WO2019213106A1 - Formes à l'état solide d'idasanutline - Google Patents

Formes à l'état solide d'idasanutline Download PDF

Info

Publication number
WO2019213106A1
WO2019213106A1 PCT/US2019/029951 US2019029951W WO2019213106A1 WO 2019213106 A1 WO2019213106 A1 WO 2019213106A1 US 2019029951 W US2019029951 W US 2019029951W WO 2019213106 A1 WO2019213106 A1 WO 2019213106A1
Authority
WO
WIPO (PCT)
Prior art keywords
idasanutlin
theta
degrees
solid state
peaks
Prior art date
Application number
PCT/US2019/029951
Other languages
English (en)
Inventor
Anantha Rajmohan MUTHUSAMY
Amit Singh
Kanhaiyalal
Original Assignee
Teva Pharmaceuticals International Gmbh
Teva Pharmaceuticals Usa, 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
Application filed by Teva Pharmaceuticals International Gmbh, Teva Pharmaceuticals Usa, Inc. filed Critical Teva Pharmaceuticals International Gmbh
Publication of WO2019213106A1 publication Critical patent/WO2019213106A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present disclosure relates to solid state forms of Idasanutlin and salts thereof, processes for preparation thereof and pharmaceutical compositions thereof.
  • Idasanutlin has the chemical name 4-((2R,3S,4R,5S)-3-(3-chloro-2- fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)- 3-methoxybenzoic acid.
  • Idasanutlin has the following chemical structure:
  • Idasanutlin is under development by Roche to treat cancer, in particular, acute myeloid leukaemia.
  • a pharmaceutical composition comprising a stabilized solid amorphous dispersion, various salts of Idasanutlin and process for preparation thereof are known from WO2014114575. Solid forms of Idasanutlin are known from WO2015158648. Polymorphs and pseudo-polymorphs are also known from Practical Synthesis of MDM2 Antagonist RG7388. Part 2: Development of the Cu(I) Catalyzed [3 + 2] Asymmetric Cycloaddition Process for the Manufacture of Idasanutlin; Org. Process Res. Dev. 2016, 20, 2057-2066.
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single compound like Idasanutlin, 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”), powder X-ray diffraction (PXRD) pattern, infrared absorption fingerprint,
  • Raman absorption fingerprint and solid state ( 13 C-) NMR spectrum.
  • One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
  • Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.
  • New salts, polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life.
  • the present disclosure relates to solid state forms of Idasanutlin and salts thereof, to processes for preparation thereof, and to pharmaceutical compositions comprising these solid state forms.
  • Idasanutlin and salts thereof for preparing other solid state forms of Idasanutlin, Idasanutlin salts and solid state forms thereof.
  • the present disclosure encompasses the above described solid state forms of Idasanutlin and salts thereof for use as a medicament, preferably for the treatment of cancer.
  • the present disclosure encompasses methods for treating cancers comprising the use of the above described solid state form of Idasanutlin and salts thereof
  • the present disclosure further provides the use of any of the solid state forms of Idasanutlin and salts thereof described according to any embodiment herein, for the preparation of a pharmaceutical composition or a pharmaceutical formulation of Idasanutlin, wherein the Idasanutlin in the pharmaceutical composition or formulation is in a solid form, wherein the solid form may be any crystalline form or an amorphous form.
  • the present disclosure further provides pharmaceutical compositions comprising the solid state forms of Idasanutlin and salts thereof according to the present disclosure.
  • compositions comprising the above described solid state forms of Idasanutlin and salts thereof and at least one pharmaceutically acceptable excipient, preferably for oral administration in a dosage forms such as tablets, capsules etc.
  • the present disclosure encompasses processes to prepare said pharmaceutical formulations of Idasanutlin comprising combining the above solid state forms and at least one pharmaceutically acceptable excipient.
  • solid state forms as defined herein, as well as the pharmaceutical compositions or formulations of the solid state form of Idasanutlin and salts thereof, can be used as medicaments, particularly for the treatment of cancer.
  • the present disclosure also provides methods of treating cancer, comprising administering a therapeutically effective amount of the solid state form of Idasanutlin and salts thereof of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from cancer, or otherwise in need of the treatment.
  • the present disclosure also provides use of the solid state forms of Idasanutlin and salts thereof of the present disclosure, or at least one of the above pharmaceutical compositions or formulations for the manufacture of a medicament for treating cancer.
  • Figure 1 shows a powder X-ray diffraction pattern ("powder XRD” or "PXRD”) of Idasanutlin form Tl.
  • FIG. 2 shows a PXRD of Idasanutlin form T2.
  • FIG. 3 shows a PXRD of Idasanutlin form T3.
  • FIG. 4 shows a PXRD of Idasanutlin form T4.
  • Figure 5 shows a PXRD of Idasanutlin form T5.
  • Figure 6 shows a PXRD of Idasanutlin form T6.
  • Figure 7 shows a PXRD of Idasanutlin form T7.
  • Figure 8 shows a PXRD of Idasanutlin form T8.
  • Figure 9 shows a PXRD of Idasanutlin form T9.
  • Figure 10 shows a PXRD of Idasanutlin form T10.
  • Figure 11 shows a PXRD of Idasanutlin form Tl 1.
  • FIG. 12 shows a PXRD of Idasanutlin form T12
  • Figure 13 shows a solid state 13 C NMR spectrum of Idasanutlin form T12
  • Figure 14 shows a solid state 13 C NMR spectrum of Idasanutlin form T12 (0- lOOppm)
  • Figure 15 shows a solid state C NMR spectrum of Idasanutlin form T12
  • Figure 16 shows a PXRD of Idasanutlin form T13
  • Figure 17 shows a solid state 13 C NMR spectrum of Idasanutlin form Tl
  • Figure 18 shows a solid state 13 C NMR spectrum of Idasanutlin form Tl (0- lOOppm)
  • Figure 19 shows a solid state 13 C NMR spectrum of Idasanutlin form Tl
  • the present disclosure relates to solid state forms of Idasanutlin, in particular to crystalline forms of Idasanutlin and salts thereof, processes for preparation thereof and pharmaceutical compositions comprising said solid state forms.
  • the solid state forms of Idasanutlin according to the present disclosure may have advantageous properties selected from at least one of: chemical or polymorphic purity, flowability, solubility, dissolution rate, bioavailability, 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, a lower degree of hygroscopicity, low content of residual solvents and advantageous processing and handling characteristics such as compressibility, or bulk density.
  • a crystal form may be referred to herein as being characterized by graphical data "as 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 can not necessarily be described by reference to numerical values or peak positions alone.
  • the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person.
  • a crystal form of Idasanutlin and salts thereof referred to herein as being characterized by graphical data "as depicted in" a Figure will thus be understood to include any crystal forms of the Idasanutlin and salts thereof, characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.
  • a solid state form (or polymorph) may be referred to herein as
  • the expression “substantially free of any other forms” will be understood to mean that the solid state form contains about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% of any other forms of the subject compound as measured, for example, by PXRD.
  • solid state of Idasanutlin and Idasanutlin salts 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% (w/w) of the subject solid state form of Idasanutlin and Idasanutlin salts.
  • the described solid state forms of Idasanutlin and Idasanutlin salts may contain from about 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 solid state forms of the same Idasanutlin and Idasanutlin salts.
  • 13 C NMR reported herein are measured at 400 MHz at a spin rate of 11 kHz, preferably at a temperature of 294.5K.
  • the term "isolated" in reference to solid state forms of Idasanutlin and Idasanutlin salts, of the present disclosure corresponds to solid state forms of Idasanutlin and Idasanutlin salts that are physically separated from the reaction mixture in which it is formed.
  • a thing e.g., a reaction mixture
  • room temperature often abbreviated "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.
  • 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 to about 18 hours, typically about 16 hours.
  • 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 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 (or dissolved) 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 (or dissolved), such that suspending (or dissolving) 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 dissolved) 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 methyl tert-butyl ether (MTBE) (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of MTBE was added.
  • MTBE methyl tert-butyl ether
  • reduced pressure refers to a pressure of about 10 mbar to about 50 mbar.
  • an“anhydrous” in relation to crystalline Idasanutlin relates to a crystalline Idasanutlin which does not include any crystalline water (or other solvents) in a defined or non defined, stoichiometric amount within the crystal.
  • an“anhydrous” form does not contain more than 1% (w/w) of either water or organic solvents as measured for example by TGA or by any other suitable method, such as Karl Fischer.
  • Idasanutlin form I is characterized by the XRPD patterns at 2-theta values of 4.9, 6.9, 7.7, 9.1, 10.9, 13.5, 14.5, 17.2, 20.4, 22.3 and 25.5.
  • the present disclosure comprises a crystalline form of Idasanutlin designated as form Tl .
  • the crystalline form Tl of Idasanutlin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 3.8, 8.0, 14.0, 14.7 and 16.7 degrees 2-theta ⁇ 0.2 degrees 2-theta; a PXRD pattern as depicted in figure 1; a solid state 13 C NMR spectrum with peaks at 120.17, 124.88, 132.28, 148.29 and 159.58 ppm ⁇ 0.2 ppm; by a solid state 13 C NMR spectrum having the following chemical shift absolute differences from a peak at 116.72 ppm ⁇ 2 ppm of 3.45, 8.16, 15.56, 17.77, 31.57 and 42.86ppm ⁇ 0.1 ppm; by a solid state 13 C NMR spectrum having the following chemical shift absolute differences from a peak at 120.17 ppm ⁇ 1 ppm of
  • Crystalline form Tl of Idasanutlin may be further characterized by the PXRD pattern having peaks at 3.8, 8.0, 14.0, 14.7 and 16.7 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having one, two, three, four or five additional peaks at 17.9, 19.6, 21.6, 23.8 and 26.7 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline form Tl of Idasanutlin may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., by PXRD pattern having peaks at 3.8, 8.0, 14.0, 14.7 and 16.7 degrees 2-theta ⁇ 0.2 degrees 2-theta and a PXRD pattern as depicted in figure 1.
  • embodiments may be an anhydrous form.
  • embodiments may have Hausner ratio less than 1.5, less than 1.45, e.g. 1.4 or less.
  • the present disclosure comprises a crystalline form of Idasanutlin designated as form T2.
  • the crystalline form T2 of Idasanutlin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 6.4, 7.6, 9.2, 11.9 and 20.0 degrees 2-theta ⁇ 0.2 degrees 2-theta; a PXRD pattern as depicted in figure 2 and combinations of these data.
  • Crystalline form T2 of Idasanutlin may be further characterized by the PXRD pattern having peaks at 6.4, 7.6, 9.2, 11.9 and 20.0 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having one, two, three, four or five additional peaks at 8.7, 15.3, 18.0, 19.4 and 25.2 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline form T2 of Idasanutlin may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., by PXRD pattern having peaks at 6.4, 7.6, 9.2, 11.9 and 20.0 degrees 2-theta ⁇ 0.2 degrees 2-theta and a PXRD pattern as depicted in figure 2.
  • embodiments may be a DMF solvate.
  • the present disclosure comprises a crystalline form of Idasanutlin designated as form T3.
  • the crystalline form T3 of Idasanutlin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 7.7, 13.1, 13.8, 15.1 and 17.4 degrees 2-theta ⁇ 0.2 degrees 2-theta; a PXRD pattern as depicted in figure 3 and combinations of these data.
  • Crystalline form T3 of Idasanutlin may be further characterized by the PXRD pattern having peaks at 7.7, 13.1, 13.8, 15.1 and 17.4 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having one, two, three, four or five additional peaks at 9.1, 19.8, 20.1, 25.5 and 26.1 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline form T3 of Idasanutlin may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., by PXRD pattern having peaks at 7.7, 13.1, 13.8, 15.1 and 17.4 degrees 2-theta ⁇ 0.2 degrees 2-theta and a PXRD pattern as depicted in figure 3.
  • embodiments may be a N,N-dimethyl acetamide solvate form.
  • the present disclosure comprises a crystalline form of Idasanutlin designated as form T4.
  • the crystalline form T4 of Idasanutlin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 6.0, 7.1, 15.0, 21.0 and 23.7 degrees 2-theta ⁇ 0.2 degrees 2-theta; a PXRD pattern as depicted in figure 4 and combinations of these data.
  • Crystalline form T4 of Idasanutlin may be further characterized by the PXRD pattern having peaks at 6.0, 7.1, 15.0, 21.0 and 23.7 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having one, two, three, four or five additional peaks at 17.9, 19.9, 24.4, 25.1 and 27.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline form T4 of Idasanutlin may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., by PXRD pattern having peaks at 6.0, 7.1, 15.0, 21.0 and 23.7 degrees 2-theta ⁇ 0.2 degrees 2-theta and a PXRD pattern as depicted in figure 4.
  • embodiments may be a DMSO solvate.
  • the present disclosure comprises a crystalline form of Idasanutlin designated as form T5.
  • the crystalline form T5 of Idasanutlin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 10.0, 10.4, 13.5, 16.6 and 17.9 degrees 2-theta ⁇ 0.2 degrees 2-theta; a PXRD pattern as depicted in figure 5 and combinations of these data.
  • Crystalline form T5 of Idasanutlin may be further characterized by the PXRD pattern having peaks at 10.0, 10.4, 13.5, 16.6 and 17.9 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks at 6.4, 20.2, 21.0, 22.7 and 23.1 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline form T5 of Idasanutlin may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., by PXRD pattern having peaks at 10.0, 10.4, 13.5, 16.6 and 17.9 degrees 2-theta ⁇ 0.2 degrees 2-theta and a PXRD pattern as depicted in figure 5.
  • embodiments may be a l,4-dioxane solvate.
  • the present disclosure comprises a crystalline form of Idasanutlin designated as form T6.
  • the crystalline form T6 of Idasanutlin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 8.6, 10.8, 12.9, 16.3, and 27.1 degrees 2-theta ⁇ 0.2 degrees 2-theta; a PXRD pattern as depicted in figure 6 and combinations of these data.
  • Crystalline form T6 of Idasanutlin may be further characterized by the PXRD pattern having peaks at 8.6, 10.8, 12.9, 16.3, and 27.1 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having one, two, three, four or five additional peaks at 6.0, 17.3, 18.7, 19.9 and 20.8 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline form T6 of Idasanutlin may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., by PXRD pattern having peaks at 8.6, 10.8, 12.9, 16.3, and 27.1 degrees 2-theta ⁇ 0.2 degrees 2-theta and a PXRD pattern as depicted in figure 6.
  • embodiments may be a NMP solvate.
  • the present disclosure comprises a crystalline form of Idasanutlin designated as form T7.
  • the crystalline form T7 of Idasanutlin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 8.6, 18.1, 19.0, 20.2 and 21.4 degrees 2-theta ⁇ 0.2 degrees 2-theta; a PXRD pattern as depicted in figure 7 and combinations of these data.
  • Crystalline form T7 of Idasanutlin may be further characterized by the PXRD pattern having peaks at 8.6, 18.1, 19.0, 20.2 and 21.4 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having one, two, three or four additional peaks at 13.5, 14.3, 17.4 and 27.7 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline form T7 of Idasanutlin may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., by PXRD pattern having peaks at 8.6, 18.1, 19.0, 20.2 and 21.4 degrees 2-theta ⁇ 0.2 degrees 2-theta and a PXRD pattern as depicted in figure 7.
  • embodiments may be an anhydrous form.
  • the present disclosure comprises a crystalline form of Idasanutlin designated as form T8.
  • the crystalline form T8 of Idasanutlin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 6.8, 8.0, 14.4, 17.5 and 23.2 degrees 2-theta ⁇ 0.2 degrees 2-theta; a PXRD pattern as depicted in figure 8 and combinations of these data.
  • Crystalline form T8 of Idasanutlin may be further characterized by the PXRD pattern having peaks at 6.8, 8.0, 14.4, 17.5 and 23.2 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having one, two, three or four additional peaks at 8.6, 10.9, 18.7 and 26.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline form T8 of Idasanutlin may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., by PXRD pattern having peaks at 6.8, 8.0, 14.4, 17.5 and 23.2 degrees 2-theta ⁇ 0.2 degrees 2-theta and a PXRD pattern as depicted in figure 8.
  • embodiments may be an ethanol solvate.
  • the present disclosure comprises a crystalline form of Idasanutlin designated as form T9.
  • the crystalline form T9 of Idasanutlin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 6.8, 8.0, 14.4, 17.5 and 23.2 degrees 2-theta ⁇ 0.2 degrees 2-theta; a PXRD pattern as depicted in figure 9 and combinations of these data.
  • Crystalline form T9 of Idasanutlin may be further characterized by the PXRD pattern having peaks at 6.8, 8.0, 14.4, 17.5 and 23.2 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having one, two, three or four additional peaks at 8.6, 10.9, 18.7 and 26.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline form T9 of Idasanutlin may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., by PXRD pattern having peaks at 6.8, 8.0, 14.4, 17.5 and 23.2 degrees 2-theta ⁇ 0.2 degrees 2-theta and a PXRD pattern as depicted in figure 9.
  • Crystalline form T9 of Idasanutlin according to any of the above embodiments may be a butyl acetate solvate.
  • the present disclosure comprises a crystalline form of Idasanutlin designated as form T10.
  • the crystalline form T10 of Idasanutlin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 6.8, 8.0, 14.4, 17.5 and 23.2 degrees 2-theta ⁇ 0.2 degrees 2-theta; a PXRD pattern as depicted in figure 10 and combinations of these data.
  • Crystalline form T10 of Idasanutlin may be further characterized by the PXRD pattern having peaks at 6.8, 8.0, 14.4, 17.5 and 23.2 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having one, two, three or four additional peaks at 8.6, 10.9, 18.7 and 26.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline form T10 of Idasanutlin may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., by PXRD pattern having peaks at 6.8, 8.0, 14.4, 17.5 and 23.2 degrees 2-theta ⁇ 0.2 degrees 2-theta and a PXRD pattern as depicted in figure 10.
  • Crystalline form T10 of Idasanutlin according to any of the above embodiments may be an acetonitrile solvate.
  • the present disclosure comprises a crystalline form of Idasanutlin designated as form Tl 1.
  • the crystalline form Tl 1 of Idasanutlin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 4.6, 6.1, 18.4, 23.3 and 25.8 degrees 2-theta ⁇ 0.2 degrees 2-theta; a PXRD pattern as depicted in figure 11 and combinations of these data.
  • Crystalline form Tl 1 of Idasanutlin may be further characterized by the PXRD pattern having peaks at 4.6, 6.1, 18.4, 23.3 and 25.8 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having one, two, three or four additional peaks at 8.0, 15.7, 23.9 and 27.5 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline form Tl 1 of Idasanutlin may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., by PXRD pattern having peaks at 4.6, 6.1, 18.4, 23.3 and 25.8 degrees 2-theta ⁇ 0.2 degrees 2-theta and a PXRD pattern as depicted in figure 11.
  • Crystalline form Tl 1 of Idasanutlin according to any of the above embodiments may be an isoamyl alcohol solvate.
  • the present disclosure comprises a crystalline form of Idasanutlin designated as form T12.
  • the crystalline form T12 of Idasanutlin can be characterized by data selected from one or more of the following: a PXRD pattern as depicted in figure 12; a solid state 13 C NMR spectrum with peaks at 112.8, 119.7, 125.9, 129.7, 155.4 and 171.3 ppm ⁇ 0.2 ppm; by a solid state 13 C NMR spectrum having the following chemical shift absolute differences from a peak at 30.8ppm ⁇ 2 ppm of 82.0, 88.9, 95.1, 98.9, 124.6 and l40.5ppm ⁇ 0.1 ppm; by a solid state 13 C NMR spectrum having the following chemical shift absolute differences from a peak at 112.8 ppm ⁇ 1 ppm of 82.0 ⁇ 0.1 ppm; or by a solid state 13 C NMR spectrum substantially as depicted in Figure 13; and combinations of these data.
  • Crystalline form T12 of Idasanutlin may be further characterized by a PXRD pattern having peak at 8.6 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline form T12 of Idasanutlin may be even further characterized by the PXRD pattern having peak at 8.6 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having one, two or three additional peaks at 14.3, 20.3 and 26.2 degrees 2-theta ⁇ 0.3 degrees 2-theta.
  • Crystalline form T12 of Idasanutlin as described in any of the above embodiments may further be characterized as having a PXRD pattern having an absence of peaks at 3.0 to 7.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline form T12 of Idasanutlin as described in any of the above embodiments may additionally be characterized as having a PXRD pattern with an absence of peaks at 3.0 to 7.0 degrees 2-theta ⁇ 0.2 degrees 2-theta, and/or an absence of peaks at 10.0 to 13.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline form T12 of Idasanutlin may be characterized by: a PXRD pattern having a peak at 8.6 degrees 2-theta ⁇ 0.2 degrees 2-theta and having an absence of peaks at 3.0 to 7.0 degrees 2-theta ⁇ 0.2 degrees 2-theta; or a PXRD pattern having peak at 8.6 degrees 2-theta ⁇ 0.2 degrees 2-theta and having an absence of peaks at 10.0 to 13.0 degrees 2-theta ⁇ 0.2 degrees 2-theta; or a PXRD pattern having peak at 8.6 degrees 2-theta ⁇ 0.2 degrees 2-theta and having an absence of peaks at 3.0 to 7.0 degrees 2- theta ⁇ 0.2 degrees 2-theta and an absence of peaks at 10.0 to 13.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline form T12 of Idasanutlin may be characterized by: a PXRD pattern having a peak at 8.6 degrees 2-theta ⁇ 0.2 degrees 2-theta and one, two or three additional peaks at 14.3, 20.3 and 26.2 degrees 2-theta ⁇ 0.3 degrees 2- theta and further having an absence of peaks at 3.0 to 7.0 degrees 2-theta ⁇ 0.2 degrees 2- theta; or a PXRD pattern having peak at 8.6 degrees 2-theta ⁇ 0.2 degrees 2-theta and one, two or three additional peaks at 14.3, 20.3 and 26.2 degrees 2-theta ⁇ 0.3 degrees 2-theta and further having an absence of peaks at 10.0 to 13.0 degrees 2-theta ⁇ 0.2 degrees 2-theta; or a PXRD pattern having peak at 8.6 degrees 2-theta ⁇ 0.2 degrees 2-theta and one, two or three additional peaks at 14.3, 20.3 and 26.2 degrees 2-theta ⁇ 0.3 degrees 2-theta; or a PX
  • crystalline form T12 of Idasanutlin may be characterized by: a PXRD pattern having a peak at: 8.6 degrees 2-theta ⁇ 0.2 degrees 2-theta, and peaks at: 14.3, 20.3 and 26.2 degrees 2-theta ⁇ 0.3 degrees 2-theta and further having an absence of peaks at 3.0 to 7.0 degrees 2-theta ⁇ 0.2 degrees 2-theta; or a PXRD pattern having a peak at 8.6 degrees 2-theta ⁇ 0.2 degrees 2-theta and peaks at 14.3, 20.3 and 26.2 degrees 2-theta ⁇ 0.3 degrees 2-theta and further having an absence of peaks at 10.0 to 13.0 degrees 2-theta ⁇ 0.2 degrees 2-theta; or a PXRD pattern having a peak at 8.6 degrees 2- theta ⁇ 0.2 degrees 2-theta and peaks at 14.3, 20.3 and 26.2 degrees 2-theta ⁇ 0.3 degrees 2- theta and further having an absence of peaks at 0.0 to 13.0 degrees 2-the
  • Crystalline form T12 of Idasanutlin may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., by PXRD pattern having peaks at 8.6 degrees 2-theta ⁇ 0.2 degrees 2-theta a solid state 13 C NMR spectrum with peaks at 112.8, 119.7, 125.9, 129.7, 155.4 and 171.3.
  • Crystalline form T12 of Idasanutlin according to any of the above embodiments may be an anhydrous form.
  • the present disclosure further comprises processes for preparing form Tl of Idasanutlin comprising: (A) precipitation of Idasanutlin from a mixture comprising acetone and water, or from a mixture comprising methanol and water, and optionally isolating crystalline Form Tl from the mixture; or (B) dissolving Idasanutlin in acetone and water, and lyophilizing the solution to obtain form Tl.
  • the process (A) comprises dissolving Idasanutlin in acetone or methanol, and adding the solution to water or ice, to precipitate form Tl of Idasanutlin.
  • the acetone or methanol is used in an amount of from about 10V to about 80V, or more preferably about 20V to about 60V relative to the Idasanutlin starting material. More preferably acetone is used in an amount of about 20V to about 50V, especially about 25 V to about 35; and methanol is preferably used in an amount of from about 35V to about 70V, more preferably about 40V to about 60V.
  • the precipitation in process (A) preferably comprises heating the mixture of Idasanutlin in acetone or methanol, preferably to a temperature of about 40-65°C, and more preferably about 45-65°C and most preferably about 50-60°C, and pouring the mixture onto water, a mixture of ice water, or ice.
  • the resulting mixture may be maintained for a period of time at a temperature below room temperature.
  • the resulting mixture is held at a temperature of about preferably to a temperature of about 0-20°C, and more preferably about 0-10°C and most preferably about 0-10°C, particularly 0 to about 5°C.
  • the resulting mixture is maintained for about 5 to about 40 minutes, more preferably about 10 to about 20 minutes.
  • the product may be isolated by any suitable method, such as filtration and dried in air.
  • the process (B) for preparing Form Tl may comprise dissolving Idasanutlin in a mixture of acetone and water, and heating to a temperature of about 30 to about 55°C, more preferably about 35 to about 50°C.
  • the lyophilisation process may comprise freezing the mixture and lyophilizing a reduced pressure (preferably about 40-200 Torr, more preferably about 80 to about 1-120 Torr) at a condenser temperature of about - l00°C to about -60°C, more preferably about -90°C to about -70°C) to obtain Form Tl of Idasanutlin.
  • the acetone:water ratio is about 4: 1 to about 1 : 1, more preferably about 3: 1 to about 1 : 1, and most preferably about 2: 1 to about 1.2: 1, and parti culary about 1.5: 1 to about 1.2: 1.
  • the total volume of acetone and water is preferably in the range of about 60-200V, or about 80-180V, or about 100-150V, and preferably about 120-130V.
  • the process may alternatively further comprise combining the Form Tl with one or more pharmaceutically acceptable excipients, preferably one or more polymeric carriers, to obtain a solid dispersion or premix comprising amorphous Idasanutlin, and optionally further comprising combining the solid dispersion or premix with one or more further pharmaceutically acceptable excipients to form a pharmaceutical composition or a pharmaceutical formulation comprising the solid dispersion.
  • the solid dispersions are preferably obtained by co-precipitation of the Idasanutlin obtained by any of the above processes with a polymeric carrier to obtain a solid dispersion comprising amorphous Idasanutlin.
  • the present invention encompasses crystalline Form Tl of Idasanutlin or a pharmaceutical composition or formulation obtainable by a process as described in any of the above embodiments.
  • the present disclosure further comprises a process for preparing form T12 of Idasanutlin comprising: (a) precipitation from a solution of Idasanutlin in a mixture comprising N-methyl-2-pyrrolidone and water, or a solution of Idasanutlin in a mixture comprising N,N-dimethylformamide and water, or a solution of Idasanutlin in a mixture comprising dimethylacetamide and water, or a solution of Idasanutlin in a mixture comprising tetrahydrofuran and water; and optionally (b) isolating crystalline Form T12 .
  • Step (a) preferably comprises preparing a solution of Idasanutlin in the organic solvent, preferably in an amount of about 2 V to about 30 V, more preferably about 3 V to about 20 V, and most preferably about 3 V to about 16V. More preferably N-methyl-2-pyrrolidone, N,N- dimethylformamide, and dimethyl acetamide is used in an amount of about 2V to about 8V, more preferably about 3 V to about 6V and preferably about 4V. Tetrahydrofuran may be used in an amount of from 10-20V, preferably 12-18V, and most preferably about 15V.
  • the precipitation in step (a) may be achieved by pouring the solution into ice-water, preferably at a temperature of 0-l0°C, more preferably about 0-5°C.
  • the resulting mixture may be stirred, preferably at a speed of about 100-500 rpm, more preferably 200-400 rpm.
  • the mixture may be held for about 8 to about 48 hours, preferably about 15 to about 30 hours, and particularly for about 24 hours prior to isolation, optionally by filtration.
  • the process may comprise dissolving Idasanutlin in a solvent selected from N-methyl-2-pyrrolidone, N,N-dimethylformamide, dimethylacetamide and
  • the present disclosure further comprises an alternative process for preparing form T12 of Idasanutlin comprising: (a) precipitation from a solution of Idasanutlin in a mixture comprising N-methyl-2-pyrrolidone and water, or a solution of Idasanutlin in a mixture comprising N,N-dimethylformamide and water, or a solution of Idasanutlin in a mixture comprising dimethylacetamide and water, or a solution of Idasanutlin in a mixture comprising tetrahydrofuran and water; and optionally (b) isolating crystalline Form T12.
  • the processes for preparing Form T12 described in any of the above embodiments may further comprise combining the Form T12 with one or more pharmaceutically acceptable excipients to prepare a pharmaceutical composition or a pharmaceutical formulation.
  • the process may alternatively further comprise combining the Form T12 with one or more pharmaceutically acceptable excipients, preferably one or more polymeric carriers, to obtain a solid dispersion or premix comprising amorphous Idasanutlin, and optionally further comprising combining the solid dispersion or premix with one or more further pharmaceutically acceptable excipients to form a pharmaceutical composition or pharmaceutical formulation comprising the solid dispersion.
  • the solid dispersion or premix is preferably obtained by co-precipitation of the Idasanutlin obtained by any of the above processes with one or more polymeric carriers to obtain a solid dispersion comprising amorphous Idasanutlin.
  • the present invention encompasses crystalline Form T12 of Idasanutlin or a pharmaceutical composition or formulation obtainable by a process as described in any of the above embodiments.
  • the present disclosure comprises a further process for preparing form T12 of Idasanutlin comprising exposing Idasanutlin Form T5 to a temperature of 40-80°C, and a relative humidity of 60-100%, preferably a temperature of 50-70°C and a relative humidity of 80-100% for a time period sufficient to obtain Form T12 of Idasanutlin.
  • the time period is from about 18 hours to about 100 hours, more preferably about 24 hours to about 80 hours, and most preferably about 48 hours to about 75 hours.
  • the process may further comprise combining the Form T12 with one or more pharmaceutically acceptable excipients to prepare a pharmaceutical composition or a pharmaceutical formulation.
  • the process may alternatively further comprise combining the Form T12 prepared with one or more pharmaceutically acceptable excipients, preferably one or more polymeric carriers, to obtain a solid dispersion or premix comprising amorphous Idasanutlin, and optionally further comprising combining the solid dispersion or premix with one or more further pharmaceutically acceptable excipients to form a pharmaceutical composition or formulation comprising the solid dispersion.
  • the solid dispersions are preferably obtained by co-precipitation of the
  • Idasanutlin obtained by any of the above processes with a polymeric carrier to obtain a solid dispersion comprising amorphous Idasanutlin.
  • the present invention encompasses crystalline Form T12 of Idasanutlin or a pharmaceutical composition or formulation obtainable by a process as described in any of the above embodiments.
  • the present disclosure comprises a crystalline form of Idasanutlin designated as form T13.
  • the crystalline form T13 of Idasanutlin can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 3.9, 4.4, 9.8,
  • Crystalline form T13 of Idasanutlin may be further characterized by the PXRD pattern having peaks at 3.9, 4.4, 9.8, 11.8. and 19.8 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having one, two, three, four or five additional peaks at 8.1, 8.7, 12.4, 14.8 and 19.1 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline form T13 of Idasanutlin may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., by PXRD pattern having peaks at 3.9, 4.4, 9.8, 11.8. and 19.8 degrees 2-theta ⁇ 0.2 degrees 2-theta and a PXRD pattern as depicted in figure 16.
  • Crystalline form T13 of Idasanutlin according to any of the above embodiments may be an anhydrous form.
  • the present disclosure also provides the use of the solid state forms of Idasanutlin base and Idasanutlin salts, for preparing other solid state forms of Idasanutlin, Idasanutlin salts and solid state forms thereof.
  • the present disclosure provides use of crystalline forms of Idasanutlin according to the present invention for the preparation of an amorphous form of Idasanutlin and/or pharmaceutical compositions or formulations comprising solid amorphous dispersion.
  • the present disclosure further encompasses processes for preparing other solid state forms of Idasanutlin, or solid state forms thereof, as well as other Idasanutlin salts or solid state forms thereof.
  • the process comprises preparing the solid state form of the present disclosure, and converting it to other solid state form of Idasanutlin.
  • the process comprises preparing the solid state form of the present disclosure, and converting it to Idasanutlin salt.
  • the conversion can be done, for example, by a process comprising reacting the obtained Idasanutlin with an appropriate acid to obtain the corresponding acid addition salt.
  • the process can comprise preparing the solid state form of the present disclosure and converting it to the Idasanutlin basic salt, by a process comprising reacting the obtained Idasanutlin with an appropriate base such as alkali/alkaline earth metal bases, ammonia or alkyl amines (preferably Ci -6 mono-, di- or trialkylamines).
  • an appropriate base such as alkali/alkaline earth metal bases, ammonia or alkyl amines (preferably Ci -6 mono-, di- or trialkylamines).
  • the present disclosure encompasses the above described solid state forms of Idasanutlin and salts thereof, for use in the preparation of pharmaceutical compositions and/or formulations, preferably for the treatment of cancer.
  • the present disclosure encompasses the use of the above described solid state forms of Idasanutlin and salts thereof, for the preparation of a pharmaceutical composition in the form of a solid dispersion comprising Idasanutlin or salt thereof.
  • the present disclosure encompasses the use of the above described solid state forms of Idasanutlin and salts thereof, or combinations thereof, for the preparation of pharmaceutical compositions and/or formulations, preferably oral formulations, e.g. tablets or capsules.
  • the present disclosure encompasses the above described solid state forms of Idasanutlin and salts thereof, for the preparation of a pharmaceutical composition or formulation, preferably an oral formulation in the form of a solid dispersion comprising Idasanutlin or salt thereof.
  • compositions comprising the solid state forms of Idasanutlin and salts thereof, or combinations thereof, according to the present disclosure.
  • Said pharmaceutical compositions may comprise a premix of at least one of the above solid state forms.
  • the premix may be, for example, in a form of solid solution or solid dispersion.
  • the present disclosure encompasses pharmaceutical formulations comprising at least one of the above described solid state forms of Idasanutlin and salts thereof, and at least one pharmaceutically acceptable excipient.
  • compositions of the present invention contain any one or a combination of the solid state forms of Idasanutlin of the present invention.
  • the pharmaceutical formulations of the present invention 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®, Polyplasdone®
  • 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 of
  • liquid pharmaceutical compositions of the present invention the active ingredient 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.
  • Such agents 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, the most preferred route of the present invention 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, preferably a powdered or granulated solid composition of the invention, 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 prepared by wet granulation. In 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 liquid typically water
  • 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 Idasanutlin is preferably formulated for administration to a mammal, preferably a human.
  • Idasanutlin can be formulated, for example, as a viscous liquid solution or suspension, preferably 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.
  • Ansel et al Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.
  • the present disclosure encompasses a process to prepare said formulations of Idasanutlin comprising combining at least one of the above solid state forms and at least one pharmaceutically acceptable excipient.
  • the present disclosure further includes a process for preparing formulations of Idasanutlin comprising combining at least one of the above solid state forms disclosed in any of the aspect or embodiment herein and at least one pharmaceutically acceptable excipient.
  • the process comprises: (a) combining at least one solid state form of Idasanutlin according to any of the disclosed aspects and embodiments, and at least one pharmaceutically acceptable excipient, preferably wherein the pharmaceutically acceptable excipient comprises at least one polymeric carrier; (b) forming a solid dispersion or premix comprising amorphous Idasanutlin and the at least one pharmaceutically acceptable excipient, and (c) optionally further comprising combining the solid dispersion or premix with one or more pharmaceutical excipients to prepare a pharmaceutical formulation.
  • step (a) comprises preparing a mixture of at least one solid state form of Idasanutlin according to any of the disclosed aspects and embodiments and at least one polymeric carrier in a solvent to form a solution, and step (b) comprises removal of the solvent to form the solid dispersion.
  • the present disclosure thus encompasses a process to prepare said solid dispersion or premix of Idasanutlin comprising dispersing at least one of the above solid state forms in a polymer matrix.
  • the process may comprise preparing a mixture of at least one crystalline form of Idasanutlin of the present invention with a polymeric carrier in a suitable solvent to provide a solution, followed by solvent removal to form a solid dispersion.
  • the solid dispersion preferably contains Idasanutlin in amorphous form.
  • Suitable polymeric carriers for preparing the solid dispersion or premix include polyvinylpyrrolidone (PVP), copovidone, hydroxypropyl methylcellulose (HPMC), cyclodextrins, povidone (e.g. povidone K30), and hydroxy propyl cellulose.
  • the ratio of Idasanutlin to polymeric carrier in the solid dispersion or premix may be 1 : 10 to 5: 1, preferably 1 :5 to 2: 1, more preferably 1 :2 to 2:1 and particularly 1 :1.5 to 1.5:1.
  • Suitable solvents for the preparation of the solid dispersion include any solvent or solvent mixtures that can dissolve Idasanutlin and the polymeric carrier.
  • the solvent comprises one or more polar solvents, preferably wherein the boiling point of the solvent or solvent mixture is l00°C or less, more preferably 80°C or less, and most preferably 60°C or less, at atmospheric pressure.
  • Suitable solvents include acetone, methanol, ethanol, THF, l,4-dioxane and l,2-dimethoxyethane, more preferably acetone and methanol and most preferably the solvent is acetone.
  • the solvent removal may be accomplished by any suitable method - e.g. spray drying, freeze drying or evaporation. Preferably evaporation, more preferably evaporated under reduced pressure, is employed.
  • the solvent removal is preferably conducted at a temperature of about 20 to about 80°C, more preferably about 30 to about 70°C, and particularly about 35 to about 50°C, preferably by evaporation under reduced pressure.
  • solid state forms as defined herein, as well as the pharmaceutical compositions or formulations of Idasanutlin can be used as medicaments, particularly for the treatment of cancer.
  • the present disclosure also provides a method of treating cancer, comprising administering a therapeutically effective amount of the solid state form of Idasanutlin of the present disclosure, or at least one of the above pharmaceutical
  • compositions or formulations to a subject suffering from cancer, in particular acute myeloid leukaemia or otherwise in need of the treatment.
  • the present disclosure also provides the use of the solid state forms of Idasanutlin of the present disclosure, or at least one of the above pharmaceutical
  • compositions or formulations for the manufacture of a medicament for treating cancer in particular acute myeloid leukaemia.
  • Powder X-ray diffraction pattern (“PXRD”) method:
  • Scan range 2 - 40 degrees 2-theta
  • Step size 0.05 degrees
  • Sample holder PMMA specimen holder ring.
  • the described peak positions were determined using silicon powder as an internal standard in an admixture with the sample measured.
  • the position of the silicon (Si) peak was corrected to silicone theoretical peak: 28.45 degrees two theta, and the positions of the measured peaks were corrected respectively (presented figures do not describe the Si peak).
  • the starting material Idasanutlin Form I may be obtained according to WO2015158648.
  • Idasanutlin Form I (0.2 g) was dissolved in acetone (15 mL) and water (10 mL) mixture in a 40 mL flat bottom lyophillization flask at 40-45°C and obtained a clear solution. The clear solution was freezed under liquid nitrogen in 5-10 in minutes. The frozen solid material was subjected to lyophllization under reduced pressure (100 Torr) at condenser temperature of about -80°C and isolated solid after about 5 hours Idasanutlin Form Tl has been confirmed by PXRD as presented in figure 1.
  • Idasanutlin Form I (0.100 g) was dissolved in N,N-dimethyl formamide (2.5 mL) and methanol (7.5 mL) solvent mixture in a 100 mL round bottom flask at 40-45°C and obtained a clear solution.
  • the clear solution was subjected to distillation under reduced pressure (10-50 mbar) at 50°C for 30 minutes and observed solid. Further, continuously dried the solid under reduced pressure in distillation flask for about 1 hour. Idasanutlin Form T2 has been confirmed by PXRD.
  • Example 3 Preparation of Idasanutlin form T2 [0165] Idasanutlin form I (0.05 g) was dissolved in N,N-dimethyl formamide (DMF) (0.2 mL) in a 15 mL round bottom test tube at 22-25°C and obtained a clear solution. The clear solution was covered with a paraffin film with a hole and kept for slow solvent evaporation at 22-25°C. After 3-days, Idasanutlin Form T2 has been confirmed by PXRD as presented in figure 2.
  • DMF N,N-dimethyl formamide
  • Idasanutlin form I (0. 50 g) was dissolved in N,N-dimethyl formamide or DMF (1.2 mL) in a 20 mL round bottom tube at 65-70°C and obtained a clear solution.
  • the clear solution was covered with a Teflon screw cap and maintained under magnetic stirring at 600 rpm and was cooled down to 25-30°C in 30 minutes. The solution was maintained at 25°C for overnight and observed solid after 16 hours. The solid was filtered and washed with 10 mL water and wet cake was dried at 30°C under vacuum oven for about 1-2 hours. Idasanutlin Form T2.has been confirmed by PXRD.
  • Idasanutlin Form I (0.100 g) was dissolved in N,N-dimethyl acetamide (0.6 mL) and methanol (1.8 mL) solvent mixture in a 100 mL round bottom flask at 40-45°C and obtained a clear solution.
  • the clear solution was subjected to distillation under reduced pressure (10-50 mbar) at 50°C for 30 minutes and observed solid. Further, continuously dried the solid under reduced pressure in distillation flask for 1 hour.
  • Idasanutlin Form T3 has been confirmed by PXRD as presented in figure 3.
  • Idasanutlin Form I (0.200 g) was dissolved in DMSO (10.00 mL) and 1 : 1 acetonitrile-water mixture (5.0 mL) in a 600 mL flat bottom lyophillization flask at 40- 45°C and obtained a clear solution. The clear solution was freezed under liquid nitrogen in 5- 10 minutes. The frozen solid material was subjected to lyophllization under reduced pressure (100 Torr) at condenser temperature of about -80°C and isolated solid after about 5 hours was analyzed. Idasanutlin Form T4 has been confirmed by PXRD as presented in figure 4.
  • Idasanutlin form I (0. 50 g) was dissolved in dimethyl sulfoxide (DMSO)( 2.1 mL) in a 20 mL round bottom tube at 65-70°C and obtained a clear solution.
  • the clear solution was covered with a Teflon screw cap and maintained under magnetic stirring at 600 rpm and was cooled down to 25-30°C in 30 minutes. The clear solution was maintained at 25°C for overnight. After 18 hours, the solid was filtered and washed with 25 mL water and wet cake was dried at 30°C under vacuum oven about 1-2 hours.
  • Idasanutlin Form T4 has been confirmed by PXRD.
  • Idasanutlin Form I (0.050 g) was dissolved in l,4-dioxane (1.2 mL) in a 15 mL round bottom test tube at 22-25°C and obtained a clear solution. The clear solution was covered with a paraffin film with a hole and kept for slow solvent evaporation at 22- 25°C. After 3-days, the obtained solid material was analyzed. Idasanutlin Form T5 has been confirmed by PXRD as presented in figure 5.
  • Idasanutlin form I (0. 50 g) was dissolved in N-Methyl-2-pyrrolidone (NMP) (1.2 mL) in a 20 mL round bottom tube at 65-70°C and obtained a clear solution.
  • NMP N-Methyl-2-pyrrolidone
  • the clear solution was covered with a Teflon screw cap and maintained under magnetic stirring at 600 rpm and was cooled down to 25-30°C in 30 minutes. The solution was maintained at 25°C for overnight and observed solid after 16 hours. The solid was filtered and washed with 10 mL water and wet cake was dried at 30°C under vacuum oven for about 1-2 hours.
  • Idasanutlin Form T6 has been confirmed by PXRD as presented in figure 6.
  • Idasanutlin Form I (1.0 g) was dissolved in tetrahydrofuran (THF) (15.0 mL) in a 50 mL flat bottom flask at 55-60°C and obtained a clear solution. The clear solution was cooled to 30-35°C and transferred in an addition funnel. The clear solution was added dropwise with addition funnel in ice-cooled water (40.0 mL) at 0-5°C in 30 minutes in a 100 mL round bottom flask under magnetic stirring at 500 rpm. After 30 minutes, reaction mass was filtered and washed with cold-water (20mL) at 0-5°C twice and dried under vacuum for 20-30 minutes. Idasanutlin Form T7 has been confirmed by PXRD as presented in figure 7.
  • Idasanutlin form I (0. 050 g) was suspended in ethanol (1.0 mL) in a 3 mL glass vial and closed with septa screw cap at 25-30°C. The slurry mass was maintained under magnetic stirring at 500 rpm at 25-30°C. After 24 hours, the slurry mass was vacuum- filtered for 10-15 minutes at 25-30°C to obtain Idasanutlin Form T8. Idasanutlin Form T8 has been confirmed by PXRD as presented in figure 8.
  • Idasanutlin form I (0. 50 g) was suspended in butyl acetate (10.0 mL) in a 20 mL reaction test tube at 0-5°C and closed with Teflon cap. The slurry mass was maintained under magnetic stirring at 500 rpm at 0-5°C. After 24 hours, the slurry mass was vacuum-filtered for 10-15 minutes at 25-30°C to obtain Idasanutlin Form T9. Idasanutlin Form T9 has been confirmed by PXRD as presented in figure 9.
  • Idasanutlin form I (0. 050 g) was suspended in acetonitrile (1.0 mL) in a 3 mL glass vial and closed with septa screw cap at 25-30°C. The slurry mass was maintained under magnetic stirring at 500 rpm at 25-30°C. After 24 hours, the slurry mass was vacuum-filtered for 10-15 minutes at 25-30°C to obtain Idasanutlin Form T10.
  • Idasanutlin Form T10 has been confirmed by PXRD as presented in figure 10.
  • Idasanutlin form I (0. 050 g) was suspended in 3 -methyl- 1 -butanol (1.0 mL) in a 3 mL glass vial and closed with septa screw cap at 25-30°C. The slurry mass was maintained under magnetic stirring at 500 rpm at 55-60°C. After 24 hours, the slurry mass cooled to 25-30°C and was vacuum-filtered for 10-15 minutes to obtain Idasanutlin Form Tl 1. Idasanutlin Form Tl 1 has been confirmed by PXRD as presented in figure 11.
  • Idasanutlin Form I (0.1 g) was dissolved in acetone (3 mL) in a 50 mL flat bottom open flask at 45-50°C to obtain a clear solution. The clear solution was heated up to 50-60°C and hot refluxing solution were poured on ice bath and maintained for 10-15 minutes at 0-5°C and filtered the solution by gravity. The white precipitate was dried in air for 10-15 minutes. Idasanutlin Form Tl has been confirmed by PXRD.
  • Idasanutlin Form I (0.1 g) was dissolved in methanol (5 mL) in a 50 mL flat bottom open flask at 45-50°C and obtained a clear solution. The clear solution was heated up to 50-60°C and hot refluxing solution were poured on ice bath and maintained for 10-15 minutes at 0-5°C and filtered the solution by gravity. The white precipitate was dried in air for 10-15 minutes. Idasanutlin Form Tl has been confirmed by PXRD.
  • Idasanutlin Form I (0.5 g) was dissolved in N-Methyl-2-pyrrolidone (NMP) (2.0 mL) in a 5 mL reaction vial with PTFE septa cap at 40-45°C and obtained a clear solution called as stock solution-A.
  • Idasanutlin stock solution-A (0.2 mL) was charged in a precooled (0-5°C) reaction vial with ice-cold water (2.0 mL) at 0-5°C and maintained under magnetic stirring at 300 rpm. The closed reaction vial was maintained under stirring and observed precipitation after 4-hours. The reaction mixture was maintained under stirring at 0- 5°C. After 24 hours, reaction mass was filtered and washed the obtained solid with water (4.0 mL) and dried under vacuum at 25-30°C for 15-20 minutes. Idasanutlin Form T12 has been confirmed by PXRD.
  • Idasanutlin Form I (0.5 g) was dissolved in Dimethylacetamide (DMAc) (2.0 mL) in a 5 mL reaction vial with PTFE septa cap at 40-45°C and obtained a clear solution called as stock solution-C.
  • Idasanutlin stock solution-C (0.2 mL) was charged in a precooled (0-5°C) reaction vial with ice-cold water (2.0 mL) at 0-5°C and maintained under magnetic stirring at 300 rpm. The closed reaction vial was maintained under stirring and observed precipitation after 4-hours. The reaction mixture was maintained under stirring at 0-5°C. After 24 hours, reaction mass was filtered and washed the solid with water (4.0 mL) and dried under vacuum at 25-30°C for 15-20 minutes. Idasanutlin Form T12 has been confirmed by PXRD.
  • reaction mass was filtered and washed the obtained solid with water (10.0 mL) and dried under vacuum at 25-30°C for 15-20 minutes. Idasanutlin Form T12 has been confirmed by PXRD.
  • Example 21 Preparation of Idasanutlin form T12 [0183] Idasanutlin Form T5 (0.3 g) was taken in an open petridish and exposed to heat and humidity at 60°C/l00%RH in a humidity chamber. After two days, solid was isolated and analyzed. Idasanutlin Form T12 has been confirmed by PXRD.
  • Idasanutlin Form T2 (0.05 g) was taken in an open petridish at 25- 30°C and kept inside an air dryer oven. The solid sample was heat up to l20°C for 30 minutes and then cooled to 30°C. Idasanutlin Form T12 has been confirmed by PXRD as presented in figure 12.
  • Idasanutlin Form I (0.05G) was suspended in methanol (1.0 mL) at 0- 5°C for 30 days under magnetic stirring at 500 rpm. After 30 days, the slurry mass was filtered and washed with methanol (1.0. mL) twice at 20-25°C and dried under vacuum for 15- 20 minutes. Solid material was analyzed. Idasanutlin Form T13 has been confirmed by
  • Idasanutlin Form Tl (0.2G), prepared according to example 15 was suspended in methanol (4.0 mL) at 0-5°C and seeded with Form T13 about 1% (obtained from ex. l). The slurry mass was stirred for 3 days at 0-5°C. After 3 days, the slurry mass was filtered and dried under vacuum for 15-20 minutes. Solid material was analyzed. Idasanutlin Form T13 has been confirmed by PXRD.
  • Idasanutlin The physical stability of Idasanutlin was investigated at different conditions: in heating, under high humidity and under pressure. Solid state forms of Idasanutlin were exposed to 20-100% RH at room temperature for 7 days. Stability in heating was investigated at l00°C for 30 minutes. Idasanutlin forms Tl and T12 are stable in heating, under pressure of 2 ton (for 1 min) and up to l00%RH for 7 days as confirmed by PXRD.
  • ptap is the tap density and pbulk is the bulk density.
  • Example 27 Preparation of Idasanutlin Amorphous solid dispersion of Idasanutlin with Copovidone (1:1 w/w ratio)
  • Idasanutlin (Form Tl) 0.20 g and copovidone (0.20 g) were dissolved in acetone (30 mL) at 22-25°C. Reaction mixture was filtered through Ely-flo to remove any undissolved particulate. The clear solution was subjected to rota-vapor distillation under reduced pressure at 40-45°C. After the solvent removal by distillation, the material is cooled to 22-25°C. Solid material was obtained. The obtained solid was a solid dispersion of amorphous form of Idasanutlin with 50% by weight copovidone (1 : 1 w/w ratio). The solid dispersion can be used as a premix for the preparation of a pharmaceutical composition or pharmaceutical formulation of Idasanutlin, for example by combining with one or more pharmaceutically acceptable excipients.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des formes à l'état solide d'idasanutline, des procédés pour leur préparation et des compositions pharmaceutiques associées.
PCT/US2019/029951 2018-04-30 2019-04-30 Formes à l'état solide d'idasanutline WO2019213106A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
ININ201811016299 2018-04-30
IN201811016299 2018-04-30
IN201811020877 2018-06-04
ININ201811020877 2018-06-04
ININ201811023318 2018-06-22
IN201811023318 2018-06-22
ININ201811031182 2018-08-20
IN201811031182 2018-08-20

Publications (1)

Publication Number Publication Date
WO2019213106A1 true WO2019213106A1 (fr) 2019-11-07

Family

ID=66542534

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2019/029951 WO2019213106A1 (fr) 2018-04-30 2019-04-30 Formes à l'état solide d'idasanutline

Country Status (1)

Country Link
WO (1) WO2019213106A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010031713A1 (fr) 2008-09-18 2010-03-25 F. Hoffmann-La Roche Ag Pyrrolidine-2-carboxamides substitués
WO2011098398A1 (fr) 2010-02-09 2011-08-18 F. Hoffmann-La Roche Ag Pyrrolidine-2-carboxamides substitués
WO2014114575A1 (fr) 2013-01-22 2014-07-31 F. Hoffmann-La Roche Ag Composition pharmaceutique à biodisponibilité ameliorée
WO2015158648A1 (fr) 2014-04-15 2015-10-22 F. Hoffmann-La Roche Ag Formes solides d'un composé pharmaceutiquement actif

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010031713A1 (fr) 2008-09-18 2010-03-25 F. Hoffmann-La Roche Ag Pyrrolidine-2-carboxamides substitués
WO2011098398A1 (fr) 2010-02-09 2011-08-18 F. Hoffmann-La Roche Ag Pyrrolidine-2-carboxamides substitués
WO2014114575A1 (fr) 2013-01-22 2014-07-31 F. Hoffmann-La Roche Ag Composition pharmaceutique à biodisponibilité ameliorée
WO2015158648A1 (fr) 2014-04-15 2015-10-22 F. Hoffmann-La Roche Ag Formes solides d'un composé pharmaceutiquement actif

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ANSEL ET AL.: "Pharmaceutical Dosage Forms and Drug Delivery Systems"
MINO R CAIRA ED - MONTCHAMP JEAN-LUC: "CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS", TOPICS IN CURRENT CHEMISTRY; [TOPICS IN CURRENT CHEMISTRY], SPRINGER, BERLIN, DE, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP001156954, ISSN: 0340-1022, [retrieved on 19990226], DOI: 10.1007/3-540-69178-2_5 *
ORG. PROCESS RES. DEV., vol. 20, 2016, pages 2057 - 2066

Similar Documents

Publication Publication Date Title
US20220144825A1 (en) Solid state forms of ripretinib
EP3765464A1 (fr) Formes à l'état solide de relugolix
US11220488B2 (en) Crystalline polymorph of Ponesimod
WO2020102302A1 (fr) Formes solides de daprodustat et leurs procédés de préparation
WO2019094409A1 (fr) Sels et formes à l'état solide d'ozanimod
US20230167156A1 (en) Solid state forms of voclosporin
AU2021213748A1 (en) Solid state forms of Mavacamten and process for preparation thereof
US20220135548A1 (en) Solid state forms of n-[2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-2(1h)-isoquinolinyl)ethyl]phenyl}-2h-tetrazol-5-yl)-4,5- dimethoxyphenyl]-4-oxo-4h-chromene-2-carboxamide and of its mesylate salt
WO2022261410A1 (fr) Formes à l'état solide de lanifibranor et leur procédé de préparation
US20220411371A1 (en) Solid state forms of lucerastat and process for preparation thereof
US11465974B2 (en) Crystalline polymorphs of Pracinostat and Pracinostat salts
EP4153574A1 (fr) Formes à l'état solide d'aprocitentan et leur procédé de préparation
WO2019213106A1 (fr) Formes à l'état solide d'idasanutline
US11434225B2 (en) Salts and solid state forms of plinabulin
EP4118084A1 (fr) Formes à l'état solide d'avapritinib et leur procédé de préparation
US11434202B2 (en) Crystalline polymorphs of Rivoceranib and Rivoceranib mesylate
WO2024069574A1 (fr) Formes à l'état solide de denifanstat
WO2023164024A1 (fr) Formes à l'état solide de gusacitinib
WO2020139670A1 (fr) Formes à l'état solide de balovaptan
WO2021216628A1 (fr) Formes solides de trifarotène et leur procédé de préparation
WO2022182699A1 (fr) Formes à l'état solide de tideglusib et leur procédé de préparation
WO2022011221A1 (fr) Formes à l'état solide de sel de mésylate n-[2-(2-{4-[2-(6,7-diméthoxy-3,4-dihydro-2(1h)-isoquinolinyl)éthyl]phényl}-2h-tétrazol-5-yl)-4,5-diméthoxyphényl]-4-oxo-4h-chromène-2-carboxamide
WO2023076205A1 (fr) Formes à l'état solide de l'ensifentrine et leur procédé de préparation
EP1768969B1 (fr) Mycophenolate de sodium cristallin

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19724309

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19724309

Country of ref document: EP

Kind code of ref document: A1