9.82, 11.48, 12.11, 12.45, 13.15, 14.00, 14.78, 15.70, 16.02, 16.50, 16.82, 17.73, 18.67, 19.66, 20.70, 21.10, 21.90, 22.41, 22.73, 23.19, 23.89, 24.34, 25.14, 26.18, 26.52, 27.05, 27.89, 28.19, 29.16, 29.97, 31.69, 32.68, 33.55, 35.00, 38.14, 39.05.
  • invention relates to Panobinostat DL-lactate monohydrate polymorph form Al-2 characterized by an XPRD pattern having 2theta values as shown in fig-3.
  • crystalline form Al-2 of Panobinostat DL-lactate monohydrate may be characterized by thermal analysis.
  • a representative DSC plot for crystalline form Al-2 of Panobinostat DL-lactate monohydrate is shown in fig. 4.
  • crystalline form Al-2 of Panobinostat DL-lactate monohydrate is characterized by a DSC plot comprising two endothermic event with an onset temperature at about 89.60 0 C and 132.53° C.
  • the present invention relates to preparation of Panobinostat DL- lactate monohydrate form Al-2 comprising
  • isolating is performed by removing the solvent from the solution to afford Panobinostat DL-lactate monohydrate. Removal of solvent is accomplished by, for example, filtering the solid, substantially complete evaporation of the solvent, concentrating the solution and filtering the solid.
  • crystalline form Al-2 may be characterized by its stability profile.
  • form Al-2 material is stable, e.g., its XRPD pattern remains substantially unchanged, upon exposure to elevated temperature, upon exposure to elevated humidity, upon exposure to one or more solvents, and/or upon compression.
  • Form Al-2 is substantially nonhygroscopic.
  • form Al-2 is stable with respect to humidity. Certain embodiments herein provide form Al-2 of Panobinostat DL-lactate which is substantially pure.
  • the present invention relates to amorphous Panobinostat DL-lactate.
  • amorphous Panobinostat DL-lactate characterized having XRPD pattern as Fig 6.
  • the present invention relates to Panobinostat adipate salt.
  • the invention provides a process for preparation of panobinostat adipate salt or its polymorph comprises adding adipic acid or adipic acid in a suitable solvent to a solution of Panobinostat in a suitable solvent and isolating the Panobinostat adipate.
  • the present invention relates to crystalline form of Panobinostat adipate.
  • invention relates to crystalline form of Panobinostat adipate characterized with an XRPD pattern showing characteristics peaks (2theta ⁇ 0.2) at 11.9, 13.80,
  • invention relates to crystalline form of Panobinostat adipate characterized having XRPD pattern as shown in Fig. 7.
  • the present invention relates to amorphous Panobinostat adipate.
  • amorphous Panobinostat adipate characterized having XRPD pattern as Fig 8.
  • the present invention relates to Panobinostat formate salt.
  • the invention provides a process for preparation of Panobinostat formate salt or its polymorph comprises adding formic acid in a suitable solvent to a solution of Panobinostat in a suitable solvent and isolating the Panobinostat formate.
  • the present invention relates to crystalline form of Panobinostat formate.
  • invention relates to crystalline form of Panobinostat formate characterized with an XRPD pattern showing characteristics peaks (2theta ⁇ 0.2) at 10.9, 12.80, 19.5, 20.1 land 21.46 further characterized by having XRPD peaks (2theta ⁇ 0.2) at 7.60, 8.51, 9.73, 10.29, 10.94, 12.84, 13.31, 13.75, 14.36, 15.72, 16.47, 17.03, 17.43, 18.05, 18.89, 19.57, 20.11, 21.46, 22.97, 23.66, 24.60, 25.95, 26.77, 30.62, 31.13, 32.26, 35.23 and 36.93.
  • the present invention relates to crystalline form of Panobinostat formate characterized having XRPD pattern shown in Fig 9.
  • the present invention relates to Panobinostat formate amorphous form.
  • amorphous Panobinostat formate characterized having XRPD pattern as Fig 10.
  • the present invention relates to Panobinostat S(+)mandelate amorphous form.
  • amorphous Panobinostat S(+)mandelate characterized having XRPD pattern as Fig 11.
  • the present invention relates to Panobinostat tosylate salt.
  • the invention provides a process for preparation of Panobinostat tosylate salt comprises adding toluene sulfonic acid or toluene sulfonic acid in a suitable solvent to a solution of Panobinostat in a suitable solvent and isolating the Panobinostat tosylate salt.
  • the amorphous form may be a substantially pure form free from any crystalline forms of Panobinostat.
  • the suitable acid is selected from DL-lactic acid, adipic acid, formic acid, S-(+)-mandelic acid.
  • the solvents that may be used in step a) of amorphous preparation comprises one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate, chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; acetonitrile; and polar aprotic solvents selected from dimethylformamide, dimethylacetamide, N- methylpyrrolidone, dimethyl sulfoxide, and mixtures thereof.
  • alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol
  • ketones selected from
  • Step b) involves isolation of an amorphous form of Panobinostat from the solution of step a).
  • the isolation may be affected by removing the solvent.
  • the techniques which may be used for the removal of solvent comprises one or more of evaporation by rotational distillation, evaporation under reduced pressure, spray drying, agitated thin film drying ("ATFD”), freeze drying (lyophilization), flash evaporation, and vacuum distillation.
  • the isolation can be effected by addition of an anti-solvent to the solution obtain in step a), optionally by concentrating the solution obtained in the step.
  • the anti-solvents comprises one or more of hydrocarbons selected from hexanes, n- heptane, n-pentane, cyclohexane, and methylcyclohexane; aromatic hydrocarbons selected from toluene, xylene, and ethylbenzene; ethers selected diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,4-dioxane, and 2-methoxy ethanol.
  • hydrocarbons selected from hexanes, n- heptane, n-pentane, cyclohexane, and methylcyclohexane
  • aromatic hydrocarbons selected from toluene, xylene, and ethylbenzene
  • ethers selected diethyl ether, diisopropyl ether, t-butyl
  • the suitable temperature used in present invention is selected from 0°C to reflux temperature of the solvent used.
  • the suitable solvents used in present invention are selected from alcohols (such as 1 - butanol, 2-butanol, ethanol, 2-ethoxyethanol, ethylene glycol, isopropanol, methanol, 2- methoxyethanol, 3-methyl-l -butanol, 1 -pentanol and 1 -propanol), amides (such as N,N- dimethylacetamide, N,N -dimethylformamide and formamide), carbonates (such as ethylene carbonate and propylene carbonate), carbon sulfide, carboxylic acids (such as acetic acid, trichloroacetic acid and trifluoroacetic acid), esters (such as butyl acetate, ethyl acetate, ethyl formate, isobutyl acetate, isopropyl acetate, methyl acetate and propyl acetate), ethers (such as anisole, bis ⁇ 2- methoxyethyl)ether,
  • novel form or salt of Panobinostat disclosed herein for use in the pharmaceutical compositions of the present invention wherein 90 volume -percent of the particles (D90) have a size of less than or equal to about 500 microns, specifically less than or equal to about 300 microns, more specifically less than or equal to about 200 microns, still more specifically less than or equal to about 100 microns, and most specifically less than or equal to about 15 microns.
  • the melting points are measured using Differential Scanning Calorimetry (DSC).
  • the equipment is a TA-Instruments DSC-Q1000 calibrated at 10°/min to give the melting point as onset value.
  • About 2 mg of sample is heated 10°/min in a loosely closed pan under nitrogen flow.
  • X-Ray powder diffractograms were measured on a PANalytical X'Pert PRO X-Ray Diffractometer using CuKal radiation. The samples were measured in reflection mode in the 2 ⁇ - range 2.5-40° using an X' accelerator detector.
  • Thermo gravimetric analysis (TGA) used for estimation of solvent/water content of dried material is performed using a TA-instruments TGA-Q500 about 10 mg sample is heated 10°/min in an open pan under nitrogen flow.
  • Panobinostat base (lOOg), THF and DL-lactic acid were added to water at ambient temperature. Reaction mixture was heated to 42 ⁇ 3°C and stirred till clear solution obtained. Activated carbon was added to reaction mixture, stirred and filtered. Benzyl alcohol was added to reaction mass at 42 ⁇ 3°C to get solid Panobinostat DL-lactate benzyl alcohol solvate. Filtered the solid and dried it. Yield: i iO.Ogm.
  • XRPD Fig 1
  • DSC Fig 2
  • Example-6 Preparation of Panobinostat DL-lactate monohydrate form Al-2:
  • Panobinostat base (2.0 g) and adipic acid (1.05 eq.) are dissolve in methanol (20.0 ml). The clear solution was evaporated to obtain solid. XPRD of the solid gives pure amorphous form of Panobinostat adipate.
  • Example-8 Preparation of crystalline Panobinostat adipate
  • Panobinostat Adipate (2.0 g) was refluxed in IPA (20.0 ml) for 24 hrs. The reaction was cooled at ambient temperature and the solid was filtered. Obtained solid was characterized by XPRD as Panobinostat Adipate crystalline form.
  • Example- 9 Preparation of crystalline Panobinostat formate
  • Panobinostat base (2.0 g) and formic acid (1.05 eq.) was added to the DM water (20 ml). The suspension was stirred for 24 hrs. The solid was filtered. Obtained solid was characterized by XPRD as Panobinostat formate crystalline form.
  • Panobinostat base (2.0 g) and formic acid (1.05 eq.) is dissolve in methanol (20.0 ml). A clear solution is evaporated to obtain solid. Obtained solid was characterized by XPRD as Amorphous form of Panobinostat formate.
  • Example- 11 Preparation of Panobinostat S-(+)-mandelate amorphous
  • Panobinostat base (2.0 g) and S-(+)-mandelic acid (1.05 eq.) is dissolve in methanol (20.0 ml). A clear solution is evaporated dryness to obtain solid. Obtained solid was characterized by XPRD as amorphous form of Panobinostat S-(+)-mandelate.
  • Panobinostat base (2.0 g) and DL- lactic acid (0.85 g) are dissolved in methanol (20.0 ml). The clear solution was evaporated to obtain solid. XPRD of the solid gives pure amorphous form of Panobinostat DL-lactate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une nouvelle forme polymorphe cristalline du sel de DL-lactate de panobinostat de formule I. Cette invention concerne également un procédé de préparation de formes cristallines de DL-lactate de panobinostat. En outre, la présente invention concerne de nouveaux sels pharmaceutiquement acceptables et des formes solides de panobinostat.
PCT/IB2017/053685 2016-06-21 2017-06-21 Nouveaux sels et formes polymorphes de panobinostat WO2017221163A1 (fr)

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ININ201621021159 2016-06-21
IN201621021159 2016-06-21
ININ201621030984 2016-09-12
IN201621030984 2016-09-12

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2654230A1 (fr) * 2006-06-12 2007-12-21 Novartis Ag Procede de production d'un lactate de n-hydroxy-3-[4-[[[2-(2-methyl-1h-indol-3-yl)ethyl]amino]methyl]phenyl]-2e-acrylamide
US20110112308A1 (en) * 2006-06-12 2011-05-12 Novartis Ag Salts of N-Hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2654230A1 (fr) * 2006-06-12 2007-12-21 Novartis Ag Procede de production d'un lactate de n-hydroxy-3-[4-[[[2-(2-methyl-1h-indol-3-yl)ethyl]amino]methyl]phenyl]-2e-acrylamide
US20110112308A1 (en) * 2006-06-12 2011-05-12 Novartis Ag Salts of N-Hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide

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