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WO2009091594A1 - Formes cristallines de lestaurtinib - Google Patents

Formes cristallines de lestaurtinib Download PDF

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Publication number
WO2009091594A1
WO2009091594A1 PCT/US2009/000312 US2009000312W WO2009091594A1 WO 2009091594 A1 WO2009091594 A1 WO 2009091594A1 US 2009000312 W US2009000312 W US 2009000312W WO 2009091594 A1 WO2009091594 A1 WO 2009091594A1
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WO
WIPO (PCT)
Prior art keywords
lestaurtinib
crystalline form
solvate
theta
group
Prior art date
Application number
PCT/US2009/000312
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English (en)
Inventor
Stephen Bierlmaier
Raymond Scott Field
R. Curtis Haltiwanger
Martin J. Jacobs
Robert E. Mckean
Mehran Yazdanian
Laurent Courvoisier
Original Assignee
Cephalon, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from TW097151909A external-priority patent/TW200936596A/zh
Application filed by Cephalon, Inc. filed Critical Cephalon, Inc.
Publication of WO2009091594A1 publication Critical patent/WO2009091594A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention pertains to lestaurtinib-containing compositions, pharmaceutical compositions comprising lestaurtinib, processes to reproducibly make them and methods of treating patients using them.
  • APIs Active pharmaceutical ingredients in pharmaceutical compositions can be prepared in a variety of different forms.
  • Such APIs can be prepared so as to have a variety of different chemical forms, including but not limited to chemical derivatives, solvates, hydrates, hemihydrates, co-crystals, anhydrous forms or salts.
  • Such APIs can also be prepared to have different physical forms.
  • the APIs may be amorphous, may have different crystalline polymorphs, or may exist in different solvation or hydration states.
  • crystalline polymorphs typically have different solubilities, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph.
  • Pharmaceutical polymorphs can also differ in properties such as shelf-life, bioavailability, morphology, vapor pressure, density, color, and compressibility. Accordingly, variation of the crystalline state of an API is one of many ways in which to modulate the physical properties thereof.
  • Lestaurtinib is a semi-synthetic, orally bioavailable receptor-tyrosine kinase inhibitor that has been shown to have therapeutic utility in treating diseases such as acute myeloid leukemia, chronic myeloid leukemia and acute lymphocytic leukemia. It is a synthetic derivative of K-252a, a fermentation product of Nonomurea longicatena, and belongs to a class of indolocarbazole alkaloids. Lestaurtinib, (CAS Registry No. 111358-88- 4), also known as (9S-(9 ⁇ ,10 ⁇ ,12 ⁇ ))-2,3,9,10,l 1,12-hexahydro-lO-hydroxy-lO-
  • Different chemical forms of lestaurtinib can have different melting points, solubilities or rates of dissolution, which physical properties, either alone or in combination, can affect its bioavailability. Because knowledge of alternative chemical forms of lestaurtinib can provide guidance during clinical development, there is an existing need for identification of different and potentially improved forms of lestaurtinib, processes to reproducibly make them and methods of treating patients using them.
  • the present invention pertains to a co-crystal comprising lestaurtinib and a second component selected from the group consisting of maleic acid, malonic acid, oxalic acid, glutaric acid, hippuric acid and urea.
  • the co-crystal comprises lestaurtinib and maleic acid, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 7.56, 8.19, 16.47, 25.90 and 26.70 degrees 2- theta.
  • the co-crystal comprises lestaurtinib and malonic acid, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 7.99, 15.16, 16.04, 26.11 and 27.17 degrees 2- theta.
  • the co-crystal comprises lestaurtinib and oxalic acid, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 6.18, 7.44, 14.96, 20.19 and 25.78 degrees 2- theta.
  • the co-crystal comprises lestaurtinib and glutaric acid, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 14.10, 14.60, 25.12, 25.56 and 26.55 degrees 2-theta.
  • the co-crystal comprises lestaurtinib and hippuric acid, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 6.77, 14.23, 18.44, 20.61 and 25.19 degrees 2- theta.
  • the co-crystal comprises lestaurtinib and urea, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 14.63, 22.24, 25.19, 25.86 and 26.56 degrees 2-theta.
  • the present invention pertains to to a co-crystal comprising lestaurtinib and a second component selected from the group consisting of maleic acid, malonic acid, oxalic acid, glutaric acid, hippuric acid and urea for use as a pharmaceutical composition, comprising said co-crystal and one or more pharmaceutically acceptable excipients, diluents or carriers.
  • the present invention pertains to a pharmaceutical composition
  • a pharmaceutical composition comprising Lestaurtinib Crystalline Form VI, Lestaurtinib Crystalline Form VII, Lestaurtinib Crystalline Form VIII, Lestaurtinib Crystalline Form IX, Lestaurtinib Crystalline Form X, Lestaurtinib Crystalline Form XI, Lestaurtinib Crystalline Form XII, Lestaurtinib Crystalline Form XIV, Lestaurtinib Crystalline Form XV, Lestaurtinib Crystalline Form XVI, Lestaurtinib Crystalline Form XX, Lestaurtinib Crystalline Form XXI, Lestaurtinib Crystalline Form XII, Lestaurtinib Crystalline Form XXIII, Lestaurtinib Crystalline Form XXIV, Lestaurtinib Crystalline Form XX
  • the lestaurtinib is Lestaurtinib Crystalline Form VI. In another aspect, the lestaurtinib is Lestaurtinib Crystalline Form VII. In another aspect, the lestaurtinib is Lestaurtinib Crystalline Form VIII. In another aspect, the lestaurtinib is Lestaurtinib Crystalline Form IX. In another aspect, the lestaurtinib is Lestaurtinib Crystalline Form X. In another aspect, the lestaurtinib is Lestaurtinib Crystalline Form XI.
  • the lestaurtinib is Lestaurtinib Crystalline Form XII. In another aspect, the lestaurtinib is Lestaurtinib Crystalline Form XIV. In another aspect, the lestaurtinib is Lestaurtinib Crystalline Form XV. In another aspect, the lestaurtinib is Lestaurtinib Crystalline Form XVI. In another aspect, the Lestaurtinib is Lestaurtinib Crystalline Form XX. In another aspect, the lestaurtinib is Lestaurtinib Crystalline Form XI.
  • the lestaurtinib is Lestaurtinib Crystalline Form XXII. In another aspect, the lestaurtinib is Lestaurtinib Crystalline Form XXIII. In another aspect, the lestaurtinib is Lestaurtinib Crystalline Form XXIV. In another aspect, the lestaurtinib is Lestaurtinib Crystalline Form XXV. In another aspect, the lestaurtinib is Lestaurtinib Crystalline Form XXVI. In another aspect, the lestaurtinib is Lestaurtinib Crystalline Form XXVII. In another aspect, the lestaurtinib is Lestaurtinib Crystalline Form XXVIII.
  • the present invention pertains to a pharmaceutical composition
  • a pharmaceutical composition comprising Lestaurtinib Crystalline Form VI, Lestaurtinib Crystalline Form VII, Lestaurtinib Crystalline Form VIII, Lestaurtinib Crystalline Form IX, Lestaurtinib Crystalline Form X, Lestaurtinib Crystalline Form XI, Lestaurtinib Crystalline Form XII, Lestaurtinib Crystalline Form XIV, Lestaurtinib Crystalline Form XV, Lestaurtinib Crystalline Form XVI, Lestaurtinib Crystalline Form XX, Lestaurtinib Crystalline Form XXI, Lestaurtinib Crystalline Form XII, Lestaurtinib Crystalline Form XXIII, Lestaurtinib Crystalline Form XXIV, Lestaurtinib Crystalline Form XX
  • Another aspect of the present invention pertains to a solvate form of lestaurtinib that is Crystalline Form VI, Crystalline Form VII, Crystalline Form VIII, Crystalline Form IX, Crystalline Form X, Crystalline Form XI, Crystalline Form XII, Crystalline Form XIV, Crystalline Form XV, Crystalline Form XVI, Crystalline Form XX, Crystalline Form XXI, Crystalline Form XXII, Crystalline Form XXIII, Crystalline Form XXIV, Crystalline Form XXV, Crystalline Form XXVI, Crystalline Form XXVII, Crystalline Form XXVIII, or a mixture thereof.
  • the solvate is Crystalline Form VI, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 14.23, 17.69, 25.79, 26.59 and 27.12 degrees 2-theta.
  • the solvate is Crystalline Form VII, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 7.58, 17.75, 17.96, 21.48 and 22.08 degrees 2-theta.
  • the solvate is Crystalline form VIII, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 7.70, 11.94, 12.05, 17.11, 17.62 and 18.05 degrees 2-theta.
  • the solvate is Crystalline Form IX, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 7.79, 12.11, 15.55, 17.83 and 21.50 degrees 2-theta.
  • the solvate is Crystalline Form X, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 7.69, 11.99, 15.46, 17.79 and 17.96 degrees 2-theta.
  • the solvate is Crystalline Form XI, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 6.71, 14.44, 25.61, 26.51 and 27.80 degrees 2-theta.
  • the solvate is Crystalline Form XII, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 7.15, 18.18, 18.77, 21.27 and 24.98 degrees 2-theta.
  • the solvate is Crystalline Form XIV, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 7.75, 13.19, 14.21, 14.67, 17.55 and 25.13 degrees 2-theta.
  • the solvate is Crystalline Form XV, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 11.05, 13.91, 17.04, 17.09 and 25.59 degrees 2-theta.
  • the solvate is Crystalline Form XVI, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 8.12, 8.18, 10.31, 10.37 and 17.49 degrees 2-theta.
  • the solvate is Crystalline Form XX, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 7.73, 15.46, 17.95, 18.07 and 22.06 degrees 2-theta.
  • the solvate is Crystalline Form XXI, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 7.74, 12.19, 15.48, 18.18 and 22.27 degrees 2-theta.
  • the solvate is Crystalline Form XXII, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 1 1.04, 13.60, 15.74, 17.04, 25.58 degrees 2-theta.
  • the solvate is Crystalline Form XXIII, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 7.03, 14.06, 14.61, 15.04 and 26.31 degrees 2-theta.
  • the solvate is Crystalline Form XXIV, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 7.66, 14.40, 14.54, 14.78 and 25.32 degrees 2-theta.
  • the solvate is Crystalline Form XXV, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 5.52, 8.35, 10.88, 11.51 and 16.28 degrees 2-theta.
  • the solvate is Crystalline Form XXVI, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 7.14, 13.00, 14.27, 16.58, 18.02 and 19.94 degrees 2-theta.
  • the solvate is Crystalline Form XXVII, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 7.63, 9.80, 12.35, 15.27 and 21.93 degrees 2-theta.
  • the solvate is Crystalline Form XXVIII, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 9.86, 13.95, 18.52, 19.76 and 25.43 degrees 2-theta.
  • An additional aspect of the present invention pertains to a pharmaceutical composition
  • a pharmaceutical composition comprising Lestaurtinib Crystalline Form XVII, Lestaurtinib Crystalline Form XVIII, Lestaurtinib Crystalline Form XIX, or a mixture thereof.
  • the lestaurtinib is Lestaurtinib Crystalline Form XVII. In another aspect, the lestaurtinib is Lestaurtinib Crystalline Form XVIII. In another aspect, the lestaurtinib is Lestaurtinib Crystalline Form XIX.
  • the present invention pertains to a pharmaceutical composition
  • a pharmaceutical composition comprising Lestaurtinib Crystalline Form XVII, Lestaurtinib Crystalline Form XVIII, Lestaurtinib Crystalline Form XIX, or a mixture thereof, further comprising amorphous lestaurtinib.
  • the present invention pertains to a crystalline anhydrate form of lestaurtinib that is Crystalline Form XVII, Crystalline Form XVIII, Crystalline Form XIX, or a mixture thereof.
  • the crystalline anhydrate is Crystalline Form XVII, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 7.90, 15.76, 19.63, 19.70 and 20.07 degrees 2- theta.
  • the crystalline anhydrate is Crystalline Form XVIII, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 7.76, 13.13, 15.64, 19.53 and 19.95 degrees 2- theta.
  • the crystalline anhydrate is Crystalline Form XIX, and is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 9.61, 11.07, 15.71, 17.07 and 18.39 degrees 2- theta ⁇
  • the present invention pertains to a pharmaceutical composition comprising Lestaurtinib Crystalline Form XIII. In another aspect, the present invention pertains to a pharmaceutical composition comprising Lestaurtinib Crystalline Form XIII, further comprising amorphous lestaurtinib.
  • the present invention pertains to a crystalline hemihydrate of lestaurtinib that is Crystalline Form XIII.
  • the crystalline hemihydrate is characterized by a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of about 6.89, 14.26, 14.73, 16.95 and 17.58 degrees 2- theta.
  • the present invention pertains to a method of treating leukemia, comprising administering to a patient in need thereof a therapeutically effective amount of a preparation prepared from a composition according to any one of the foregoing forms.
  • the leukemia is selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and chronic lymphocytic leukemia.
  • FIG. 1 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib free base
  • FIG.2 is a 1 H Nuclear Magnetic Resonance (NMR) spectrum for lestaurtinib free base
  • FIG. 3 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo-Gravimetric Analysis (TGA) Thermogram overlay of lestaurtinib free base;
  • DSC Differential Scanning Calorimetry
  • TGA Thermo-Gravimetric Analysis
  • FIG. 4 is an X-ray Powder Diffractogram (XRPD) of the lestaurtinib:maleic acid co- crystal;
  • FIG. 5 is a 1 H Nuclear Magnetic Resonance (NMR) spectrum for the lestaurtinib:maleic acid co-crystal
  • FIG. 6 is an X-ray Powder Diffractogram (XRPD) of the lestaurtinib:malonic acid co- crystal
  • FIG. 7 is a 1 H Nuclear Magnetic Resonance (NMR) spectrum for the lestaurtinib:malonic acid co-crystal;
  • FIG. 8 is an X-ray Powder Diffractogram (XRPD) of the lestaurtinib: oxalic acid co-crystal;
  • FIG. 9 is a 1 H Nuclear Magnetic Resonance (NMR) spectrum for the lestaurtinib:oxalic acid co-crystal;
  • FIG. 10 is an X-ray Powder Diffractogram (XRPD) of the lestaurtinib:glutaric acid co- crystal;
  • FIG. 11 is a 1 H Nuclear Magnetic Resonance (NMR) spectrum for the lestaurtinib:glutaric acid co-crystal;
  • FIG. 12 is an X-ray Powder Diffractogram (XRPD) of the lestaurtinib:hippuric acid co- crystal;
  • FIG. 13 is a 1 H Nuclear Magnetic Resonance (NMR) spectrum for the lestaurtinib:hippuric acid co-crystal;
  • FIG. 14 is an X-ray Powder Diffractogram (XRPD) of the lestaurtinib:urea co-crystal;
  • FIG. 15 is a 1 H Nuclear Magnetic Resonance (NMR) spectrum for the lestaurtinib :urea co-crystal;
  • FIG. 16 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form VI;
  • FIG. 17 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of lestaurtinib Crystalline Form VI;
  • FIG. 18 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form VII;
  • FIG. 19 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of lestaurtinib Crystalline Form VII;
  • FIG. 20 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form VIII;
  • FIG. 21 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of lestaurtinib Crystalline Form VIII;
  • FIG. 22 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form IX;
  • FIG. 23 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of lestaurtinib Crystalline Form IX;
  • DSC Differential Scanning Calorimetry
  • TGA Thermo- Gravimetric Analysis
  • FIG. 24 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form X;
  • FIG. 25 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of lestaurtinib Crystalline Form X;
  • DSC Differential Scanning Calorimetry
  • TGA Thermo- Gravimetric Analysis
  • FIG. 26 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form XI;
  • FIG. 27 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of lestaurtinib Crystalline Form XI;
  • DSC Differential Scanning Calorimetry
  • TGA Thermo- Gravimetric Analysis
  • FIG. 28 is a 1 H Nuclear Magnetic Resonance (NMR) spectrum for lestaurtinib Crystalline Form XI;
  • FIG. 29 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form XII;
  • FIG. 30 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of lestaurtinib Crystalline Form XII;
  • DSC Differential Scanning Calorimetry
  • TGA Thermo- Gravimetric Analysis
  • FIG. 31 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form XIII;
  • FIG. 32 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of lestaurtinib Crystalline Form XIII;
  • DSC Differential Scanning Calorimetry
  • TGA Thermo- Gravimetric Analysis
  • FIG. 33 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form XIV;
  • FIG. 34 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of lestaurtinib Crystalline Form XIV;
  • DSC Differential Scanning Calorimetry
  • TGA Thermo- Gravimetric Analysis
  • FIG. 35 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form XV;
  • FIG. 36 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of lestaurtinib Crystalline Form XV;
  • DSC Differential Scanning Calorimetry
  • TGA Thermo- Gravimetric Analysis
  • FIG. 37 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form XVI;
  • FIG. 38 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form XVII
  • FIG. 39 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of lestaurtinib Crystalline Form XVII;
  • DSC Differential Scanning Calorimetry
  • TGA Thermo- Gravimetric Analysis
  • FIG. 40 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form XVIII;
  • FIG. 41 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form XIX;
  • FIG. 42 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of lestaurtinib Crystalline Form XIX;
  • DSC Differential Scanning Calorimetry
  • TGA Thermo- Gravimetric Analysis
  • FIG. 43 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form XX;
  • FIG. 44 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form XXI;
  • FIG. 45 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form XXII;
  • FIG. 46 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of lestaurtinib Crystalline Form XXII;
  • DSC Differential Scanning Calorimetry
  • TGA Thermo- Gravimetric Analysis
  • FIG. 47 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form XXIII;
  • FIG. 48 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo-
  • FIG. 49 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form XXIV;
  • FIG. 50 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of lestaurtinib Crystalline Form XXIV;
  • DSC Differential Scanning Calorimetry
  • TGA Thermo- Gravimetric Analysis
  • FIG. 51 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form XXV;
  • FIG. 52 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of lestaurtinib Crystalline Form XXV;
  • DSC Differential Scanning Calorimetry
  • TGA Thermo- Gravimetric Analysis
  • FIG. 53 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form XXVI;
  • FIG. 54 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form XXVII;
  • FIG. 55 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of lestaurtinib Crystalline Form XXVII;
  • DSC Differential Scanning Calorimetry
  • TGA Thermo- Gravimetric Analysis
  • FIG. 56 is an X-ray Powder Diffractogram (XRPD) of lestaurtinib Crystalline Form XXVIII;
  • FIG. 57 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of lestaurtinib Crystalline Form XXVIII;
  • DSC Differential Scanning Calorimetry
  • TGA Thermo- Gravimetric Analysis
  • FIG. 58 is a 1 H Nuclear Magnetic Resonance (NMR) spectrum for lestaurtinib Crystalline Form XXVIII;
  • This invention pertains to co-crystalline, solvate, crystalline hemihydrate and crystalline anhydrous forms of lestaurtinib. It is meant to be understood that the term "lestaurtinib,” as used herein, without a designation of crystallinity or lack thereof, means a particular co- crystalline, solvate, crystalline hemihydrate or crystalline anhydrous form of lestaurtinib, lestaurtinib in solution or a mixture thereof.
  • Crystalline lestaurtinib is characterized as a pale yellow powder of small particle size.
  • the differential scanning calorimetry (DSC) scan for lestaurtinib shows an endotherm maximum at 282 0 C.
  • Thermal gravimetric analysis (TGA) of the compound was done using a 5 °C/min temperature ramp from room temperature to 350 0 C.
  • the thermogram for lestaurtinib shows a 0.41% weight loss through 350 0 C.
  • FIG. 1 shows the XRPD trace of lestaurtinib free base.
  • FIG.2 shows the 1 H NMR spectrum of lestaurtinib free base.
  • FIG. 3 shows the DSC / TGA overlay of lestaurtinib free base. Representative XRPD peaks for lestaurtinib free base are listed in the following Table 1. Table 1. Lestaurtinib free base XRPD peaks
  • amorphous means lacking a characteristic crystal shape or crystalline structure.
  • anhydrate refers to a chemical compound lacking the presence of water.
  • anti-solvent means a solvent in which a compound is substantially insoluble.
  • co-crystal means a crystalline composition comprised of two or more unique components, wherein no covalent chemical modification of the components occurs as a result of the co-crystal formation.
  • crystalline means having a regularly repeating arrangement of molecules or external face planes.
  • crystalline composition refers to a solid chemical compound or mixture of compounds that provides a characteristic pattern of peaks when analyzed by x-ray powder diffraction; this includes, but is not limited to, polymorphs, solvates, hydrates, co-crystals, and desolvated solvates.
  • hemihydrate refers to a chemical compound for which the molecular ratio of water molecules to anhydrous compound is 1 :2.
  • isolated means separating a compound from a solvent, anti-solvent, or a mixture of solvent and anti-solvent to provide a solid, semisolid or syrup. This is typically accomplished by means such as centrifugation, filtration with or without vacuum, filtration under positive pressure, distillation, evaporation or a combination thereof. Isolating may or may not be accompanied by purifying during which the chemical, chiral or chemical and chiral purity of the isolate is increased.
  • Purifying is typically conducted by means such as crystallization, distillation, extraction, filtration through acidic, basic or neutral alumina, filtration through acidic, basic or neutral charcoal, column chromatography on a column packed with a chiral stationary phase, filtration through a porous paper, plastic or glass barrier, column chromatography on silica gel, ion exchange chromatography, recrystallization, normal-phase high performance liquid chromatography, reverse-phase high performance liquid chromatography, trituration and the like.
  • polymorph or “polymorphism,” as used herein, refer to the occurrence of different crystalline arrangements for the same molecules.
  • concentrate refers to a substance dissolved in another substance, usually the component of a solution present in the lesser amount.
  • solution refers to a mixture containing at least one solvent and at least one compound at least partially dissolved in the solvent.
  • solvate means a crystalline composition of variable stoichiometry formed by a solute and an organic solvent as defined herein.
  • solvent means a substance, typically a liquid, that is capable of completely or partially dissolving another substance, typically a solid.
  • Solvents for the practice of this invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethylsulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone (butanone), l-methyl-2-pyrrolidinone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, propionitrile, pyridine,
  • therapeutically effective amount refers to the amount determined to be required to produce the physiological effect intended and associated with a given drug, as measured according to established pharmacokinetic methods and techniques, for the given administration route. Appropriate and specific therapeutically effective amounts can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques. The effective dose will vary depending upon a number of factors, including the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, the formulation of the active agent with appropriate excipients, and the route of administration.
  • Mixtures comprising lestaurtinib and solvent may or may not have chemical and diastereomeric impurities, which, if present, may be completely soluble, partially soluble or essentially insoluble in the solvent.
  • the level of chemical or diastereomeric impurity in the mixture may be lowered before or during isolation of lestaurtinib solvates by means such as distillation, extraction, filtration through acidic, basic or neutral alumina, filtration through acidic, basic or neutral charcoal, column chromatography on a column packed with a chiral stationary phase, filtration through a porous paper, plastic or glass barrier, column chromatography on silica gel, ion exchange chromatography, recrystallization, normal-phase high performance liquid chromatography, reverse-phase high performance liquid chromatography, trituration and the like.
  • Mixtures of lestaurtinib and solvent, wherein the lestaurtinib is completely dissolved in the solvent may be prepared from a crystalline lestaurtinib, amorphous lestaurtinib or a mixture thereof.
  • solvents for the practice of this invention are at a low enough concentration that they do not interfere with the intended use of the solvent in which they are present.
  • Solvents used were HPLC, reagent or USP grade and were used as received.
  • lestaurtinib is useful for treating a variety of therapeutic indications.
  • lestaurtinib is useful for the treatment of cancers such as carcinomas of the pancreas, prostate, breast, thyroid, colon and lung; malignant melanomas; glioblastomas; neuroectodermal-derived tumors including WiIm 's tumor, neuroblastomas and medulloblastomas; and leukemias such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL); pathological conditions of the prostate such as prostatic hypertrophy or prostate cancer; carcinomas of the pancreas, such as pancreatic ductal adenocarcinoma (PDAC); hyperproliferative disorders such as prolifer
  • the invention includes a method of treating acute myeloid leukemia (AML), and myeloproliferative disorders (MPDs) including chronic mylogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), chronic idiopathic myelofibrosis (CIMF/ AMM), chronic eosinophilic leukemia (CEL), chronic neutrophilic leukemia (CNL), and hypereasinophilic syndrome (HEL). More preferably, the invention includes a method of treating acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • MPDs myeloproliferative disorders
  • CML chronic mylogenous leukemia
  • PV polycythemia vera
  • ET essential thrombocythemia
  • CIMF/ AMM chronic idiopathic myelofibrosis
  • CEL chronic eosinophilic leukemia
  • CEL chronic neutrophilic leukemia
  • Lestaurtinib can be administered by any means that results in contact of the active agent with the agent's site of action in the body of the patient. Lestaurtinib can be administered by any conventional means available, either as an individual therapeutic agent or in combination with other therapeutic agents. Lestaurtinib is preferably administered to a patient in need thereof in therapeutically effective amounts for the treatment of the diseases and disorders described herein.
  • therapeutically effective amounts of lestaurtinib can be readily determined by an attending diagnostician by use of conventional techniques.
  • the effective dose can vary depending upon a number of factors, including type and extent of progression of the disease or disorder, overall health of a particular patient, biological efficacy of the lestaurtinib, formulation of the lestaurtinib, and route of administration of the forms of lestaurtinib.
  • Lestaurtinib can also be administered at lower dosage levels with gradual increases until the desired effect is achieved.
  • the phrase “about 50 mg” includes ⁇ 10% of 50 or from 45 to 55 mg.
  • Typical dose ranges of lestaurtinib in its free form comprise from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • a typical dose range of free form lestaurtinib comprises from about 0.01 mg/kg to 10 mg/kg of body weight per day.
  • Daily doses for adult humans includes about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 90, 100, 120, 140, 160 and 200 mg and an equivalent dose for a human child.
  • Lestaurtinib can be administered in one or more unit dose forms and can also be administered one to four times daily, including twice daily (BID).
  • Examples of free form lestaurtinib administration comprise from about 1 to about 400 mg administered one to four times a day; from about 10 mg to about 200 mg BID; from 20-80 mg BID; from 60-100 mg BID, and; from about 40, 60, 80, or 100 mg BID.
  • Dosages of free form lestaurtinib can also be in the form of liquids or suspensions in a concentration of between 15 to 25 mg/mL, 16 mg/mL or 25 mg/mL.
  • the liquid or suspension dosage forms of free form lestaurtinib can include the equivalent of the doses (mg) described above.
  • dosages of free form lestaurtinib can include 1 to 5 mL of the 25 mg/mL solution, or 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, or 4 mL of the 25 mg/mL solution, wherein a 60 mg dose of free form lestaurtinib can be provided in 2.4 mL of solution, an 80 mg dose of free form lestaurtinib can be provided in 3.2 mL of solution and a 100 mg dose of free form lestaurtinib can be provided in 4 mL of solution. Additionally, a 20 mg dose of fre form lestaurtinib can be provided with a 1.25 mL of a 16 mg/mL solution.
  • the daily dose of free form lestaurtinib can range from 1 mg to 5 mg/kg
  • a daily dose of free form lestaurtinib is from about 1 to 3 mg/kg or from about 1.2 to 2.5 mg/kg, or about 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8 or 3 mg/kg.
  • an oral unit dose of free form lestaurtinib is one that is necessary to achieve a blood serum level of about 0.05 to 20 ⁇ g/mL or from about 1 to 20 ⁇ g/mL in a patient.
  • Lestaurtinib can be formulated into pharmaceutical compositions by mixing the forms with one or more pharmaceutically acceptable excipients. It is meant to be understood that pharmaceutical compositions include any form of lestaurtinib or any combination thereof.
  • pharmaceutically acceptable excipients includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • solvents dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutical active substances is well known in the art, such as in Remington: The
  • Excipients for preparation of compositions comprising forms of lestaurtinib to be administered orally include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1 ,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl celluose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glyco
  • Excipients for preparation of compositions comprising forms of lestaurtinib to be administered ophthalmically or orally include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water and mixtures thereof.
  • Excipients for preparation of compositions comprising forms of lestaurtinib to be administered osmotically include, for example, chlorofluoro-hydrocarbons, ethanol, water and mixtures thereof.
  • Excipients for preparation of compositions comprising forms of lestaurtinib to be administered parenterally include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water and mixtures thereof.
  • Excipients for preparation of compositions comprising forms of lestaurtinib to be administered rectally or vaginally include, for example, cocoa butter, polyethylene glycol, wax and mixtures thereof.
  • Dosage forms of lestaurtinib and compositions comprising lestaurtinib depend upon the route of administration. Any route of administration is contemplated, including oral, mucosal (e.g. ocular, intranasal, pulmonary, gastric, intestinal, rectal, vaginal and uretheral) or parenteral (e.g. subcutaneous, intradermal, intramuscular, intravenous, or intraperitoneal.
  • mucosal e.g. ocular, intranasal, pulmonary, gastric, intestinal, rectal, vaginal and uretheral
  • parenteral e.g. subcutaneous, intradermal, intramuscular, intravenous, or intraperitoneal.
  • compositions are most preferably administered orally, preferably in forms such as tablets, capsules, powders, pills, liquids/suspensions or gels/suspensions or emulsions, lyophillizates and all other different forms described in patents and applications mentioned herein, more preferably as tablets, capsules and liquids/suspensions or gels/suspensions.
  • the administration vehicle can comprise one or more pharmaceutically acceptable carriers that are likely to ensure the solid state or crystalline form's stability (e.g. a suspension in oil).
  • Lestaurtinib can be formulated as a variety of pharmaceutical compositions and dosage forms, such as those described in U.S. Patents 6,200,968 and 6,660,729 and PCT Publication No. 04/037928, each of which is incorporated herein by reference.
  • the lestaurtinib can be formulated as microemulsions or dispersions.
  • Crystalline forms of lestaurtinib can be made by synthetic chemical processes, examples of which are shown herein below. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that moieties susceptable to undesired reaction may be protected and deprotected, as necessary.
  • X-ray powder diffraction (XRPD) patterns for the samples were acquired on a Bruker AXS C2 GADDS diffractometer using Cu Ka radiation (40 kV, 40 mA), automated XYZ stage, laser video microscope for auto-sample positioning and a HiStar 2- dimensional area detector.
  • X-ray optics consisted of a single G ⁇ bel multilayer mirror coupled with a pinhole collimator of 0.3 mm. Beam divergence, i.e. the effective size of the X-ray beam on the sample, was approximately 4 mm.
  • a ⁇ - ⁇ continuous scan mode was employed with a sample to detector distance of 20 cm which provided an effective 2 ⁇ range of 3.2 - 29.8 °.
  • a typical exposure time of a sample was 120 seconds.
  • Samples run under ambient conditions were prepared as flat plate specimens using powder as received without grinding. Approximately 1-2 mg of the sample was lightly pressed on a glass slide to obtain a flat surface. Samples run under non-ambient conditions were mounted on a silicon wafer with heat conducting compound. The sample was then heated to the appropriate temperature at ca. 20 °C/minute and subsequently held isothermally for ca 1 minute before data collection was initiated.
  • Powder XRD patterns were also recorded on a PANalytical X'Pert Pro diffractometer equipped with an X'celerator detector using Cu Ka radiation at 40 kV and 40 mA. K ⁇ l radiation is obtained with a highly oriented crystal (Gel 11) incident beam monochromator. A 10mm beam mask, and fixed (1/4°) divergence and anti-scatter (1/8°) slits were inserted on the incident beam side. A fixed 0.10 mm receiving slit was inserted on the diffracted beam side. The X-ray powder pattern scan was collected from ca. 2 to 40° 20 with a 0.0080° step size and 96.06 sec counting time which resulted in a scan rate of approximately 0.5°/min. The sample was spread on a glass plate or a silicon zero background (ZBG) plate for the measurement. The sample was rotated at 4°/min on a PANalytical PW3064 Spinner.
  • ZBG silicon zero background
  • VT Variable Temperature
  • Low Humidity XRPD experiments were performed with an Anton Paar TTK450 chamber that was computer controlled for temperature only.
  • the humidity in the chamber could be effectively reduced to very low RH conditions by flowing nitrogen gas through the TTK450 chamber.
  • Thermal curves were acquired using a Perkin-Elmer Sapphire DSC unit equipped with an autosampler running Pyris software version 6.0 calibrated with Indium prior to analysis. Solid samples of 1-11 mg were weighed into 20 ⁇ L aluminum open samples pans. The DSC cell was then purged with nitrogen and the temperature heated from 0° to 300°C at 10°C/min.
  • Thermal curves were also acquired using a Perkin-Elmer Pyris 1 TGA unit running Pyris software version 6.0 calibrated with calcium oxalate monohydrate. TGA samples between 1-15 mg were monitored for percent weight loss as heated from 25° to 400°C at 10°C/min in a furnace purged with Nitrogen at ca. 50 mL/min.
  • FIG. 4 shows the XRPD pattern for the lestaurtinibimaleic acid co-crystal.
  • FIG. 5 shows the 1 H NMR spectrum for the lestaurtinibrmaleic acid co-crystal. Representative XRPD peaks for the lestaurtinib:maleic acid co-crystal are listed in the following Table 2.
  • representative XRPD peaks for the lestaurtinib:maleic acid co-crystal comprise one or more peaks selected from the group consisting of about 7.56, 8.19, 8.82, 13.15, 15.21, 16.47, 17.87, 22.15, 25.90 and 26.70 degrees 2-theta.
  • representative XRPD peaks for the lestaurtinib:maleic acid co-crystal comprise one or more peaks selected from the group consisting of about 7.56, 8.19, 16.47, 25.90 and 26.70 degrees 2-theta.
  • FIG. 6 shows the XRPD pattern for the lestaurtinib:malonic acid co-crystal.
  • FIG. 7 shows the 1 H NMR spectrum for the lestaurtinib:malonic acid co-crystal. Representative XRPD peaks for the lestaurtinib:malonic acid co-crystal are listed in the following Table 3.
  • representative XRPD peaks for the lestaurtinib :malonic acid co-crystal comprise one or more peaks selected from the group consisting of about 5.78, 7.99, 15.16, 15.55, 16.04, 19.47, 20.06, 20.86, 21.71, 26.1 1 and 27.17 degrees 2-theta.
  • representative XRPD peaks for the lestaurtinib:malonic acid co-crystal comprise one or more peaks selected from the group consisting of about 7.99, 15.16, 16.04, 26.11 and 27.17 degrees 2-theta.
  • EXAMPLE 3 Lestaurtinib - oxalic acid co-crystal
  • Solid was isolated by filtration and dried under ambient conditions for 1 hour before analysis.
  • FIG. 8 shows the XRPD pattern for the lestaurtinib:oxalic acid co-crystal.
  • FIG. 9 shows the 1 H NMR spectrum for the lestaurtinibroxalic acid co-crystal. Representative XRPD peaks for the lestaurtinib:oxalic acid co-crystal are listed in the following Table 4.
  • representative XRPD peaks for the lestaurtinib:oxalic acid co-crystal comprise one or more peaks selected from the group consisting of about 6.18, 7.44, 10.07, 13.94, 14.96, 16.68, 20.19, 25.78, 26.50 and 26.85 degrees 2-theta.
  • representative XRPD peaks for the lestaurtinib:oxalic acid co-crystal comprise one or more peaks selected from the group consisting of about 6.18, 7.44, 14.96, 20.19 and 25.78 degrees 2-theta.
  • Solid was isolated by filtration and dried under ambient conditions for 1 hour before analysis.
  • FIG. 10 shows the XRPD pattern for the lestaurtinib:glutaric acid co-crystal.
  • FIG. 11 shows the 1 H NMR spectrum for the lestaurtinib: glutaric acid co-crystal. Representative XRPD peaks for the lestaurtinib:glutaric acid co-crystal are listed in the following Table 5.
  • representative XRPD peaks for the lestaurtinib:glutaric acid co-crystal comprise one or more peaks selected from the group consisting of about 13.15, 14.10, 14.60, 14.98, 17.49, 19.87, 20.46, 25.12, 25.56 and 26.55, degrees 2-theta.
  • representative XRPD peaks for the lestaurtinib:glutaric acid co-crystal comprise one or more peaks selected from the group consisting of about 14.10, 14.60, 25.12, 25.56 and 26.55 degrees 2-theta.
  • Solid was isolated by filtration and dried under ambient conditions for 1 hour before analysis.
  • FIG. 12 shows the XRPD pattern for the lestaurtinib:hippuric acid co-crystal.
  • FIG. 13 shows the 1 H NMR spectrum for the lestaurtinib:hippuric acid co-crystal. Representative XRPD peaks for the lestaurtinib:hippuric acid co-crystal are listed in the following Table 6.
  • representative XRPD peaks for the lestaurtinib:hippuric acid co-crystal comprise one or more peaks selected from the group consisting of about 6.77, 14.23, 18.44, 20.61 and 25.19 degrees 2-theta.
  • FIG. 14 shows the XRPD pattern for the lestaurtinib rurea co-crystal.
  • FIG. 15 shows the 1 H NMR spectrum for the lestaurtinib:urea co-crystal. Representative XRPD peaks for the lestaurtinib:urea co-crystal are listed in the following Table 7.
  • representative XRPD peaks for the lestaurtinibrurea co-crystal comprise one or more peaks selected from the group consisting of about 14.14, 14.63, 15.02, 17.51, 19.72, 22.24, 24.58, 25.19, 25.86 and 26.56 degrees 2- theta.
  • representative XRPD peaks for the lestaurtinib:urea co-crystal comprise one or more peaks selected from the group consisting of about 14.63, 22.24, 25.19, 25.86 and 26.56 degrees 2-theta.
  • FIG. 16 shows the XRPD pattern for the Lestaurtinib Crystalline Form VI.
  • FIG. 17 shows the DSC/TGA overlay of the Lestaurtinib Crystalline Form VI.
  • Representative XRPD peaks for the Lestaurtinib Crystalline Form VI are listed in the following Table 8.
  • representative XRPD peaks for Lestaurtinib Crystalline Form VI comprise one or more peaks selected from the group consisting of about 8.05, 14.23, 15.14, 17.69, 19.86, 23.07, 25.79, 26.59, 27.12 and 39.77 degrees 2-theta.
  • representative XRPD peaks for Lestaurtinib Crystalline Form VI comprise one or more peaks selected from the group consisting of about 14.23, 17.69, 25.79, 26.59 and 27.12 degrees 2-theta.
  • the solid was isolated by decantation and allowed to dry on absorbant paper before analysis.
  • 40 mg of amorphous form of lestaurtinib in 400 ⁇ L of solvent were slurried in formamide. These mixtures were slurried for 48 hours with alternating 4 hour periods at 50°C and 5°C (-0.5°C/min).
  • the solid was isolated by filtration. The material was dried at 40°C under house vacuum during 1 hour.
  • FIG. 18 shows the XRPD pattern for Lestaurtinib Crystalline Form VII.
  • FIG. 19 shows the DSC /TGA overlay of Lestaurtinib Crystalline Form VII. Representative XRPD peaks for Lestaurtinib Crystalline Form VII are listed in the following Table 9.
  • representative XRPD peaks for the Lestaurtinib:propionitrile solvate comprise one or more peaks selected from the group consisting of about 7.58, 13.98, 14.35, 15.28, 17.75, 17.96, 21.48, 22.08, 24.25 and 25.42 degrees 2-theta.
  • representative XRPD peaks for the Lestaurtinib:propionitrile solvate comprise one or more peaks selected from the group consisting of about 7.58, 17.75, 17.96, 21.48 and 22.08 degrees 2-theta.
  • the solid material was isolated by decantation and solid allowed to dry on absorbant paper before analysis.
  • FIG. 20 shows the XRPD pattern for Lestaurtinib Crystalline Form VIII.
  • FIG. 21 shows the DSC/TGA overlay of Lestaurtinib Crystalline Form VIII. Representative XRPD peaks for Lestaurtinib Crystalline Form VIII are listed in the following Table 10.
  • representative XRPD peaks for Lestaurtinib Crystalline Form VIII comprise one or more peaks selected from the group consisting of about 7.70, 9.79, 11.94, 12.05, 14.42, 17.11, 17.62, 18.05, 21.24 and 22.06 degrees 2-theta.
  • representative XRPD peaks for Lestaurtinib Crystalline Form VIII comprise one or more peaks selected from the group consisting of about 7.70, 11.94, 12.05, 17.11, 17.62 and 18.05 degrees 2-theta.
  • the solid was isolated by decantation and the sticky solid allowed to dry on absorbant paper. When dry, the solid was ground to a powder using a mortar and pestle.
  • FIG. 22 shows the XRPD pattern for Lestaurtinib Crystalline Form IX.
  • FIG. 23 shows the DSC/TGA overlay of Lestaurtinib Crystalline Form IX. Representative XRPD peaks for Lestaurtinib Crystalline Form IX are listed in the following Table 11.
  • representative XRPD peaks for Lestaurtinib Crystalline Form IX comprise one or more peaks selected from the group consisting of about 7.79, 9.85, 12.11, 15.55, 17.14, 17.83, 19.07, 21.50, 22.09 and 25.43 degrees 2-theta.
  • representative XRPD peaks for Lestaurtinib Crystalline Form IX comprise one or more peaks selected from the group consisting of about 7.79, 12.11, 15.55, 17.83 and 21.50 degrees 2-theta.
  • FIG. 24 shows the XRPD pattern for Lestaurtinib Crystalline Form X.
  • FIG. 25 shows the DSC / TGA overlay of the Lestaurtinib Crystalline Form X. Representative XRPD peaks for Lestaurtinib Crystalline Form X are listed in the following Table 12.
  • representative XRPD peaks for Lestaurtinib Crystalline Form X comprise one or more peaks selected from the group consisting of about 7.69, 11.86, 1 1.99, 15.46, 17.79, 17.96, 19.56, 21.52, 22.07 and 25.35 degrees 2-theta.
  • representative XRPD peaks for Lestaurtinib Crystalline Form X comprise one or more peaks selected from the group consisting of about 7.69, 11.99, 15.46, 17.79, and 17.96 degrees 2-theta.
  • EXAMPLE 12 Lestaurtinib Crystalline Form XI (1:3 formamide solvate)
  • FIG. 26 shows the XRPD pattern for the Lestaurtinib Crystalline Form XI.
  • FIG. 27 shows the DSC / TGA overlay of the Lestaurtinib Crystalline Form XI.
  • FIG. 28 shows the 1 H NMR spectrum for the Lestaurtinib Crystalline Form XI. Representative XRPD peaks for the Lestaurtinib Crystalline Form XI are listed in the following Table 13.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XI comprise one or more peaks selected from the group consisting of about 6.71, 14.44, 15.10, 17.11, 18.55, 19.54, 21.18, 25.61, 26.51 and 27.80 degrees 2-theta.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XI comprise one or more peaks selected from the group consisting of about 6.71, 14.44, 25.61, 26.51 and 27.80 degrees 2-theta.
  • EXAMPLE 13 Lestaurtinib Crystalline Form XII (chlorobenzene solvate)
  • FIG. 29 shows the XRPD pattern for the lestaurtinib Crystalline Form XII.
  • FIG. 30 shows the DSC / TGA overlay of the Lestaurtinib Crystalline Form XII. Representative XRPD peaks for the Lestaurtinib Crystalline Form XII are listed in the following Table 14.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XII comprise one or more peaks selected from the group consisting of about 6.50, 7.15, 13.04, 14.17, 14.45, 18.18, 18.77, 21.27, 22.43 and 24.98 degrees 2-theta.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XII comprise one or more peaks selected from the group consisting of about 7.15, 18.18, 18.77, 21.27, and 24.98 degrees 2-theta.
  • FIG. 31 shows the XRPD pattern for the Lestaurtinib Crystalline Form XIII.
  • FIG. 32 shows the DSC / TGA overlay of the Lestaurtinib Crystalline Form XIII. Representative XRPD peaks for the Lestaurtinib Crystalline Form XIII are listed in the following Table 15.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XIII comprise one or more peaks selected from the group consisting of about 6.89, 7.18, 8.24, 8.54, 14.26, 14.73, 15.11, 16.95, 17.58 and 25.17 degrees 2-theta.
  • representative XRPD peaks for the Lestaurtinib Crytalline Form XIII comprise one or more peaks selected from the group consisting of about 6.89, 14.26, 14.73, 16.95 and 17.58 degrees 2-theta.
  • FIG. 33 shows the XRPD pattern for the Lestaurtinib Crystalline Form XIV.
  • FIG. 34 shows the DSC / TGA overlay of the Lestaurtinib Crystalline Form XIV. Representative XRPD peaks for the Lestaurtinib Crystalline Form XIV solvate are listed in the following Table 16.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XIV comprise one or more peaks selected from the group consisting of about 6.82, 7.75, 13.19, 14.21, 14.67, 15.06, 15.48,17.55, 17.92 and 25.13 degrees 2-theta.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XIV comprise one or more peaks selected from the group consisting of about 7.75, 13.19, 14.21, 14.67, 17.55 and 25.13 degrees 2-theta.
  • a solution of lestaurtinib in N.N. dimethylacetamide was allowed to slowly evaporate to dryness under ambient conditions. The rate of evaporation was constrained by use of air tight film covers containing small holes.
  • FIG. 35 shows the XRPD pattern for the Lestaurtinib Crystalline Form XV.
  • FIG. 36 shows the DSC / TGA overlay of the Lestaurtinib Crystalline Form XV. Representative XRPD peaks for the Lestaurtinib Crystalline Form XV are listed in the following Table 17.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XV comprise one or more peaks selected from the group consisting of about 7.80, 9.56, 11.05, 13.91, 15.58, 15.93, 17.04, 17.09, 25.59 and 25.64 degrees 2-theta.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XV comprise one or more peaks selected from the group consisting of about 11.05, 13.91, 17.04, 17.09 and 25.59 2-theta.
  • FIG. 37 shows the XRPD pattern for the Lestaurtinib Crystalline Form XVI. Representative XRPD peaks for the Lestaurtinib Crystalline Form XVI are listed in the following Table 18.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XVI comprise one or more peaks selected from the group consisting of about 8.12, 8.18, 10.31, 10.37, 13.58, 17.01, 17.49, 18.10, 18.36 and 22.62 degrees 2-theta.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XVI comprise one or more peaks selected from the group consisting of about 8.12, 8.18, 10.31, 10.37 and 17.49 degrees 2-theta.
  • amorphous form of lestaurtinib was added to a glass vial (2.0 mL, 32 x 11.6 mm). Chlorobenzene or toluene was added in 1.0 mL increments followed by heating with stirring to the boiling point until dissolved. The solution was not formed by the addition of a total of 10 mL of solvent, the mixture was syringe filtered (5 ⁇ Nylon membrane) and the solutions was allowed to slowly evaporate to dryness under ambient conditions. The solid was isolated by filtration.
  • amorphous form of lestaurtinib was added to a glass scintillation vial (20 mL, 26 x 56 mm). Chlorobenzene was added in 0.5 to 1.0 mL increments followed by heating with stirring to the boiling point until dissolved. If a solution was not formed by the addition of a total of 10 mL of solvent, the mixture was syringe filtered (5 ⁇ nylon membrane). One mL increments of the anti-solvent diisopropyl ether were then added to the solutions until the cloud point was reached. These mixtures were capped and allowed to cool to room temperature overnight and any solid that formed was isolated by suction filtration. The solid obtained was allowed to dry overnight in the fume hood. If no solid formed on adding 10 mL of antisolvent, the solution was allowed to evaporate in the fume hood until dry and any residue was examined by XRPD.
  • FIG. 38 shows the XRPD pattern for the Lestaurtinib Crystalline Form XVII.
  • FIG. 39 shows the DSC / TGA overlay of the Lestaurtinib Crystalline Form XVII. Representative XRPD peaks for the Lestaurtinib Crystalline Form XVII are listed in the following Table 19.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XVII comprise one or more peaks selected from the group consisting of about 7.90, 13.24, 13.29, 13.86, 15.76, 18.54, 19.63, 19.70, 20.07and 27.56 degrees 2-theta.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XVII comprise one or more peaks selected from the group consisting of about 7.90, 15.76, 19.63, 19.70 and 20.07 degrees 2-theta.
  • Crystalline Form XVIII was obtained as 20 mg of Crystalline Form XVII was heated to 200°C under nitrogen flow in an Anton Paar TK450 camera.
  • FIG. 40 shows the XRPD pattern for the Lestaurtinib Crystalline Form XVIII. Representative XRPD peaks for the Lestaurtinib Crystalline Form XVIII are listed in the following Table 20.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XVIII comprise one or more peaks selected from the group consisting of about 7.76, 9.13, 13.13, 15.64, 16.61, 18.38, 19.53, 19.95 and 27.45 degrees 2- theta.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XVIII comprise one or more peaks selected from the group consisting of about 7.76, 13.13, 15.64, 19.53 and 19.95 degrees 2-theta.
  • Crystalline Form XIX was obtained as 20 mg of Crystalline Form XXIV was dried at room temperature during 3 days.
  • FIG. 41 shows the XRPD pattern for the Lestaurtinib Crystalline Form XIX.
  • FIG. 42 shows the DSC / TGA overlay of the Lestaurtinib Crystalline Form XIX. Representative XRPD peaks for the Lestaurtinib Crystalline Form XIX are listed in the following Table 21.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XIX comprise one or more peaks selected from the group consisting of about 7.86, 9.61, 11.07, 13.64, 13.73, 15.71, 16.66, 17.07, 18.39 and 20.40 degrees 2-theta.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XIX comprise one or more peaks selected from the group consisting of about 9.61, 11.07, 15.71, 17.07 and 18.39 degrees 2-theta.
  • FIG. 43 shows the XRPD pattern for the Lestaurtinib Crystalline Form XX. Representative XRPD peaks for the Lestaurtinib Crystalline Form XX are listed in the following Table 22.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XX comprise one or more peaks selected from the group consisting of about 7.73, 12.22, 14.42, 15.46, 17.95, 18.07, 18.12, 21.51, 22.06 and 25.41 degrees 2-theta.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XX comprise one or more peaks selected from the group consisting of about 7.73, 15.46, 17.95, 18.07 and 22.06 degrees 2-theta.
  • FIG. 44 shows the XRPD pattern for the Lestaurtinib Crystalline Form XXI. Representative XRPD peaks for the Lestaurtinib Crystalline Form XXI are listed in the following Table 23.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XXI comprise one or more peaks selected from the group consisting of about 7.74, 7.80, 12.19, 14.64, 15.48, 17.92, 18.18, 18.23, 21.61 and 22.27 degrees 2-theta.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XXI comprise one or more peaks selected from the group consisting of about 7.74, 12.19, 15.48, 18.18, and 22.27 degrees 2-theta.
  • FIG. 45 shows the XRPD pattern for the LestaurtinibCrystalline Form XXII.
  • FIG. 46 shows the DSC / TGA overlay of the Lestaurtinib Crystalline Form XXII. Representative XRPD peaks for the Lestaurtinib Crystalline Form XXII are listed in the following Table 24.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XXII comprise one or more peaks selected from the group consisting of about 7.88, 9.62, 11.04, 13.60, 14.18, 15.74, 17.04, 24.96, 25.58 and 25.88 degrees 2-theta.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XXII comprise one or more peaks selected from the group consisting of about 11.04, 13.60, 15.74, 17.04 and 25.58 degrees 2-theta.
  • a solution of lestaurtinib in formamide was allowed to slowly evaporate to dryness under ambient conditions.
  • the rate of evaporation was constrained by use of air tight film covers containing small holes.
  • FIG. 47 shows the XRPD pattern for the Lestaurtinib Crystalline Form XXIII.
  • FIG. 48 shows the DSC / TGA overlay of the Lestaurtinib Crystalline Form XXIII. Representative XRPD peaks for the Lestaurtinib Crystalline Form XXIII are listed in the following Table 25.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XXIII comprise one or more peaks selected from the group consisting of about 7.03, 7.62, 14.06, 14.61, 14.77, 15.04, 17.14, 18.85, 26.31 and 27.20 degrees 2-theta.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XXIII comprise one or more peaks selected from the group consisting of about 7.03, 14.06, 14.61, 15.04 and 26.31 degrees 2-theta.
  • Form I of lestaurtinib was slurried in methanol (10 volumes (40 mg in 400 ⁇ L)). The sample was heated from 20°C to 80°C at a rate of 4.8°C/min and after 30 minutes cooled at a slow rate (0.25°C/min) to a final temperature of 5°C and kept at that temperature for 18 h. The solid was isolated by filtration. The material was dried at 40°C under house vacuum for 1 hour.
  • FIG. 49 shows the XRPD pattern for the Lestaurtinib Crystalline form XXIV.
  • FIG. 50 shows the DSC / TGA overlay of the Lestaurtinib Crystalline form XXIV. Representative XRPD peaks for the Lestaurtinib Crystalline form XXIV are listed in the following Table 26.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XXIV comprise one or more peaks selected from the group consisting of about 7.66, 14.40, 14.54, 14.78, 14.94, 15.32, 17.81, 25.32, 26.24 and 26.50 degrees 2-theta.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XXIV comprise one or more peaks selected from the group consisting of about 7.66, 14.40, 14.54, 14.78 and 25.32 degrees 2-theta.
  • a solution of lestaurtinib in N-methylpyrrolidinone was allowed to slowly evaporate to dryness under ambient conditions.
  • the rate of evaporation was constrained by use of air tight film covers containing small holes.
  • FIG. 51 shows the XRPD pattern for the Lestaurtinib Crystalline Form XXV.
  • FIG. 52 shows the DSC / TGA overlay of the Lestaurtinib Crystalline Form XXV. Representative XRPD peaks for the Lestaurtinib Crystalline Form XXV are listed in the following Table 27.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XXV comprise one or more peaks selected from the group consisting of about 5.52, 7.54, 8.35, 10.88, 11.51, 12.94, 16.28, 17.22, 17.79, and 21.71 degrees 2-theta.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XXV comprise one or more peaks selected from the group consisting of about 5.52, 8.35, 10.88, 11.51 and 16.28 degrees 2-theta.
  • FIG. 53 shows the XRPD pattern for the Lestaurtinib Crystalline Form XXVI. Representative XRPD peaks for the Lestaurtinib Crystalline Form XXVI are listed in the following Table 28.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XXVI comprise one or more peaks selected from the group consisting of about 7.14, 8.90, 10.39, 13.00, 13.35, 14.27, 16.58, 18.02, 19.94 and 21.33 degrees 2-theta.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XXVI comprise one or more peaks selected from the group consisting of about 7.14, 13.00, 14.27, 18.02 and 19.94 degrees 2-theta.
  • EXAMPLE 28 Lestaurtinib Crystalline Form XXVII (proplyene carbonate solvate)
  • FIG. 54 shows the XRPD pattern for the Lestaurtinib Crystalline Form XXVII.
  • FIG. 55 shows the DSC/TGA overlay of the Lestaurtinib Crystalline Form XXVII.
  • Representative XRPD peaks for the Lestaurtinib Crystalline Form XXVII are listed in the following Table 29.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XXVII comprise one or more peaks selected from the group consisting of about 7.63, 9.80, 12.35, 15.27, 19.66, 21.59 and 21.93 degrees 2-theta.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XXVII comprise one or more peaks selected from the group consisting of about 7.63, 9.80, 12.35, 15.27 and 21.93 degrees 2-theta.
  • FIG. 56 shows the XRPD pattern for the Lestaurtinib Crystalline Form XXVIII.
  • FIG. 57 shows the DSC / TGA overlay of the Lestaurtinib Crystalline Form XXVIII.
  • FIG. 58 shows the 1 H NMR spectrum for the Lestaurtinib Crystalline Form XXVIII. Representative XRPD peaks for the Lestaurtinib Crystalline Form XXVIII are listed in the following Table 30.
  • Lestaurtinib Crystalline Form XXVIII comprise one or more peaks selected from the group consisting of about 7.06, 9.86, 13.95, 18.52, 19.76, 20.30, 21.61, 23.28, 25.43 and 26.59 degrees 2-theta.
  • representative XRPD peaks for the Lestaurtinib Crystalline Form XXVIII comprise one or more peaks selected from the group consisting of about 9.86, 13.95, 18.52, 19.76 and 25.43 degrees 2-theta.
  • a solution of lestaurtinib in N.N. dimethylacetamide was allowed to slowly evaporate to dryness under ambient conditions. The rate of evaporation was constrained by use of air tight film covers containing small holes.
  • a solution of lestaurtinib in N.N dimethylformamide was allowed to slowly evaporate to dryness under ambient conditions. The rate of evaporation was constrained by use of air tight film covers containing small holes.
  • One of the molecules of lestaurtinib, molecule A, and one of the molecules of solvent are disordered.
  • the disordered N.N. dimethylformamide is hydrogen bound to molecule A the disordered lestaurtinib. The disorder is part of the hydrogen bonding pattern.
  • peak heights in a XRPD spectrum may vary and will be dependent on variables such as the temperature, crystal size or morphology, sample preparation, or sample height in the analysis well of the Bruker AXS C2 GADDS or PANalytical X'Pert Pro X-Ray Diffraction Pattern Systems. It is also meant to be understood that peak positions may vary when measured with different radiation sources. For example, Cu-Ka i, Mo-Ka, Co-Ka and Fe-Ka radiation, having wavelengths of 1.54060 A, 0.7107 A, 1.7902 A and 1.9373 A, respectively, may provide peak positions that differ from those measured with Cu-Ka radiation.

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Abstract

L'invention concerne de nouvelles formes cristallines de lestaurtinib consistant en six formes co-cristallines, dix-neuf formes solvate, trois formes anhydrate et une forme hémihydrate. Elle concerne également des procédés servant à les préparer et les utiliser.
PCT/US2009/000312 2008-01-16 2009-01-16 Formes cristallines de lestaurtinib WO2009091594A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0303697A1 (fr) * 1987-03-09 1989-02-22 Kyowa Hakko Kogyo Co., Ltd. Derives de la substance physiologiquement active k-252
WO2004078161A1 (fr) * 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Compositions co-cristallines pharmaceutiques de medicaments, notamment de carbamazeptine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophene, aspirine, flurbiprofene, phenytoine et ibuprofene
WO2007070444A1 (fr) * 2005-12-09 2007-06-21 Abbott Laboratories Forme cristalline 1 de lestaurtinib, anhydrate de lestaurimib cristallin et lestaurimib amorphe

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0303697A1 (fr) * 1987-03-09 1989-02-22 Kyowa Hakko Kogyo Co., Ltd. Derives de la substance physiologiquement active k-252
WO2004078161A1 (fr) * 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Compositions co-cristallines pharmaceutiques de medicaments, notamment de carbamazeptine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophene, aspirine, flurbiprofene, phenytoine et ibuprofene
WO2007070444A1 (fr) * 2005-12-09 2007-06-21 Abbott Laboratories Forme cristalline 1 de lestaurtinib, anhydrate de lestaurimib cristallin et lestaurimib amorphe

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