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WO2017042700A1 - Solid forms of valsartan and sacubitril - Google Patents

Solid forms of valsartan and sacubitril Download PDF

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Publication number
WO2017042700A1
WO2017042700A1 PCT/IB2016/055335 IB2016055335W WO2017042700A1 WO 2017042700 A1 WO2017042700 A1 WO 2017042700A1 IB 2016055335 W IB2016055335 W IB 2016055335W WO 2017042700 A1 WO2017042700 A1 WO 2017042700A1
Authority
WO
WIPO (PCT)
Prior art keywords
salt
sacubitril
valsartan
solid
another embodiment
Prior art date
Application number
PCT/IB2016/055335
Other languages
French (fr)
Inventor
Siddamal Reddy PUTAPATRI
Bhushan B. KHAIRNAR
Gyanendra Pandey
Kaptan Singh
Mohan Prasad
Original Assignee
Sun Pharmaceutical Industries Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sun Pharmaceutical Industries Limited filed Critical Sun Pharmaceutical Industries Limited
Publication of WO2017042700A1 publication Critical patent/WO2017042700A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives

Definitions

  • the present invention provides solid forms comprising valsartan and sacubitril.
  • the present invention provides solid salt forms comprising valsartan and sacubitril.
  • the present invention further provides an amorphous solid salt form comprising sacubitril and valsartan.
  • the present invention further provides processes for the preparation of the solid forms as described herein.
  • the present invention further provides pharmaceutical compositions and a method of treatment of medical conditions responsive to the solid forms as described herein.
  • U.S. Patent No. 5,399,578 provides processes for the preparation of valsartan of Formula I.
  • U.S. Patent No. 5,217,996 provides processes for the preparation of sacubitril of
  • PCT Publication No. WO 2007/056546 describes a dual-acting compound, such supramolecular complex, comprising: (a) an angiotensin receptor antagonist; (b) a neutral endopeptidase inhibitor (NEPi); and optionally (c) a pharmaceutically acceptable cation.
  • NEPi neutral endopeptidase inhibitor
  • the present invention provides solid forms comprising valsartan and sacubitril.
  • the present invention provides solid salt forms comprising valsartan and sacubitril.
  • the present invention further provides an amorphous solid salt form comprising sacubitril and valsartan.
  • the present invention further provides processes for the preparation of the solid forms as described herein.
  • the present invention further provides pharmaceutical compositions and a method of treatment of medical conditions responsive to the solid forms as described herein.
  • Figure 1 depicts an X-ray Powder Diffraction (XRPD) pattern of an amorphous sodium salt form comprising sacubitril and valsartan as prepared according to Example 1.
  • XRPD X-ray Powder Diffraction
  • Figure 2 depicts an Infrared (IR) absorption spectrum of an amorphous sodium salt form comprising sacubitril and valsartan as prepared according to Example 1.
  • IR Infrared
  • Figure 3 depicts a Differential Scanning Calorimetry (DSC) thermogram of an amorphous sodium salt form comprising sacubitril and valsartan as prepared according to Example 1.
  • DSC Differential Scanning Calorimetry
  • Figure 4 depicts a Raman spectrum of an amorphous sodium salt form comprising sacubitril and valsartan as prepared according to Example 1.
  • Figures 5 and 6 depict Scanning Microscopic Images (SEM) of an amorphous sodium salt form comprising sacubitril and valsartan as prepared according to Example 1.
  • Figure 7 depicts an XRPD pattern of an amorphous sodium salt form comprising sacubitril and valsartan as prepared according to Example 6.
  • Figure 8 depicts an XRPD pattern of an amorphous sodium salt form comprising sacubitril and valsartan as prepared according to Example 6 when stored at a temperature of 25°C ⁇ 2°C and at a relative humidity of 60% ⁇ 5% for 6 months.
  • solid form refers to a form that includes salts, mixed salts, co-crystals, mixed crystals, complexes containing intermolecular or intramolecular interactions, combinations of two ingredients with non-covalent or non-ionic interactions, solid dispersions, co-precipitates, and complexes with long range interactions.
  • crystalline refers to a solid with long-range or short- range crystalline order and with varied degree of crystallinity, for example at least an 80% degree of crystallinity.
  • the degree of crystallinity is calculated on the basis of percentage area in the X-ray powder diffraction (XRPD) pattern.
  • amorphous refers to a solid without long-range crystalline order and is essentially free of crystalline forms.
  • essentially free of crystalline forms refers to amorphous forms having less than a 20% degree of crystallinity as determined by percentage area in the XRPD pattern.
  • amorphous also refers to solid material which lacks a regular crystalline structure.
  • stable refers to an amorphous solid salt form in which the XRPD pattern of the polymorphic form, the chromatographic purity, and the description do not change when stored at a temperature of 25 °C ⁇ 2°C and at a relative humidity of 60% ⁇ 5% for 1 month or more.
  • hydrophilous refers to a form with varied amount and distribution of water, for example having surface water, bound water, or a combination thereof.
  • surface water refers to water adsorbed on the surface of a solid form which can be removed easily, for example, by keeping the solid form in dry air.
  • bound water refers to water entrapped within the solid form which is difficult to remove by common drying techniques.
  • treating includes combining, mixing, triturating, suspending, or contacting valsartan or its salt, sacubitril or its salt, a source of cation and a solvent in any of the sequences.
  • the term "adding or added,” as used herein, refers to dissolving, combining, slurrying, stirring, mixing, triturating, suspending, contacting, or combinations thereof.
  • the term "Ci-6 alkyl,” as used herein, refers to straight or branched aliphatic hydrocarbons, or cyclic aliphatic hydrocarbons, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, t-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • clathrate refers to non-stoichiometric substances in which lattice structures composed of first molecular components (host molecules) trap or encage one or more other molecular components (guest molecules) in what resembles a crystal-like structure.
  • the term “clathrates” also includes inclusion compounds, hydrates, gas hydrates, methane hydrates, natural gas hydrates, and CO 2 hydrates.
  • solid dispersion refers to systems having small solid-state particles of one phase dispersed in another solid-state phase.
  • co-crystal refers to a crystalline material that includes two or more unique components held together by a weak interaction in a stoichiometric ratio, wherein at least one of the compounds is a co-crystal former and wherein each component of the co-crystal has distinctive physical characteristics such as structure, melting point, and heat of fusion.
  • a first aspect of the present invention provides a solid form comprising valsartan and sacubitril.
  • the solid form is a salt form.
  • the salt is a monovalent salt or a bivalent salt.
  • the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NRt + (wherein R is hydrogen or Ci-6 alkyl).
  • the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
  • the salt is benzathine, choline, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine, or benzylamine.
  • the salt is a mixed salt.
  • the mixed salt comprises monovalent or bivalent ions.
  • the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NRt + (wherein R is hydrogen or Ci-6 alkyl).
  • the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
  • the salt is present in the form of a supramolecular complex, co-crystal, chelate, mixed co-crystal, co-precipitate, solid dispersion, co-crystal complex, clathrate, or a combination thereof.
  • the salt is linked through an ionic bond, co-ordinate bond, covalent bond, hydrogen bond, van der Waals forces, or ⁇ - ⁇ stacking.
  • the solid form is in crystalline or in amorphous form.
  • the solid form may exist with a varied amount of water, for example, in a hydrous or in an anhydrous form.
  • the water is either surface water, bound water, or a combination thereof.
  • a second aspect of the present invention provides a solid salt form comprising valsartan and sacubitril.
  • the salt is a monovalent salt or a bivalent salt.
  • the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NR t + (wherein R is hydrogen or Ci-6 alkyl).
  • the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
  • the salt is benzathine, choline, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine, or benzylamine.
  • the salt is a mixed salt.
  • the mixed salt comprises of monovalent or bivalent ions.
  • the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NR t + (wherein R is hydrogen or Ci-6 alkyl).
  • the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
  • the salt is present in the form of a supramolecular complex, co-crystal, mixed co-crystal, co-precipitate, solid dispersion, chelate, co-crystal complex, clathrate, or a combination thereof.
  • the salt is linked through an ionic bond, co-ordinate bond, covalent bond, hydrogen bond, van der Waals forces, or ⁇ - ⁇ stacking.
  • the salt form is in crystalline or in amorphous form.
  • the salt form may exist with a varied amount of water, for example, in a hydrous or in an anhydrous form. In hydrous form, the water is either surface water, bound water, or a combination thereof.
  • a third aspect of the present invention provides an amorphous solid salt form comprising valsartan and sacubitril.
  • the amorphous form is in salt form.
  • the salt is a monovalent salt or a bivalent salt.
  • the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NR t + (wherein R is hydrogen or Ci-6 alkyl).
  • the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
  • the salt is benzathine, choline, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine, or benzylamine.
  • the salt is a mixed salt.
  • the mixed salt comprises of monovalent or bivalent ions.
  • the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NR t + (wherein R is hydrogen or Ci-6 alkyl).
  • the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
  • the salt is present in the form of a supramolecular complex, co-crystal, chelate, mixed co-crystal, co-precipitate, solid dispersion, co-crystal complex, clathrate, or a combination thereof.
  • the salt is linked through an ionic bond, co-ordinate bond, covalent bond, hydrogen bond, van der Waals forces, or ⁇ - ⁇ stacking.
  • the amorphous form exists with a varied amount of water, for example, in a hydrous or in an anhydrous form.
  • the water is either surface water, bound water, or a combination thereof.
  • the amorphous sodium salt form comprising valsartan and sacubitril has an XRPD pattern as depicted in Figures 1, 7 and 8.
  • the amorphous sodium salt form comprising valsartan and sacubitril has an IR absorption spectrum as depicted in Figure 2.
  • the amorphous sodium salt form comprising valsartan and sacubitril has a DSC thermogram as depicted in Figure 3.
  • the amorphous sodium salt form comprising valsartan and sacubitril has a DSC thermogram having endothermic peaks at about 102.5°C and 238.8°C.
  • the amorphous sodium salt form comprising valsartan and sacubitril has a Raman spectrum as depicted in Figure 4.
  • the amorphous sodium salt form comprising valsartan and sacubitril has an SEM image as depicted in Figures 5 and 6.
  • the amorphous sodium salt form comprising valsartan and sacubitril remains stable, in terms of XRPD, when stored at a temperature of 25°C ⁇ 2°C and at a relative humidity of 60% ⁇ 5% relative humidity (RH) for 6 months ( Figures 7 and 8).
  • the amorphous sodium salt form comprising valsartan and sacubitril also remains stable when stored at a temperature of 25°C ⁇ 2°C and at a relative humidity of 60% ⁇ 5% relative humidity (RH) for 6 months in terms of the chromatographic purity and description as depicted in table 1.
  • a fourth aspect of the present invention provides a process for the preparation of a solid form comprising valsartan and sacubitril, wherein the process comprises treating valsartan or a salt thereof and sacubitril or a salt thereof with a source of cation in a solvent.
  • the solid form is a salt form.
  • the salt is a monovalent salt or a bivalent salt.
  • the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NR t + (wherein R is hydrogen or Ci-6 alkyl).
  • the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
  • the salt is benzathine, choline, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine, or benzylamine.
  • the salt is a mixed salt.
  • the mixed salt comprises of monovalent or bivalent ions.
  • the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NR t + (wherein R is hydrogen or Ci-6 alkyl).
  • the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
  • the salt is present in the form of a supramolecular complex, co-crystal, mixed co-crystal, co-precipitate, solid dispersion, chelate, co-crystal complex, clathrate, or a combination thereof.
  • the salt is linked through an ionic bond, co-ordinate bond, covalent bond, hydrogen bond, van der Waals forces, or ⁇ - ⁇ stacking.
  • the solid form is in crystalline or in amorphous form.
  • the solid form exists with a varied amount of water, for example, in a hydrous or in an anhydrous form.
  • the water is either surface water, bound water, or a combination thereof.
  • the salt of valsartan is selected from the group consisting of sodium, potassium, barium, calcium, lithium, cesium, and strontium.
  • the salt of sacubitril is selected from the group consisting of sodium, potassium, barium, calcium, lithium, cesium, and strontium.
  • Valsartan may be prepared by any method known in the art, for example, as disclosed in U.S. Patent No. 5,399,578.
  • Valsartan salts may be prepared by any method known in the art, for example, as disclosed in PCT Publication No. WO 02/06253.
  • Sacubitril may be prepared by any method known in the art, for example, as disclosed in U.S. Patent No. 5,217,996. Sacubitril salts may be prepared by any method known in the art, for example, as disclosed in PCT Publication No. WO 03/059345.
  • the source of cation consists of monovalent or divalent cations.
  • the source of the cations consists of hydroxides, carbonates, or bicarbonates of monovalent or bivalent cations.
  • the hydroxide source of the monovalent and the divalent cations include sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, zinc hydroxide, rubidium hydroxide, ammonium hydroxide, and strontium hydroxide.
  • the carbonate source of the monovalent and the divalent cations include sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, barium carbonate, magnesium carbonate, calcium carbonate, zinc carbonate, rubidium carbonate, ammonium carbonate, and strontium carbonate.
  • the bicarbonate source of the monovalent and the divalent cations include sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, barium bicarbonate, magnesium bicarbonate, calcium bicarbonate, zinc bicarbonate, rubidium bicarbonate, ammonium bicarbonate, and strontium bicarbonate.
  • the source of the cations also includes benzathine, choline chloride, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine chloride, or benzylamine.
  • the solvent is selected from the group consisting of water, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
  • ketones include acetone and methyl ethyl ketone.
  • esters include ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
  • ethers include methyl t-butyl ether and tetrahydrofuran.
  • alkanols include primary, secondary, and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, n-propanol, 2-propanol, and butanol.
  • halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • polar aprotic solvents examples include N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone. These solvents can also be used as anti-solvents for isolation and also for the purification of solid forms.
  • the treatment of valsartan or a salt thereof, sacubitril or a salt thereof, and a source of cation is carried out at a temperature of about 10°C to about 50°C, preferably at about 20°C to about 40°C.
  • the treatment of valsartan or a salt thereof, sacubitril or a salt thereof, and a source of cation is carried out for about 2 hours to about 10 hours, preferably for about 2 hours to about 8 hours.
  • the solid form is isolated using common isolation techniques such as evaporation, evaporation under vacuum, cooling, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the solid form is dried using common drying techniques such as vacuum drying, thin film drying, spray drying, freeze drying, open air drying, drying under nitrogen, or a combination thereof.
  • a fifth aspect of the present invention provides a process for the preparation of a solid salt form comprising valsartan and sacubitril, wherein the process comprises treating valsartan or a salt thereof, sacubitril or a salt thereof, and a salt-forming agent in a solvent.
  • the salt is a monovalent salt or a bivalent salt.
  • the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NR 4 + (wherein R is hydrogen or Ci-6 alkyl).
  • the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
  • the salt is benzathine, choline, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine, or benzylamine.
  • the salt is a mixed salt.
  • the mixed salt comprises monovalent or bivalent ions.
  • the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NR t + (wherein R is hydrogen or Ci-6 alkyl).
  • the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
  • the salt is present in the form of supramolecular complex, co-crystal, mixed co-crystal, co-precipitate, solid dispersion, chelate, co-crystal complex, clathrate, or a combination thereof.
  • the salt is linked through an ionic bond, co-ordinate bond, covalent bond, hydrogen bond, van der Waals forces, or ⁇ - ⁇ stacking.
  • the solid salt form is in crystalline or in amorphous form.
  • the solid form may exist with a varied amount of water, for example, in a hydrous or in an anhydrous form. In hydrous form, the water is either surface water, bound water, or a combination thereof.
  • the salt of valsartan is selected from the group consisting of sodium, potassium, barium, calcium, lithium, cesium, and strontium.
  • the salt of sacubitril is selected from the group consisting of sodium, potassium, barium, calcium, lithium, cesium, and strontium.
  • Valsartan may be prepared by any method known in the art, for example, as disclosed in U.S. Patent No. 5,399,578.
  • Valsartan salts may be prepared by any method known in the art, for example, as disclosed in PCT Publication No. WO 02/06253.
  • Sacubitril may be prepared by any method known in the art, for example, as disclosed in U.S. Patent No. 5,217,996. Sacubitril salts may be prepared by any method known in the art, for example, as disclosed in PCT Publication No. WO 03/059345.
  • the salt-forming agent consists of hydroxides, carbonates, or bicarbonate s of monovalent or bivalent cations.
  • the hydroxides of the monovalent and the divalent cations include sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, zinc hydroxide, rubidium hydroxide, ammonium hydroxide, and strontium hydroxide.
  • the carbonates of the monovalent and the divalent cations include sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, barium carbonate, magnesium carbonate, calcium carbonate, zinc carbonate, rubidium carbonate, ammonium carbonate, and strontium carbonate.
  • the bicarbonates of the monovalent and the divalent cations include sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, barium bicarbonate, magnesium bicarbonate, calcium bicarbonate, zinc bicarbonate, rubidium bicarbonate, ammonium bicarbonate, and strontium bicarbonate.
  • the salt-forming agent also includes benzathine, choline chloride, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine chloride, or benzylamine.
  • the solvent is selected from the group consisting of water, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
  • ketones include acetone and methyl ethyl ketone.
  • esters include ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
  • ethers include methyl t-butyl ether and tetrahydrofuran.
  • alkanols include primary, secondary, and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, n-propanol, 2-propanol, and butanol.
  • halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • polar aprotic solvents examples include N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone. These solvents can also be used as anti-solvents for isolation and also for the purification of solid forms.
  • the treatment of valsartan or a salt thereof, sacubitril or a salt thereof, and a source of cation is carried out at a temperature of about 10°C to about 50°C, preferably at about 20°C to about 40°C.
  • the treatment of valsartan or a salt thereof, sacubitril or a salt thereof, and a source of cation is carried out for about 2 hours to about 10 hours, preferably for about 2 hours to about 8 hours.
  • the salt form is isolated using common isolation techniques such as evaporation, evaporation under vacuum, cooling, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
  • the salt form is dried using common drying techniques such as vacuum drying, thin film drying, spray drying, freeze drying, open air drying, drying under nitrogen, or a combination thereof.
  • a sixth aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising solid forms comprising valsartan, sacubitril, and a carrier.
  • the solid form is a salt form.
  • the salt is a monovalent salt or a bivalent salt.
  • the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NR t + (wherein R is hydrogen or Ci-6 alkyl).
  • the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
  • the salt is benzathine, choline, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine, or benzylamine.
  • the salt is a mixed salt.
  • the mixed salt comprises monovalent or bivalent ions.
  • the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NR t + (wherein R is hydrogen or Ci-6 alkyl).
  • the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
  • the salt is present in the form of a supramolecular complex, co-crystal, mixed co-crystal, co-precipitate, solid dispersion, chelate, co-crystal complex, clathrate, or a combination thereof.
  • the salt is linked through an ionic bond, co-ordinate bond, covalent bond, hydrogen bond, van der Waals forces, or ⁇ - ⁇ stacking.
  • the solid form is in crystalline or in amorphous form.
  • the solid form may exist with a varied amount of water, for example, in a hydrous or in an anhydrous form. In hydrous form, the water is either surface water, bound water, or a combination thereof.
  • the pharmaceutical composition may be manufactured by a dry formulation process such as a direct compression or roller compaction process.
  • the pharmaceutical composition can be formulated by mixing the solid form with at least one pharmaceutically acceptable excipient and further processing the mixture into suitable dosage forms such as tablets and capsules.
  • a seventh aspect of the present invention provides a method of treating or preventing cardiovascular or renal condition or a medical condition responsive to valsartan and/or sacubitril in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the solid forms comprising valsartan, sacubitril, and a carrier.
  • the solid form is a salt form.
  • the salt is monovalent salt or bivalent salt.
  • the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NRt + (wherein R is hydrogen or Ci-6 alkyl).
  • the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
  • the salt is benzathine, choline, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine, or benzylamine.
  • the salt is a mixed salt.
  • the mixed salt comprises of monovalent or bivalent ions.
  • the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NRt + (wherein R is hydrogen or Ci-6 alkyl).
  • the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
  • the salt is present in the form of a supramolecular complex, co-crystal, mixed co-crystal, co-precipitate, solid dispersion, chelate, co-crystal complex, clathrate, or a combination thereof.
  • the salt is linked through an ionic bond, co-ordinate bond, covalent bond, hydrogen bond, van der Waals forces, or ⁇ - ⁇ stacking.
  • the solid form is in crystalline or in amorphous form.
  • the solid form may exist with a varied amount of water, for example, in a hydrous or in an anhydrous form. In hydrous form, the water is either surface water, bound water, or a combination thereof.
  • the cardiovascular condition or disease is selected from the group consisting of hypertension, heart failure (acute or chronic), congestive heart failure, left ventricular dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, and angina (unstable or stable); and the renal condition or diseases is selected from the group consisting of renal insufficiency (diabetic or non-diabetic), glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and renal vascular hypertension.
  • heart failure acute or chronic
  • congestive heart failure left ventricular dysfunction
  • hypertrophic cardiomyopathy diabetic cardiac myopathy
  • supraventricular and ventricular arrhythmias atrial fibrillation
  • atrial flutter detrimental vascular remodeling
  • myocardial infarction and its sequelae atherosclerosis
  • XRPD of the samples was determined by using a PANalytical ® instrument; Model X'pert PRO; Detector: X'celerator ® .
  • Raman spectrum of the sample measured by a dispersive Raman spectrometer with a 785 nm laser excitation source.
  • Example 1 Preparation of a sodium salt comprising valsartan and sacubitril
  • Sacubitril 60 g was added to acetone (200 mL) at 20°C to 30°C followed by the addition of a solution of valsartan (61.8 g) in acetone (280 mL). The reaction mixture was stirred at 20°C to 30°C for 15 minutes. Sodium hydroxide (17 g in 40 mL of water) was added drop-wise to the reaction mixture with stirring, and then the stirring continued for 2 hours at 20°C to 30°C. Acetone was recovered (200 mL) from the reaction mixture at 30°C, and then isopropyl acetate (100 mL) was added. The solvent was recovered (300 mL) from the reaction mixture at 30°C.
  • step a) The solid (115 g) obtained in step a) was added to methanol (460 mL) at 20°C to
  • Figure 1 depicts an X-ray Powder Diffraction (XRPD) pattern.
  • FIG. 1 depicts an Infrared (IR) absorption spectrum.
  • FIG. 3 depicts a Differential Scanning Calorimetry (DSC) thermogram.
  • Figure 4 depicts a Raman spectrum
  • FIGS. 5 and 6 depict a Scanning Microscopic Image (SEM).
  • Example 2 Preparation of a lithium salt comprising valsartan and sacubitril
  • Sacubitril (4.6 g) was added to acetone (50 mL) at 20°C to 30°C followed by the addition of a solution of valsartan (4.62 g) in acetone (5 mL) at 20°C to 30°C for 15 minutes.
  • Lithium hydroxide (1.78 g in 15 mL of water) was added to the reaction mixture drop-wise, and then the reaction mixture was stirred at 20°C to 30°C for 3 hours.
  • the solvent was recovered (20 mL) from the reaction mixture at 30°C. Isopropyl acetate (30 mL) was added to the reaction mixture, and then the solvent was completely recovered from the reaction mixture.
  • Sacubitril (5 g) was added to acetone (55 mL) at 20°C to 30°C followed by the addition of valsartan (5.18 g). The reaction mixture was stirred at 20°C to 30°C for 15 minutes. Barium hydroxide (11.6 g in 70 mL of water) was added to the reaction mixture drop-wise, and then the reaction mixture was stirred at 20°C to 30°C for 2 hours. The solvent was recovered (125 mL) from the reaction mixture at 30°C. Isopropyl acetate (50 mL) was added to the reaction mixture, and then the solvent was completely recovered from the reaction mixture. Acetone (80 mL) was added to the reaction mixture, and then the reaction mixture was stirred at 20°C to 30°C for 5 hours. The solid obtained was dried under vacuum at 45°C for 12 hours to obtain the solid form.
  • Sacubitril (5 g) was added to acetone (25 mL) at 20°C to 25 °C.
  • Valsartan (5.18 g) in acetone (25 mL) was added to the mixture. The mixture was stirred for 10 minutes at 20°C to 25°C, and then cooled to 0°C to 5°C.
  • a potassium hydroxide solution (2.05 g in 10 mL water) was added to the reaction mixture, and then the mixture was stirred at 20°C to 25°C for 1 hour.
  • Acetone 50 mL was recovered from the reaction mixture at 40°C under 680 mm to 710 mm of Hg pressure.
  • Acetone 50 mL was added to the reaction mixture, and was further recovered (50 mL) from the reaction mixture at 40°C under 680 mm to 710 mm of Hg pressure.
  • Methyl t-butyl ether 50 mL was added to the reaction mixture, and then the mixture was stirred at 20°C to 25 °C for 5 minutes.
  • the reaction mixture was filtered under nitrogen atmosphere to obtain a solid material.
  • the solid material obtained was dried under 680 mm to 710 mm of Hg at 20°C to 25°C for 16 hours to obtain the title compound.
  • Example 5 Preparation of a calcium salt comprising sacubitril and valsartan Sacubitril (5 g) was added to acetone (25 mL) at 20°C to 25 °C. Valsartan (5.18 g) in acetone (25 mL) was added to the mixture. The mixture was stirred for 10 minutes at 20°C to 25°C, and then cooled to 0°C to 5°C. A calcium chloride solution (4.05 g in 10 mL of water) was added to the reaction mixture, and then the mixture was stirred at 20°C to 25°C for 1 hour. Acetone (50 mL) was recovered from the reaction mixture at 40°C under 680 mm to 710 mm of Hg.
  • Acetone 50 mL was added to the reaction mixture, and then recovered under vacuum at 40°C under 680 mm to 710 mm of Hg to obtain a solid material.
  • Methyl t-butyl ether 50 mL was added to the reaction mixture at 20°C to 25°C, and then the mixture was stirred at 20°C to 25 °C for 5 minutes.
  • the reaction mixture was filtered under nitrogen atmosphere to obtain a solid material.
  • the solid material obtained was dried under 680 mm to 710 mm of Hg at 20°C to 25°C for 16 hours to obtain the title compound.
  • Example 6 Preparation of a sodium salt comprising sacubitril and valsartan
  • Sacubitril (47 g) was added to acetone (270 mL) at 20°C to 30°C followed by the addition of a solution of valsartan (49.7 g) in acetone (200 mL).
  • the reaction mixture was stirred at 20°C to 30°C for 15 minutes.
  • the reaction mixture was cooled to 5°C to 10°C.
  • Sodium carbonate (19.39 g in 60 mL of water) was added to the reaction mixture with stirring, and then the stirring was continued for 2 hours at 20°C to 30°C.
  • Acetone was recovered (300 mL) from the reaction mixture at 30°C, and then isopropyl acetate (100 mL) was added. The solvent was recovered at 30°C up to solid residue.
  • step a) The solid (66 g) obtained in step a) was added to methyl i-butyl ether (500 mL) and methanol (20 mL). The reaction mixture was stirred at 20°C to 30°C for 2 hours. The solid obtained was filtered, and then methanol (310 mL) was added to the reaction mixture. The reaction mixture was stirred at 30°C for 15 minutes to obtain a clear solution. Methanol (310 mL) was recovered from the reaction mixture. Methyl t-butyl ether (160 mL) was added to the reaction mixture, and then recovered at 30°C to 35°C. Methyl t-butyl ether (300 mL) was added to the reaction mixture, and then the mixture was stirred for 5 minutes. The solid (85 g) obtained was filtered under nitrogen. The solid obtained was dried under 680 mm to 710 mm of Hg to obtain the solid.
  • Figure 7 depicts an X-ray Powder Diffraction (XRPD) pattern.
  • Figure 8 depicts an X-ray Powder Diffraction (XRPD) pattern when stored at a temperature of 25 ⁇ 2°C and at a relative humidity of 60 ⁇ 5% relative humidity (RH) for 6 months.
  • XRPD X-ray Powder Diffraction

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Abstract

The present invention provides solid forms comprising valsartan and sacubitril. The present invention provides solid salt forms comprising valsartan and sacubitril. The present invention further provides an amorphous solid salt form comprising sacubitril and valsartan. The present invention further provides processes for the preparation of the solid forms as described herein. The present invention further provides pharmaceutical compositions and a method of treatment of medical conditions responsive to the solid forms as described herein.

Description

SOLID FORMS OF VALSARTAN AND SACUBITRIL
Field of the Invention
The present invention provides solid forms comprising valsartan and sacubitril. The present invention provides solid salt forms comprising valsartan and sacubitril. The present invention further provides an amorphous solid salt form comprising sacubitril and valsartan. The present invention further provides processes for the preparation of the solid forms as described herein. The present invention further provides pharmaceutical compositions and a method of treatment of medical conditions responsive to the solid forms as described herein.
Background of the Invention
U.S. Patent No. 5,399,578 provides processes for the preparation of valsartan of Formula I.
Figure imgf000002_0001
FORMULA I
U.S. Patent No. 5,217,996 provides processes for the preparation of sacubitril of
Formula II.
Figure imgf000002_0002
FORMULA II
PCT Publication No. WO 2007/056546 describes a dual-acting compound, such supramolecular complex, comprising: (a) an angiotensin receptor antagonist; (b) a neutral endopeptidase inhibitor (NEPi); and optionally (c) a pharmaceutically acceptable cation.
Summary of the Invention
The present invention provides solid forms comprising valsartan and sacubitril.
The present invention provides solid salt forms comprising valsartan and sacubitril. The present invention further provides an amorphous solid salt form comprising sacubitril and valsartan. The present invention further provides processes for the preparation of the solid forms as described herein. The present invention further provides pharmaceutical compositions and a method of treatment of medical conditions responsive to the solid forms as described herein.
Brief Description of the Drawings
Figure 1 depicts an X-ray Powder Diffraction (XRPD) pattern of an amorphous sodium salt form comprising sacubitril and valsartan as prepared according to Example 1.
Figure 2 depicts an Infrared (IR) absorption spectrum of an amorphous sodium salt form comprising sacubitril and valsartan as prepared according to Example 1.
Figure 3 depicts a Differential Scanning Calorimetry (DSC) thermogram of an amorphous sodium salt form comprising sacubitril and valsartan as prepared according to Example 1.
Figure 4 depicts a Raman spectrum of an amorphous sodium salt form comprising sacubitril and valsartan as prepared according to Example 1.
Figures 5 and 6 depict Scanning Microscopic Images (SEM) of an amorphous sodium salt form comprising sacubitril and valsartan as prepared according to Example 1.
Figure 7 depicts an XRPD pattern of an amorphous sodium salt form comprising sacubitril and valsartan as prepared according to Example 6.
Figure 8 depicts an XRPD pattern of an amorphous sodium salt form comprising sacubitril and valsartan as prepared according to Example 6 when stored at a temperature of 25°C ±2°C and at a relative humidity of 60% ± 5% for 6 months.
Detailed Description of the Invention
The term "about," as used herein, refers to any value which lies within the range defined by a number up to ± 10% of the value. The term "solid form," as used herein, refers to a form that includes salts, mixed salts, co-crystals, mixed crystals, complexes containing intermolecular or intramolecular interactions, combinations of two ingredients with non-covalent or non-ionic interactions, solid dispersions, co-precipitates, and complexes with long range interactions.
The term "crystalline," as used herein, refers to a solid with long-range or short- range crystalline order and with varied degree of crystallinity, for example at least an 80% degree of crystallinity. The degree of crystallinity is calculated on the basis of percentage area in the X-ray powder diffraction (XRPD) pattern.
The term "amorphous," as used herein, refers to a solid without long-range crystalline order and is essentially free of crystalline forms. The term "essentially free of crystalline forms" refers to amorphous forms having less than a 20% degree of crystallinity as determined by percentage area in the XRPD pattern. The term
"amorphous" also refers to solid material which lacks a regular crystalline structure.
The term "stable" refers to an amorphous solid salt form in which the XRPD pattern of the polymorphic form, the chromatographic purity, and the description do not change when stored at a temperature of 25 °C ± 2°C and at a relative humidity of 60% ± 5% for 1 month or more.
The term "hydrous," as used herein, refers to a form with varied amount and distribution of water, for example having surface water, bound water, or a combination thereof.
The term "surface water," as used herein, refers to water adsorbed on the surface of a solid form which can be removed easily, for example, by keeping the solid form in dry air.
The term "bound water," as used herein, refers to water entrapped within the solid form which is difficult to remove by common drying techniques.
The term "treating" includes combining, mixing, triturating, suspending, or contacting valsartan or its salt, sacubitril or its salt, a source of cation and a solvent in any of the sequences.
The term "adding or added," as used herein, refers to dissolving, combining, slurrying, stirring, mixing, triturating, suspending, contacting, or combinations thereof. The term "Ci-6 alkyl," as used herein, refers to straight or branched aliphatic hydrocarbons, or cyclic aliphatic hydrocarbons, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, t-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
The term "clathrate," as used herein, refers to non-stoichiometric substances in which lattice structures composed of first molecular components (host molecules) trap or encage one or more other molecular components (guest molecules) in what resembles a crystal-like structure. The term "clathrates" also includes inclusion compounds, hydrates, gas hydrates, methane hydrates, natural gas hydrates, and CO2 hydrates.
The term "solid dispersion," as used herein, refers to systems having small solid- state particles of one phase dispersed in another solid-state phase.
The term "co-crystal," as used herein, refers to a crystalline material that includes two or more unique components held together by a weak interaction in a stoichiometric ratio, wherein at least one of the compounds is a co-crystal former and wherein each component of the co-crystal has distinctive physical characteristics such as structure, melting point, and heat of fusion.
A first aspect of the present invention provides a solid form comprising valsartan and sacubitril.
In an embodiment of this aspect, the solid form is a salt form. In another embodiment, the salt is a monovalent salt or a bivalent salt. In another embodiment, the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NRt+ (wherein R is hydrogen or Ci-6 alkyl). In another embodiment, the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
In another embodiment, the salt is benzathine, choline, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine, or benzylamine.
In another embodiment, the salt is a mixed salt. In another embodiment, the mixed salt comprises monovalent or bivalent ions. In another embodiment, the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NRt+ (wherein R is hydrogen or Ci-6 alkyl). In another embodiment, the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt. In another embodiment, the salt is present in the form of a supramolecular complex, co-crystal, chelate, mixed co-crystal, co-precipitate, solid dispersion, co-crystal complex, clathrate, or a combination thereof. In another embodiment, the salt is linked through an ionic bond, co-ordinate bond, covalent bond, hydrogen bond, van der Waals forces, or π-π stacking.
In another embodiment, the solid form is in crystalline or in amorphous form. In another embodiment, the solid form may exist with a varied amount of water, for example, in a hydrous or in an anhydrous form. In a hydrous form, the water is either surface water, bound water, or a combination thereof.
A second aspect of the present invention provides a solid salt form comprising valsartan and sacubitril.
In an embodiment of this aspect, the salt is a monovalent salt or a bivalent salt. In another embodiment, the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NRt + (wherein R is hydrogen or Ci-6 alkyl). In another embodiment, the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
In another embodiment, the salt is benzathine, choline, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine, or benzylamine.
In another embodiment, the salt is a mixed salt. In another embodiment, the mixed salt comprises of monovalent or bivalent ions. In another embodiment, the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NRt + (wherein R is hydrogen or Ci-6 alkyl). In another embodiment, the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
In another embodiment, the salt is present in the form of a supramolecular complex, co-crystal, mixed co-crystal, co-precipitate, solid dispersion, chelate, co-crystal complex, clathrate, or a combination thereof. In another embodiment, the salt is linked through an ionic bond, co-ordinate bond, covalent bond, hydrogen bond, van der Waals forces, or π-π stacking.
In another embodiment, the salt form is in crystalline or in amorphous form. In another embodiment, the salt form may exist with a varied amount of water, for example, in a hydrous or in an anhydrous form. In hydrous form, the water is either surface water, bound water, or a combination thereof. A third aspect of the present invention provides an amorphous solid salt form comprising valsartan and sacubitril.
In an embodiment of this aspect, the amorphous form is in salt form. In another embodiment, the salt is a monovalent salt or a bivalent salt. In another embodiment, the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NRt + (wherein R is hydrogen or Ci-6 alkyl). In another embodiment, the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
In another embodiment, the salt is benzathine, choline, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine, or benzylamine.
In another embodiment, the salt is a mixed salt. In another embodiment, the mixed salt comprises of monovalent or bivalent ions. In another embodiment, the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NRt + (wherein R is hydrogen or Ci-6 alkyl). In another embodiment, the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
In another embodiment, the salt is present in the form of a supramolecular complex, co-crystal, chelate, mixed co-crystal, co-precipitate, solid dispersion, co-crystal complex, clathrate, or a combination thereof. In another embodiment, the salt is linked through an ionic bond, co-ordinate bond, covalent bond, hydrogen bond, van der Waals forces, or π-π stacking.
In another embodiment, the amorphous form exists with a varied amount of water, for example, in a hydrous or in an anhydrous form. In hydrous form, the water is either surface water, bound water, or a combination thereof.
The amorphous sodium salt form comprising valsartan and sacubitril has an XRPD pattern as depicted in Figures 1, 7 and 8.
The amorphous sodium salt form comprising valsartan and sacubitril has an IR absorption spectrum as depicted in Figure 2.
The amorphous sodium salt form comprising valsartan and sacubitril has a DSC thermogram as depicted in Figure 3.
The amorphous sodium salt form comprising valsartan and sacubitril has a DSC thermogram having endothermic peaks at about 102.5°C and 238.8°C. The amorphous sodium salt form comprising valsartan and sacubitril has a Raman spectrum as depicted in Figure 4.
The amorphous sodium salt form comprising valsartan and sacubitril has an SEM image as depicted in Figures 5 and 6.
The amorphous sodium salt form comprising valsartan and sacubitril remains stable, in terms of XRPD, when stored at a temperature of 25°C ± 2°C and at a relative humidity of 60% ± 5% relative humidity (RH) for 6 months (Figures 7 and 8). The amorphous sodium salt form comprising valsartan and sacubitril also remains stable when stored at a temperature of 25°C ± 2°C and at a relative humidity of 60% ± 5% relative humidity (RH) for 6 months in terms of the chromatographic purity and description as depicted in table 1.
Table 1: Storage Condition: 25°C ± 2°C and 60% ± 5% relative humidity (RH)
Figure imgf000008_0001
A fourth aspect of the present invention provides a process for the preparation of a solid form comprising valsartan and sacubitril, wherein the process comprises treating valsartan or a salt thereof and sacubitril or a salt thereof with a source of cation in a solvent.
In an embodiment of this aspect, the solid form is a salt form. In another embodiment, the salt is a monovalent salt or a bivalent salt. In another embodiment, the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NRt + (wherein R is hydrogen or Ci-6 alkyl). In another embodiment, the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
In another embodiment, the salt is benzathine, choline, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine, or benzylamine.
In another embodiment, the salt is a mixed salt. In another embodiment, the mixed salt comprises of monovalent or bivalent ions. In another embodiment, the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NRt + (wherein R is hydrogen or Ci-6 alkyl). In another embodiment, the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
In another embodiment, the salt is present in the form of a supramolecular complex, co-crystal, mixed co-crystal, co-precipitate, solid dispersion, chelate, co-crystal complex, clathrate, or a combination thereof. In another embodiment, the salt is linked through an ionic bond, co-ordinate bond, covalent bond, hydrogen bond, van der Waals forces, or π-π stacking.
In another embodiment, the solid form is in crystalline or in amorphous form. In another embodiment, the solid form exists with a varied amount of water, for example, in a hydrous or in an anhydrous form. In hydrous form, the water is either surface water, bound water, or a combination thereof.
The salt of valsartan is selected from the group consisting of sodium, potassium, barium, calcium, lithium, cesium, and strontium. The salt of sacubitril is selected from the group consisting of sodium, potassium, barium, calcium, lithium, cesium, and strontium.
Valsartan may be prepared by any method known in the art, for example, as disclosed in U.S. Patent No. 5,399,578. Valsartan salts may be prepared by any method known in the art, for example, as disclosed in PCT Publication No. WO 02/06253.
Sacubitril may be prepared by any method known in the art, for example, as disclosed in U.S. Patent No. 5,217,996. Sacubitril salts may be prepared by any method known in the art, for example, as disclosed in PCT Publication No. WO 03/059345.
The source of cation consists of monovalent or divalent cations. The source of the cations consists of hydroxides, carbonates, or bicarbonates of monovalent or bivalent cations. The hydroxide source of the monovalent and the divalent cations include sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, zinc hydroxide, rubidium hydroxide, ammonium hydroxide, and strontium hydroxide. The carbonate source of the monovalent and the divalent cations include sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, barium carbonate, magnesium carbonate, calcium carbonate, zinc carbonate, rubidium carbonate, ammonium carbonate, and strontium carbonate. The bicarbonate source of the monovalent and the divalent cations include sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, barium bicarbonate, magnesium bicarbonate, calcium bicarbonate, zinc bicarbonate, rubidium bicarbonate, ammonium bicarbonate, and strontium bicarbonate.
In another embodiment, the source of the cations also includes benzathine, choline chloride, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine chloride, or benzylamine.
The solvent is selected from the group consisting of water, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
Examples of ketones include acetone and methyl ethyl ketone. Examples of esters include ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of ethers include methyl t-butyl ether and tetrahydrofuran. Examples of alkanols include primary, secondary, and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, n-propanol, 2-propanol, and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of polar aprotic solvents include N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone. These solvents can also be used as anti-solvents for isolation and also for the purification of solid forms.
The treatment of valsartan or a salt thereof, sacubitril or a salt thereof, and a source of cation is carried out at a temperature of about 10°C to about 50°C, preferably at about 20°C to about 40°C.
The treatment of valsartan or a salt thereof, sacubitril or a salt thereof, and a source of cation is carried out for about 2 hours to about 10 hours, preferably for about 2 hours to about 8 hours.
The solid form is isolated using common isolation techniques such as evaporation, evaporation under vacuum, cooling, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof.
The solid form is dried using common drying techniques such as vacuum drying, thin film drying, spray drying, freeze drying, open air drying, drying under nitrogen, or a combination thereof.
A fifth aspect of the present invention provides a process for the preparation of a solid salt form comprising valsartan and sacubitril, wherein the process comprises treating valsartan or a salt thereof, sacubitril or a salt thereof, and a salt-forming agent in a solvent. In an embodiment of this aspect, the salt is a monovalent salt or a bivalent salt. In another embodiment, the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NR4 + (wherein R is hydrogen or Ci-6 alkyl). In another embodiment, the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
In another embodiment, the salt is benzathine, choline, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine, or benzylamine.
In another embodiment, the salt is a mixed salt. In another embodiment, the mixed salt comprises monovalent or bivalent ions. In another embodiment, the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NRt + (wherein R is hydrogen or Ci-6 alkyl). In another embodiment, the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt. In another embodiment, the salt is present in the form of supramolecular complex, co-crystal, mixed co-crystal, co-precipitate, solid dispersion, chelate, co-crystal complex, clathrate, or a combination thereof. In another embodiment, the salt is linked through an ionic bond, co-ordinate bond, covalent bond, hydrogen bond, van der Waals forces, or π-π stacking.
In another embodiment, the solid salt form is in crystalline or in amorphous form. In another embodiment, the solid form may exist with a varied amount of water, for example, in a hydrous or in an anhydrous form. In hydrous form, the water is either surface water, bound water, or a combination thereof.
The salt of valsartan is selected from the group consisting of sodium, potassium, barium, calcium, lithium, cesium, and strontium. The salt of sacubitril is selected from the group consisting of sodium, potassium, barium, calcium, lithium, cesium, and strontium.
Valsartan may be prepared by any method known in the art, for example, as disclosed in U.S. Patent No. 5,399,578. Valsartan salts may be prepared by any method known in the art, for example, as disclosed in PCT Publication No. WO 02/06253.
Sacubitril may be prepared by any method known in the art, for example, as disclosed in U.S. Patent No. 5,217,996. Sacubitril salts may be prepared by any method known in the art, for example, as disclosed in PCT Publication No. WO 03/059345.
The salt-forming agent consists of hydroxides, carbonates, or bicarbonate s of monovalent or bivalent cations. The hydroxides of the monovalent and the divalent cations include sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, zinc hydroxide, rubidium hydroxide, ammonium hydroxide, and strontium hydroxide. The carbonates of the monovalent and the divalent cations include sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, barium carbonate, magnesium carbonate, calcium carbonate, zinc carbonate, rubidium carbonate, ammonium carbonate, and strontium carbonate. The bicarbonates of the monovalent and the divalent cations include sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, barium bicarbonate, magnesium bicarbonate, calcium bicarbonate, zinc bicarbonate, rubidium bicarbonate, ammonium bicarbonate, and strontium bicarbonate.
In another embodiment, the salt-forming agent also includes benzathine, choline chloride, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine chloride, or benzylamine.
The solvent is selected from the group consisting of water, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
Examples of ketones include acetone and methyl ethyl ketone. Examples of esters include ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of ethers include methyl t-butyl ether and tetrahydrofuran. Examples of alkanols include primary, secondary, and tertiary alcohols having from one to six carbon atoms. Suitable alkanols include methanol, ethanol, n-propanol, 2-propanol, and butanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of polar aprotic solvents include N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone. These solvents can also be used as anti-solvents for isolation and also for the purification of solid forms.
The treatment of valsartan or a salt thereof, sacubitril or a salt thereof, and a source of cation is carried out at a temperature of about 10°C to about 50°C, preferably at about 20°C to about 40°C.
The treatment of valsartan or a salt thereof, sacubitril or a salt thereof, and a source of cation is carried out for about 2 hours to about 10 hours, preferably for about 2 hours to about 8 hours.
The salt form is isolated using common isolation techniques such as evaporation, evaporation under vacuum, cooling, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof. The salt form is dried using common drying techniques such as vacuum drying, thin film drying, spray drying, freeze drying, open air drying, drying under nitrogen, or a combination thereof.
A sixth aspect of the present invention provides a pharmaceutical composition comprising solid forms comprising valsartan, sacubitril, and a carrier.
In an embodiment of this aspect, the solid form is a salt form. In another embodiment, the salt is a monovalent salt or a bivalent salt. In another embodiment, the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NRt + (wherein R is hydrogen or Ci-6 alkyl). In another embodiment, the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
In another embodiment, the salt is benzathine, choline, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine, or benzylamine.
In another embodiment, the salt is a mixed salt. In another embodiment, the mixed salt comprises monovalent or bivalent ions. In another embodiment, the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NRt + (wherein R is hydrogen or Ci-6 alkyl). In another embodiment, the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
In another embodiment, the salt is present in the form of a supramolecular complex, co-crystal, mixed co-crystal, co-precipitate, solid dispersion, chelate, co-crystal complex, clathrate, or a combination thereof. In another embodiment, the salt is linked through an ionic bond, co-ordinate bond, covalent bond, hydrogen bond, van der Waals forces, or π-π stacking.
In another embodiment, the solid form is in crystalline or in amorphous form. In another embodiment, the solid form may exist with a varied amount of water, for example, in a hydrous or in an anhydrous form. In hydrous form, the water is either surface water, bound water, or a combination thereof.
In another embodiment, the pharmaceutical composition may be manufactured by a dry formulation process such as a direct compression or roller compaction process. In another embodiment, the pharmaceutical composition can be formulated by mixing the solid form with at least one pharmaceutically acceptable excipient and further processing the mixture into suitable dosage forms such as tablets and capsules. A seventh aspect of the present invention provides a method of treating or preventing cardiovascular or renal condition or a medical condition responsive to valsartan and/or sacubitril in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the solid forms comprising valsartan, sacubitril, and a carrier.
In an embodiment of this aspect, the solid form is a salt form. In another embodiment, the salt is monovalent salt or bivalent salt. In another embodiment, the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NRt+ (wherein R is hydrogen or Ci-6 alkyl). In another embodiment, the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
In another embodiment, the salt is benzathine, choline, diethanolamine, ethylenediamine, meglumine, diethylamine, piperazine, or benzylamine.
In another embodiment, the salt is a mixed salt. In another embodiment, the mixed salt comprises of monovalent or bivalent ions. In another embodiment, the monovalent salt is lithium, sodium, potassium, rubidium, cesium, or NRt+ (wherein R is hydrogen or Ci-6 alkyl). In another embodiment, the bivalent salt is barium, magnesium, calcium, zinc, or strontium salt.
In another embodiment, the salt is present in the form of a supramolecular complex, co-crystal, mixed co-crystal, co-precipitate, solid dispersion, chelate, co-crystal complex, clathrate, or a combination thereof. In another embodiment, the salt is linked through an ionic bond, co-ordinate bond, covalent bond, hydrogen bond, van der Waals forces, or π-π stacking.
In another embodiment, the solid form is in crystalline or in amorphous form. In another embodiment, the solid form may exist with a varied amount of water, for example, in a hydrous or in an anhydrous form. In hydrous form, the water is either surface water, bound water, or a combination thereof.
In another embodiment, the cardiovascular condition or disease is selected from the group consisting of hypertension, heart failure (acute or chronic), congestive heart failure, left ventricular dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, and angina (unstable or stable); and the renal condition or diseases is selected from the group consisting of renal insufficiency (diabetic or non-diabetic), glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and renal vascular hypertension.
Methods
XRPD of the samples was determined by using a PANalytical® instrument; Model X'pert PRO; Detector: X'celerator®.
IR of the samples was recorded using a PerkinElmer® instrument, potassium bromide pellet method.
DSC of the samples was recorded using a Mettler-Toledo® 82 le instrument.
Raman spectrum of the sample measured by a dispersive Raman spectrometer with a 785 nm laser excitation source.
SEM was performed using a Jeol® JSM 6010LV.
Water content was measured using a Metrohm® KF titrator in a methanol medium.
While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
EXAMPLES
Example 1 : Preparation of a sodium salt comprising valsartan and sacubitril
Step a):
Sacubitril (60 g) was added to acetone (200 mL) at 20°C to 30°C followed by the addition of a solution of valsartan (61.8 g) in acetone (280 mL). The reaction mixture was stirred at 20°C to 30°C for 15 minutes. Sodium hydroxide (17 g in 40 mL of water) was added drop-wise to the reaction mixture with stirring, and then the stirring continued for 2 hours at 20°C to 30°C. Acetone was recovered (200 mL) from the reaction mixture at 30°C, and then isopropyl acetate (100 mL) was added. The solvent was recovered (300 mL) from the reaction mixture at 30°C. Isopropyl acetate (100 mL) was further added to the reaction mixture, and then the solvent was recovered under reduced pressure (680 mm to 710 mm of Hg) at 30°C. Methyl i-butyl ether (800 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 12 hours at 20°C to 30°C. The solid obtained was filtered under nitrogen.
Yield: 127.5 g.
Step b):
The solid (115 g) obtained in step a) was added to methanol (460 mL) at 20°C to
30°C and the mixture was stirred for 10 minutes to 15 minutes. Methanol was recovered (460 mL) from the reaction mixture under reduced pressure (680 mm to 710 mm of Hg) at 30°C. Isopropyl acetate (115 mL) was added to the reaction mixture, and then the solvent was recovered from the reaction mixture under reduced pressure (680 mm to 710 mm of Hg) at 30°C. Methyl /-butyl ether (60 mL) was added to the reaction mixture, and then the solvent was recovered from the reaction mixture. Methyl /-butyl ether (400 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 5 minutes at 20°C to 30°C. The solid obtained was filtered under nitrogen, and then dried under vacuum to obtain the amorphous solid form.
Yield: 106 g.
Moisture content: 2.79% (by KF).
Figure 1 depicts an X-ray Powder Diffraction (XRPD) pattern.
Figure 2 depicts an Infrared (IR) absorption spectrum.
Figure 3 depicts a Differential Scanning Calorimetry (DSC) thermogram.
Figure 4 depicts a Raman spectrum.
Figures 5 and 6 depict a Scanning Microscopic Image (SEM).
Example 2: Preparation of a lithium salt comprising valsartan and sacubitril
Sacubitril (4.6 g) was added to acetone (50 mL) at 20°C to 30°C followed by the addition of a solution of valsartan (4.62 g) in acetone (5 mL) at 20°C to 30°C for 15 minutes. Lithium hydroxide (1.78 g in 15 mL of water) was added to the reaction mixture drop-wise, and then the reaction mixture was stirred at 20°C to 30°C for 3 hours. The solvent was recovered (20 mL) from the reaction mixture at 30°C. Isopropyl acetate (30 mL) was added to the reaction mixture, and then the solvent was completely recovered from the reaction mixture. Isopropyl acetate (20 mL) was again added to the reaction mixture, and then the solvent was completely recovered from the reaction mixture. Acetone (30 mL) was added to the reaction mixture, and then the solvent was recovered. Acetone (50 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 12 hours, then filtered, and then washed with acetone (50 mL). The solid obtained was dried under nitrogen for 30 minutes to obtain the solid form.
Yield: 8.1 g.
Example 3 : Preparation of a barium salt comprising valsartan and sacubitril
Sacubitril (5 g) was added to acetone (55 mL) at 20°C to 30°C followed by the addition of valsartan (5.18 g). The reaction mixture was stirred at 20°C to 30°C for 15 minutes. Barium hydroxide (11.6 g in 70 mL of water) was added to the reaction mixture drop-wise, and then the reaction mixture was stirred at 20°C to 30°C for 2 hours. The solvent was recovered (125 mL) from the reaction mixture at 30°C. Isopropyl acetate (50 mL) was added to the reaction mixture, and then the solvent was completely recovered from the reaction mixture. Acetone (80 mL) was added to the reaction mixture, and then the reaction mixture was stirred at 20°C to 30°C for 5 hours. The solid obtained was dried under vacuum at 45°C for 12 hours to obtain the solid form.
Yield: 11.3 g.
Example 4: Preparation of a potassium salt comprising sacubitril and valsartan
Sacubitril (5 g) was added to acetone (25 mL) at 20°C to 25 °C. Valsartan (5.18 g) in acetone (25 mL) was added to the mixture. The mixture was stirred for 10 minutes at 20°C to 25°C, and then cooled to 0°C to 5°C. A potassium hydroxide solution (2.05 g in 10 mL water) was added to the reaction mixture, and then the mixture was stirred at 20°C to 25°C for 1 hour. Acetone (50 mL) was recovered from the reaction mixture at 40°C under 680 mm to 710 mm of Hg pressure. Acetone (50 mL) was added to the reaction mixture, and was further recovered (50 mL) from the reaction mixture at 40°C under 680 mm to 710 mm of Hg pressure. Methyl t-butyl ether (50 mL) was added to the reaction mixture, and then the mixture was stirred at 20°C to 25 °C for 5 minutes. The reaction mixture was filtered under nitrogen atmosphere to obtain a solid material. The solid material obtained was dried under 680 mm to 710 mm of Hg at 20°C to 25°C for 16 hours to obtain the title compound.
Yield: 11 g.
Example 5 : Preparation of a calcium salt comprising sacubitril and valsartan Sacubitril (5 g) was added to acetone (25 mL) at 20°C to 25 °C. Valsartan (5.18 g) in acetone (25 mL) was added to the mixture. The mixture was stirred for 10 minutes at 20°C to 25°C, and then cooled to 0°C to 5°C. A calcium chloride solution (4.05 g in 10 mL of water) was added to the reaction mixture, and then the mixture was stirred at 20°C to 25°C for 1 hour. Acetone (50 mL) was recovered from the reaction mixture at 40°C under 680 mm to 710 mm of Hg. Acetone (50 mL) was added to the reaction mixture, and then recovered under vacuum at 40°C under 680 mm to 710 mm of Hg to obtain a solid material. Methyl t-butyl ether (50 mL) was added to the reaction mixture at 20°C to 25°C, and then the mixture was stirred at 20°C to 25 °C for 5 minutes. The reaction mixture was filtered under nitrogen atmosphere to obtain a solid material. The solid material obtained was dried under 680 mm to 710 mm of Hg at 20°C to 25°C for 16 hours to obtain the title compound.
Yield: 11.5 g.
Example 6: Preparation of a sodium salt comprising sacubitril and valsartan
Step a):
Sacubitril (47 g) was added to acetone (270 mL) at 20°C to 30°C followed by the addition of a solution of valsartan (49.7 g) in acetone (200 mL). The reaction mixture was stirred at 20°C to 30°C for 15 minutes. The reaction mixture was cooled to 5°C to 10°C. Sodium carbonate (19.39 g in 60 mL of water) was added to the reaction mixture with stirring, and then the stirring was continued for 2 hours at 20°C to 30°C. Acetone was recovered (300 mL) from the reaction mixture at 30°C, and then isopropyl acetate (100 mL) was added. The solvent was recovered at 30°C up to solid residue. Isopropyl acetate (50 mL) was further added to the reaction mixture, and then the solvent was recovered under reduced pressure (680 mm to 710 mm of Hg) at 30°C. Acetone (200 mL) was added, and then was completely recovered. Methyl /-butyl ether (100 mL) was added to the reaction mixture, and then was recovered. Acetone (300 mL) was added to the reaction mixture, and then was recovered to obtain the solid which was filtered under nitrogen.
Yield: 106 g.
Step b):
The solid (66 g) obtained in step a) was added to methyl i-butyl ether (500 mL) and methanol (20 mL). The reaction mixture was stirred at 20°C to 30°C for 2 hours. The solid obtained was filtered, and then methanol (310 mL) was added to the reaction mixture. The reaction mixture was stirred at 30°C for 15 minutes to obtain a clear solution. Methanol (310 mL) was recovered from the reaction mixture. Methyl t-butyl ether (160 mL) was added to the reaction mixture, and then recovered at 30°C to 35°C. Methyl t-butyl ether (300 mL) was added to the reaction mixture, and then the mixture was stirred for 5 minutes. The solid (85 g) obtained was filtered under nitrogen. The solid obtained was dried under 680 mm to 710 mm of Hg to obtain the solid.
Yield: 51 g.
Figure 7 depicts an X-ray Powder Diffraction (XRPD) pattern.
Figure 8 depicts an X-ray Powder Diffraction (XRPD) pattern when stored at a temperature of 25±2°C and at a relative humidity of 60±5% relative humidity (RH) for 6 months.
Chromatographic Purity (%): 99.6.

Claims

We Claim:
1. A solid form comprising valsartan and sacubitril.
2. The solid form according to claim 1, wherein the solid form comprising valsartan and sacubitril is in salt form.
3. The solid form according to claim 1, wherein the solid form comprising valsartan and sacubitril is in crystalline form.
4. The solid form according to claim 1, wherein the solid form comprising valsartan and sacubitril is in amorphous form.
5. The solid form according to claim 1, wherein the solid form comprising valsartan and sacubitril is in hydrous form.
6. The solid form according to claim 1, wherein the solid form comprising valsartan and sacubitril is in anhydrous form.
7. A solid salt form comprising valsartan and sacubitril.
8. An amorphous solid salt form comprising valsartan and sacubitril.
9. The solid form according to claim 8, wherein the amorphous solid salt form
comprising valsartan and sacubitril is stable.
10. A process for the preparation of a solid form comprising valsartan and sacubitril, wherein the process comprises treating valsartan or a salt thereof and sacubitril or a salt thereof with a source of cation in a solvent.
11. A process for the preparation of a solid salt form comprising valsartan and sacubitril, wherein the process comprises treating valsartan or a salt thereof, sacubitril or a salt thereof, and a salt-forming agent in a solvent.
12. The process according to claim 10 or 11, wherein the salt of sacubitril is selected from the group consisting of sodium, potassium, barium, calcium, lithium, cesium, and strontium.
13. The process according to claim 10 or 11, wherein the salt of valsartan is selected from the group consisting of sodium, potassium, barium, calcium, lithium, cesium, and strontium.
14. The process according to claim 10 or 11, wherein the source of cation or salt-forming agents are hydroxides, carbonates, or bicarbonates of monovalent or bivalent cations.
15. The process according to claim 10 or 11, wherein the solvent is selected from the group consisting of water, ketones, esters, ethers, alkanols, halogenated hydrocarbons, polar aprotic solvents, and mixtures thereof.
16. A pharmaceutical composition comprising solid forms comprising valsartan,
sacubitril, and a carrier.
17. A method of treating or preventing cardiovascular or renal condition or a medical condition responsive to valsartan and/or sacubitril in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the solid forms comprising valsartan, sacubitril, and a carrier.
PCT/IB2016/055335 2015-09-07 2016-09-07 Solid forms of valsartan and sacubitril WO2017042700A1 (en)

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