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WO2025224069A1 - Co-cristaux de finérénone, de pecavaptan et d'inhibiteurs de sglt2 - Google Patents

Co-cristaux de finérénone, de pecavaptan et d'inhibiteurs de sglt2

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Publication number
WO2025224069A1
WO2025224069A1 PCT/EP2025/060873 EP2025060873W WO2025224069A1 WO 2025224069 A1 WO2025224069 A1 WO 2025224069A1 EP 2025060873 W EP2025060873 W EP 2025060873W WO 2025224069 A1 WO2025224069 A1 WO 2025224069A1
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WIPO (PCT)
Prior art keywords
equal
crystal
api
acid
formula
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English (en)
Inventor
Lars BÄRFACKER
Peter Kolkhof
Hartmut Schirok
Joan BENET
Nicolas Tesson
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Bayer AG
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Bayer AG
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Publication of WO2025224069A1 publication Critical patent/WO2025224069A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/06—Oxalic acid
    • C07C55/07—Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/08—Malonic acid
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/22—Tricarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/04—Monocyclic monocarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D309/06—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention refers to a co-crystal according to any one of formulae (I), (II), (III), (IV), (V), (VI) and/or (VII)
  • CF is a co-former selected from organic excipient, inorganic excipient, acidic excipient, basic excipient and mixtures thereof;
  • API is an active pharmaceutical ingredient selected from sodium glucose linked transporter 2 inhibitor (SGLT2-i) and pecavaptan; a is above 0 to equal or below 10; b is above 0 to equal or below 10; c is above 0 to equal or below 10;
  • API is an active pharmaceutical ingredient selected from sodium glucose linked transporter 2 inhibitor (SGLT2-i) and pecavaptan; a is above 0 to equal or below 10; b is above 0 to equal or below 10;
  • API is an active pharmaceutical ingredient selected from sodium glucose linked transporter 2 inhibitor (SGLT2-i) and pecavaptan; S is a solvent; a is above 0 to equal or below 10; b is above 0 to equal or below 10; d is above 0 to equal or below 15;
  • CF is a co-former selected from organic excipient, inorganic excipient, acidic excipient, basic excipient and mixtures thereof; a is above 0 to equal or below 10; c is above 0 to equal or below 10;
  • CF is a co-former selected from organic excipient, inorganic excipient, acidic excipient, basic excipient and mixtures thereof;
  • API is an active pharmaceutical ingredient selected from sodium glucose linked transporter 2 inhibitor (SGLT2-i), and pecavaptan;
  • S is a solvent; a is above 0 to equal or below 10; b is above 0 to equal or below 10; c is above 0 to equal or below 10; d is above 0 to equal or below 15;
  • CF is a co-former selected from organic excipient, inorganic excipient, acidic excipient, basic excipient and mixtures thereof;
  • API is an active pharmaceutical ingredient selected from sodium glucose linked transporter 2 inhibitor (SGLT2-i);
  • S is a solvent; b is above 0 to equal or below 10; c is above 0 to equal or below 10; d is equal or above 0 to equal or below 15.
  • the invention refers to a pharmaceutical formulation comprising any one of co-crystals according to formulae (I), (II), (III), (IV), (V), (VI) and/or (VII), the medical use of these co-crystals or the pharmaceutical formulation comprising such co-crystal(s) as well as to a process for preparing these co-crystals.
  • the invention further refers to crystalline forms of and/or Empagliflozin as well as pharmaceutical comprising such crystalline forms.
  • Amorphous solids may be considered as an option, however, these solids have their own limitations related to stability.
  • the composition and the arrangement of molecules/ions in a crystal lattice directly affects the crystal properties.
  • Co-crystals can be made for drugs containing sensitive functional groups as well as for drugs containing non-ionizable moieties.
  • Co-crystals have established a new paradigm in the solid-state modification. These are multicomponent systems.
  • API active pharmaceutical ingredient
  • Co-crystals can be composed of two or more compounds and held together by non-covalent interactions. They can also be present in form of a complex.
  • Co-crystal formation occurs via co -crystallization.
  • Co-crystallization methods include a solvent evaporation technique, an anti-solvent method, a solvent drop grinding method, a slurry technique, and a solid state grinding method.
  • co-formers may be employed. Selection of suitable coformers and screening of co-crystals for a drug are the main challenges to overcome during the process of co-crystal development. Despite of several co-crystal screening methods available, there is no confirmed way to predict whether two or more molecules will form a co-crystal. There are a lot of factors that govern the co-crystallization process and still there is a need for better understanding of this process. Moreover, the co-crystal structure cannot be predicted from the available sources.
  • co-crystals a new solid crystalline form
  • superior physico-chemical properties such as melting point, chemical stability, mechanical stability, pharmacokinetic behavior, solubility, tabletability, bioavailability, taste masking, and the like.
  • This co-crystal form may also increase the solubility and dissolution rate of the drug. Thereby, the bioavailability can be changed by changing the absorption rate of the drug in the human body.
  • the SGLT2 inhibitor Empagliflozin is disclosed in International Patent Publication WO 2006/117359, has a water solubility of only 0.11 mg/mL and is also poorly stable. This fact may not allow for the required quality.
  • empagliflozin has the disadvantage that it is difficult to maintain constant quality due to its poor stability as a pharmaceutical raw material, maybe also limiting shelf-life in the end.
  • empagliflozin can be transferred into a co-crystal.
  • Finerenone has also a high molecular weight and is poorly soluble in water.
  • One object is therefore the provision of an improved form of these drugs.
  • co-crystals can be formed between two APIs.
  • Such multidrug co-crystals can be used for developing combination therapies. Such combinations may be useful in preventing multi-drug resistance, can synergistically increase the action of the drugs, reduce side effects, and the like.
  • Finerenone- Pecavaptan EP 3900722 Al
  • Finerenone-SGLT2 inhibitors WO 2021214023 Al
  • a further object is the provision of an improved combination. This is solved by the provision of the co-crystals according to the invention.
  • the invention refers to a co-crystal according to formula (I)
  • CF is a co-former selected from organic excipient, inorganic excipient, acidic excipient, basic excipient and mixtures thereof;
  • API is an active pharmaceutical ingredient selected from sodium glucose linked transporter 2 inhibitor (SGLT2-i) and pecavaptan; a is above 0 to equal or below 10; b is above 0 to equal or below 10; c is above 0 to equal or below 10.
  • the invention refers to a co-crystal according to formula (II)
  • API is an active pharmaceutical ingredient selected from sodium glucose linked transporter 2 inhibitor (SGLT2-i) and pecavaptan; a is above 0 to equal or below 10; b is above 0 to equal or below 10.
  • the invention refers to a co-crystal according to formula (III)
  • API is an active pharmaceutical ingredient selected from sodium glucose linked transporter 2 inhibitor (SGLT2-i) and pecavaptan; S is a solvent; a is above 0 to equal or below 10; b is above 0 to equal or below 10; d is above 0 to equal or below 15.
  • the invention refers to a co-crystal according to formula (IV)
  • CF is a co-former selected from organic excipient, inorganic excipient, acidic excipient, basic excipient and mixtures thereof; a is above 0 to equal or below 10; c is above 0 to equal or below 10.
  • the invention refers to a co-crystal according to formula (V)
  • CF is a co-former selected from organic excipient, inorganic excipient, acidic excipient, basic excipient, and mixtures thereof;
  • S is a solvent; a is above 0 to equal or below 10; c is above 0 to equal or below 10; d is above 0 to equal or below 15.
  • the invention refers to a co-crystal according to formula (VI)
  • CF is a co-former selected from organic excipient, inorganic excipient, acidic excipient, basic excipient and mixtures thereof;
  • API is an active pharmaceutical ingredient selected from sodium glucose linked transporter 2 inhibitor (SGLT2-i), and pecavaptan;
  • S is a solvent; a is above 0 to equal or below 10; b is above 0 to equal or below 10; c is above 0 to equal or below 10; d is above 0 to equal or below 15; wherein at least one of a and/or b is not equal to 0.
  • the invention refers to a co-crystal according to formula (VII)
  • CF is a co-former selected from organic excipient, inorganic excipient, acidic excipient, basic excipient and mixtures thereof;
  • API is an active pharmaceutical ingredient selected from sodium glucose linked transporter 2 inhibitor (SGLT2-i);
  • S is a solvent; b is above 0 to equal or below 10; c is above 0 to equal or below 10; d is equal or above 0 to equal or below 15.
  • Finerenone which is (S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6- naphthyridin-3 -carboxamide, a compound according to formula (VIII) is a mineralocorticoid receptor antagonist (MR antagonist).
  • MR antagonist mineralocorticoid receptor antagonist
  • Pecavaptan which is 5-(4-chlorophenyl)-2-( ⁇ l-(3-chlorophenyl)-5-[(lS)-l-hydroxyethyl]-lH-l,2,4- triazol-3-yl ⁇ methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-one
  • a compound of formula (IX) is a dual vasopressin antagonist (Via and V2).
  • Via and V2 The synthesis, pharmacological properties and pharmaceutical formulations/dosage forms are described in detail in WO 2016/071212 Al.
  • SGUT2 inhibitors are canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, remogliflozin, sergliflozin, sotagliflozin, and tofogliflozin.
  • Canagliflozin which is (2S,3R,4R,5S,6R)-2-(3- ⁇ [5-(4-fluorophenyl)thiophen-2-yl]methyl ⁇ -4- methylphenyl)-6-(hydroxymethyl)oxane-3,4,5-triol (CAS-number: 842133-18-0) and is depicted in formula (X) or (Xa) (hemihydrate) below is also known as Invokana® (market product by e.g. Janssen Pharmaceuticals, comprises canagliflozin hydrate), is a sodium -glucose cotransporter 2 (SGLT2) inhibitor used in the management of type 2 diabetes mellitus along with lifestyle changes including diet and exercise.
  • SGLT2 sodium -glucose cotransporter 2
  • Ertugliflozin which is (lS,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-l- (hydroxymethyl)-6,8-dioxabicyclo[3.2. l]octane-2,3,4-triol and is depicted in formula (XIII) below is marketed under the trade name Steglatro® and is a drug for the treatment of type 2 diabetes. It is described in US 8080580. In the United States, it was approved by the Food and Drug Administration for use as a monotherapy and as a fixed dose combination with either sitagliptin or with metformin.
  • Ipragliflozin is depicted in formula (XIV) below is a pharmaceutical drug for treatment of type 2 diabetes.
  • the compound and methods of its synthesis are described in e.g. WO 2004/080990 Al.
  • XV gliflozin
  • NASH non-alcoholic steatohepatitis
  • Remogliflozin was discovered by the Japanese company Kissei Pharmaceutical and is currently being developed by BHV Pharma.
  • Sergliflozin which is depicted in formula (XVI) and is (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-[2-[(4- methoxyphenyl)methyl]phenoxy]oxane-3,4,5-triol
  • sergliflozin etabonate which is depicted in formula (XVIa) below and is ethyl [(2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-[2-[(4- methoxyphenyl)methyl]phenoxy]oxan-2-yl]methyl carbonate
  • XVI (XVIa) is being developed by GlaxoSmithKline in form of sergliflozin etabonate and is an investigational antidiabetic drug.
  • “Etabonate” refers to the ethyl carbonate group.
  • the remaining structure, which is the active substance, is called sergliflozin.
  • Sotagliflozin which is (2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6- methylsulfanyloxane-3,4,5-triol and is depicted in formula (XVII) below is a drug approved in EU for certain patients with type I diabetes. It is marketed under the trade name Zynquista® and it was developed by Sanofi.
  • WO 2017202351 Al describes a crystal form of sotagliflozin, a method for preparation thereof and use thereof.
  • XVIII is a drug for the treatment of diabetes mellitus and is being developed by Chugai Pharma in collaboration with Kowa and Sanofi. It is an inhibitor of SGLT2.
  • the United States Adopted Name tofogliflozin applies to the monohydrate, which is the form used as a drug.
  • the International Nonproprietary Name tofogliflozin applies to the anhydrous compound and the drug form is referred to as tofogliflozin hydrate.
  • the API is a SGLT2 inhibitor selected from canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, remogliflozin, sotagliflozin, sergliflozin, and tofogliflozin.
  • the API is a SGLT2 inhibitor selected from dapagliflozin, canagliflozin, and empagliflozin.
  • the is a SGLT2 inhibitor selected from dapagliflozin and empagliflozin.
  • the API is the SGLT2 inhibitor dapagliflozin.
  • the API is the SGLT2 inhibitor empagliflozin. In one embodiment the API is selected from dapagliflozin, canagliflozin, and empagliflozin and pecavaptan. In one embodiment the API is pecavaptan.
  • the co-crystal according to any one of formulae (I), (II), (III), (IV), (V), and/or (VI) is a polymorph.
  • the co-crystal according to formula (II) is a polymorph.
  • the co-crystal according to formula (III) is a polymorph.
  • the co-crystal according to formula (IV) is a polymorph.
  • the co-crystal according to formula (V) is a polymorph.
  • the co-crystal according to formula (VI) is a polymorph.
  • the co-crystal according to formula (VII) is a polymorph.
  • Co-formers are co-crystallizing agents that interact non-ionically with active pharmaceutical ingredients in a crystal lattice.
  • CF can have high water solubility and can be non-volatile. Active ingredients and suitable CF can cause interactions e.g. through hydrogen bonds, van der Waals interaction, and 7i-7i stacking.
  • An obstacle is selecting a CF.
  • the CF should be suited for the specific API.
  • the CF also needs to be generally recognized as safe (GRAS). It is difficult to know a priori which CF will form cocrystals.
  • the current selection for co-crystal discovery involves an expensive, time-consuming, and, at the early stages of pharmaceutical development, API material -limited experimental screen.
  • the CF is selected from organic excipient, inorganic excipient, acidic excipient, basic excipient and mixtures thereof.
  • the CF can be in a salted anionic or cationic form.
  • the CF is a carboxylic acid.
  • the CF is a proteinogenic amino acid. In one embodiment, the CF is a proteinogenic amino acid selected from a positively charged proteinogenic amino acid, negatively charges proteinogenic amino acid, a polar uncharged proteinogenic amino acid, a hydrophobic proteinogenic amino acid, and mixtures thereof.
  • the CF is a proteinogenic amino acid selected from arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, glycine, proline, cysteine, selenocysteine, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, and mixtures thereof.
  • the CF is selected from a carboxylic acid or mixtures thereof.
  • the carboxylic acid n is a Ci-Cio-alkyl-carboxylic acid.
  • Ci-Cioalkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, scc-butyl.
  • said group has 1, 2, 3 or 4 carbon atoms (“CiC4alkyl”), e.g.
  • CiCsalkyl a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or tert-butyl group, more particularly 1, 2 or 3 carbon atoms (“CiCsalkyl”), e.g. a methyl, ethyl, w-propyl or isopropyl group.
  • the carboxylic acid is a Ci-Cio-alkyl-mono-carboxylic acid. In one embodiment the carboxylic acid is a Ci- alkyl-Cio-di -carboxylic acid. In one embodiment the carboxylic acid is a Ci-Ce- alkyl -carboxylic acid. In one embodiment the carboxylic acid is a Ci- Ce-mono-carboxylic acid. In one embodiment the carboxylic acid is a Ci- Ce- alkyl-di-carboxylic acid. In one embodiment the carboxylic acid is a C1-C5- alkyl-carboxylic acid.
  • the carboxylic acid is a C1-C5- alkyl-monocarboxylic acid. In one embodiment the carboxylic acid is a C1-C5- alkyl-di-carboxylic acid. In one embodiment the carboxylic acid is a C1-C4- alkyl-carboxylic acid. In one embodiment the carboxylic acid is a C1-C4- alkyl-mono-carboxylic acid. In one embodiment the carboxylic acid is a C1-C4- alkyl-di- carboxylic acid.
  • the CF is selected from ascorbic acid, betaine HC1, citric acid, formic acid, fumaric acid, gentisic acid, glutaric acid, L-camitine HC1, L-cysteine, L-cysteine HC1, L-lysine HC1, L-malic acid, L-proline, L-pyroglutamic acid, L-tartaric acid, malonic acid, nicotinamide, oxalic acid, succinic acid, hydrochloric acid and mixtures thereof.
  • the CF is selected from ascorbic acid, betaine HC1, citric acid, formic acid, fumaric acid, gentisic acid, glutaric acid, L-camitine HC1, L-cysteine, L-cysteine HC1, L-lysine HC1, L-malic acid, L-proline, L-pyroglutamic acid, L-tartaric acid, malonic acid, nicotinamide, oxalic acid, succinic acid and mixtures thereof.
  • the CF is selected from ascorbic acid, citric acid, fumaric acid, gentisic acid, L- cysteine, L-cysteine HC1, L-malic acid, L-proline, tartaric acid, L-tartaric acid, malonic acid, oxalic acid, and mixtures thereof.
  • the CF is selected from ascorbic acid, citric acid, fumaric acid, gentisic acid, L- cysteine, L-cysteine HC1, L-malic acid, tartaric acid, L-tartaric acid, malonic acid, oxalic acid, and mixtures thereof.
  • the CF is selected from ascorbic acid, fumaric acid, and mixtures thereof.
  • the CF is selected from L-proline.
  • the CF is selected from citric acid, oxalic acid, and mixtures thereof.
  • the CF is selected from gentisic acid, L-cysteine, L-cysteine HC1, L-malic acid, tartaric acid, L-tartaric acid, malonic acid, oxalic acid, and mixtures thereof.
  • the CF is selected from gentisic acid, malonic acid, and mixtures thereof.
  • the CF is selected from gentisic acid, oxalic acid, malonic acid, tartaric acid, citric acid, L-malic acid, L-tartaric acid, L-cysteine HC1 and mixtures thereof.
  • the CF is selected from gentisic acid, oxalic acid, malonic acid, tartaric acid, citric acid, L-malic acid, L-tartaric acid, L-cysteine HC1, L-proline, and mixtures thereof.
  • the CF is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulphonic acid, trifluoromethane sulfonic acid, benzene sulfonic acid, p -toluene sulfonic acid, 1 -naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, lactic acid, succinic acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid acetate, benzoic acid, besylate, bromide, camsylate, carbonate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, iodide, isethionate, lactate, lactobionate, malate, maleate, mesylate,
  • Example of nonpolar solvents are pentane, hexane, benzene, chloroform, and diethyl ether.
  • Example of aprotic -polar solvent are dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide, acetone, pyridine, sulfolane, and hexamethyl phosphoric triamde (HMPT).
  • Example of polar protic solvent are water, methanol, ethanol, isopropyl alcohol and acetic acid.
  • S is selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethylsulfoxid, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof.
  • S is selected from water, acetone, acetonitrile, dioxane, ethyl acetate, isobutyl acetate, methanol, tetrahydrofuran, and mixtures thereof.
  • S is selected from acetonitrile, methanol, isobutyl acetate, acetonitrile, tetrahydrofuran, ethyl acetate, acetone, and mixtures thereof.
  • a is from above 0 to equal or below 10. In one embodiment, a is from above 0 to equal or below 9. In one embodiment, a is from above 0 to equal or below 9. In one embodiment, a is from above 0 to equal or below 8. In one embodiment, a is from above 0 to equal or below 7. In one embodiment, a is from above 0 to equal or below 6. In one embodiment, a is from above 0 to equal or below 5. In one embodiment, a is from above 0 to equal or below 4. In one embodiment, a is from above 0 to equal or below 3. In one embodiment, a is from above 0 to equal or below 2. In one embodiment, a is from above 0 to equal or below 1. In one embodiment, a is from above 0 to equal or below 0.5.
  • a is equal or above 1 to equal or below 2. In one embodiment, a is equal or above 1 to equal or below 3. In one embodiment, a is equal or above 1 to equal or below 4. In one embodiment, a is equal or above 1 to equal or below 5. In one embodiment, a is equal or above 2 to equal or below 3. In one embodiment, a is equal or above 2 to equal or below 4. In one embodiment, a is equal or above 2 to equal or below 5. In one embodiment, a is equal or above 3 to equal or below 4. In one embodiment, a is equal or above 4 to equal or below 5. In one embodiment, a is selected from 0.05, 0.1, 0.15, 0.2, 0.25, 0.3,
  • a is selected from 0.25, 0.3, 0.4, 0.5, 1, 2 and 3. In one embodiment, a is above 0. In one embodiment, a is 0.25. In one embodiment, a is 0.3. In one embodiment, a is 0.5. In one embodiment, a is 1. In one embodiment, a is 2. In one embodiment, a is 3. In one embodiment, a is 4. In one embodiment, a is 5.
  • b is from above 0 to equal or below 10. In one embodiment, b is from above 0 to equal or below 9. In one embodiment, b is from above 0 to equal or below 9. In one embodiment, b is from above 0 to equal or below 8. In one embodiment, b is from above 0 to equal or below 7. In one embodiment, b is from above 0 to equal or below 6. In one embodiment, b is from above 0 to equal or below 5. In one embodiment, b is from above 0 to equal or below 4. In one embodiment, b is from above 0 to equal or below 3. In one embodiment, b is from above 0 to equal or below 2. In one embodiment, b is from above 0 to equal or below 1 In one embodiment, b is equal or above 1 to equal or below 2.
  • b is equal or above 1 to equal or below 3. In one embodiment, b is equal or above 1 to equal or below 4. In one embodiment, b is equal or above 1 to equal or below 5. In one embodiment, b is equal or above 2 to equal or below 3. In one embodiment, b is equal or above 2 to equal or below 4. In one embodiment, b is equal or above 2 to equal or below 5. In one embodiment, b is equal or above 3 to equal or below 4. In one embodiment, b is equal or above 4 to equal or below 5.
  • b is selected from 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65.
  • b is selected from 0.25, 0.3, 0.4, 0.5, 1, 2 and 3. In one embodiment, b is above 0. In one embodiment, b is 0.25. In one embodiment, b is 0.3. In one embodiment, b is 0.5. In one embodiment, b is 1. In one embodiment, b is 2. In one embodiment, b is 3. In one embodiment, b is 4. In one embodiment, b is 5.
  • c is from above 0 to equal or below 10. In one embodiment, c is from above 0 to equal or below 9. In one embodiment, c is from above 0 to equal or below 9. In one embodiment, c is from above 0 to equal or below 8. In one embodiment, c is from above 0 to equal or below 7. In one embodiment, c is from above 0 to equal or below 6. In one embodiment, c is from above 0 to equal or below 5. In one embodiment, c is from above 0 to equal or below 4. In one embodiment, c is from above 0 to equal or below 3. In one embodiment, c is from above 0 to equal or below 2. In one embodiment, c is equal or above 1 to equal or below 2. In one embodiment, c is equal or above 1 to equal or below 3.
  • c is equal or above 1 to equal or below 4. In one embodiment, c is equal or above 1 to equal or below 5. In one embodiment, c is equal or above 2 to equal or below 3. In one embodiment, c is equal or above 2 to equal or below 4. In one embodiment, c is equal or above 2 to equal or below 5. In one embodiment, c is equal or above 3 to equal or below 4. In one embodiment, c is equal or above 4 to equal or below 5.
  • c is selected from 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55,
  • c is selected from 0.25, 0.3, 0.4, 0.5, 1, 2 and 3. In one embodiment, c is above O.In one embodiment, c is 0.25. In one embodiment, c is 0.3. In one embodiment, c is 0.5. In one embodiment, c is 1. In one embodiment, c is 2. In one embodiment, c is 3. In one embodiment, c is 4. In one embodiment, c is 5.
  • d is from above 0 to equal or below 15. In one embodiment, d is from above 0 to equal or below 14. In one embodiment, d is from above 0 to equal or below 13. In one embodiment, d is from above 0 to equal or below 12. In one embodiment, d is from above 0 to equal or below 11. In one embodiment, d is from above 0 to equal or below 10. In one embodiment, d is from above 0 to equal or below 9. In one embodiment, d is from above 0 to equal or below 9. In one embodiment, d is from above 0 to equal or below 8. In one embodiment, d is from above 0 to equal or below 7. In one embodiment, d is from above 0 to equal or below 6. In one embodiment, d is from above 0 to equal or below 10.
  • d is from above 0 to equal or below 9. In one embodiment, d is from above 0 to equal or below 8. In one embodiment, c is from above 0 to equal or below 7. In one embodiment, d is from above 0 to equal or below 6. In one embodiment, d is from above 0 to equal or below 5. In one embodiment, d is from above 0 to equal or below 4. In one embodiment, d is from above 0 to equal or below 3. In one embodiment, d is from above 0 to equal or below 2. In one embodiment, d is from above 0 to equal or below 1.
  • d is equal or above 0 to equal or below 15. In one embodiment, d is equal or above 0 to equal or below 14. In one embodiment, d is equal or above 0 to equal or below 13. In one embodiment, d is equal or above 0 to equal or below 12. In one embodiment, d is equal or above 0 to equal or below 11. In one embodiment, d is equal or above 0 to equal or below 10. In one embodiment, d is equal or above 0 to equal or below 9. In one embodiment, d is equal or above 0 to equal or below 9. In one embodiment, d is equal or above 0 to equal or below 8. In one embodiment, d is equal or above 0 to equal or below 7. In one embodiment, d is equal or above 0 to equal or below 6.
  • d is equal or above 0 to equal or below 10. In one embodiment, d is equal or above 0 to equal or below 9. In one embodiment, d is equal or above 0 to equal or below 8. In one embodiment, c is from above 0 to equal or below 7. In one embodiment, d is equal or above 0 to equal or below 6. In one embodiment, d is equal or above 0 to equal or below 5. In one embodiment, d is equal or above 0 to equal or below 4. In one embodiment, d is equal or above 0 to equal or below 3. In one embodiment, d is equal or above 0 to equal or below 2. In one embodiment, d is equal or above 0 to equal or below 1.
  • d is 0.
  • d is selected from 0, 1, 2, 3, 4, 5, 6, 8, 9 and 10. In one embodiment, d is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 and 9. In one embodiment, d is selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8. In one embodiment, d is selected from 0, 1, 2, 3, 4, 5, 6 and 7. In one embodiment, d is selected from 0, 1, 2, 3, 4, 5 and 6. In one embodiment, d is selected from 0, 1, 2, 3, 4, 5 and 6. In one embodiment, d is selected from 0, 1, 2, 3 and 4. In one embodiment, d is selected from 0, 1, 2 and 3. In one embodiment, d is selected from 0.5, 1 and 2.
  • d is selected from 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65. 0.75, 0.8, 0.85, 0.9. 0.95, 1.05, 1, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65. 1.75, 1.8, 1.85, 1.9. 1.95, 2, 2.05, 2.1, 2.15, 2.2, 2.25, 2.3, 2.35, 2.4, 2.45, 2.5, 2.55, 2.6, 2.65. 2.75, 2.8, 2.85, 2.9. 2.95, 3, 3.05, 3.1, 3.15, 3.2, 3.25, 3.3, 3.35, 3.4, 3.45, 3.5, 3.55, 3.6, 3.65. 3.75, 3.8, 3.85, 3.9. 3.95, 4, 4.05,
  • a is above 0 to equal or below 5
  • b is above 0 to equal or below 5
  • c is above 0 to equal or below 5
  • d is above 0 to equal or below 5.
  • a is above 0 to equal or below 4
  • b is above 0 to equal or below 4
  • c is above 0 to equal or below 4
  • d is above 0 to equal or below 4.
  • a is above 0 to equal or below 3
  • b is above 0 to equal or below 3
  • c is above 0 to equal or below 3
  • d is above 0 to equal or below 3.
  • a is above 0 to equal or below 2
  • b is above 0 to equal or below 2
  • c is above 0 to equal or below 2
  • d is above 0 to equal or below 2.
  • a is above 0 to equal or below 1
  • b is above 0 to equal or below 1
  • c is above 0 to equal or below 1
  • d is above 0 to equal or below 1.
  • a is above 0 to equal or below 5
  • b is above 0 to equal or below 5
  • c is above 0 to equal or below 5
  • d is equal or above 0 to equal or below 5.
  • a is above 0 to equal or below 4
  • b is above 0 to equal or below 4
  • c is above 0 to equal or below 4
  • d is equal or above 0 to equal or below 4.
  • a is above 0 to equal or below 3
  • b is above 0 to equal or below 3
  • c is above 0 to equal or below 3
  • d is equal or above 0 to equal or below 3.
  • a is above 0 to equal or below 2
  • b is above 0 to equal or below 2
  • c is above 0 to equal or below 2
  • d is equal or above 0 to equal or below 2.
  • a is above 0 to equal or below 1
  • b is above 0 to equal or below 1
  • c is above 0 to equal or below 1
  • d is equal or above 0 to equal or below 1.
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (I)
  • a is above 0 to equal or below 5; b is above 0 to equal or below 5; c is above 0 to equal or below 10; wherein the API is selected from dapagliflozin, empagliflozin and pecavaptan; wherein CF is selected from ascorbic acid, betaine HC1, citric acid, formic acid, fumaric acid, gentisic acid, glutaric acid, L- carnitine HC1, L-cysteine, L-cysteine HC1, L-lysine HC1, L-malic acid, L-proline, L-pyroglutamic acid, L-tartaric acid, malonic acid, nicotinamide, oxalic acid, succinic acid, and mixtures thereof.
  • the API is selected from dapagliflozin, empagliflozin and pecavaptan
  • CF is selected from ascorbic acid, betaine HC1, citric acid, formic acid, fumaric acid, gent
  • the co-crystal is a co-crystal according to formula (I)
  • a is above 0 to equal or below 5; b is above 0 to equal or below 5; c is above 0 to equal or below 10; wherein the API is selected from dapagliflozin, empagliflozin and pecavaptan; wherein the CF is selected from ascorbic acid, citric acid, fumaric acid, gentisic acid, L-cysteine, L-cysteine HC1, L-malic acid, L-proline, tartaric acid, L-tartaric acid, malonic acid, oxalic acid, and mixtures thereof.
  • the co-crystal is a co-crystal according to formula (I)
  • a is above 0 to equal or below 3; b is above 0 to equal or below 3; c is above 0 to equal or below 3; wherein the API is selected from dapagliflozin, empagliflozin and pecavaptan; CF is selected from ascorbic acid, betaine HC1, citric acid, formic acid, fumaric acid, gentisic acid, glutaric acid, L-camitine HC1, L-cysteine, L-cysteine HC1, L-lysine HC1, L-malic acid, L-proline, L-pyroglutamic acid, L-tartaric acid, malonic acid, nicotinamide, oxalic acid, succinic acid, and mixtures thereof.
  • the API is selected from dapagliflozin, empagliflozin and pecavaptan
  • CF is selected from ascorbic acid, betaine HC1, citric acid, formic acid, fumaric acid, gentisic acid
  • the co-crystal is a co-crystal according to formula (I)
  • a is selected from 0.5, 1 and 2; b is selected from 0.25, 0.4, 0.5, 1 and 2; c is from 0.5, 1 and 2; wherein the API is selected from dapagliflozin, empagliflozin and pecavaptan; wherein CF is selected from ascorbic acid, betaine HC1, citric acid, formic acid, fumaric acid, gentisic acid, glutaric acid, L- camitine HC1, L-cysteine, L-cysteine HC1, L-lysine HC1, L-malic acid, L-proline, L-pyroglutamic acid, L-tartaric acid, malonic acid, nicotinamide, oxalic acid, succinic acid, and mixtures thereof.
  • the co-crystal is a co-crystal according to formula (I)
  • a is above 0 to equal or below 5; b is above 0 to equal or below 5; c is above 0 to equal or below 10; wherein the API is selected from empagliflozin and dapagliflozin, wherein the CF is selected from ascorbic acid, citric acid, fumaric acid, gentisic acid, L-cysteine, L-cysteine HC1, L-malic acid, L-proline, tartaric acid, L-tartaric acid, malonic acid, oxalic acid, and mixtures thereof.
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • a is selected from 0.5, 1 and 2; b is selected from 0.25, 0.4, 0.5, 1 and 2; c is from 0.5, 1 and 2; wherein the API is selected from empagliflozin and dapagliflozin; wherein the CF is selected from ascorbic acid, citric acid, fumaric acid, gentisic acid, L-cysteine, L-cysteine HC1, L-malic acid, L-proline, tartaric acid, L-tartaric acid, malonic acid, oxalic acid, and mixtures thereof.
  • the co-crystal is a co-crystal according to formula (I)
  • a is above 0 to equal or below 5; b is above 0 to equal or below 5; c is above 0 to equal or below 10; wherein the API is empagliflozin; wherein the CF is selected from ascorbic acid, citric acid, fumaric acid, gentisic acid, L-betaine HCL, L-Carnitine HCL, L-cysteine, L-cysteine HC1, L-malic acid, L-proline, tartaric acid, L-tartaric acid, malonic acid, oxalic acid, and mixtures thereof.
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • a is selected from 0.5, 1 and 2; b is selected from 0.25, 0.4, 0.5, 1 and 2; c is from 0.5, 1 and 2; wherein the API is empagliflozin; wherein CF is selected from citric acid, oxalic acid, and mixtures thereof.
  • the co-crystal is a co-crystal according to formula (I)
  • a is selected from 0.5, 1 and 2; b is selected from 0.25, 0.4, 0.5, 1 and 2; c is from 0.5, 1 and 2;wherein the API is empagliflozin; wherein the CF is selected from ascorbic acid, citric acid, fumaric acid, gentisic acid, L-betaine HCL, L-Carnitine HCL, L-cysteine, L-cysteine HC1, L-malic acid, L-proline, tartaric acid, L-tartaric acid, malonic acid, oxalic acid, and mixtures thereof.
  • the co-crystal is a co-crystal according to formula (I)
  • a is above 0 to equal or below 5; b is above 0 to equal or below 5; c is above 0 to equal or below 10; wherein the API is dapagliflozin; wherein the CF is selected from ascorbic acid, citric acid, fumaric acid, gentisic acid, L-betaine HCL, L-Carnitine HCL, L-cysteine, L-cysteine HC1, L-malic acid, L-proline, tartaric acid, L-tartaric acid, malonic acid, oxalic acid, and mixtures thereof.
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I) wherein a is above O to equal or below 1; b is above O to equal or below 0.5; c is above O to equal or below 1 ; wherein the API is dapagliflozin; wherein CF is selected from citric acid, oxalic acid, and mixtures thereof.
  • the co-crystal is a co-crystal according to formula (I)
  • a is selected from 0.5, 1 and 2; b is selected from 0.25, 0.4, 0.5, 1 and 2; c is from 0.5, 1 and 2; wherein the API is dapagliflozin; wherein CF is selected from citric acid, oxalic acid, and mixtures thereof.
  • the co-crystal is a co-crystal according to formula (I)
  • a is selected from 0.5, 1 and 2; b is selected from 0.25, 0.4, 0.5, 1 and 2; c is from 0.5, 1 and 2;wherein the API is dapagliflozin; wherein the CF is selected from ascorbic acid, citric acid, fumaric acid, gentisic acid, L-betaine HCL, L-Carnitine HCL, L-cysteine, L-cysteine HC1, L-malic acid, L-proline, tartaric acid, L-tartaric acid, malonic acid, oxalic acid, and mixtures thereof.
  • the co-crystal is a co-crystal according to formula (I)
  • a is selected from 1 and 2; wherein b is 1, 2, 3 and 4; wherein c is selected from 1, 2, 3 and 4; wherein the API is dapagliflozin;
  • CF is selected from ascorbic acid, betaine HC1, citric acid, formic acid, fumaric acid, gentisic acid, glutaric acid, L-camitine HC1, L-cysteine, L-cysteine HC1, L-lysine HC1, L- malic acid, L-proline, L-pyroglutamic acid, L-tartaric acid, malonic acid, nicotinamide, oxalic acid, succinic acid, and mixtures thereof.
  • the co-crystal is a co-crystal according to formula (I)
  • a is selected from 1 and 2; wherein b is 1; wherein c is selected from 1 and 2; wherein the API is dapagliflozin; wherein the CF is selected from 1-proline, 1-pyroglutamic acid, fumaric acid, L-tartaric acid, citric acid, L-malic acid, oxalic acid, and mixtures thereof.
  • the co-crystal is a co-crystal according to formula (I)
  • a is selected from 1 and 2; wherein b is 1, 2, 3 and 4; wherein c is selected from 1, 2, 3 and 4; wherein the API is pecavaptan;
  • CF is selected from ascorbic acid, betaine HC1, citric acid, formic acid, fumaric acid, gentisic acid, glutaric acid, L-camitine HC1, L-cysteine, L-cysteine HC1, L-lysine HC1, L- malic acid, L-proline, L-pyroglutamic acid, L-tartaric acid, malonic acid, nicotinamide, oxalic acid, succinic acid, and mixtures thereof.
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • a is selected from 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65. 0.75, 0.8, 0.85, 0.9. 0.95, 1.05, 1, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65. 1.75, 1.8, 1.85, 1.9. 1.95, 2, 2.05, 2.1, 2.15, 2.2, 2.25, 2.3, 2.35, 2.4, 2.45, 2.5, 2.55, 2.6, 2.65. 2.75, 2.8, 2.85, 2.9. 2.95, 3, 3.05,
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • a is selected from 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65. 0.75, 0.8, 0.85, 0.9. 0.95, 1.05, 1, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65. 1.75, 1.8, 1.85, 1.9. 1.95, 2, 2.05, 2.1, 2.15, 2.2, 2.25, 2.3, 2.35, 2.4, 2.45, 2.5, 2.55, 2.6, 2.65. 2.75, 2.8, 2.85, 2.9. 2.95, 3, 3.05,
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • a is selected from 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65. 0.75, 0.8, 0.85, 0.9. 0.95, 1.05, 1, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65. 1.75, 1.8, 1.85, 1.9. 1.95, 2, 2.05, 2.1, 2.15, 2.2, 2.25, 2.3, 2.35, 2.4, 2.45, 2.5, 2.55, 2.6, 2.65. 2.75, 2.8, 2.85, 2.9. 2.95, 3, 3.05,
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • a is selected from 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65. 0.75, 0.8, 0.85, 0.9. 0.95, 1.05, 1, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65. 1.75, 1.8, 1.85, 1.9. 1.95, 2, 2.05, 2.1, 2.15, 2.2, 2.25, 2.3, 2.35, 2.4, 2.45, 2.5, 2.55, 2.6, 2.65. 2.75, 2.8, 2.85, 2.9.
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (I)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II) (Finerenone) a * (API)b
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II) (Finerenone) a * (API)b
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II) (Finerenone) a * (API)b
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • a is selected from 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65. 0.75, 0.8, 0.85, 0.9. 0.95, 1.05, 1, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65. 1.75, 1.8, 1.85, 1.9. 1.95, 2, 2.05, 2.1, 2.15, 2.2, 2.25, 2.3, 2.35, 2.4, 2.45, 2.5, 2.55, 2.6, 2.65. 2.75, 2.8, 2.85, 2.9.
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II) (Finerenone) a * (API)b
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (II)
  • the co-crystal is a co-crystal according to formula (III)
  • the co-crystal is a co-crystal according to formula (III)
  • HI wherein a is above 0 to equal or below 5; b is above 0 to equal or below 5; d is above 0 to 10; wherein the API is selected from dapagliflozin, empagliflozin and pecavaptan, wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene, and mixtures thereof.
  • S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, die
  • the co-crystal is a co-crystal according to formula (III)
  • a is above 0 to equal or below 3; b is above 0 to equal or below 3; d is above 0 to 5; wherein the API is selected from dapagliflozin, empagliflozin, and pecavaptan, wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof.
  • S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl
  • the co-crystal is a co-crystal according to formula (III)
  • the co-crystal is a co-crystal according to formula (III)
  • the co-crystal is a co-crystal according to formula (III)
  • the co-crystal is a co-crystal according to formula (III)
  • the co-crystal is a co-crystal according to formula (III)
  • HI wherein a is above 0 to equal or below 3 ; b is above 0 to equal or below 2; wherein the API is empagliflozin or dapagliflozin; d is above 0 to 5; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof.
  • S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dio
  • the co-crystal is a co-crystal according to formula (III)
  • HI wherein a is above 0 to equal or below 3 ; b is above 0 to equal or below 1 ; wherein the API is empagliflozin or dapagliflozin; d is above 0 to 5; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof.
  • S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, di
  • the co-crystal is a co-crystal according to formula (III)
  • the co-crystal is a co-crystal according to formula (III)
  • a is above 0 to equal or below 2; b is above 0 to equal or below 3 ; wherein the API is empagliflozin or dapagliflozin; d is above 0 to 5; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof.
  • S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane,
  • the co-crystal is a co-crystal according to formula (III)
  • the co-crystal is a co-crystal according to formula (III)
  • the co-crystal is a co-crystal according to formula (III)
  • the co-crystal is a co-crystal according to formula (III)
  • HI wherein a is 3; b is 1; wherein the API is empagliflozin or dapagliflozin; d is above 0 to 5; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof.
  • S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, eth
  • the co-crystal is a co-crystal according to formula (III)
  • HI wherein a is 3; b is 2; wherein the API is empagliflozin or dapagliflozin; d is above 0 to 5; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof.
  • S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, eth
  • the co-crystal is a co-crystal according to formula (III)
  • the co-crystal is a co-crystal according to formula (III)
  • the co-crystal is a co-crystal according to formula (III)
  • the co-crystal is a co-crystal according to formula (III)
  • the co-crystal is a co-crystal according to formula (III)
  • the co-crystal is a co-crystal according to formula (III)
  • HI wherein a is 0.25; b is 1; wherein the API is empagliflozin or dapagliflozin; d is above 0 to 5; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof.
  • S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, e
  • the co-crystal is a co-crystal according to formula (III)
  • a is selected from 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65. 0.75, 0.8, 0.85, 0.9. 0.95, 1.05, 1, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65. 1.75, 1.8, 1.85, 1.9. 1.95, 2, 2.05, 2.1, 2.15, 2.2, 2.25, 2.3, 2.35, 2.4, 2.45, 2.5, 2.55, 2.6, 2.65. 2.75, 2.8, 2.85, 2.9. 2.95, 3, 3.05,
  • b is 1; wherein the API is empagliflozin or dapagliflozin; d is above 0 to 5; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof.
  • S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol,
  • the co-crystal is a co-crystal according to formula (III)
  • API empagliflozin or dapagliflozin
  • d is above 0 to 5
  • S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof.
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (IV)
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • V wherein a is above 0 to equal or below 5; c is above 0 to equal or below 5; d is above 0 to equal or below 10; wherein CF is selected from ascorbic acid, citric acid, fumaric acid, gentisic acid, L-L-cysteine, L- cysteine HC1, L-malic acid, L-proline, tartaric acid, L-tartaric acid, malonic acid, oxalic acid, and mixtures thereof; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran,
  • the co-crystal is a co-crystal according to formula (V)
  • V wherein a is above 0 to equal or below 3; c is above 0 to equal or below 3; d is above 0 to equal or below 10; wherein CF is selected from ascorbic acid, citric acid, fumaric acid, gentisic acid, L-cysteine, L- cysteine HC1, L-malic acid, L-proline, tartaric acid, L-tartaric acid, malonic acid, oxalic acid, and mixtures thereof; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, tol
  • the co-crystal is a co-crystal according to formula (V) (Finerenone) a * (CF) c * (S)d
  • V wherein a is above 0 to equal or below 3; c is above 0 to equal or below 3; d is above 0 to equal or below 10; wherein CF is selected from gentisic acid, L-cysteine, L-cysteine HC1, L-malic acid, L-tartaric acid, tartaric acid, malonic acid, oxalic acid, and mixture thereof; wherein S is a solvent selected from acetonitrile, methanol, isobutyl acetate, tetrahydrofuran, ethyl acetate, acetone and mixtures thereof.
  • the co-crystal is a co-crystal according to formula (V)
  • c is 1; wherein d is above 0 to 5; wherein CF is selected from gentisic acid, L-cysteine, L-cysteine HC1, L-malic acid, L-tartaric acid, tartaric acid, malonic acid, oxalic acid, and mixture thereof; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof.
  • S is a solvent selected from acetone, acetonitrile, chloroform, cyclohe
  • the co-crystal is a co-crystal according to formula (V)
  • V wherein a is 1; wherein c is selected from 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65. 0.75, 0.8, 0.85, 0.9. 0.95, 1.05, 1, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65. 1.75,
  • d is above 0 to 5; wherein CF is selected from gentisic acid, L-cysteine, L-cysteine HC1, L-malic acid, L-tartaric acid, tartaric acid, malonic acid, oxalic acid, and mixture thereof; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof.
  • S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichlorome
  • the co-crystal is a co-crystal according to formula (V)
  • V wherein a is above 0 to equal or below 3; c is above 0 to equal or below 3; d is above 0 to equal or below 10; wherein CF is gentisic acid; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof.
  • S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sul
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • V wherein a is above 0 to equal or below 3; c is above 0 to equal or below 3; d is above 0 to equal or below 10; wherein CF is gentisic acid; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof; wherein the x-ray diffractogram of the cocrystal exhibits at least one or more of peak maxima of the 2 theta angle according to table 6.
  • the co-crystal is a co-crystal according to formula (V)
  • V wherein a is above 0 to equal or below 3; c is above 0 to equal or below 3; d is above 0 to equal or below 10; wherein CF is gentisic acid; wherein S is a solvent selected from acetonitrile, methanol and mixtures thereof; wherein the x-ray diffractogram of the co-crystal exhibits at least one or more of peak maxima of the 2 theta angle according to table 6.
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • V wherein a is above 0 to equal or below 3; c is above 0 to equal or below 3; d is above 0 to equal or below 10; wherein CF is oxalic acid; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof.
  • S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl s
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • V wherein a is above 0 to equal or below 3; c is above 0 to equal or below 3; d is above 0 to equal or below 10; wherein CF is oxalic acid; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof; wherein the x-ray diffractogram of the cocrystal exhibits at least one or more of peak maxima of the 2 theta angle according to table 7.
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • V wherein a is above 0 to equal or below 3; c is above 0 to equal or below 3; d is above 0 to equal or below 10; wherein CF is malonic acid; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof.
  • S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V) wherein a is above 0 to equal or below 3; c is above 0 to equal or below 3; d is above 0 to equal or below 10; wherein CF is malonic acid; wherein S is acetonitril.
  • the co-crystal is a co-crystal according to formula (V)
  • V wherein a is above 0 to equal or below 3; c is above 0 to equal or below 3; d is above 0 to equal or below 10; wherein CF is malonic acid; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof; wherein the x-ray diffractogram of the cocrystal exhibits at least one or more of peak maxima of the 2 theta angle according to table 8.
  • the co-crystal is a co-crystal according to formula (V)
  • V wherein a is above 0 to equal or below 3; c is above 0 to equal or below 3; d is above 0 to equal or below 10; wherein CF is malonic acid; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof; wherein the x-ray diffractogram of the cocrystal exhibits at least one or more of peak maxima of the 2 theta angle according to table 9b.
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • V wherein a is above 0 to equal or below 3; c is above 0 to equal or below 3; d is above 0 to equal or below 10; wherein CF is tartaric acid; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof.
  • S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfox
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • V wherein a is above 0 to equal or below 3; c is above 0 to equal or below 3; d is above 0 to equal or below 10; wherein CF is L-malic acid; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof.
  • S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sul
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V) (Finerenone) a * (CF) c * (S)d
  • the co-crystal is a co-crystal according to formula (V)
  • V wherein a is above 0 to equal or below 3; c is above 0 to equal or below 3; d is above 0 to equal or below 10; wherein CF is L-cysteine HC1; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone, tert-butyl-methyl ether, tetrahydrofuran, toluene, water, xylene and mixtures thereof.
  • S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, di
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (V)
  • the co-crystal is a co-crystal according to formula (VI)
  • the co-crystal is a co-crystal according to formula (VI)
  • a is above 0 to equal or below 5; b is above 0 to equal or below 5; c is above 0 to equal or below 5; d is above 0 to 10; wherein the API is selected from dapagliflozin, empagliflozin and pecavaptan, wherein CF is selected from ascorbic acid, citric acid, fumaric acid, gentisic acid, L-cysteine, L-cysteine HC1, L-malic acid, L-proline, tartaric acid, L-tartaric acid, malonic acid, oxalic acid, and mixtures thereof; wherein S is a solvent selected from acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethyl sulfoxide, ethyl acetate, ethanol, heptane, isobutyl acetate, isopropyl acetate
  • the co-crystal is a co-crystal according to formula (VI)
  • the co-crystal is a co-crystal according to formula (VI)
  • the co-crystal is a co-crystal according to formula (VI)
  • the co-crystal is a co-crystal according to formula (VI)
  • the co-crystal is a co-crystal according to formula (VI)
  • the co-crystal is a co-crystal according to formula (VI)
  • the co-crystal is a co-crystal according to formula (VI)
  • the co-crystal is a co-crystal according to formula (VI)
  • the co-crystal is a co-crystal according to formula (VI) (Finerenone) a *(API)b * (CF) c * (S)d
  • the co-crystal is a co-crystal according to formula (VII)
  • CF is a co-former selected from organic excipient, inorganic excipient, acidic excipient, basic excipient and mixtures thereof;
  • API is an active pharmaceutical ingredient selected from sodium glucose linked transporter 2 inhibitor (SGLT2-i);
  • S is a solvent; b is above 0 to equal or below 10; c is above 0 to equal or below 10; d is equal or above 0 to equal or below 15.
  • the co-crystal is a co-crystal according to formula (VII)
  • CF is a co-former selected from organic excipient, inorganic excipient, acidic excipient, basic excipient and mixtures thereof;
  • API is an active pharmaceutical ingredient selected from 1.
  • S is a solvent;
  • b is above 0 to equal or below 10;
  • c is above 0 to equal or below 10;
  • d is above 0 to equal or below 15.
  • the co-crystal is a co-crystal according to formula (VII)
  • CF is a co-former selected from organic excipient, inorganic excipient, acidic excipient, basic excipient and mixtures thereof;
  • API is a SGLT2 inhibitor selected from pecavaptan, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, remogliflozin, sotagliflozin, sergliflozin, and tofogliflozin;
  • S is a solvent;
  • b is above 0 to equal or below 10;
  • c is above 0 to equal or below 10;
  • d is equal or above 0 to equal or below 15.
  • the co-crystal is a co-crystal according to formula (VII)
  • CF is a co-former selected from organic excipient, inorganic excipient, acidic excipient, basic excipient and mixtures thereof;
  • API is an active pharmaceutical ingredient selected from sodium glucose linked transporter 2 inhibitor (SGLT2-i);
  • S is a solvent; b is above 0 to equal or below 10; c is above 0 to equal or below 10; d is equal or above 0 to equal or below 15.
  • the co-crystal is a co-crystal according to formula (VII)
  • API is a SGLT2 inhibitor selected from pecavaptan, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, remogliflozin, sotagliflozin, sergliflozin, and tofogliflozin; wherein CF is selected from ascorbic acid, betaine HC1, citric acid, formic acid, fumaric acid, gentisic acid, glutaric acid, L-camitine HC1, L-cysteine, L-cysteine HC1, L-lysine HC1, L-malic acid, L-proline, L- pyroglutamic acid, L-tartaric acid, malonic acid, nicotinamide, oxalic
  • the co-crystal is a co-crystal according to formula (VII)
  • API is a SGLT2 inhibitor selected from pecavaptan, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, remogliflozin, sotagliflozin, sergliflozin, and tofogliflozin; wherein CF is selected from ascorbic acid, betaine HC1, citric acid, formic acid, fumaric acid, gentisic acid, glutaric acid, L-camitine HC1, L-cysteine, L-cysteine HC1, L-lysine HC1, L-malic acid, L-proline, L- pyroglutamic acid, L-tartaric acid, malonic acid, nicotinamide, oxalic
  • the co-crystal is a co-crystal according to formula (VII)
  • VII wherein b is above 0 to equal or below 5; c is above 0 to equal or below 5; d is equal or above 0 to equal or below 10; wherein API is selected from dapagliflozin and empagliflozin; wherein CF is selected from ascorbic acid, betaine HC1, citric acid, formic acid, fumaric acid, gentisic acid, glutaric acid, L-camitine HC1, L-cysteine, L-cysteine HC1, L-lysine HC1, L-malic acid, L-proline, L-pyroglutamic acid, L-tartaric acid, malonic acid, nicotinamide, oxalic acid, succinic acid, and mixtures thereof: wherein S is a solvent selected from water, acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethylsulfoxid,
  • the co-crystal is a co-crystal according to formula (VII)
  • VII wherein b is above 0 to equal or below 3; c is above 0 to equal or below 3; d is equal or above 0 to equal or below 3; wherein API is selected from dapagliflozin and empagliflozin; wherein CF is selected from ascorbic acid, betaine HC1, citric acid, formic acid, fumaric acid, gentisic acid, glutaric acid, L-camitine HC1, L-cysteine, L-cysteine HC1, L-lysine HC1, L-malic acid, L-proline, L-pyroglutamic acid, L-tartaric acid, malonic acid, nicotinamide, oxalic acid, succinic acid, and mixtures thereof; wherein S is a solvent selected from water, acetone, acetonitrile, chloroform, cyclohexane, dichloromethane, diethyl ether, dioxane, dimethylsulfoxid,
  • the co-crystal is a co-crystal according to formula (VII) (API) b *(CF) c * (S) d
  • VII wherein b is above 0 to equal or below 5; c is above 0 to equal or below 5; d is equal or above 0 to equal or below 5; wherein API is selected from dapagliflozin; wherein CF is selected from L-proline, oxalic acid, citric acid, and mixtures thereof; wherein S is a solvent selected from acetone, methanol, dioxane, ethyl acetate, tetrahydrofuran.
  • the co-crystal is a co-crystal according to formula (VII)
  • the co-crystal is a co-crystal according to formula (VII)
  • the co-crystal is a co-crystal according to formula (VII)
  • the co-crystal is a co-crystal according to formula (VII)
  • the co-crystal is a co-crystal according to formula (VII)
  • VII wherein b is above 0 to equal or below 5; c is above 0 to equal or below 5; d is equal or above 0 to equal or below 5; wherein API is dapagliflozin; wherein CF is selected from L-proline, citric acid, and mixtures thereof; wherein S is a solvent selected from acetone, methanol, dioxane, ethyl acetate, tetrahydrofuran.
  • the co-crystal is a co-crystal according to formula (VII)
  • the co-crystal is a co-crystal according to formula (VII)
  • the co-crystal is a co-crystal according to formula (VII)
  • VII wherein b is above 0 to equal or below 5; c is above 0 to equal or below 5; d is equal or above 0 to equal or below 5; wherein API is selected from empagliflozin; wherein CF is selected from L-proline, oxalic acid, citric acid, and mixtures thereof: wherein S is a solvent selected from acetone, methanol, dioxane, ethyl acetate, tetrahydrofuran.
  • the co-crystal is a co-crystal according to formula (VII)
  • the co-crystal is a co-crystal according to formula (VII)
  • the co-crystal is a co-crystal according to formula (VII)
  • CF is a co-former selected from organic excipient, inorganic excipient, acidic excipient, basic excipient and mixtures thereof;
  • API is an active pharmaceutical ingredient selected from sodium glucose linked transporter 2 inhibitor (SGLT2-i);
  • S is a solvent; b is above 0 to equal or below 10; c is above 0 to equal or below 10; d is 0.
  • the co-crystal is a co-crystal according to formula (VII)
  • the co-crystal is a co-crystal according to formula (VII)
  • VII wherein b is above 0 to equal or below 5; c is above 0 to equal or below 5; d is 0; wherein API is selected from empagliflozin; wherein CF is selected from L-proline, oxalic acid, citric acid, and mixtures thereof.
  • the co-crystal is a co-crystal according to formula (VII)
  • the co-crystal is a co-crystal according to formula (VII)
  • the co-crystal is a co-crystal according to formula (I)

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  • Engineering & Computer Science (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un co-cristal selon l'une quelconque des formules (I), (II), (III), (IV), (V), (VI) et/ou (VII). En outre, l'invention concerne une formulation pharmaceutique comprenant l'un quelconque des co-cristaux selon les formules (I), (II), (III), (IV), (V), (VI) et/ou (VII), l'utilisation médicale de ces co-cristaux ou de la formulation pharmaceutique comprenant de tels co-cristaux ainsi qu'un procédé de préparation de ces co-cristaux. L'invention concerne en outre des formes cristallines et/ou de l'empagliflozine ainsi que des produits pharmaceutiques comprenant de telles formes cristallines.
PCT/EP2025/060873 2024-04-23 2025-04-22 Co-cristaux de finérénone, de pecavaptan et d'inhibiteurs de sglt2 Pending WO2025224069A1 (fr)

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