WO2022240802A1 - Formes à l'état solide de sels de sitravatinib et leur procédé de préparation - Google Patents

Formes à l'état solide de sels de sitravatinib et leur procédé de préparation Download PDF

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WO2022240802A1
WO2022240802A1 PCT/US2022/028466 US2022028466W WO2022240802A1 WO 2022240802 A1 WO2022240802 A1 WO 2022240802A1 US 2022028466 W US2022028466 W US 2022028466W WO 2022240802 A1 WO2022240802 A1 WO 2022240802A1
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sitravatinib
theta
degrees
malic acid
crystalline
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PCT/US2022/028466
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English (en)
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Nikolina JANTON
Helena CERIĆ
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Teva Pharmaceuticals International Gmbh
Teva Pharmaceuticals Usa, Inc.
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Publication of WO2022240802A1 publication Critical patent/WO2022240802A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present disclosure encompasses solid state forms of sitravatinib salts, processes for the preparation thereof, and pharmaceutical compositions thereof.
  • the present disclosure includes solid state forms of sitravatinib malate, sitravatinib hydrochloride, sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate, processes for preparation thereof, and pharmaceutical compositions thereof.
  • Sitravatinib belongs to a class of compounds that inhibit protein tyrosine kinase activity and thus may be useful for the treatment of cancer, such as lung cancer including non small cell lung cancer (NSCLC).
  • cancer such as lung cancer including non small cell lung cancer (NSCLC).
  • Polymorphism the occurrence of different crystalline forms is a property of some molecules and molecular complexes.
  • a single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties, like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”).
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • infrared absorption fingerprint e.g., infrared absorption fingerprint
  • solid state ( 13 C) NMR spectrum are examples of techniques that may be used to distinguish different polymorphic forms of a compound.
  • Different salts and solid state forms (including solvated forms and co-crystals) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts of an active pharmaceutical ingredient may also give rise to a variety of polymorphs, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.
  • New solid state forms, salts, co -crystals and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
  • New solid state forms, co -crystals and salts of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, such as a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). Thus, additional solid state forms of sitravatinib and sitravatinib salts remain desirable.
  • the present disclosure provides crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate, processes for preparation thereof, and pharmaceutical compositions thereof. These crystalline polymorphs can be used to prepare other solid state forms of sitravatinib, sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate or other salts of sitravatinib and their solid state forms.
  • the present disclosure provides crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and/or sitravatinib succinate for use in the preparation of pharmaceutical compositions and/or formulations for use in medicine, such as for the treatment of patients with cancer.
  • the present disclosure provides pharmaceutical compositions including crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and/or sitravatinib succinate according to the present disclosure.
  • the present disclosure encompasses pharmaceutical formulations including the described crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and/or sitravatinib succinate or pharmaceutical compositions including the described crystalline polymorphs of above mentioned compounds and at least one pharmaceutically acceptable excipient.
  • the present disclosure includes processes for preparing the above mentioned pharmaceutical compositions.
  • the processes include combining any one or mixtures of the crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and/or sitravatinib succinate with at least one pharmaceutically acceptable excipient.
  • sitravatinib hydrochloride sitravatinib malate sitravatinib tartarate, sitravatinib fumarate and/or sitravatinib succinate as defined herein and the pharmaceutical compositions or formulations of them may be used as medicaments, in embodiments for the treatment of patients with NSCLC.
  • the present disclosure also provides the use of crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, for the manufacture of medicaments for cancer.
  • Figure 1 shows a characteristic X-Ray powder diffraction (XRPD) of Sitravatinib hydrochloride form A.
  • Figure 2 shows a charaOcteristic XRPD of crystalline form of Sitravatinib malate form A.
  • Figure 3 shows a characteristic XRPD of an amorphous sitravatinib malate.
  • Figure 4 shows a characteristic XRPD of crystalline form of Sitravatinib malate form B.
  • Figure 5 shows a characteristic XRPD of crystalline form of Sitravatinib malate form C.
  • Figure 6 shows a characteristic XRPD of crystalline form of Sitravatinib malate form D.
  • Figure 7 shows a characteristic XRPD of crystalline form of Sitravatinib malate form E.
  • Figure 8 shows a characteristic XRPD of crystalline form of Sitravatinib malate form F.
  • Figure 9 shows a characteristic XRPD of crystalline form of Sitravatinib tartarate form A.
  • Figure 10 shows a characteristic XRPD of crystalline form of Sitravatinib succinate form A.
  • Figure 11 shows a characteristic XRPD of crystalline form of Sitravatinib fumarate form A.
  • Figure 12 shows a 13 C solid state NMR spectrum of Sitravatinib malate form A (200-0 ppm).
  • Figure 13 shows a 13 C solid state NMR spectrum of Sitravatinib malate Form C (200-0 ppm).
  • Figure 14 shows a 13 C solid state NMR spectrum of Sitravatinib Fumarate form A (200-0 ppm).
  • Figure 15 shows a 13 C solid state NMR spectrum of Sitravatinib hydrochloride form A (200-0 ppm).
  • Figure 16 shows a 13 C solid state NMR spectrum of Sitravatinib tartarate form A (200-0 ppm).
  • the present disclosure encompasses solid state forms of sitravatinib hydrochloride, sitravatinib malate (particularly sitravatinib L-malate), sitravatinib tartarate (particularly sitravatinib L-tartarate), sitravatinib fumarate and sitravatinib succinate, including crystalline polymorphs of sitravatinib hydrochloride form A, sitravatinib malate (particularly sitravatinib L- malate) forms A-F, sitravatinib tartarate (particularly sitravatinib L-tartarate) form A, sitravatinib fumarate form A and sitravatinib succinate form A, processes for preparation thereof, and pharmaceutical compositions thereof.
  • Solid state properties of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate, sitravatinib succinate and crystalline polymorphs thereof can be influenced by controlling the conditions under which they are obtained in solid form.
  • a solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms.
  • the expression “substantially free of any other forms” will be understood to mean that the solid state form contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, about 0.5% (w/w) or less or about 0% of any other forms of the subject compound as measured, for example, by XRPD.
  • Such forms include, for example, other crystalline forms of sitravatinib and/or salts thereof and/or amorphous
  • crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject crystalline polymorphs respectively.
  • the described crystalline polymorphs of sitravatinib compounds mentioned above may contain from about 0.5% to about 20% (w/w) or 1% to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more other crystalline polymorph of sitravatinib or salts thereof.
  • the crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate of the present disclosure have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability (such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion), stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility, and bulk density.
  • a crystalline polymorph of sitravatinib malate, sitravatinib hydrochloride and sitravatinib fumarate as described in any aspect or embodiment of the present disclosure may be stable, for example to grinding.
  • Crystalline sitravatinib malate form A as described in any aspect or embodiment of the present disclosure may be especially stable to conditions of grinding.
  • Crystalline sitravatinib malate form A, crystalline fumarate form A, crystalline tartarate form A and crystalline succinate form A as described in any aspect or embodiment of the present disclosure may also have improved solubility.
  • a solid state form such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure.
  • Such data include, for example, powder X-ray diffractograms and solid state NMR spectra.
  • the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone.
  • a crystal form of sitravatinib hydrochloride, sitravatinib malate or sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of above mentioned sitravatinib compounds characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.
  • anhydrous in relation to crystalline forms of the present disclosure relates to a crystalline form which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would typically not contain more than 1% (w/w), of either water or organic solvents as measured, for example, by TGA or by Karl Fischer analysis.
  • sitravatinib hydrochloride refers to a salt of sitravatinib and hydrochloric acid, wherein the molar ratio between sitravatinib and hydrochloric acid is between about 1 : 1 to about 1:3, preferably about 1:1.
  • sitravatinib malate refers to a salt of sitravatinib and malic acid or other complexes (co-crystals) including sitravatinib and malic acid (particularly amorphous form, and any of crystalline Forms A, B, C, D, E, or F), wherein the malic acid is L-malic acid, D-malic acid or mixtures thereof (including racemic mixtures i.e., D, L-malic acid).
  • sitravatinib malate refers to a salt of sitravatinib and malic acid or complex (co-crystal) including sitravatinib and malic acid (particularly amorphous form, and any of crystalline Forms A, B, C, D, E, or F), wherein the malic acid is L-malic acid.
  • the molar ratio of Sitravatinib to malic acid is from about 1:2 to about 2:1, about 1:1.5 to about 1.5:1, about 1:1.2 to about 1.2:1, about 1:1.1 to about 1.1:1, and preferably about 1:1.
  • the molar ratio between sitravatinib and malic acid is about 1:1.
  • the term “tartaric acid” includes L-tartaric acid, D- tartaric acid, or mixtures such as a racemic mixture, i.e. D,L- tartaric acid.
  • the tartaric acid in the salt of sitravatinib with tartaric acid may be L- tartaric acid, D- tartaric acid or mixtures thereof, including D,L- tartaric acid.
  • the tartaric acid in the salt of sitravatinib with tartaric acid is L- tartaric acid.
  • sitravatinib tartarate refers to salt of sitravatinib and tartaric acid, wherein the molar ratio between sitravatinib and tartaric acid (preferably L- tartaric acid) is between about 1 : 1 to about 1 :2, preferably about 1:1.
  • sitravatinib succinate refers to salt of sitravatinib and succinic acid, wherein the molar ratio between sitravatinib and succinic acid is between about 1 : 1 to about 1 :2, preferably about 1:1.
  • sitravatinib fumarate refers to salt of sitravatinib and fumaric acid, wherein the molar ratio between sitravatinib and fumaric acid is between about 1 : 1 to about 1 :2, preferably about 1:1.
  • solvate refers to a crystal form that incorporates a solvent in the crystal structure.
  • the solvent is water
  • the solvate is often referred to as a "hydrate.”
  • the solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.
  • the water may originate from any part of the process from added water where indicated, from residual water which may be present, or from atmospheric water vapour.
  • a thing e.g., a reaction mixture
  • room temperature or “ambient temperature,” often abbreviated as “RT ”
  • RT room temperature
  • room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.
  • the amount of solvent employed in a chemical process may be referred to herein as a number of “volumes” or “vol” or “V.”
  • a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent.
  • this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent.
  • v/v may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added.
  • a process or step may be referred to herein as being carried out “overnight.” This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in embodiments about 16 hours.
  • reduced pressure refers to a pressure that is less than atmospheric pressure.
  • reduced pressure may be from about 10 mbar to about 50 mbar.
  • ambient conditions refer to atmospheric pressure and a temperature of 22-24°C.
  • water content is measured by Karl Fischer (KF) analysis.
  • the present disclosure includes a crystalline polymorph of sitravatinib hydrochloride, designated Form A.
  • the crystalline Form A of sitravatinib hydrochloride may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; an X-ray powder diffraction pattern having peaks at 6.9, 16.3, 17.7, 23.9 and 24.9 degrees 2-theta ⁇ 0.2 degrees 2-theta; a 13 C solid state NMR spectrum with characteristic peaks: 169.7, 135.4, 100.7, 62.5 ⁇ 0.2 ppm; a 13 C solid state NMR spectrum having characteristic chemical shift differences between peaks at 169.7, 135.4, 100.7, 62.5 and a reference peak at 11.9 ⁇ 0.2 ppm of: 157.8, 123.5, 88.8 and 50.6 ⁇ 0.1 ppm; a 13 C solid state NMR spectrum substantially as depicted in Figure 15, and combinations of these data.
  • Crystalline Form A of sitravatinib hydrochloride may be further characterized by an X- ray powder diffraction pattern having peaks at 6.9, 16.3, 17.7, 23.9 and 24.9 degrees 2-theta ⁇
  • Crystalline Form A of sitravatinib hydrochloride may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 6.9, 12.3, 15.8, 16.3, 17.7, 18.8, 21.4, 23.9,
  • Crystalline Form A of sitravatinib hydrochloride may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 6.9, 16.3, 17.7, 23.9 and 24.9 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1; and combinations thereof.
  • Crystalline Form A sitravatinib hydrochloride may be anhydrous.
  • the above crystalline polymorph can be used to prepare other crystalline polymorphs of sitravatinib or sitravatinib salts.
  • the present disclosure includes a crystalline polymorph of sitravatinib malate, designated Form A.
  • Crystalline sitravatinib malate Form A may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 2; an X-ray powder diffraction pattern having peaks at 6.0, 8.5, 9.5, 14.6 and 15.3 degrees 2-theta ⁇ 0.2 degrees 2-theta; a solid state 13 C NMR spectrum having characteristic peaks at 150.2, 133.7, 69.6 and 66.2 ⁇ 0.2 ppm; A solid state 13 C NMR having characteristic chemical shift differences between peaks at 150.2, 133.7, 69.6, 66.2 and a reference peak at 13.4 ⁇ 0.2 ppm of: 136.8, 120.3, 56.2 and 52.8 ⁇ 0.1 ppm; a solid state 13 C NMR spectrum as depicted in figure 12, and combinations of these data.
  • Crystalline sitravatinib malate Form A may be further characterized by an X-ray powder diffraction pattern having peaks at 6.0, 8.5, 9.5, 14.6 and 15.3 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having any one, two, three, four or five additional peaks selected from 12.0, 13.5,
  • Crystalline Form A of sitravatinib malate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 6.0, 8.5, 9.5, 12.0, 13.5, 14.6, 15.3, 20.3, 21.1, 21.9 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline Sitravatinib malate Form A may be polymorphically pure.
  • crystalline sitravatinib malate Form A may be a hydrate.
  • sitravatinib malate form A may contain from about 4% to about 8%, about 4.5 to about 7.5%, about 5% to about 7%, about 5.5% to about 7%, about 6 to about 6.7% of water or about 6.52% (by weight) of water as measured by Karl-Fischer (KF).
  • Crystalline sitravatinib malate Form A may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 6.0, 8.5, 9.5, 14.6 and 15.3 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 2; and combinations thereof.
  • Crystalline Sitravatinib Form A may be advantageously stable, for example to conditions of liquid assisted grinding, e.g. grinding with 0.02 mL of solvent such as 2-propanol on a sample of 50 gram for 2 minutes
  • Sitravatinib malate form A may be prepared by the methods disclosed herein.
  • the present disclosure includes a crystalline polymorph of sitravatinib malate, designated Form B.
  • Crystalline sitravatinib malate Form B may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 4; an X-ray powder diffraction pattern having peaks at 7.0, 10.5, 11.4, 12.3 and 20.6 degrees 2- theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
  • Crystalline sitravatinib malate Form B may be further characterized by an X-ray powder diffraction pattern having peaks at 7.0, 10.5, 11.4, 12.3 and 20.6 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having any one, two, three, four or five additional peaks selected from 5.7, 13.7,
  • Crystalline Form B of sitravatinib malate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 5.7, 7.0, 10.5, 11.4, 12.3, 13.7, 14.3, 16.2, 20.6, 25.2 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline sitravatinib malate Form B may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.0,
  • crystalline sitravatinib malate Form B may be polymorphically pure.
  • crystalline sitravatinib malate Form B may be a solvate. Specifically 1-pentanol solvate.
  • the present disclosure includes a crystalline polymorph of sitravatinib malate, designated Form C.
  • Crystalline sitravatinib malate Form C may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 5; an X-ray powder diffraction pattern having peaks at 9.8, 14.0, 15.7, 16.3 and 18.2 degrees 2- theta ⁇ 0.2 degrees 2-theta; a solid state 13 C NMR spectrum having characteristic peaks at 168.2,
  • Crystalline sitravatinib malate Form C may be further characterized by an X-ray powder diffraction pattern having peaks at 9.8, 14.0, 15.7, 16.3 and 18.2 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having any one, two, three, four or five additional peaks selected from 8.9, 12.3, 13.1, 17.0 and 20.6 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form C of sitravatinib malate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 8.9, 9.8, 12.3, 13.1, 14.0, 15.7, 16.3, 17.0, 18.2, 20.6 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline Sitravatinib malate Form C may be polymorphically pure.
  • crystalline sitravatinib malate Form C may be a hydrate.
  • crystalline Form C may contain from: about 3 to about 5%, about 3.5 to about 4.5%, or about 4.2% (by weight) of water, as determined by Karl -Fischer (KF).
  • Crystalline sitravatinib malate Form C may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 9.8, 14.0, 15.7, 16.3 and 18.2 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 5; and combinations thereof.
  • Crystalline sitravatinib malate Form C may be prepared by the methods disclosed herein.
  • the present disclosure includes a crystalline polymorph of sitravatinib malate, designated Form D.
  • Crystalline sitravatinib malate Form D may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 6; an X-ray powder diffraction pattern having peaks at 8.2, 10.1, 12.3, 17.8 and 21.7 degrees 2- theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
  • Crystalline sitravatinib malate Form D may be further characterized by an X-ray powder diffraction pattern having peaks at 8.2, 10.1, 12.3, 17.8 and 21.7 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having any one, two, three, four or five additional peaks selected from 6.2, 13.2, 14.5, 16.1 and 20.6 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form D of sitravatinib malate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 6.2, 8.2, 10.1, 12.3, 13.2, 14.5, 16.1, 17.8, 20.6 and
  • Crystalline sitravatinib malate Form D may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 8.2,
  • the present disclosure includes a crystalline polymorph of sitravatinib malate, designated Form E.
  • Crystalline sitravatinib malate Form E may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 7; an X-ray powder diffraction pattern having peaks at 5.8, 9.2, 11.6, 12.3 and 14.7 degrees 2- theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
  • Crystalline sitravatinib malate Form E may be further characterized by an X-ray powder diffraction pattern having peaks at 5.8, 9.2, 11.6, 12.3 and 14.7 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having any one, two, three, four or five additional peaks selected from 8.4, 18.2,
  • Crystalline Form E of sitravatinib malate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 5.8, 8.4, 9.2, 11.6, 12.3, 14.7, 18.2, 19.2, 20.2 and
  • Crystalline sitravatinib malate Form E may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 5.8, 9.2, 11.6, 12.3, 14.7 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 7; and combinations thereof.
  • the present disclosure includes a crystalline polymorph of sitravatinib malate, designated Form F.
  • Crystalline sitravatinib malate Form F may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 8; an X-ray powder diffraction pattern having peaks at 8.8, 11.4, 12.5, 16.1 and 16.6 degrees 2- theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
  • Crystalline sitravatinib malate Form F may be further characterized by an X-ray powder diffraction pattern having peaks at 8.8, 11.4, 12.5, 16.1, 16.6 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having any one, two, three, four or five additional peaks selected from 7.8, 14.3, 15.5, 18.2, 20.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form F of sitravatinib malate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 7.8, 8.8, 11.4, 12.5, 14.3, 15.5, 16.1, 16.6, 18.2, 20.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline sitravatinib malate Form F may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 8.8,
  • Crystalline polymorph of sitravatinib malate designated Form A-F as described in any aspect or embodiment or any of the disclosure herein may be a salt of sitravatinib and malic acid, wherein the malic acid can be L-malic acid, D-malic acid, or a mixture of L-malic acid and D- malic acid (such as a racemic mixture, i.e., D, L-malic acid), and preferably a salt of sitravatinib and L-malic acid.
  • crystalline polymorph of sitravatinib malate designated Form A-F may be a co-crystal or complex of sitravatinib and malic acid, wherein the malic acid can be L-malic acid, D-malic acid, or a mixture of L-malic acid and D-malic acid (such as a racemic mixture, i.e., D, L-malic acid), and preferably a co-crystal or complex of sitravatinib and L-malic acid.
  • the present disclosure further provides a general process for preparing a salt of Sitravatinib and malic acid, preferably a crystalline salt of Sitravatinib and malic acid, and more preferably a crystalline salt of Sitravatinib and L-malic acid.
  • the salt of Sitravatinib and malic acid may be any form, including amorphous form, or forms A-F as described herein.
  • the process may comprise: (i) combining Sitravatinib and malic acid, optionally L-malic acid in the presence of one or more solvents to form a mixture; (ii) optionally isolating, and (iii) optionally drying the salt.
  • the present disclosure particularly provides a general process for preparing a crystalline salt of Sitravatinib and malic acid, preferably Sitravatinib and L-malic acid, comprising: (i) combining Sitravatinib and malic acid, preferably L-malic acid in the presence of one or more solvents to form a mixture; (ii) optionally isolating the crystalline salt; and (iii) optionally drying the crystalline salt.
  • the mixture in step (i) from which the crystalline salt may be isolated is in the form of a suspension.
  • the sitravatinib starting material is in a solution comprising one or more solvents, or alternatively the Sitravatinib starting material and malic acid (preferably L-malic acid), are combined with one or more polar solvents.
  • the above described general process may be used for preparing Form A of the crystalline salt of Sitravatinib and malic acid as described in any aspect or embodiment of the disclosure.
  • step (i) of the above process comprises combining a mixture of Sitravatinib in one or more polar solvents with the malic acid, preferably L-malic acid, optionally under heating and optionally cooling the mixture; or wherein step (i) comprises combining Sitravatinib and malic acid, preferably L-malic acid, and a polar solvent.
  • the mixture of Sitravatinib in one or more polar solvents is preferably a solution.
  • the solution may be optionally heated, typically to a temperature of about 30°C to about 80°C, about 35°C to about 70°C, about 40°C to about 60°C, or about 45°C to about 55°C, or about 45°C to about 50°C.
  • the malic acid preferably L-malic acid
  • the mixture in step (i) is heated, preferably to temperature of: about 30°C to about 80°C, about 35°C to about 70°C, about 40°C to about 60°C, or about 45°C to about 55°C, or about 45°C to about 50°C.
  • the heating may be carried out for any suitable period of time, for example about 5 minutes to about 3 hours, about 10 minutes to about 2 hours, about 15 minutes to about 1 hour, or about 30 minutes.
  • the mixture can be cooled in step (i), optionally to a temperature of: about 5°C to about 30°C, about 10°C to about 30°C, about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C, prior to isolation of the salt.
  • the cooling may be optionally stirred, for example for a period of about 1 hour to about 72 hours, about 3 hours to about 48 hours, about 5 hours to about 36 hours, about 6 hours to about 24 hours, about 8 hours to about 10 hours.
  • the polar solvent comprises, consists of, or consists essentially of an alcohol or a ketone, or a combination thereof; preferably a C1-3 alcohol or a C3-6 ketone, or a combination thereof; more preferably methanol, acetone, or methyl ethyl ketone, or a combination thereof; and particularly methanol, acetone, methyl ethyl ketone, or a combination of methanol and acetone or methanol and methyl ethyl ketone.
  • the salt may be isolated by any suitable procedure and may be optionally dried.
  • step (i) may comprise combining the Sitravatinib starting material and malic acid, optionally L-malic acid, with one or more polar solvents, (ii) optionally heating, and (iii) optionally cooling the mixture.
  • the mixture may be heated to a temperature of about 40°C to about 90°C, about 45°C to about 80°C, about 50°C to about 70°C, or about 55°C to about 65°C, or about 60°C.
  • the heating may be carried out for any suitable period of time, particularly for a period of about 5 minutes to about 3 hours, about 10 minutes to about 2 hours, about 15 minutes to about 1 hour, or about 30 minutes to obtain a suspension.
  • the mixture in step (i) can be cooled, optionally to a temperature of: about 5°C to about 30°C, about 10°C to about 30, about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.
  • a further quantity of the polar solvent may be added.
  • the mixture may be stirred for a suitable period of time, typically about 1 hour to about 72 hours, about 3 hours to about 48 hours, about 5 hours to about 36 hours, about 6 hours to about 24 hours, about 8 hours to about 10 hours.
  • the polar solvent comprises, consists of, or consists essentially of an alcohol, preferably a Ci-3 alcohol, and more preferably methanol.
  • step (ii) comprises isolating the salt from the mixture, optionally by filtration, decantation or centrifuge, optionally by filtration.
  • the amorphous salt of Sitravatinib and malic acid may be prepared by evaporation (e.g.
  • the solvent or solvents preferably wherein the solvent comprises a mixture of acetone/water, optionally in a volume ratio of about 5: 1 to about 1:5, about 5: 1 to about 1 :2, about 4: 1 to about 1:1, about 4: 1 to about 2: 1, or about 3 : 1) from a solution of Sitravatinib and malic acid (preferably L-malic acid), preferably under reduced pressure for a suitable period of time.
  • the molar ratio of Sitravatinib to malic acid, optionally L-malic acid is from about 1:2 to about 2:1, about 1:1.5 to about 1.5:1, about 1:1.2 to about 1.2:1, about 1:1.1 to about 1.1:1, and preferably about 1:1.
  • the malic acid is L-malic acid.
  • the drying in step (iii) may be carried out under reduced pressure, preferably at a temperature of: about 40°C to about 90°C, about 45°C to about 80°C, about 50°C to about 70°C, or about 55°C to about 65°C, or about 60°C, for any suitable period of time, preferably for a period of: about 2 to about 12 hours, about 4 to about 8 hours, or about 6 hours, or to reach a constant mass.
  • the drying may be carried out at room temperature for a suitable period of time.
  • the process as described herein may further comprise a step of combining the salt of Sitravatinib and malic acid with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.
  • the present disclosure includes a crystalline polymorph of sitravatinib tartarate, designated Form A.
  • Crystalline sitravatinib tartarate Form A may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 9; an X-ray powder diffraction pattern having peaks at 5.9, 9.3, 12.5, 15.0 and 17.2 degrees 2-theta ⁇ 0.2 degrees 2-theta; a 13 C solid state NMR spectrum with characteristic peaks: 177.6, 129.4, 74.5, 59.9 ⁇ 0.2 ppm; a 13 C solid state NMR spectrum having characteristic chemical shift differences between peaks at 177.6, 129.4, 74.5, 59.9 and a reference peak at 14.1 ⁇ 0.2 ppm of: 163.5, 115.3, 60.4 and 45.8 ⁇ 0.1 ppm; a 13 C solid state NMR spectrum substantially as depicted in Figure 16, and combinations of these data.
  • Crystalline sitravatinib tartarate Form A may be further characterized by an X-ray powder diffraction pattern having peaks at 5.9, 9.3, 12.5, 15.0 and 17.2 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from
  • Crystalline Form A of sitravatinib tartarate may alternatively be characterized by an X- ray powder diffraction pattern having peaks at 4.2, 5.9, 8.3, 9.3, 12.5, 15.0, 17.2, 17.7, 20.9 and 22.9 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline sitravatinib tartarate Form A may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 5.9,
  • Crystalline polymorph of sitravatinib tartarate Form A as described in any aspect or embodiment or any of the disclosure herein may be a salt of sitravatinib and tartaric acid, wherein the tartaric acid can be L-tartaric acid, D-tartaric acid, or a mixture of L-tartaric acid and D-tartaric acid (such as a racemic mixture, i.e., D, L-tartaric acid), and preferably a salt of sitravatinib and L-tartaric acid.
  • crystalline polymorph of sitravatinib tartarate designated Form A may be a co-crystal or complex of sitravatinib and tartaric acid, wherein the tartaric acid can be L-tartaric acid, D- tartaric acid, or a mixture of L-tartaric acid and D-tartaric acid (such as a racemic mixture, i.e., D, L-tartaric acid), and preferably a co-crystal or complex of sitravatinib and L-tartaric acid.
  • the tartaric acid can be L-tartaric acid, D- tartaric acid, or a mixture of L-tartaric acid and D-tartaric acid (such as a racemic mixture, i.e., D, L-tartaric acid)
  • a racemic mixture i.e., D, L-tartaric acid
  • the present disclosure includes a crystalline polymorph of sitravatinib succinate, designated Form A.
  • Crystalline sitravatinib succinate Form A may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 10; an X-ray powder diffraction pattern having peaks at 6.2, 7.6, 9.8, 11.3 and 12.4 degrees 2-theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
  • Crystalline sitravatinib succinate Form A may be further characterized by an X-ray powder diffraction pattern having peaks at 6.2, 7.6, 9.8, 11.3 and 12.4 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 10.5, 17.3, 20.5, 21.3 and 23.7 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form A of sitravatinib succinate may alternatively be characterized by an X- ray powder diffraction pattern having peaks at 6.2, 7.6, 9.8, 10.5, 11.3 12.4, 17.3, 20.5, 21.3 and 23.7 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline sitravatinib succinate Form A may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 6.2, 7.6, 9.8, 11.3 and 12.4 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 10; and combinations thereof.
  • the present disclosure includes a crystalline polymorph of sitravatinib fumarate, designated Form A.
  • Crystalline sitravatinib fumarate Form A may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 11; an X-ray powder diffraction pattern having peaks at 5.8, 9.2, 11.7, 12.5 and 20.8 degrees 2-theta ⁇ 0.2 degrees 2-theta; a solid state 13 C NMR spectrum having characteristic peaks at 172.2, 146.5, 133.8, 99.4 ⁇ 0.2 ppm; 172.2, 146.5, 133.8, 99.4 and a reference peak at 13.9 ⁇ 0.2 ppm of: 158.3, 132.6, 119.9 and 85.5 ⁇ 0.1 ppm; a solid state 13 C NMR spectrum as depicted in figure 14; and combinations of these data.
  • Crystalline sitravatinib fumarate Form A may be further characterized by an X-ray powder diffraction pattern having peaks at 5.8, 9.2, 11.7, 12.5 and 20.8 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 14.5, 17.1, 18.0, 19.3 and 23.9 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form A of sitravatinib fumarate may alternatively be characterized by an X- ray powder diffraction pattern having peaks at 5.8, 9.2, 11.7, 12.5, 14.5, 17.1, 18.0, 19.3, 20.8 and 23.9 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline Sitravatinib fumarate Form A may be polymorphically pure.
  • crystalline sitravatinib fumarate Form A may be a hydrate.
  • crystalline sitravatinib fumarate Form A may contain about 4 to about 6, about 4.5 to about 5.5, or about 5 % (by weight) of water determined by Karl- Fischer (KF).
  • Crystalline sitravatinib fumarate Form A may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 5.8, 9.2, 11.7, 12.5 and 20.8 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 11; and combinations thereof.
  • any of the solid state forms of Sitravatinib salts may be polymorphically pure, e.g. the form may be substantially free of any other solid state forms of the subject Sitravatinib salt.
  • a solid state form of Sitravatinib malate may be polymorphically pure, and may be substantially free of any other solid state forms of the subject Sitravatinib salt, i.e.
  • Sitravatinib malate for example Sitravatinib L-malate may be polymorphically pure and may be substantially free of any other solid state forms of Sitravatinib L-malate).
  • any of the solid state forms of the Sitravatinib salts may contain: about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, about 0.5% (w/w) or less, about 0.2% (w/w) or less, about 0.1% (w/w) or less, or about 0%, of any other solid state forms of the subject compound, preferably as measured by XRPD.
  • any of the disclosed crystalline forms of the Sitravatinib salts described herein may be substantially free of any other solid state forms of the subject Sitravatinib salt, and may contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject solid state form of the Sitravatinib salt.
  • the present disclosure also encompasses the use of crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, tartarate, succinate and fumarate of the present disclosure for the preparation of pharmaceutical compositions thereof.
  • the present disclosure includes processes for preparing the above mentioned pharmaceutical compositions.
  • the processes include combining any one or a combination of the crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate of the present disclosure with at least one pharmaceutically acceptable excipient.
  • compositions of the present invention contain the solid state form of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate of the present disclosure.
  • the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.
  • Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle.
  • Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfme cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
  • microcrystalline cellulose e.g., Avicel®
  • microfme cellulose lactose
  • starch pregelatinized starch
  • calcium carbonate calcium sulfate
  • sugar dextrates
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g.
  • Methocel® liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.
  • povidone e.g. Kollidon®, Plasdone®
  • pregelatinized starch sodium alginate, and starch.
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac- Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.
  • alginic acid include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac- Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplas
  • Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
  • Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
  • a dosage form such as a tablet is made by the compaction of a powdered composition
  • the composition is subjected to pressure from a punch and dye.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
  • Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
  • Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
  • Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • liquid pharmaceutical compositions of the present invention sitravatinib hydrochloride and sitravatinib malate and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
  • Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
  • a viscosity enhancing agent include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.
  • Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.
  • a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate.
  • the solid compositions of the present invention include powders, granulates, aggregates, and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the route of administration is oral.
  • the dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
  • Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.
  • the dosage form of the present invention can be a capsule containing the composition, in embodiments a powdered or granulated solid composition of the present disclosure, within either a hard or soft shell.
  • the shell can be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
  • compositions and dosage forms can be formulated into compositions and dosage forms according to methods known in the art.
  • a composition for tableting or capsule filling can be prepared by wet granulation.
  • wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules.
  • the granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size.
  • the granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.
  • a tableting composition can be prepared conventionally by dry blending.
  • the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.
  • a blended composition can be compressed directly into a compacted dosage form using direct compression techniques.
  • Direct compression produces a more uniform tablet without granules.
  • Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
  • a capsule filling of the present invention can comprise any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.
  • a pharmaceutical formulation of sitravatinib compounds of this disclosure can be administered.
  • the compounds of this disclosure may be formulated for administration to a mammal, in embodiments a human, by injection sitravatinib compounds of this disclosure can be formulated, for example, as a viscous liquid solution or suspension, in embodiments a clear solution, for injection.
  • the formulation can contain one or more solvents.
  • a suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity.
  • Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. See, e.g., Ansel et ah, Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.
  • the crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate, sitravatinib succinate and the pharmaceutical compositions and/or formulations thereof of the present disclosure can be used as medicaments, in embodiments of patients with cancer diseases including lung cancer.
  • the present disclosure also provides methods of treating lung cancer diseases by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of sitravatinib compounds of the present disclosure, or at least one of the above pharmaceutical compositions and/or formulations, to a subject in need of the treatment.
  • the sample was powdered in a mortar and pestle and applied directly on a silicon plate holder.
  • Solid state nuclear magnetic resonance (“ssNMR”) method Solid state nuclear magnetic resonance (ssNMR) method
  • Solid state NMR analysis was done at Joint Laboratory of Solid State NMR Spectroscopy in Prague, Czech Republic.
  • the spectra was measured at 11.7 T using a Bruker Avance III HD 500 US/WB NMR spectrometer (Karlsruhe, Germany, 2013).
  • the 13 C CP/MAS NMR spectra employing cross-polarization were acquired using the standard pulse scheme at spinning frequency of 11 kHz.
  • the recycle delay was 8 s and the cross-polarization contact time was 2 ms.
  • Sitravatinib used for the below examples can be prepared according to any procedure known from the literature for example as appear in International Publication No. WO 2009/026717.
  • Example 1 Preparation of Sitravatinib hydrochloride Form A
  • Sitravatinib (80 mg) was dissolved in methanol/methyl tert-butyl ether (18 mL; 1 : 1 v/v) by heating to about 50°C. Hydrochloric acid, 37% (0.018 mL) was added in one portion and the reaction mixture was stirred for 30 minutes after which crystallization occurred. The heating was discontinued and the suspension was left to cool down to room temperature and then was stirred for 12 hours. The solid was filtered and analyzed by XRPD and identified as Sitravatinib hydrochloride form A ( Figure 1).
  • Sitravatinib malate form C (0.1 grams) was placed in ‘Anton Paar TTK 450’ chamber on Philips X'Pert PRO X-ray powder diffractometer. The sample was heated up to 100°C by heating rate 5°C/min and analysed by XRPD. Sitravatinib malate form D as in Figure 6 was obtained.
  • Sitravatinib malate form C (0.6 grams) was suspended in toluene (20 mL) at 110°C and stirred for 5 hours. Solid was isolated by vacuum filtration and analysed by XRPD. Sitravatinib malate form E was obtained. An XRPD pattern is shown in Figure 7.
  • Sitravatinib (1.0 g) was dissolved in MEK (25 mL) by heating to 45-50°C. Z-Malic acid (256 mg) was added to the solution. The obtained suspension was stirred for 30 minutes at about 45°C, then cooled to room temperature and stirred overnight. The solid was filtered and dried in a vacuum oven at 60°C for 6 hours. Obtained product was analyzed by XRPD. Sitravatinib malate form A was obtained.

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Abstract

La présente divulgation concerne des formes à l'état solide de sels de sitravatinib, des procédés pour leur préparation, et des compositions pharmaceutiques de celles-ci. La présente divulgation concerne des formes à l'état solide de malate de sitravatinib, de chlorhydrate de sitravatinib, de tartrate de sitravatinib, de fumarate de sitravatinib et de succinate de sitravatinib, leurs procédés de préparation, et des compositions pharmaceutiques de celles-ci.
PCT/US2022/028466 2021-05-10 2022-05-10 Formes à l'état solide de sels de sitravatinib et leur procédé de préparation WO2022240802A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009026717A1 (fr) 2007-08-29 2009-03-05 Methylgene Inc. Inhibiteurs de l'activité protéine tyrosine kinase
WO2021050580A1 (fr) 2019-09-10 2021-03-18 Mirati Therapeutics, Inc. Forme cristalline d'un inhibiteur de la tyrosine kinase multiple, son procédé de préparation et son utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009026717A1 (fr) 2007-08-29 2009-03-05 Methylgene Inc. Inhibiteurs de l'activité protéine tyrosine kinase
WO2021050580A1 (fr) 2019-09-10 2021-03-18 Mirati Therapeutics, Inc. Forme cristalline d'un inhibiteur de la tyrosine kinase multiple, son procédé de préparation et son utilisation

Non-Patent Citations (1)

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Title
ANSEL ET AL., PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS

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