EP2089012A2 - Polymorphes de la n²-(1,1'-biphényl-4-ylcarbonyl)-n¹[2-(4-fluorophényl)-1,1-diméthyléthyl]-l-alpha-glutamine - Google Patents

Polymorphes de la n²-(1,1'-biphényl-4-ylcarbonyl)-n¹[2-(4-fluorophényl)-1,1-diméthyléthyl]-l-alpha-glutamine

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Publication number
EP2089012A2
EP2089012A2 EP07864234A EP07864234A EP2089012A2 EP 2089012 A2 EP2089012 A2 EP 2089012A2 EP 07864234 A EP07864234 A EP 07864234A EP 07864234 A EP07864234 A EP 07864234A EP 2089012 A2 EP2089012 A2 EP 2089012A2
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EP
European Patent Office
Prior art keywords
polymorph
fluorophenyl
glutamine
biphenyl
ylcarbonyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP07864234A
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German (de)
English (en)
Inventor
Jennifer Q. Liang
Qiuxia Trisha Wang
Mann-Ching Sherry Ku
Ronald S. Michalak
W. James Huang
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Wyeth LLC
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Wyeth LLC
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Publication date
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Publication of EP2089012A2 publication Critical patent/EP2089012A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/83—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated

Definitions

  • the invention relates to novel polymorphic forms of N 2 -(l,l'-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)- 1 , 1 -dimethylethyl]-L- ⁇ -glutamine, methods of preparing the polymorphic forms, compositions containing the polymorphic forms, and methods of treatment using the polymorphic forms.
  • N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine is a modulator of metalloproteinases, as described in U.S. Patent Application No. 11/484,005, having Publication No. 2007/0043066, and in International Patent Application No. PCT/US2006/027066, having Publication No. WO 2007/008994, the entire disclosures of which is incorporated herein by reference in their entireties.
  • MMPs matrix metalloproteinases
  • Aggrecanases are members of the ADAMTS (A disintegrin and metalloproteinase with thrombospondin motifs) family of proteins.
  • Aggrecanase-1 and aggrecanase-2 have been designated ADAMTS-4 and ADAMTS-5, respectively (Tang BL, Int JBiochem Cell Biol 2001, 33, 33-44).
  • the ADAMTS family is involved in cleaving aggrecan, a cartilage component also known as the large aggregating chondroitin sulphate proteoglycan (Abbaszade I et al., J Biol Chem 1999, 274, 23443-23450), procollagen processing (Colige A et al., Proc Natl Acad Sci USA 1997, 94, 2374-2379), angiogenesis (Vazquez F et al., J Biol Chem 1999, 274, 23349-23357), inflammation (Kuno K et al., J Biol Chem 1997, 272, 556-562) and tumor invasion (Masui T. et al., J Biol Chem 1997, 272, 556-562). MMPs have been shown to cleave aggrecan as well.
  • the loss of aggrecan has been implicated in the degradation of articular cartilage in arthritic diseases.
  • osteoarthritis is a debilitating disease which affects at least 30 million Americans. Degradation of articular cartilage and the resulting chronic pain can severely reduce quality of life.
  • An early and important characteristic of the osteoarthritic process is loss of aggrecan from the extracellular matrix, resulting in deficiencies in the biomechanical characteristics of the cartilage.
  • MMPs and aggrecanases are known to play a role in many disorders in which extracellular protein degradation or destruction occurs, such as cancer, asthma, chronic obstructive pulmonary disease ("COPD”), atherosclerosis, age-related macular degeneration, myocardial infarction, corneal ulceration and other ocular surface diseases, hepatitis, aortic aneurysms, tendonitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft versus host disease, diabetes, inflammatory bowel disease, shock, invertebral disc degeneration, stroke, osteopenia, and periodontal diseases.
  • COPD chronic obstructive pulmonary disease
  • atherosclerosis age-related macular degeneration
  • myocardial infarction corneal ulceration and other ocular surface diseases
  • hepatitis hepatitis
  • aortic aneurysms tendonitis
  • the invention provides polymorphs of N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-
  • polymorphs of Form A, Form B, Form C, Form E, Form F, Form G and pseudo Form A including crystalline polymorphs of Form A, Form B, Form C, Form E, Form F, Form G and pseudo Form A, and amorphous polymorph Form D.
  • the polymorph is a substantially pure polymorph of Form A, Form B, Form C, Form D, Form E, Form F, Form G, or pseudo Form A.
  • the invention also provides methods for the preparation of the crystalline polymorph of Form A, which comprises dissolving N 2 -(l, l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4- fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine in an organic solvent to form a solution and evaporating the organic solvent to form the crystalline polymorph of Form A.
  • Crystalline polymorph Form A of N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l- dimethylethyl]-L- ⁇ -glutamine prepared by the methods of the invention is also provided by the invention.
  • the invention also provides methods for the preparation of the crystalline polymorph of Form B.
  • the methods comprise converting polymorph Form A to polymorph Form B.
  • the methods comprise crystallizing polymorph Form B from a mixture of N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4- fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine in a solvent mixture, and isolating the crystalline polymorph Form B.
  • Crystalline polymorph Form B of N 2 -(l,l'-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine prepared by the methods of the invention is also provided by the invention.
  • the invention also provides methods for the preparation of the crystalline polymorph of Form C.
  • the methods comprise converting polymorph Form A to polymorph Form C.
  • Crystalline polymorph Form C of N 2 -(l,l'-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine prepared by the methods of the invention is also provided by the invention.
  • the invention also provides methods for the preparation of the polymorph of
  • the methods comprise converting polymorph Form A to polymorph Form D.
  • the methods comprise equilibrating a slurry of N 2 -( 1 , 1 '-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)- 1 , 1 -dimethylethyl] -L- ⁇ -glutamine in a solvent mixture, and isolating the amorphous polymorph Form D.
  • Amorphous polymorph Form D ofN 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ - glutamine prepared by the methods of the invention is also provided by the invention.
  • the invention also provides methods for the preparation of the crystalline polymorph of Form E. In some embodiments, the methods comprise converting polymorph Form A to polymorph Form E.
  • the methods comprise equilibrating a slurry of N 2 -( 1 , 1 '-biphenyl-4-ylcarbonyl)-N 1 - [2-(4-fluorophenyl)- 1 , 1 -dimethylethyl] -L- ⁇ - glutamine in a solvent mixture, and isolating the crystalline polymorph Form E.
  • Crystalline polymorph Form E of N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l- dimethylethyl]-L- ⁇ -glutamine prepared by the methods of the invention is also provided by the invention.
  • the invention also provides methods for the preparation of the crystalline polymorph of Form F, which comprises equilibrating a slurry of N 2 -(l,l'-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine in a solvent, and isolating the crystalline polymorph Form F.
  • Crystalline polymorph Form F of N 2 -(l,l'- biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine prepared by the methods of the invention is also provided by the invention.
  • the invention also provides methods for the preparation of the crystalline polymorph of Form G, which comprises equilibrating a slurry of N 2 -(l,l'-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine in in a solvent mixture, and isolating the crystalline polymorph Form G.
  • Crystalline polymorph Form G of N 2 -( 1 , 1 '-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)- 1 , 1 -dimethylethyl] -L- ⁇ -glutamine prepared by the methods of the invention is also provided by the invention.
  • the invention also provides methods for the preparation of the crystalline polymorph of pseudo Form A, which comprises dissolving N 2 -(l,l'-biphenyl-4-ylcarbonyl)- N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine in an organic solvent to form a solution and evaporating the organic solvent to form the crystalline polymorph of pseudo Form A.
  • Crystalline polymorph pseudo Form A of N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4- fluoropheny I)- 1,1 -dimethylethyl] -L- ⁇ -glutamine prepared by the methods of the invention is also provided by the invention.
  • the invention further provides compositions comprising N 2 -( 1 , 1 '-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine of polymorph Form A, Form B, Form C, Form D, Form E, Form F, Form G or pseudo Form A, and a pharmaceutically acceptable carrier.
  • compositions consisting essentially of N 2 -( 1 , 1 '-biphenyM-ylcarbonyFj-N 1 -[2-(4-fluorophenyl)- 1,1- dimethylethyl] -L- ⁇ -glutamine of polymorph Form A, Form B, Form C, Form D, Form E, Form F, Form G or pseudo Form A, and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is suitable for oral administration and the composition comprises an oral dosage form.
  • the invention provides methods of inhibiting the activity of a metalloproteinase, in an animal in need thereof, which comprises, administering to the animal an effective dose of an inventive composition.
  • the metalloproteinase is a matrix metalloproteinase or an aggrecanase.
  • the aggrecanase is aggrecanase-1 or aggrecanase-2.
  • the animal is a mammal, e.g., a mouse, rat, sheep, pig, cow, monkey or human. In some embodiments, the mammal is a human.
  • the invention provides methods for treating a metalloproteinase-related disorder, in an animal in need thereof, which comprises, administering to the animal an effective dose of an inventive composition.
  • the metalloproteinase is a matrix metalloproteinase or an aggrecanase.
  • the aggrecanase is aggrecanase-1 or aggrecanase-2.
  • the metalloproteinase-related disorder is selected from arthritic disorders, osteoarthritis, cancer, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, atherosclerosis, age-related macular degeneration, myocardial infarction, corneal ulceration and other ocular surface diseases, hepatitis, aortic aneurysms, tendonitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft versus host disease, diabetes, inflammatory bowel disease, shock, invertebral disc degeneration, stroke, osteopenia and periodontal diseases.
  • the animal is a mammal, e.g., a mouse, rat, sheep, pig, cow, monkey or human. In some embodiments, the mammal is a human.
  • FIG. 1 shows a powder XRD (X-ray diffraction) pattern of polymorph Form
  • FIG. 2 shows a powder XRD pattern of polymorph Form B.
  • FIG. 3 shows a powder XRD pattern of polymorph Form C.
  • FIG. 4 shows a powder XRD pattern of polymorph Form E.
  • FIG. 5 shows a powder XRD pattern of polymorph pseudo Form A.
  • FIG. 6 shows a DSC (differential scanning calorimetry) thermogram of polymorph Form A.
  • FIG. 7 shows a DSC thermogram of polymorph Form B.
  • FIG. 8 shows a DSC thermogram of polymorph Form C.
  • FIG. 9 shows a DSC thermogram of polymorph Form E.
  • FIG. 10 shows a DSC thermogram of polymorph pseudo Form A.
  • FIG. 11 shows DSC thermograms of samples of N 2 -(l,l'-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)- 1 , 1 -dimethylethyl]-L- ⁇ -glutamine.
  • FIG. 12 shows XRD patterns of samples, initially containing polymorph Form
  • FIG. 13 shows HPLC (high-performance liquid chromatography) chromatograms of samples of N 2 -( 1 , 1 '-biphenyl-4-ylcarbonyl)-N 1 - [2-(4-fluorophenyl)- 1,1- dimethylethyl]-L- ⁇ -glutamine.
  • FIG. 14 shows results of a hot stage microscope study of a sample containing polymorph Form B.
  • FIG. 15 shows XRD patterns of a starting material containing polymorph
  • FIG. 16 shows an XRD pattern showing conversion of polymorph Form B to polymorph Form A at 100 0 C.
  • FIG. 17 shows a DVS (Dynamic Vapor Sorption) isotherm plot of a sample containing polymorph Form B.
  • FIG. 18 shows water adsorption/desorption of a sample containing polymorph
  • FIG. 19 shows an equilibrium moisture sorption isotherm after 20 days for a sample containing polymorph Form B.
  • FIG. 20 is a scheme showing the degradation products of N 2 -(l,l'-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)- 1 , 1 -dimethylethyl]-L- ⁇ -glutamine.
  • FIG. 21 shows a proposed degradation pathway for N 2 -(l , 1 '-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)- 1 , 1 -dimethylethyl]-L- ⁇ -glutamine.
  • FIG. 22 shows a solubility and pH profile for N 2 -(l,l'-biphenyl-4-ylcarbonyl)-
  • FIG. 23 shows a DSC thermogram of polymorph Form C.
  • FIG. 24 shows a TGA (thermal gravimetric analysis) thermogram of polymorph Form C.
  • FIG. 25 shows a DSC thermogram showing slow cooling crystallization of N 2 -
  • FIG. 26 shows XRD patterns comparing fast versus slow anti-solvent addition of isopropyl alcohol to a solution of N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-
  • FIG. 27 shows XRD patterns of various polymorphs of N 2 -(l,l'-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine, including Form F
  • FIG. 28 shows DSC thermograms of various polymorphs of N 2 -(l,l'-biphenyl-
  • FIG. 29 shows TGA profiles of various polymorphs of N 2 -(l,l'-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)- 1 , 1 -dimethylethyl]-L- ⁇ -glutamine.
  • FIG. 30 shows TGA and DSC profiles of original N 2 -(l,l'-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)- 1 , 1 -dimethylethyl]-L- ⁇ -glutamine.
  • FIG. 31 shows TGA and DSC profiles of the product prepared by cooling followed by anti-solvent addition of ethanol and water.
  • FIG. 32 shows TGA and DSC profiles of the product prepared by anti-solvent addition of isopropyl alcohol in water.
  • FIG. 33 shows TGA and DSC thermograms of polymorph pseudo Form A.
  • FIG. 34 shows XRD patterns comparing polymorph pseudo Form A with the starting material N 2 -( 1 , 1 l -biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)- 1 , 1 -dimethylethyl]-
  • FIG. 35 shows DSC thermograms comparing polymorph pseudo Form A with the starting material N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l- dimethylethyl]-L- ⁇ -glutamine.
  • FIG. 36 shows the temperature effect on the rate of transformation from pseudo Form A to a lower melting polymorph form.
  • FIG. 37 shows the effect of ethanol on the rate of transformation from pseudo
  • the invention provides for different polymorphs of the compound N -(1,1'- biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine, having the formula (I):
  • This compound is alternatively named (5)-4-(4-phenylphenylcarbonylamino)-5-oxo-5-(l,l- dimethyl-2-(4-fluorophenyl)-ethylamino)-pentanoic acid.
  • the invention provides polymorphs of N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-
  • polymorphs of Form A, Form B, Form C, Form E, Form F, Form G and pseudo Form A including crystalline polymorphs of Form A, Form B, Form C, Form E, Form F, Form G and pseudo Form A, and amorphous polymorph Form D.
  • the polymorph is a substantially pure polymorph of Form A, Form B, Form C, Form D, Form E, Form F, Form G, or pseudo Form A.
  • the polymorph has a powder X-ray diffraction pattern comprising peaks at diffraction angles (degrees 2 ⁇ ) of about 7.45, 8.01, 15.40, 17.67, 18.49, 19.71 and 20.44 (Form A); of about 6.32, 13.12, 21.01, 23.36, 24.23 and 26.02 (Form B); of about 6.41, 12.54, 14.34, 16.90, 17.80, 19.16, 23.93, 25.40 and 26.52 (Form C); of about 6.44, 12.59, 18.54, 19.09, 22.04 and 25.57 (Form E); of about 5.80, 6.24, 17.84, 18.50, 20.42 and 20.76 (Form F); of about 5.90, 11.50, 13.16, 17.84, 20.20, 21.20, 22.50, and 26.70 (Form G); or of about 7.45, 8.01, 15.17, 17.67, 18.49, 19.71 and 20.44 (pseudo Form A).
  • polymorph Form A has a powder X-ray diffraction pattern comprising peaks at diffraction angles (degrees 2 ⁇ ) of about 7.45, 8.01, 15.40, 17.67, 18.49, 19.71, 20.44, and 21.60.
  • polymorph Form C has a powder X-ray diffraction pattern comprising peaks at diffraction angles (degrees 2 ⁇ ) of about 6.41, 12.54, 14.34, 16.90, 17.80, 18.50, 19.16, 23.93, 25.40 and 26.52.
  • polymorph Form F has a powder X-ray diffraction pattern comprising peaks at diffraction angles (degrees 2 ⁇ ) of about 5.80, 6.24, 10.00, 13.00, 17.50, 18.00, 17.84, 18.50, 20.42 and 20.76.
  • polymorph Form G has a powder X-ray diffraction pattern comprising peaks at diffraction angles (degrees 2 ⁇ ) of about 5.90, 11.50, 12.50, 13.16, 17.84, 20.20, 21.20, 22.50, and 26.70.
  • the term "about" means the stated value ⁇ 0.2 degrees.
  • the polymorph has a powder X-ray diffraction pattern substantially as shown in Figure 1 (Form A), Figure 2 (Form B), Figure 3 (Form C), Figure 4, (Form E), Figure 5 (pseudo Form A), or Figure 27 (Form F, first trace from top; Form G, second trace from top).
  • the polymorph has a DSC extrapolated melting temperature onset of about 134°C (Form A), 83°C (Form B), 83-89°C (Form C), 80 0 C (Form E), 83°C (Form F), 83°C (Form G) or 138°C (pseudo Form A).
  • the invention also provides methods for the preparation of the crystalline polymorph of Form A, which comprises dissolving N 2 -(l, l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4- fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine in an organic solvent to form a solution and evaporating the organic solvent to form the crystalline polymorph which is a substantially pure polymorph of Form A.
  • the organic solvent is selected from: a mixture of ethyl acetate and heptane; toluene; isopropyl acetate; acetonitrile; a mixture of acetone and water; tert-butyl methyl ether; and a mixture of isopropyl acetate and heptane.
  • Crystalline polymorph Form A of N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)- l,l-dimethylethyl]-L- ⁇ -glutamine prepared by the methods of the invention is also provided by the invention.
  • the invention also provides methods for the preparation of the crystalline polymorph of Form B.
  • the methods comprise equilibrating a slurry of polymorphic Form A in ethanol and water, wherein the polymorph Form A is converted to polymorph Form B, and isolating the crystalline polymorph Form B.
  • the methods comprise stirring a suspension of polymorph Form A in 2% Tween 80 at about 20-25°C for about 0.5 hr, wherein the polymorph Form A is converted to polymorph Form B, and isolating the crystalline polymorph Form B.
  • the methods comprise stirring a suspension of polymorph Form A in water at about 20-25 °C for about 12- 24 hr, wherein the polymorph Form A is converted to polymorph Form B, and isolating the crystalline polymorph Form B.
  • the methods comprise crystallizing polymorph Form B from a mixture of N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4- fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine in ethanol and water, ethanol and heptane(s), or isopropanol and water, and isolating the crystalline polymorph Form B.
  • Crystalline polymorph Form B of N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)- l,l-dimethylethyl]-L- ⁇ -glutamine prepared by the methods of the invention is also provided by the invention.
  • the invention also provides methods for the preparation of the crystalline polymorph of Form C.
  • the methods comprise equilibrating a slurry of polymorphic Form A in ethanol and water, wherein the polymorph Form A is converted to polymorph Form C, and isolating the crystalline polymorph Form C.
  • the methods comprise equilibrating a slurry of N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4- fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine in ethanol and water, and isolating the crystalline polymorph Form C.
  • Crystalline polymorph Form C of N 2 -(l,l'-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine prepared by the methods of the invention is also provided by the invention.
  • the invention also provides methods for the preparation of the polymorph of
  • the methods comprise equilibrating a slurry of polymorphic Form A in acetone and water, wherein the polymorph Form A is converted to polymorph Form D, and isolating the amorphous polymorph Form D.
  • the methods comprise equilibrating a slurry of N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4- fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine in acetone and water, and isolating the amorphous polymorph Form D.
  • Amorphous polymorph Form D of N 2 -(l,l'-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine prepared by the methods of the invention is also provided by the invention.
  • the invention also provides methods for the preparation of the crystalline polymorph of Form E.
  • the methods comprise equilibrating a slurry of polymorphic Form A in isopropyl alcohol (IPA) and water, wherein the polymorph Form A is converted to polymorph Form E, and isolating the crystalline polymorph Form E.
  • the methods comprise equilibrating a slurry of N -(l,l'-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine in IPA and water, and isolating the crystalline polymorph Form E.
  • Crystalline polymorph Form E of N 2 -(l,l'- biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine prepared by the methods of the invention is also provided by the invention.
  • the invention also provides methods for the preparation of the crystalline polymorph of Form F, which comprises equilibrating a slurry of N 2 -(l,l'-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine in ethanol at about 50°C, and isolating the crystalline polymorph Form F.
  • Crystalline polymorph Form F of N 2 - (1,1 l -biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)- 1 , 1 -dimethylethyl]-L- ⁇ -glutamine prepared by the methods of the invention is also provided by the invention.
  • the invention also provides methods for the preparation of the crystalline polymorph of Form G, which comprises equilibrating a slurry of N 2 -(l,l'-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine in ethanol and water at about 20-25°C, and isolating the crystalline polymorph Form G.
  • Crystalline polymorph Form G of N 2 -( 1 , 1 '-biphenyM-ylcarbonyO-N 1 - [2-(4-fluorophenyl)- 1 , 1 -dimethylethyl] -L- ⁇ - glutamine prepared by the methods of the invention is also provided by the invention.
  • the invention also provides methods for the preparation of the crystalline polymorph of pseudo Form A, which comprises dissolving N 2 -(l,l'-biphenyl-4-ylcarbonyl)- N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine in an organic solvent to form a solution and evaporating the organic solvent to form the crystalline polymorph which is a substantially pure polymorph of pseudo Form A.
  • the organic solvent is selected from: a mixture of ethyl acetate and heptane; toluene; isopropyl acetate; acetonitrile; a mixture of acetone and water; tert-butyl methyl ether; and a mixture of isopropyl acetate and heptane.
  • Crystalline polymorph pseudo Form A of N 2 -(l,l'-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine prepared by the methods of the invention is also provided by the invention.
  • Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice.
  • Amorphous solids consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice.
  • Solvates are crystalline solid adducts containing either stoichiometric or nonstoichiometric amounts of a solvent incorporated within the crystal structure. If the incorporated solvent is water, the solvates are also commonly known as hydrates.
  • polymorphs refer to different polymorphic forms of the same compound and includes, but is not limited to, other solid state molecular forms including solvation products and amorphous forms of the same compound.
  • the term “polymorph” refers to any one such form.
  • Different polymorphs of a given compound may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, crystal shape, compaction behavior, flow properties, and/or solid state stability.
  • Unstable polymorphs generally convert to the more thermodynamically stable forms at a given temperature after a sufficient period of time. Metastable forms are unstable polymorphs that slowly convert to stable forms.
  • a metastable pharmaceutical solid form can change crystalline structure or solvate/desolvate in response to changes in environmental conditions, processing, or over time.
  • the stable form exhibits the highest melting point and the most chemical stability; however, metastable forms may also have sufficient chemical and physical stability to render them pharmaceutically acceptable.
  • Chemical stability refers to stability in chemical properties, such as thermal stability, light stability, and moisture stability.
  • the different polymorphs of compound (I) include: Polymorph Form A, a higher melting point form and anhydrous; Polymorph Form B, a lower melting point form and a monohydrate; Polymorph Form C, a lower melting point form and a sesquihydrate; a pseudo Form A, and Polymorph Forms D, E, F, and G. It has been surprisingly found that the higher melting point Form A is less stable than lower melting point Form B. [0075] Except as otherwise indicated, the term "about" modifying a value means the nominal value ⁇ 3%.
  • the polymorph forms of the invention are preferentially substantially pure, meaning each form contains less than 15%, preferably less than 10%, preferably less than 5%, preferably less than 1% by weight of impurities, including other polymorphic forms of compound (I).
  • Some embodiments provided by the invention are compositions wherein at least 50% by weight of the total of N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)- l,l-dimethylethyl]-L- ⁇ -glutamine in the composition is present as the crystalline polymorph.
  • At least 70%, at least 80%, or at least 90% by weight of the total of N 2 -( 1 , 1 '-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)- 1 , 1 -dimethylethyl] -L- ⁇ -glutamine in the composition is present as the crystalline polymorph.
  • compositions consisting essentially ofN 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4- fluoropheny I)- 1,1 -dimethylethyl] -L- ⁇ -glutamine wherein at least 97-99% by weight of the N 2 -( 1 , 1 '-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)- 1 , 1 -dimethylethyl] -L- ⁇ -glutamine is present in the composition as the crystalline polymorph.
  • the polymorph forms of the invention can also be present in mixtures.
  • the invention further provides compositions comprising N 2 -(l,l'-biphenyl-4- ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine of polymorph Form A, Form B, Form C, Form D, Form E, Form F, Form G or pseudo Form A, and a pharmaceutically acceptable carrier.
  • At least 50% by weight of the total of N 2 -(l , 1 l -biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)- 1, 1 -dimethylethyl]-L- ⁇ - glutamine in the composition is present as the polymorph.
  • at least 70%, at least 80%, or at least 90% by weight of the total of N 2 -(l,l'-biphenyl-4-ylcarbonyl)- N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine in the composition is present as the polymorph.
  • compositions consisting essentially of N 2 - (l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine of polymorph Form A, Form B, Form C, Form D, Form E, Form F, Form G or pseudo Form A, and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is suitable for oral administration and the composition comprises an oral dosage form.
  • X-ray powder diffraction patterns of solid phases were recorded with a Scintag Advanced Diffraction System X2 using Cu KR radiation, a tube voltage of 45 kV, and a tube current of 40 mA. The intensities were measured from 3° to 45° at a continuous scan rate of 4.5°/min.
  • N 2 -(l, l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)- l,l-dimethylethyl]-L- ⁇ -glutamine also differ in their DSC (differential scanning calorimetry) onset of melting temperatures, as determined by a Shimadzu D50 instrument, at a scan rate of 10 0 C per minute. Depending on the rate of heating, i.e.
  • the endotherms of the polymorphs may vary by about 0.01-10 0 C, or about 0-5 0 C, above or below the determined endotherms. The observed endotherm may also differ from instrument to instrument for any given sample.
  • the crystalline polymorph of Form B has a DSC extrapolated melting temperature onset of about 80-89°C, or about 134-138°C.
  • Figures 6-10 show DSC thermograms for the various polymorphic forms.
  • Polymorphs of the invention may be obtained by crystallization from a solution or slurry of compound (I), with each polymorph resulting by crystallization from a different crystallization solvent.
  • a crystallization solvent refers to a solvent or combination of solvents used to crystallize a polymorph of compound (I) to preferentially form the substantially pure polymorph form.
  • the crystallization solvent can be seeded with one or more crystals of a particular polymorph in order to promote formation of that particular crystal in the crystallization solvent.
  • Polymorphs of the invention may also be obtained by recrystallization from a solution or slurry containing a different form of the polymorph.
  • polymorph Form B can be obtained by recrystallizing polymorph Form A in an appropriate solvent.
  • a polymorph of the invention may be formulated as a pharmaceutical composition.
  • Pharmaceutical compositions of the invention comprise a polymorph and a pharmaceutically acceptable carrier, wherein the polymorph is present in the composition in an amount that is effective to treat the condition of interest.
  • concentration of the compounds described herein in a therapeutic composition will vary depending upon a number of factors, including the dosage of the drug to be administered and the route of administration. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
  • Pharmaceutically acceptable carriers are familiar to those skilled in the art.
  • compositions can be formulated as liquid solutions, and include carriers such as saline and sterile water.
  • the compositions can also be formulated as pills, capsules, granules, or tablets which contain the polymorph along with diluents, dispersing and surface active agents, binders, and lubricants.
  • One skilled in the art may formulate the compositions in an appropriate manner, and in accordance with accepted practices, such as those described in Remington: The Science and Practice of Pharmacy, 20th edition, Alfonso R. Gennaro (ed.), Lippincott Williams & Wilkins, Baltimore, MD (2000).
  • the invention also provides methods of inhibiting the activity of a metalloproteinase.
  • the metalloproteinase can be, for example, a matrix metalloproteinase or an aggrecanase, such as aggrecanase- 1 or aggrecanase-2.
  • the invention further provides methods of treating metalloproteinase-related disorders, such as arthritic disorders, osteoarthritis, cancer, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, atherosclerosis, age-related macular degeneration, myocardial infarction, corneal ulceration and other ocular surface diseases, hepatitis, aortic aneurysms, tendonitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft versus host disease, diabetes, inflammatory bowel disease, shock, invertebral disc degeneration, stroke, osteopenia, and periodontal diseases.
  • metalloproteinase-related disorders such as arthritic disorders, osteoarthritis, cancer, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, atherosclerosis, age-related macular degeneration, myocardial infar
  • a pharmaceutical composition comprising a polymorph of compound (I).
  • the animal is a mammal, e.g., a mouse, rat, sheep, pig, cow, monkey or human.
  • the mammal is a human.
  • the methods of the invention include systemic administration of a polymorph as disclosed herein, preferably in the form of a pharmaceutical composition.
  • systemic administration includes both oral and parenteral methods of administration.
  • suitable compositions include powders, granules, pills, tablets and capsules as well as liquids, syrups, suspensions and emulsions.
  • compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives.
  • the compounds of the present invention can be prepared in aqueous injection solutions that may contain buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions.
  • pharmaceutically acceptable carriers and the manufacture of compositions containing N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4- fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine and one or more such carriers methods of administration, determination of effective doses and the like, reference is made to U.S.
  • the polymorphs of the invention may be synthesized in according with the following non-limiting examples, which are illustrative.
  • Fmoc-L-Glu-(OtBu)-OH hydrate was combined with toluene. The mixture was stirred and concentrated. After cooling, 2-(4-Fluorophenyl)-l,l-dimethylethylamine hydrochloride, isobutyl chloroformate, and 4-methylmorpholine were added and stirred. The mixture was heated, combined with water and the organic phase was separated. The organic phase was mixed with diethylamine, stirred and concentrated. Heptane(s), hydrochloric acid and water were added and the aqueous phase separated. The aqueous phase was extracted with a mixture of toluene and heptane(s) and further extractions with a mixture of toluene and heptane(s) may be repeated as needed.
  • the aqueous phase was combined with tert-butyl methyl ether and aqueous potassium carbonate, stirred and the organic phase separated. Optionally, the aqueous phase was back extracted with tert-butyl methyl ether. Organic phases were combined and washed with brine to give a solution of 4-Amino-4-[2-(4-fluorophenyl)-l,l- dimethylethylcarbamoyl]butyric acid tert-butyl ester in tert-butyl methyl ether. Or, the organic phase was dried over anhydrous magnesium sulfate and filtered.
  • the solid product was mixed with toluene, stirred and cooled. Trifluoroacetic acid was added and the mixture was heated. The mixture was cooled, concentrated, mixed with aqueous potassium acetate, tetrahydrofuran or ethyl acetate and the organic phase separated. The organic phase was combined with aqueous potassium acetate and water and the organic phase separated. THF or ethyl acetate was added as needed.
  • the organic phase was clarified as needed, then combined with heptane(s) to precipitate N 2 -( 1 , 1 '-biphenyl-4-ylcarbonyl)-N 1 - [2-(4-fluorophenyl)- 1 , 1 -dimethylethyl]-L- ⁇ - glutamine.
  • the organic phase was concentrated, diluted with toluene, filtered, washed and dried to give N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l- dimethylethyl]-L- ⁇ -glutamine.
  • Anhydrous polymorph Form A was formed by dissolving the starting material compound (I) in an organic solvent to form a solution and evaporating the organic solvent to form the crystalline polymorph.
  • the organic solvent can be a mixture of ethyl acetate (EtAc) and heptane; toluene; isopropyl acetate (IPAc); acetonitrile; a mixture of acetone and water; tert-butyl methyl ether; or a mixture of isopropyl acetate and heptane.
  • Polymorph Form B can be formed by crystallization from a mixture in ethanol and water, in ethanol and heptane(s), or isopropanol and water.
  • N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l- dimethylethyl]-L- ⁇ -glutamine was combined with ethanol, stirred and heated (if needed).
  • Example 4 Polymorphic conversion study of polymorph Form A to polymorph Form B in various aqueous media
  • Sample preparation (1) Sample A, starting from a Sample E containing polymorph pseudo Form A, stirred in 100 mg/mL in 2% Tween80, solidified to a paste in about 30 minutes, was washed and centrifuged (3 times), then vacuum dried.
  • Sample B starting from a Sample E containing polymorph pseudo Form A, stirred in 100 mg/mL in water, solidified to a paste after overnight stirring, and was then vacuum dried.
  • Sample D in 2% Tween 80 or water. Although containing the same polymorph Form A as determined by XRD, Sample D is more stable in aqueous conditions compared to Sample E (Table 2).
  • Polymorph pseudo Form A was obtained from a scaled up preparation of polymorph Form A (Sample E). Polymorphic conversions of unstable pseudo Form A to Form B were observed with Sample E. Polymorphic conversions occurred in water (Sample B) and in 2% Tween 80 (Sample A) suspensions as evidenced by changes in XRD patterns and DSC endotherms ( Figure 11).
  • Example 5 Polymorph screening using Tox formulation stability as the primary endpoint
  • Sample E was initially produced as anhydrous Form A by evaporative crystallization from ethyl acetate (EtAc)/heptane without seeding. In order to generate more polymorphic forms, Sample E was slurried in nine different solvents, producing a total of nine 1-g scale batches and one 10-g scale batch. The detailed solvent crystallization information is summarized in Table 3.
  • Table 6 summarizes various solid-state properties of samples used in toxicological formulation assessments.
  • the material with XRD pattern B from the ethanol/water system was characterized as polymorph Form B.
  • Sample E containing polymorph pseudo Form A, was reworked to yield Sample F, containing stable polymorph Form B.
  • the first crop of the reworked Sample E contained more than one mole equivalent of water and was characterized as a sesquihydrate (polymorph Form C), which was subsequently dried to the stoichiometric moisture content of 3.54% for the monohydrate Form B.
  • Table 7 summarizes various properties of the polymorphs of the invention.
  • the monohydrate polymorph Form B starts to dehydrate around 83°C by DSC and TGA (thermal gravimetric) analysis. It is completely dehydrated by ⁇ 110 0 C. As shown by hot stage microscopy, the material dehydrates with collapse of the crystal lattice starting at 89°C, and re-crystallizes as needle-like crystals around 100 0 C ( Figure 14).
  • Polymorph Form B (Sample F) was stressed with vacuum drying at 40 0 C.
  • the monohydrate (polymorph Form B) can be produced from the sesquihydrate (polymorph Form C) using a vacuum oven and has sufficient heat stability for at least 3 months at 40 0 CIl 5% RH (relative humidity). Conversion to the anhydrate will not occur until about 80 0 C.
  • Sample F was subject to Dynamic Vapor Sorption (DVS) analysis at room temperature.
  • the sample was first analyzed by Karl Fischer (KF) titration containing initial moisture content of 3.7% for the monohydrate form.
  • RH cycling started at 50% relative humidity (RH) to 100% RH and down to 0% RH and then back up to 100% RH.
  • RH cycling started at 50% relative humidity (RH) to 100% RH and down to 0% RH and then back up to 100% RH.
  • RH cycling 50% relative humidity (RH) to 100% RH and down to 0% RH and then back up to 100% RH.
  • a 3- hour/step equilibration period was found insufficient, so the run was repeated with a 6-hour period, which was still not sufficient.
  • the DVS moisture sorption isotherm using the 6-hour equilibration period is presented in Figure 17.
  • the DVS scan showed hysteresis with two relatively stable Forms: the Form B monohydrate, stable from 0-50%RH and the Form C sesquihydrate, stable from 30-100% RH.
  • an equilibrium moisture study using desiccators containing saturated salt solutions for humidity control was performed.
  • Sample F was incubated at 0%, 15%, 31%, 66%, 87%, and 100% RH in room temperature for up to 20 days.
  • Samples were periodically assayed by KF titration to give the kinetic profiles.
  • XRD analysis was performed at the end of 20 days. The data is summarized in Table 8 with kinetic and equilibrium data plotted in Figures 18 and 19.
  • XRD data indicated the presence of the monohydrate at 0-47% RH and the sesquihydrate at 66-100% RH, which is consistent with DVS data.
  • the kinetic data showed significant moisture pickup at 66-100% RH within the first day.
  • the monohydrate did lose some water after 20 days at 0% RH (2.78%) and gained some water at 47% RH (4.19%). There was no moisture content plateau for the sesquihydrate.
  • Sample D containing anhydrous polymorph Form A demonstrated chemical stability after 14-day storage at room temperature, in temperatures up to 80 0 C, and in a light box (510 fc).
  • Sample F containing polymorph Form B was further investigated at 40°C/75% RH using open and closed vials for 3 months.
  • the monohydrate was also found to be chemically stable, but exhibited polymorphic conversion from Form B to Form C, as shown by DSC and XRD analysis, after 1 -month storage at 40°C/75% RH. Water content after 1- month storage at 40°C/75% RH also increased to 5.4%. Therefore, the monohydrate needs to be stored in hermetically sealed containers in order to prevent conversion to the sesquihydrate.
  • Data collected after 2 months of storage at 40°C/75% RH is summarized in Table 9.
  • N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4- fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine was solubilized at 387 ⁇ g/mL with 25% acetonitrile in acid, base, peroxide and water under heat and light stress conditions. The results indicate that the compound is subject to acid and peroxide degradation.
  • the acid degradation mechanism is hydrolysis of the two amide bonds.
  • N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine is an acid with a pKa of 5.3 as measured from a pH solubility profile.
  • the pH solubility profile was generated first with Sample D containing polymorph Form A, and then with Sample F containing polymorph Form B, in HCl/NaOH solutions. After 24 hour equilibration, suspensions were centrifuged and the supernatants assayed by HPLC. The samples were not filtered since there is significant compound loss due to filter binding.
  • the pH-solubility profile is presented Figure 22.
  • solubility at pH ⁇ 4 is -4.5 ug/mL for Sample D but below the HPLC detection limit of 11 ng/mL for Sample F. Above pH 4, solubility increases with increasing pH for both batches. At pH 12.8, the solubility is 4.7 mg/mL, which represents the solubility of the sodium salt.
  • Solubility S 0 -[10 (pH - pKB) + 1], where So is the intrinsic solubility of the free acid.
  • a pKa value of 5.3 was determined via nonlinear regression analysis using the computer program, SigmaPlus. The curve fitting results are shown in Table 10.
  • the measured pKa of 5.3 is lower than the calculated pKa value of 4.4 from the computdrugp& ⁇ /c program based on the Hammett and Taft equation. It is theorized that the steric shielding from the two aromatic ring systems may reduce the acidity of the carboxylic group.
  • propranolol which has a permeability that is not as high as metoprolol
  • the FDA calibration compound was used as the FDA calibration compound.
  • the apical pH was controlled at 6 and basolateral pH at pH 7.
  • verapamil was used as a competitive inhibitor of the Pgp (P-glycoprotein) transporter.
  • the ratios to propranolol were 1.00 and 0.77 with and without verapamil. Since verapamil did not enhance compound permeability, Pgp is not involved. The two values were averaged to give a mean ratio of 0.88, indicating low permeability.
  • the B— »A/A— >B ratios were low at 0.3 and 0.3, with and without verapamil, respectively, indicating again no efflux but active transport.
  • N 2 -(l,l'-biphenyl-4-ylcarbonyl)-N 1 -[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- ⁇ -glutamine showed high permeability in the in situ rat perfusion model.
  • the permeability was 18.2 nm/sec, which is higher than the 14.5 nm/sec value obtained for metoprolol (Table 13).
  • Table 13 Rat Perfusion study using Metoprolol as Reference
  • Metoprolol Compound (I) Ratio to Metoprolol 20 ⁇ g/mL 20 ⁇ g/mL
  • Polymorph Form C was formed by crystallization from a slurry in ethanol and water.
  • Form C are shown in Figures 23 and 24, respectively.
  • Polymorph Form D was formed by crystallization from a slurry in acetone and water.
  • Example 10 Preparation of polymorph Form E
  • Polymorph Form E was formed by crystallization from a slurry in isopropyl alcohol (IPA) and water.
  • Polymorph Form F was formed by crystallization from a slurry in ethanol at about 5O 0 C.
  • Polymorph Form G was formed by crystallization from a slurry in ethanol and water at about 20-25 0 C.
  • Example 13 Solubility of N 2 -(l.r-biphenyl-4-ylcarbonyl)-N 1 -r2-(;4-fluorophenyl)-l.l- dimethylethyli-L- ⁇ -glutamine
  • Sample 7 was prepared by slow cooling in an attempt to increase the crystallinity. However, the solution did not crystallize even cooled to room temperature. Crystallization occurred after stirring for overnight. The final product contained mostly low crystalline material with a very small amount of higher melting point form which is shown in the DSC profile ( Figure 25). Table 16. Anti-solvent addition crystallization
  • Sample 11 was prepared by a process of slow anti-solvent addition in an attempt to increase crystallinity. Sample 11 did show improved crystallinity over fast water addition, as shown with Sample 9. XRD patterns of the two Samples are shown in Figure 26.
  • Samples prepared from anti-solvent addition of IPA and water (Sample 11), a slurry of ethanol and water (Sample 21), and a slurry in ethanol at 50 0 C (Sample 25) were analyzed by GC (gas chromatography) to detect residue solvent to determine the cause of weight loss observed in the TGA experiments. There was no detectable amount of solvent found in all three samples.
  • Polymorph pseudo Form A was formed by dissolving the starting material compound (I) in an organic solvent to form a solution and evaporating the organic solvent to form the crystalline polymorph.
  • the organic solvent can be a mixture of ethyl acetate (EtAc) and heptane; toluene; isopropyl acetate (IPAc); acetonitrile; a mixture of acetone and water; tert-butyl methyl ether; or a mixture of isopropyl acetate and heptane.
  • EtAc ethyl acetate
  • IPAc isopropyl acetate
  • Example 16 Characterization of polymorph pseudo Form A

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Abstract

L'invention concerne de nouvelles formes polymorphes de la N2-(1,1'-biphényl-4-ylcarbonyl)-N1-[2-(4-fluorophényl)-1,1-diméthyléthyl]-L-α-glutamine, des procédés de préparation des formes polymorphes, des compositions contenant les formes polymorphes et des procédés de traitement utilisant les formes polymorphes.
EP07864234A 2006-11-09 2007-11-09 Polymorphes de la n²-(1,1'-biphényl-4-ylcarbonyl)-n¹[2-(4-fluorophényl)-1,1-diméthyléthyl]-l-alpha-glutamine Withdrawn EP2089012A2 (fr)

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US85779206P 2006-11-09 2006-11-09
US85779106P 2006-11-09 2006-11-09
US85779406P 2006-11-09 2006-11-09
PCT/US2007/084314 WO2008058278A2 (fr) 2006-11-09 2007-11-09 Polymorphes de la n2-(1,1'-biphényl-4-ylcarbonyl)-n1-[2-(4-fluorophényl)-1,1-diméthyléthyl]-l-α-glutamine

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