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WO2010039798A2 - Amorphous compositions of sunitinib base and l-malic acid - Google Patents

Amorphous compositions of sunitinib base and l-malic acid Download PDF

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Publication number
WO2010039798A2
WO2010039798A2 PCT/US2009/058975 US2009058975W WO2010039798A2 WO 2010039798 A2 WO2010039798 A2 WO 2010039798A2 US 2009058975 W US2009058975 W US 2009058975W WO 2010039798 A2 WO2010039798 A2 WO 2010039798A2
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WIPO (PCT)
Prior art keywords
combination
malic acid
composition
amorphous
sunitinib
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Ceased
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PCT/US2009/058975
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French (fr)
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WO2010039798A3 (en
Inventor
Alexandr Jegorov
Ales Gavenda
Pavel Vraspir
Judith Aronhime
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Teva Pharmaceutical Industries Ltd
Teva Pharmaceuticals USA Inc
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Teva Pharmaceutical Industries Ltd
Teva Pharmaceuticals USA Inc
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Priority to CA2704448A priority Critical patent/CA2704448A1/en
Publication of WO2010039798A2 publication Critical patent/WO2010039798A2/en
Publication of WO2010039798A3 publication Critical patent/WO2010039798A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2

Definitions

  • the invention encompasses a combination of a pharmaceutically acceptable excipient and a composition of sunitinib base and L-malic acid, and processes for the preparation thereof.
  • sunitinib salts such as sunitinib malate of the following formula:
  • Sunitinib malate is a multi-kinase inhibitor marketed in the United States under the trade name SUTENT ® by Pfizer, Inc.
  • SUTENT ® is approved by the FDA for the treatment of gastrointestinal stromal tumor after disease progression or intolerance to imatinib mesylate and for the treatment of advanced renal cell carcinoma.
  • SUTENT ® is available as hard-shell capsules containing an amount of sunitinib malate that is equivalent to 12.5 mg, 25 mg, or 50 mg of sunitinib.
  • the capsules contain sunitinib malate together with the inactive ingredients mannitol, croscarmellose sodium, povidone (K-25) and magnesium stearate.
  • U.S. Patent No. 6,573,293 refers to the preparation of sunitinib base and salts thereof, as well as the use of these salts.
  • the '293 patent refers to the synthesis of sunitinib base by condensing 5-formyl-2,4-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide with 5-fluoro-l,3-dihydro-indol-2-one in ethanol in the presence of pyrrolidine. See '293 patent, col. 204, 11. 33-50 (example 80, alternative synthesis).
  • the sunitinib base thus prepared was isolated from the reaction mixture by filtration, washed with ethanol, slurried in ethanol, isolated from the slurry by filtration, washed with ethanol, and dried under vacuum to give an orange solid. See id.
  • U.S. Patent No. 7,119,209 also refers to the preparation of sunitinib base.
  • the '209 patent refers to the preparation of sunitinib base by reacting 4-(1H- imidazol-l-ylcarbonyl)-3, 5 -dimethyl- lH-pyrrole-2-carbaldehyde, N, N- diethylethylenediamine, 5-fluorooxindole in acetonitrile in the presence of triethylamine. See '209 patent, col. 15, 11. 1-36.
  • the sunitinib base thus prepared was isolated from the reaction mixture by filtration, washed with acetonitrile, and dried under vacuum.
  • the invention encompasses a combination of a pharmaceutically acceptable excipient selected from a group consisting of microcrystallinecellulose, polyvinylpyrrolidone, cyclodextrin, and disaccharide or derivatives thereof and an amorphous composition of sunitinib base and L-malic acid; wherein the combination is either amorphous or semi- crystalline, when the pharmaceutically acceptable excipient is cyclodextrin or disaccharide, the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 : 1 (w/w); when the pharmaceutically acceptable excipient is polyvinylpyrrolidone, the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 :2 (w/w); when the pharmaceutically acceptable excipient is microcrystalline cellulose, the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 :10 (w/w).
  • a pharmaceutically acceptable excipient selected from a group consisting of microcrystallinecellulose,
  • Figure 1 illustrates a powder X-ray diffraction pattern of a semi-crystalline combination of microcrystalline cellulose and an amorphous composition of sunitinib base and L-malic acid combined with microcrystalline cellulose in a ratio of 10:1 w/w, respectively obtained by drying.
  • Figure 2 illustrates a powder X-ray diffraction pattern of microcrystalline cellulose.
  • Figure 3 illustrates a powder X-ray diffraction pattern of an amorphous combination of beta-cyclodextrin and an amorphous composition of sunitinib base and L- malic acid, in a ratio of 1 : 1 w/w, respectively obtained by lyophilization.
  • Figure 4 illustrates a powder X-ray diffraction pattern of an amorphous combination of trehalose and an amorphous composition of sunitinib base and L-malic acid, in a ratio of 1 : 1.4 w/w, respectively obtained by lyophilization.
  • Figure 5 illustrates a powder X-ray diffraction pattern of an amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid, in a ratio of 1 : 1 w/w, respectively obtained by lyophilization.
  • Figure 6 illustrates a powder X-ray diffraction pattern of an amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid, in a ratio of 1 : 1 w/w, respectively obtained by lyophilization.
  • Figure 7 illustrates a powder X-ray diffraction pattern of an amorphous combination of polyvinylpyrrolidone and an amorphous composition of sunitinib base and L- malic acid combined in a ratio of 2:1 w/w, respectively obtained by lyophilization.
  • Figure 8 illustrates a powder X-ray diffraction pattern of crystalline composition G containing Sunitinib base and L-malic acid obtained by lyophilization
  • Figure 9 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of Polyoxyethylene-polyoxypropylene block polymer (Poloxamer 407) and a composition of sunitinib base and L-malic acid in a ratio of 1 :2.8 w/w, respectively obtained by lyophilization.
  • Figure 10 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of Polyoxyethylene-polyoxypropylene block polymer (Poloxamer 407) and a composition of sunitinib base and L-malic acid in a ratio of 1 :1 w/w, respectively obtained by lyophilization.
  • Figure 11 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of Polyoxy ethylene -polyoxypropylene block polymer (Poloxamer 188) and a composition of sunitinib base and L-malic acid in a ratio of 1 :1 w/w, respectively obtained by lyophilization.
  • Figure 12 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of Polyoxy ethylene -polyoxypropylene block polymer (Poloxamer 188) and a composition of sunitinib base and L-malic acid in a ratio of 1.7:1 w/w, respectively obtained by lyophilization.
  • Figure 13 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of hypromellose and a composition of sunitinib base and L-malic acid in a ratio of 1 :2.8 w/w, respectively obtained by lyophilization.
  • Figure 14 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of polyethyleneglycol and a composition of sunitinib base and L-malic acid in a ratio of 1 :7 w/w, respectively obtained by lyophilization.
  • Figure 15 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of dulcite and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 16 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of dulcite and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 17 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of fructose and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 18 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of polyoxyl 40 hydrogenated castor oil and a composition of sunitinib base and
  • Figure 19 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of sucrose and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 20 illustrates a powder X-ray diffraction pattern of a crystalline combination of mannit and a composition of sunitinib base and L-malic acid in a ratio of 1 :1 w/w, respectively obtained by lyophilization.
  • Figure 21 illustrates a powder X-ray diffraction pattern of a crystalline combination of mannit and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 22 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of galactose and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 23 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of 2-hydroxyethyl octadecanoate and a composition of sunitinib base and L- malic acid in a ratio of 1 : 1 w/w, respectively obtained by lyophilization.
  • Figure 24 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of trehalose and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 25 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of polyvinylpyrrolidone and a composition of sunitinib base and L-malic acid in a ratio of 1 :2.8 w/w, respectively obtained by lyophilization.
  • Figure 26 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of maltose and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 27 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of maltose and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 28 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of lactose and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 29 illustrates a powder X-ray diffraction pattern of crystalline composition G containing Sunitinib base and L-malic acid prepared by spray drying.
  • Figure 30 illustrates a powder X-ray diffraction pattern of a semi-crystalline combination of lactose and a composition of sunitinib base and L-malic acid in a ratio of 1 : 1 w/w, respectively, prepared by spray drying.
  • Figure 31 illustrates a powder X-ray diffraction pattern of an amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid in a ratio of 1 : 1 w/w, respectively, prepared by spray drying.
  • w/w refers to g/g.
  • crystalline sunitinib malate form I refers to a crystalline form characterized by diffraction peaks at about 13.2 and 24.2 degrees two-theta ⁇ 0.2 degrees 2-theta, and more preferably, at about 13.2, 19.4, 24.2 and 25.5 degrees two- theta ⁇ 0.2 degrees 2-theta.
  • composition G of Sunitinib base and L-malic acid refers to a composition containing Sunitinib base and L-malic acid characterized by a PXRD pattern having any 5 peaks at positions selected from the group consisting of: 6.2, 7.7, 9.3, 12.4, 14.5, 23.2 and 27.4 ⁇ 0.2 degrees 2-theta.
  • the present invention offers a new combination of an amorphous composition of sunitinib base and L-malic acid that is combined with a pharmaceutically acceptable excipient, wherein the entire combination is either semi-crystalline (see figure 1) or amorphous (see figures 3-6).
  • the composition of sunitinib base and L-malic acid is amorphous. See figures 1, and 3-7 where no peaks of sunitinib base and L-malic acid are evident; in figure 1 the evident peaks are of the excipient (see comparison between figure 1 and 2).
  • Amorphous is herein defined as a composition having PXRD pattern with one broad bump with at most one peak that can be assigned to a crystalline composition of sunitinib base and L-malic acid superimposed on the broad bump.
  • Silicon-crystalline is herein defined as a composition having PXRD pattern that contains peaks that can be detected and assigned to a composition of sunitinib base and
  • the invention encompasses a combination of a pharmaceutically acceptable excipient selected from a group consisting of microcrystalline cellulose, polyvinylpyrrolidone, cyclodextrin, and disaccharide or derivatives thereof and an amorphous composition of sunitinib base and L-malic acid; wherein the combination is either amorphous or semi-crystalline; when the pharmaceutically acceptable excipient is cyclodextrin or disaccharide, the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 : 1 (w/w), the pharmaceutically acceptable excipient is polyvinylpyrrolidone and the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 :2 (w/w), the pharmaceutically acceptable excipient is microcrystalline cellulose and the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 :10 (w/w).
  • a pharmaceutically acceptable excipient selected from a group consisting of microcrystalline cellulose, poly
  • the amorphous composition of sunitinib base and L-malic acid is polymorphically pure.
  • polymorphically pure amorphous refers to a composition of sunitinib base and L-malic acid that has a PXRD pattern without all the following list of peaks at 6.2, 7.7, 9.3, 12.4, 14.6, 23.2 and 27.2 ⁇ 0.5 degrees 2-theta that can be detected and/or assigned to a composition of sunitinib base and L-malic acid.
  • the cellulose derivative is microcrystalline cellulose.
  • the cyclodextrin derivative is beta-cyclodextrin.
  • the disaccharide derivative is either trehalose, lactose or maltose.
  • the ratio between sunitinib base and L-malic acid is 1 : 1 mole/mole.
  • the semi-crystalline combination of microcrystalline cellulose and the amorphous composition of sunitinib base and L-malic acid in a ratio of 10:1 (w/w), respectively, can be characterized by PXRD pattern as depicted in figure 1.
  • the amorphous combination of beta-cyclodextrin and an amorphous composition of sunitinib base and L-malic acid in a ratio of 1 :1 (w/w), respectively, can be characterized by PXRD pattern as depicted in figure 3.
  • the amorphous combination trehalose and an amorphous composition of sunitinib base and L-malic acid in a ratio of 1 : 1.4 (w/w), respectively, can be characterized by
  • the amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid in a ratio of 1 : 1 (w/w), respectively, can be characterized by
  • the amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid in a ratio of 1 : 1 (w/w), respectively, can be characterized by
  • the amorphous combination of polyvinylpyrrolidone and an amorphous composition of sunitinib base and L-malic acid in a ratio of 2:1 (w/w), respectively, can be characterized by PXRD pattern as depicted in figure 7.
  • the amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid in a ratio of 1 : 1 w/w, can be characterized by PXRD pattern as depicted in figure 31.
  • the above combination can be prepared by a process comprising removing water from a mixture comprising Sunitinib base, L-malic acid and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from a group consisting of cellulose, polyvinylpyrrolidone, cyclodextrin, disaccharide or derivatives thereof, when the pharmaceutically acceptable excipient is cyclodextrin or disaccharide and the ratio between the amorphous composition and the pharmaceutical acceptable excipient is about 1 : 1 (w/w), the pharmaceutically acceptable excipient is polyvinylpyrrolidone and the ratio between the amorphous composition and the pharmaceutical acceptable excipient is about 1 :2 (w/w), the pharmaceutically acceptable excipient is cellulose and the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 :10
  • the mixture consists essentially of water, Sunitinib base, L-malic acid and a pharmaceutically acceptable excipient, as mentioned above.
  • the said mixture is a suspension or solution.
  • the mixture is a suspension that is provided by dissolving Sunitinib malate in water and combining the obtained solution with the said pharmaceutically acceptable excipient to obtain the said suspension.
  • the mixture is a solution that is provided by dissolving
  • the dissolution is done by heating to a temperature of about 50 0 C to about 100 0 C. More preferably, the dissolution is done by heating to a temperature of about
  • water is removed by drying, lyophilizing or spray-drying the said mixture.
  • the drying is done by heating the mixture to a temperature of about
  • the drying is done at a temperature of about 90 0 C.
  • water is removed under reduced pressure, for example 0.05 to about 300 mBar, preferably at a pressure of about 1 to about 20 mBar, more preferably the drying is done at a pressure of about 10 mBar.
  • the drying is done for a period of about 2 hours.
  • Lyophilization is also known as freeze drying.
  • the mixture is frozen.
  • the frozen mass is then subjected to a pressure of less than about one atmosphere, to remove the solvent.
  • the lyophilization is done at a temperature of about -30 0 C to about
  • the lyophilization is done at a pressure of about 0.1 to about 1 mBar.
  • Sunitinib base (6 g) was dissolved in dioxane (160 ml) at 100 0 C and the hot solution was filtered and the filter was cleaned with additional dioxane (40 ml).
  • L-malic acid (2.02 g in 10 ml of water) was added. The solution was heated for 15 min to 100 0 C, allowed to cool to 20 0 C within 30 min, and allowed to crystallize overnight (12 hrs). Crystals were recovered by filtration, washed with t-BME (20 ml) and allowed to dry for 5 hrs on air.
  • Example 1 Preparation of a semi-crystalline combination of microcrystalline cellulose and an amorphous composition of sunitinib base and L-malic acid
  • Sunitinib L-malate (form I, 400 mg) was dissolved in water at 80 0 C (8 ml) and microcrystalline cellulose (4 g) was added. The suspension thus formed was dried at 10 mBar at 90 0 C for 1 hour providing a semi-crystalline combination of cellulose and an amorphous composition of sunitinib base and L-malic acid was obtained.
  • Example 2 Preparation of an amorphous combination of beta-cyclodextrin and an amorphous composition of sunitinib base and L-malic acid.
  • Beta-Cyclodextrin 150 mg was added, boiled for 3 min, allowed to cool, frozen -30 C, lyophilized, 1 mBar. An amorphous combination of Beta-Cyclodextrin and an amorphous composition of sunitinib base and L-malic acid was obtained.
  • Example 3 Preparation of an amorphous combination of trehalose and an amorphous composition of sunitinib base and L-malic acid.
  • Sunitinib malate 140 mg, Form I
  • trehalose 100 mg
  • An amorphous combination of trehalose and an amorphous composition of sunitinib base and L-malic acid was obtained.
  • Example 4 Preparation of an amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid.
  • Sunitinib malate (150 mg, Form I) and lactose (150 mg) were dissolved in water (10 ml) by heating to 100 0 C for 5 min, allowed to cool, frozen by liquid N 2 to about - 50 0 C, lyophilised, 10 Pa, 24 h. An amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid was obtained.
  • Example 4a Preparation of an amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid.
  • Sunitinib malate 150 mg, Form I
  • lactose 250 mg
  • water 10 ml
  • An amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid was obtained.
  • Example 5 Preparation of an amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid.
  • Sunitinib malate (150 mg, Form I) and maltose (150 mg) were dissolved in water (10 ml) by heating to 100 0 C for 5 min, allowed to cool, frozen by liquid N 2 to about - 50 0 C, lyophilised, 10 Pa, 24 h. An amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid was obtained.
  • Example 6 Preparation of an amorphous combination of polyvinylpyrrolidone (Polyvidone 25) and an amorphous composition of sunitinib base and L-malic acid [0077] Sunitinib malate (150 mg, Form I) and Polyvinylpyrrolidone (Polyvidone 25)
  • Sunitinib malate 140 mg, Form II
  • Polyoxyethylene-polyoxypropylene block polymer 50 mg
  • a semi crystalline combination of Polyoxyethylene-polyoxypropylene block polymer and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate (150 mg, Form I) and Polyoxyethylene-polyoxypropylene block polymer (150 mg) were dissolved in water (10 ml) b heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about -50 C, lyophilised, 10 Pa, 24 h
  • a semi crystalline combination of Polyoxyethylene-polyoxypropylene block polymer and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate 150 mg, Form I
  • Lutrol F68 150 mg
  • a semi crystalline combination of Lutrol F68 and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate 150 mg, Form I
  • Lutrol F68 250 mg
  • a semi crystalline combination of Lutrol F68 and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate 140 mg, Form II
  • polyethyleneglycole 20 mg
  • a semi crystalline combination of polyethyleneglycole and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate 150 mg, Form I
  • dulcite 100 mg
  • water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h.
  • a semi crystalline combination of dulcite and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate 150 mg, Form I
  • dulcite 250 mg
  • water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h.
  • a semi crystalline combination of dulcite and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate 150 mg, Form I
  • fructose 100 mg
  • water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h.
  • a semi crystalline combination of fructose and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate (150 mg, Form I) and mannit (150 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h.
  • a crystalline combination of mannit and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate 150 mg, Form I
  • mannit 250 mg
  • water 10 ml
  • mannit 250 mg
  • a crystalline combination of mannit and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate (150 mg, Form I) and galactose (150 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h.
  • a semi crystalline combination of galactose and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate (150 mg, Form I) and 2-hydroxy ethyl octadecanoate (150 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about -50 C, lyophilised, 10 Pa, 24 h.
  • a semi crystalline combination of 2- hydroxyethyl octadecanoate and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate 140 mg, Form I
  • trehalose 50 mg
  • water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 100 C, lyophilised, 1 mBar.
  • a semi crystalline combination of trehalose and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate 150 mg, Form I
  • lactose 100 mg
  • a semi crystalline combination of lactose and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Example 30 Preparation of an amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid by spray drying

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Abstract

Combinations of a pharmaceutically acceptable excipient selected from the group consisting of microcrystalline cellulose, polyvinylpyrrolidone, cyclodextrin, and disaccharide or derivatives thereof and acomposition of sunitinib base and L-malic acid were prepared.

Description

AMORPHOUS COMPOSITIONS OF SUNITINIB BASE AND L-MALIC ACID
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Patent Application
Serial. Nos. 61/101,527, filed September 30, 2008; 61/117,413 filed November 24, 2008; 61/143,477, filed January 9, 2009 and 61/159,644, filed March 12, 2009, which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The invention encompasses a combination of a pharmaceutically acceptable excipient and a composition of sunitinib base and L-malic acid, and processes for the preparation thereof.
BACKGROUND OF THE INVENTION
[0003] Sunitinib base, N-[2-(diethylamino) ethyl]-5-[(Z)-(5-fluoro- 1 , 2-dihydro-2- oxo-3H-indol-3-ylidine) methyl]-2, 4-dimethyl-lH-pyrrole-3-carboxamide, of the following formula:
Figure imgf000002_0001
can be used as an intermediate in the preparation of sunitinib salts, such as sunitinib malate of the following formula:
Figure imgf000002_0002
[0004] Sunitinib malate is a multi-kinase inhibitor marketed in the United States under the trade name SUTENT® by Pfizer, Inc. SUTENT® is approved by the FDA for the treatment of gastrointestinal stromal tumor after disease progression or intolerance to imatinib mesylate and for the treatment of advanced renal cell carcinoma. SUTENT® is available as hard-shell capsules containing an amount of sunitinib malate that is equivalent to 12.5 mg, 25 mg, or 50 mg of sunitinib. The capsules contain sunitinib malate together with the inactive ingredients mannitol, croscarmellose sodium, povidone (K-25) and magnesium stearate.
[0005] U.S. Patent No. 6,573,293 ('"293 patent") refers to the preparation of sunitinib base and salts thereof, as well as the use of these salts. The '293 patent refers to the synthesis of sunitinib base by condensing 5-formyl-2,4-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide with 5-fluoro-l,3-dihydro-indol-2-one in ethanol in the presence of pyrrolidine. See '293 patent, col. 204, 11. 33-50 (example 80, alternative synthesis). The sunitinib base thus prepared was isolated from the reaction mixture by filtration, washed with ethanol, slurried in ethanol, isolated from the slurry by filtration, washed with ethanol, and dried under vacuum to give an orange solid. See id.
[0006] U.S. Patent No. 7,119,209 ('"209 patent") also refers to the preparation of sunitinib base. The '209 patent refers to the preparation of sunitinib base by reacting 4-(1H- imidazol-l-ylcarbonyl)-3, 5 -dimethyl- lH-pyrrole-2-carbaldehyde, N, N- diethylethylenediamine, 5-fluorooxindole in acetonitrile in the presence of triethylamine. See '209 patent, col. 15, 11. 1-36. The sunitinib base thus prepared was isolated from the reaction mixture by filtration, washed with acetonitrile, and dried under vacuum. See id. [0007] U.S. Patent Application Publication Nos. 2003/0069298 and 2007/0191458 refer to the preparation of sunitinib L-malate, and also disclose two polymorphs thereof. [0008] The discovery of new polymorphic forms and their combination with pharmaceutical acceptable excipients can improve the performance characteristics of a pharmaceutical product.
SUMMARY OF THE INVENTION
[0009] In one embodiment, the invention encompasses a combination of a pharmaceutically acceptable excipient selected from a group consisting of microcrystallinecellulose, polyvinylpyrrolidone, cyclodextrin, and disaccharide or derivatives thereof and an amorphous composition of sunitinib base and L-malic acid; wherein the combination is either amorphous or semi- crystalline, when the pharmaceutically acceptable excipient is cyclodextrin or disaccharide, the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 : 1 (w/w); when the pharmaceutically acceptable excipient is polyvinylpyrrolidone, the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 :2 (w/w); when the pharmaceutically acceptable excipient is microcrystalline cellulose, the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 :10 (w/w).
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] Figure 1 illustrates a powder X-ray diffraction pattern of a semi-crystalline combination of microcrystalline cellulose and an amorphous composition of sunitinib base and L-malic acid combined with microcrystalline cellulose in a ratio of 10:1 w/w, respectively obtained by drying.
[0011] Figure 2 illustrates a powder X-ray diffraction pattern of microcrystalline cellulose.
[0012] Figure 3 illustrates a powder X-ray diffraction pattern of an amorphous combination of beta-cyclodextrin and an amorphous composition of sunitinib base and L- malic acid, in a ratio of 1 : 1 w/w, respectively obtained by lyophilization.
[0013] Figure 4 illustrates a powder X-ray diffraction pattern of an amorphous combination of trehalose and an amorphous composition of sunitinib base and L-malic acid, in a ratio of 1 : 1.4 w/w, respectively obtained by lyophilization.
[0014] Figure 5 illustrates a powder X-ray diffraction pattern of an amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid, in a ratio of 1 : 1 w/w, respectively obtained by lyophilization.
[0015] Figure 6 illustrates a powder X-ray diffraction pattern of an amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid, in a ratio of 1 : 1 w/w, respectively obtained by lyophilization.
[0016] Figure 7 illustrates a powder X-ray diffraction pattern of an amorphous combination of polyvinylpyrrolidone and an amorphous composition of sunitinib base and L- malic acid combined in a ratio of 2:1 w/w, respectively obtained by lyophilization.
[0017] Figure 8 illustrates a powder X-ray diffraction pattern of crystalline composition G containing Sunitinib base and L-malic acid obtained by lyophilization
(zoomed view of relevant peaks). [0018] Figure 9 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of Polyoxyethylene-polyoxypropylene block polymer (Poloxamer 407) and a composition of sunitinib base and L-malic acid in a ratio of 1 :2.8 w/w, respectively obtained by lyophilization.
[0019] Figure 10 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of Polyoxyethylene-polyoxypropylene block polymer (Poloxamer 407) and a composition of sunitinib base and L-malic acid in a ratio of 1 :1 w/w, respectively obtained by lyophilization.
[0020] Figure 11 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of Polyoxy ethylene -polyoxypropylene block polymer (Poloxamer 188) and a composition of sunitinib base and L-malic acid in a ratio of 1 :1 w/w, respectively obtained by lyophilization.
[0021] Figure 12 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of Polyoxy ethylene -polyoxypropylene block polymer (Poloxamer 188) and a composition of sunitinib base and L-malic acid in a ratio of 1.7:1 w/w, respectively obtained by lyophilization.
[0022] Figure 13 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of hypromellose and a composition of sunitinib base and L-malic acid in a ratio of 1 :2.8 w/w, respectively obtained by lyophilization.
[0023] Figure 14 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of polyethyleneglycol and a composition of sunitinib base and L-malic acid in a ratio of 1 :7 w/w, respectively obtained by lyophilization.
[0024] Figure 15 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of dulcite and a composition of sunitinib base and L-malic acid in a ratio of
1 :1.5 w/w, respectively obtained by lyophilization.
[0025] Figure 16 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of dulcite and a composition of sunitinib base and L-malic acid in a ratio of
1.7:1 w/w, respectively obtained by lyophilization.
[0026] Figure 17 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of fructose and a composition of sunitinib base and L-malic acid in a ratio of
1 :1.5 w/w, respectively obtained by lyophilization.
[0027] Figure 18 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of polyoxyl 40 hydrogenated castor oil and a composition of sunitinib base and
L-malic acid in a ratio of 1 : 3.8 w/w, respectively obtained by lyophilization. [0028] Figure 19 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of sucrose and a composition of sunitinib base and L-malic acid in a ratio of
1 :1.5 w/w, respectively obtained by lyophilization.
[0029] Figure 20 illustrates a powder X-ray diffraction pattern of a crystalline combination of mannit and a composition of sunitinib base and L-malic acid in a ratio of 1 :1 w/w, respectively obtained by lyophilization.
[0030] Figure 21 illustrates a powder X-ray diffraction pattern of a crystalline combination of mannit and a composition of sunitinib base and L-malic acid in a ratio of
1.7:1 w/w, respectively obtained by lyophilization.
[0031 ] Figure 22 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of galactose and a composition of sunitinib base and L-malic acid in a ratio of
1 : 1 w/w, respectively obtained by lyophilization.
[0032] Figure 23 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of 2-hydroxyethyl octadecanoate and a composition of sunitinib base and L- malic acid in a ratio of 1 : 1 w/w, respectively obtained by lyophilization.
[0033] Figure 24 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of trehalose and a composition of sunitinib base and L-malic acid in a ratio of
1 :2.8 w/w, respectively obtained by lyophilization.
[0034] Figure 25 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of polyvinylpyrrolidone and a composition of sunitinib base and L-malic acid in a ratio of 1 :2.8 w/w, respectively obtained by lyophilization.
[0035] Figure 26 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of maltose and a composition of sunitinib base and L-malic acid in a ratio of
1 :1.5 w/w, respectively obtained by lyophilization.
[0036] Figure 27 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of maltose and a composition of sunitinib base and L-malic acid in a ratio of
1.7:1 w/w, respectively obtained by lyophilization.
[0037] Figure 28 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of lactose and a composition of sunitinib base and L-malic acid in a ratio of
1 :1.5 w/w, respectively obtained by lyophilization.
[0038] Figure 29 illustrates a powder X-ray diffraction pattern of crystalline composition G containing Sunitinib base and L-malic acid prepared by spray drying. [0039] Figure 30 illustrates a powder X-ray diffraction pattern of a semi-crystalline combination of lactose and a composition of sunitinib base and L-malic acid in a ratio of 1 : 1 w/w, respectively, prepared by spray drying.
[0040] Figure 31 illustrates a powder X-ray diffraction pattern of an amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid in a ratio of 1 : 1 w/w, respectively, prepared by spray drying.
DETAILED DESCRIPTION OF THE INVENTION
[0041] As used herein the term "w/w" refers to g/g.
[0042] As used herein, the term "crystalline sunitinib malate form I" refers to a crystalline form characterized by diffraction peaks at about 13.2 and 24.2 degrees two-theta± 0.2 degrees 2-theta, and more preferably, at about 13.2, 19.4, 24.2 and 25.5 degrees two- theta± 0.2 degrees 2-theta.
[0043] As used herein, the term "composition G of Sunitinib base and L-malic acid" refers to a composition containing Sunitinib base and L-malic acid characterized by a PXRD pattern having any 5 peaks at positions selected from the group consisting of: 6.2, 7.7, 9.3, 12.4, 14.5, 23.2 and 27.4 ± 0.2 degrees 2-theta.
[0044] The present invention offers a new combination of an amorphous composition of sunitinib base and L-malic acid that is combined with a pharmaceutically acceptable excipient, wherein the entire combination is either semi-crystalline (see figure 1) or amorphous (see figures 3-6). In the provided combination the composition of sunitinib base and L-malic acid is amorphous. See figures 1, and 3-7 where no peaks of sunitinib base and L-malic acid are evident; in figure 1 the evident peaks are of the excipient (see comparison between figure 1 and 2).
[0045] Attempts to prepare amorphous sunitinib malate or an amorphous composition of sunitinib base and L-malic acid without an excipient (see Ex. 7 and 28) or even with an excipient (see Ex. 8-27 and 29) were unsuccessful, i.e., the sunitinib base-L-malic acid composition was not amorphous. In the obtained product, peaks of crystalline composition of sunitinib base and L-malic acid are evident. Evidence for the presence of the crystalline composition of sunitinib base and L-malic acid can be detected by at least two peaks from the following list of peaks at 6.2, 7.7, 9.3, 12.4, 14.6, 23.2 and 27.2 ± 0.5 degrees 2-theta. [0046] "Amorphous" is herein defined as a composition having PXRD pattern with one broad bump with at most one peak that can be assigned to a crystalline composition of sunitinib base and L-malic acid superimposed on the broad bump.
[0047] "Semi-crystalline" is herein defined as a composition having PXRD pattern that contains peaks that can be detected and assigned to a composition of sunitinib base and
L-malic acid or to the pharmaceutically acceptable excipient.
[0048] The peaks that can be assigned for the crystalline composition of sunitinib base and L-malic acid are described above.
[0049] In one embodiment, the invention encompasses a combination of a pharmaceutically acceptable excipient selected from a group consisting of microcrystalline cellulose, polyvinylpyrrolidone, cyclodextrin, and disaccharide or derivatives thereof and an amorphous composition of sunitinib base and L-malic acid; wherein the combination is either amorphous or semi-crystalline; when the pharmaceutically acceptable excipient is cyclodextrin or disaccharide, the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 : 1 (w/w), the pharmaceutically acceptable excipient is polyvinylpyrrolidone and the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 :2 (w/w), the pharmaceutically acceptable excipient is microcrystalline cellulose and the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 :10 (w/w).
[0050] Preferably, the amorphous composition of sunitinib base and L-malic acid is polymorphically pure. As used herein the term "polymorphically pure" amorphous refers to a composition of sunitinib base and L-malic acid that has a PXRD pattern without all the following list of peaks at 6.2, 7.7, 9.3, 12.4, 14.6, 23.2 and 27.2 ± 0.5 degrees 2-theta that can be detected and/or assigned to a composition of sunitinib base and L-malic acid.
[0051] Preferably, the cellulose derivative is microcrystalline cellulose. Preferably, the cyclodextrin derivative is beta-cyclodextrin. Preferably, the disaccharide derivative is either trehalose, lactose or maltose. Preferably, the ratio between sunitinib base and L-malic acid is 1 : 1 mole/mole.
[0052] The semi-crystalline combination of microcrystalline cellulose and the amorphous composition of sunitinib base and L-malic acid in a ratio of 10:1 (w/w), respectively, can be characterized by PXRD pattern as depicted in figure 1.
[0053] The amorphous combination of beta-cyclodextrin and an amorphous composition of sunitinib base and L-malic acid in a ratio of 1 :1 (w/w), respectively, can be characterized by PXRD pattern as depicted in figure 3. [0054] The amorphous combination trehalose and an amorphous composition of sunitinib base and L-malic acid in a ratio of 1 : 1.4 (w/w), respectively, can be characterized by
PXRD pattern as depicted in figure 4.
[0055] The amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid in a ratio of 1 : 1 (w/w), respectively, can be characterized by
PXRD pattern as depicted in figure 5.
[0056] The amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid in a ratio of 1 : 1 (w/w), respectively, can be characterized by
PXRD pattern as depicted in figure 6.
[0057] The amorphous combination of polyvinylpyrrolidone and an amorphous composition of sunitinib base and L-malic acid in a ratio of 2:1 (w/w), respectively, can be characterized by PXRD pattern as depicted in figure 7.
[0058] The amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid in a ratio of 1 : 1 w/w, can be characterized by PXRD pattern as depicted in figure 31.
[0059] The above combination can be prepared by a process comprising removing water from a mixture comprising Sunitinib base, L-malic acid and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from a group consisting of cellulose, polyvinylpyrrolidone, cyclodextrin, disaccharide or derivatives thereof, when the pharmaceutically acceptable excipient is cyclodextrin or disaccharide and the ratio between the amorphous composition and the pharmaceutical acceptable excipient is about 1 : 1 (w/w), the pharmaceutically acceptable excipient is polyvinylpyrrolidone and the ratio between the amorphous composition and the pharmaceutical acceptable excipient is about 1 :2 (w/w), the pharmaceutically acceptable excipient is cellulose and the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 :10
(w/w). Preferably, the mixture consists essentially of water, Sunitinib base, L-malic acid and a pharmaceutically acceptable excipient, as mentioned above.
[0060] Preferably, the said mixture is a suspension or solution.
[0061] In some embodiments, the mixture is a suspension that is provided by dissolving Sunitinib malate in water and combining the obtained solution with the said pharmaceutically acceptable excipient to obtain the said suspension.
[0062] In other embodiments, the mixture is a solution that is provided by dissolving
Sunitinib malate and the pharmaceutically acceptable excipient in water. [0063] Preferably, the dissolution is done by heating to a temperature of about 500C to about 1000C. More preferably, the dissolution is done by heating to a temperature of about
800C.
[0064] Preferably, water is removed by drying, lyophilizing or spray-drying the said mixture.
[0065] Preferably, the drying is done by heating the mixture to a temperature of about
300C to about 1000C, thus removing water from the mixture. More preferably, the drying is done at a temperature of about 900C. Typically, water is removed under reduced pressure, for example 0.05 to about 300 mBar, preferably at a pressure of about 1 to about 20 mBar, more preferably the drying is done at a pressure of about 10 mBar.
[0066] Preferably, the drying is done for a period of about 2 hours.
[0067] Lyophilization is also known as freeze drying. In the current lyophilization process, the mixture is frozen. The frozen mass is then subjected to a pressure of less than about one atmosphere, to remove the solvent.
[0068] Preferably, the lyophilization is done at a temperature of about -300C to about
-1000C. Preferably, the lyophilization is done at a pressure of about 0.1 to about 1 mBar.
EXAMPLES
PXRD
[0069] XRD diffraction was performed on X-Ray powder diffractometer: Philips
X'pert Pro powder diffractometer, CuKa radiation, λ = 1.5418 A. X'Celerator detector active length (2 theta) = 2.122 mm, laboratory temperature 22-25°C. Zero background sample- holders. Prior to analysis the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass. Measurement parameters: Scan range: at least 3 - 40° 2-theta; Scan mode: continuous; Step size: 0.0167°; Time per step: 21 s; Sample spin: 16 rpm; Sample holder: quartz plate. Preparation of crystalline sunitinib malate form I
[0070] Sunitinib base (6 g) was dissolved in dioxane (160 ml) at 100 0C and the hot solution was filtered and the filter was cleaned with additional dioxane (40 ml). L-malic acid (2.02 g in 10 ml of water) was added. The solution was heated for 15 min to 100 0C, allowed to cool to 20 0C within 30 min, and allowed to crystallize overnight (12 hrs). Crystals were recovered by filtration, washed with t-BME (20 ml) and allowed to dry for 5 hrs on air.
Successful lvophilization and drying examples:
Example 1 : Preparation of a semi-crystalline combination of microcrystalline cellulose and an amorphous composition of sunitinib base and L-malic acid
[0071] Sunitinib L-malate (form I, 400 mg) was dissolved in water at 80 0C (8 ml) and microcrystalline cellulose (4 g) was added. The suspension thus formed was dried at 10 mBar at 90 0C for 1 hour providing a semi-crystalline combination of cellulose and an amorphous composition of sunitinib base and L-malic acid was obtained.
Example 2: Preparation of an amorphous combination of beta-cyclodextrin and an amorphous composition of sunitinib base and L-malic acid.
[0072] Sunitinib malate (150 mg, Form I ) was dissolved in boiling water (10 ml).
Beta-Cyclodextrin (150 mg) was added, boiled for 3 min, allowed to cool, frozen -30 C, lyophilized, 1 mBar. An amorphous combination of Beta-Cyclodextrin and an amorphous composition of sunitinib base and L-malic acid was obtained.
Example 3: Preparation of an amorphous combination of trehalose and an amorphous composition of sunitinib base and L-malic acid.
[0073] Sunitinib malate (140 mg, Form I) and trehalose (100 mg) were dissolved in water (10 ml) by heating to 100 0C for 5 min, allowed to cool, frozen by liquid N2 to about - 100 0C, lyophilised, 1 mBar. An amorphous combination of trehalose and an amorphous composition of sunitinib base and L-malic acid was obtained.
Example 4: Preparation of an amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid.
[0074] Sunitinib malate (150 mg, Form I) and lactose (150 mg) were dissolved in water (10 ml) by heating to 100 0C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 0C, lyophilised, 10 Pa, 24 h. An amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid was obtained.
Example 4a: Preparation of an amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid.
[0075] Sunitinib malate (150 mg, Form I) and lactose (250 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h. An amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid was obtained.
Example 5: Preparation of an amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid.
[0076] Sunitinib malate (150 mg, Form I) and maltose (150 mg) were dissolved in water (10 ml) by heating to 100 0C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 0C, lyophilised, 10 Pa, 24 h. An amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid was obtained.
Example 6: Preparation of an amorphous combination of polyvinylpyrrolidone (Polyvidone 25) and an amorphous composition of sunitinib base and L-malic acid [0077] Sunitinib malate (150 mg, Form I) and Polyvinylpyrrolidone (Polyvidone 25)
(300 mg) were dissolved in water (10 ml) by heating to 100 0C for 5 min, allowed to cool, frozen by liquid N2 to about -50 0C, lyophilised, 10 Pa, 24 h. An amorphous composition of combination of polyvinylpyrrolidone (Polyvidone 25) and an amorphous composition of sunitinib base and L-malic acid, was obtained.
Comparative Examples: Unsuccessful attempts to prepare amorphous sunitinib malate/ composition containing sunitinib base and L-malic acid:
Example 7:
[0078] Sunitinib L-malate (form I, 500 mg) was slurried in 10 ml water, and then the slurry was lyophilized. A crystalline composition G containing sunitinib base and malic acid was obtained as determined by XRPD. Example 8:
[0079] Sunitinib malate (140 mg, Form II) and Polyoxyethylene-polyoxypropylene block polymer (50 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about -100 C, lyophilised, 1 mBar. A semi crystalline combination of Polyoxyethylene-polyoxypropylene block polymer and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Example 9:
[0080] Sunitinib malate (150 mg, Form I) and Polyoxyethylene-polyoxypropylene block polymer (150 mg) were dissolved in water (10 ml) b heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about -50 C, lyophilised, 10 Pa, 24 h A semi crystalline combination of Polyoxyethylene-polyoxypropylene block polymer and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Example 10:
[0081] Sunitinib malate (150 mg, Form I) and Lutrol F68 (150 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h. A semi crystalline combination of Lutrol F68 and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Example 11 :
[0082] Sunitinib malate (150 mg, Form I) and Lutrol F68 (250 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h. A semi crystalline combination of Lutrol F68 and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Example 12:
[0083] Sunitinib malate (140 mg, Form II) and Hypromellose (50 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about -100 C, lyophilised, 1 mBar. A semi crystalline combination of Hypromellose and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD. Example 13:
[0084] Sunitinib malate (140 mg, Form II) and polyethyleneglycole (20 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about -100 C, lyophilised, 1 mBar. A semi crystalline combination of polyethyleneglycole and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Example 14:
[0085] Sunitinib malate (150 mg, Form I) and dulcite (100 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h. A semi crystalline combination of dulcite and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Example 15:
[0086] Sunitinib malate (150 mg, Form I) and dulcite (250 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h. . A semi crystalline combination of dulcite and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Example 16:
[0087] Sunitinib malate (150 mg, Form I) and fructose (100 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h. . A semi crystalline combination of fructose and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Example 17:
[0088] Sunitinib malate (150 mg, Form I) and polyoxyl 40 hydrogenated castor oil
(40 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about -50 C, lyophilised, 10 Pa, 24 h. A semi crystalline combination of polyoxyl 40 hydrogenated castor oil and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD. Example 18:
[0089] Sunitinib malate (150 mg, Form I) and sucrose (100 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h. A semi crystalline combination of sucrose and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Example 19:
[0090] Sunitinib malate (150 mg, Form I) and mannit (150 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h. A crystalline combination of mannit and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Example 20:
[0091] Sunitinib malate (150 mg, Form I) and mannit (250 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h. A crystalline combination of mannit and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Example 21 :
[0092] Sunitinib malate (150 mg, Form I) and galactose (150 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h. A semi crystalline combination of galactose and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Example 22:
[0093] Sunitinib malate (150 mg, Form I) and 2-hydroxy ethyl octadecanoate (150 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about -50 C, lyophilised, 10 Pa, 24 h. A semi crystalline combination of 2- hydroxyethyl octadecanoate and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Example 23 :
[0094] Sunitinib malate (140 mg, Form I) and trehalose (50 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 100 C, lyophilised, 1 mBar. A semi crystalline combination of trehalose and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Example 24:
[0095] Sunitinib malate (140 mg, Form II) and PVP (50 mg) were dissolved in water
(10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about -100 C, lyophilised, 1 mBar. A semi crystalline combination of PVP and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Example 25 :
[0096] Sunitinib malate (150 mg, Form I) and maltose (100 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h. A semi crystalline combination of maltose and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Example 26:
[0097] Sunitinib malate (150 mg, Form I) and maltose (250 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h. A semi crystalline combination of maltose and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Example 27:
[0098] Sunitinib malate (150 mg, Form I) and lactose (100 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h. A semi crystalline combination of lactose and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Example 28:
[0099] 15.0 grams of sunitinib malate (form I) were dissolved in 285.0 grams of water at 700C. After cooling to 200C, the 5% w/w solution was spray dried under the given settings: inlet temperature 1500C; pump flow 5mL/minute, aspirator 100%. Outlet temperature was 94-98°C. The product was recovered in the product collecting vessel. A semi crystalline composition of sunitinib base and L-malic acid was obtained as determined by XRPD. Example 29:
[00100] 15.0 grams of sunitinib malate (form I) were dissolved in 285.0 grams of water at 700C. After cooling to 200C, 100 grams of the resulting 5% w/w solution was mixed with 5.0 grams of lactose. The resulting solution spray dried under the given settings: inlet temperature 150 0C; pump flow 5mL/minute, aspirator 100%. Outlet temperature was 112- 114 0C. The product was recovered in the product collecting vessel. A semi crystalline combination of lactose and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
Successful spray drying example:
Example 30: Preparation of an amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid by spray drying
[00101] 15.0 grams of sunitinib malate (form I) were dissolved in 285.0 grams of water at 700C. After cooling to 200C, 100 grams of the resulting 5% w/w solution was mixed with 7.5 grams of maltose. The resulting solution spray dried under the given settings: inlet temperature 150 0C; pump flow 5mL/minute, aspirator 100%. Outlet temperature was 96- 98°C. The product was recovered in the product collecting vessel. An amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid was obtained as determined by XRPD.

Claims

What is claimed is:
1. A combination of a pharmaceutically acceptable excipient selected from a group consisting of cellulose, polyvinylpyrrolidone, cyclodextrin, disaccharide, or derivatives thereof, and a composition of sunitinib base and L-malic acid; wherein the combination is either amorphous or semi-crystalline; when the pharmaceutically acceptable excipient is cyclodextrin, disaccharide, or a derivative thereof, the ratio between the composition and the pharmaceutically acceptable excipient is about 1 : 1 (w/w); when the pharmaceutically acceptable excipient is polyvinylpyrrolidone or a derivative thereof, the ratio between the composition and the pharmaceutically acceptable excipient is about 1 :2 (w/w); when the pharmaceutically acceptable excipient is cellulose or a derivative thereof, the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 :10 (w/w).
2. The combination of claim 1, wherein the composition of sunitinib base and L-malic acid is polymorphically pure amorphous.
3. The combination of claim 1, wherein the excipient is microcrystalline cellulose, beta- cyclodextrin, trehalose, lactose or maltose.
4. The combination of claim 1, wherein the ratio between sunitinib base and L-malic acid is about 1 : 1 mole/mole.
5. The combination of claim 3, wherein the combination is semi-crystalline, wherein the excipient is microcrystalline cellulose, wherein the composition of sunitinib base and L-malic acid is amorphous, wherein the ratio of the combination is about 10:1 (w/w), respectively, and wherein the combination is characterized by a PXRD pattern as depicted in figure 1.
6. The combination of claim 3, wherein the combination is amorphous, wherein the excipient is beta-cyclodextrin, and wherein the ratio of the combination is about 1 : 1 (w/w), respectively, and wherein the combination is characterized by a PXRD pattern as depicted in figure 3.
7. The combination of claim 3, wherein the combination is amorphous, the excipient is trehalose, and wherein the ratio of the combination is about 1 : 1.4 (w/w), respectively, and wherein the combination is characterized by a PXRD pattern as depicted in figure 4.
8. The combination of claim 3, wherein the combination is amorphous, the excipient is lactose, and wherein the ratio of the combination is about 1 : 1 (w/w), respectively, and wherein the combination is characterized by a PXRD pattern as depicted in figures 5,
31 or a combination thereof.
9. The combination of claim 3, wherein the combination is amorphous, the excipient is maltose, and wherein the ratio of the combination is about 1 : 1 (w/w), respectively, and wherein the combination is characterized by a PXRD pattern as depicted in figure 6.
10. The combination of claim 3, wherein the combination is amorphous, wherein the excipient is polyvinylpyrrolidone, and wherein the ratio of the combination is about 2:1 (w/w), respectively, and wherein the combination is characterized by a PXRD pattern as depicted in figure 7.
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WO2020216450A1 (en) 2019-04-25 2020-10-29 Synthon B.V. Pharmaceutical composition comprising amorphous sunitinib
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WO2015031604A1 (en) 2013-08-28 2015-03-05 Crown Bioscience, Inc. Gene expression signatures predictive of subject response to a multi-kinase inhibitor and methods of using the same
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