WO2017035170A1 - Formes à l'état solide de maléate de cédiranib - Google Patents

Formes à l'état solide de maléate de cédiranib Download PDF

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WO2017035170A1
WO2017035170A1 PCT/US2016/048251 US2016048251W WO2017035170A1 WO 2017035170 A1 WO2017035170 A1 WO 2017035170A1 US 2016048251 W US2016048251 W US 2016048251W WO 2017035170 A1 WO2017035170 A1 WO 2017035170A1
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Prior art keywords
cediranib
crystalline form
theta
degrees
maleate
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PCT/US2016/048251
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English (en)
Inventor
Igor AVDEJEV
Dubravka Pavlicic
Ratkaj MARINA
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Pliva Hrvatska D.O.O
Teva Pharmaceuticaks Usa, Inc.
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Publication of WO2017035170A1 publication Critical patent/WO2017035170A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present disclosure relates to solid state forms of Cediranib maleate, processes for preparation thereof and pharmaceutical compositions thereof.
  • Cediranib has the chemical name 4-[(4-fluoro-2-methyl-lH-indol-5-yl)oxy]-6- methoxy-7-[3-(l-pyrrolidinyl)propoxy]quinazoline.
  • Cediranib has the following chemical structure:
  • Cediranib is an orally active vascular endothelial growth factor receptor 2
  • VEGFR2 tyrosine kinase inhibitor
  • Cediranib is known from US 7,074,800. Cediranib base, Cediranib maleate and crystalline forms thereof as well as the preparation of the crystalline forms are described in US 8,859,570 (US * 570).
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single compound, like Cediranib, 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”), X-ray powder diffraction (XRPD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state ( 13 C-) NMR spectrum.
  • TGA thermogravimetric analysis -
  • DSC differential scanning calorimetry -
  • XRPD X-ray powder diffraction
  • 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 (polymorphic 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.
  • Discovering new salts, solid state forms and solvates of a pharmaceutical product can provide 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 salts or polymorphic forms.
  • 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. For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Cediranib and salts thereof, for example of Cediranib maleate.
  • the present disclosure relates to solid state forms of Cediranib maleate, processes for preparation thereof, and pharmaceutical compositions comprising these solid state forms.
  • the present disclosure provides a crystalline form of Cediranib maleate designated as Form D (defined herein) and a crystalline form of Cediranib maleate designated as form F (defined herein).
  • Form D a crystalline form of Cediranib maleate
  • form F a crystalline form of Cediranib maleate designated as form F (defined herein).
  • the present disclosure also provides the uses of any one or a combination of the above described solid state forms of Cediranib maleate for preparing other solid state forms of Cediranib maleate, Cediranib base and/or other Cediranib salts and solid state forms thereof.
  • the present disclosure also provides any one or a combination of the above described solid state forms of Cediranib maleate of the present disclosure for use in the preparation of other solid state forms of Cediranib maleate, Cediranib base and/or other Cediranib salts and solid state forms thereof.
  • the present disclosure further provides processes for preparing Cediranib base, other salts of Cediranib or solid state forms thereof.
  • the present disclosure encompasses any one of the above described solid state forms of Cediranib maleate and/or combinations thereof for use in the preparation of pharmaceutical compositions and/or formulations, optionally for the treatment of cancer.
  • the present disclosure encompasses uses of any one of the above described solid state forms of Cediranib maleate and/or combinations thereof for the preparation of pharmaceutical compositions and/or formulations.
  • the present disclosure further provides pharmaceutical compositions comprising any one of, or a mixture of, the solid state forms of Cediranib maleate according to the present disclosure.
  • the present disclosure encompasses pharmaceutical formulations comprising any one of the above described solid state forms of Cediranib maleate and/or combinations thereof and at least one pharmaceutically acceptable excipient.
  • the present disclosure encompasses processes to prepare said pharmaceutical formulations of Cediranib maleate comprising combining any one of the above described solid state forms and/or combinations thereof and at least one pharmaceutically acceptable excipient.
  • any of the solid state forms defined herein and/or combinations thereof as well as the pharmaceutical compositions or formulations of the solid state forms of Cediranib maleate 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 any one of the solid state forms of Cediranib maleate of the present disclosure and/or combinations thereof, 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 uses of any one of the solid state forms of Cediranib maleate of the present disclosure and/or combinations thereof, or at least one of the above pharmaceutical compositions or formulations for the manufacture of medicaments for treating cancer.
  • Figure 1 shows an X-ray powder diffractogram (XRPD) of form D of Cediranib maleate.
  • Figure 2 shows an XRPD of form E of Cediranib maleate.
  • Figure 3 shows an XRPD of form C of Cediranib maleate.
  • Figure 4 shows an XRPD of form F of Cediranib maleate.
  • Figure 5 shows an XRPD of amorphous Cediranib maleate.
  • Figure 6 shows an XRPD of a crystalline form of Cediranib base prepared according to the process described in US'570.
  • Figure 7 shows a Raman spectrum of form D of Cediranib maleate.
  • Figure 8 shows a Raman spectrum of form F of Cediranib maleate.
  • the present disclosure relates to solid state forms of Cediranib maleate, processes for preparation thereof and pharmaceutical compositions comprising at least one of, or a
  • the disclosure also relates to the conversion of Cediranib maleate and its solid state forms to other solid state forms of Cediranib maleate, Cediranib base or other salts and solid state forms thereof of Cediranib.
  • the Cediranib maleate and solid state forms thereof 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 Cediranib maleate 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 Cediranib maleate, 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 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% or less, about 10%> or less, about 5% or less, about 2% or less, about 1%) or less, about 0.5% or less, about 0.1%> or less or 0% of any other forms of the subject compound as measured, for example, by XRPD.
  • solid state of Cediranib maleate 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), greater than about 99.5% (w/w), greater than about 99.9%) (w/w), or al00% of the subject solid state form of Cediranib maleate.
  • the described solid state forms of Cediranib maleate 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 Cediranib maleate.
  • the data may be corrected to wavelength of 1.5418 respectively.
  • Raman spectroscopy was measured using 1064 nm excitation laser, a CaF 2 beam splitter and Ge detector.
  • the term "isolated" in reference to solid state forms of Cediranib maleate of the present disclosure corresponds to solid state forms of Cediranib maleate that is physically separated from the reaction mixture in which it is formed.
  • a thing e.g., a reaction mixture
  • room temperature often abbreviated "RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located.
  • room temperature is from about 20°C to about 30°C, 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, about 10 to about 18 hours, or about 16 hours.
  • wet crystalline form refers to a polymorph that was not dried using any conventional techniques to remove residual solvent. Examples for such conventional techniques can be, but not limited to, evaporation, vacuum drying, oven drying, drying under nitrogen flow, etc.
  • dry crystalline form refers to a polymorph that was dried using any conventional techniques to remove residual solvent.
  • conventional techniques can be, but are not limited to, evaporation, vacuum drying, oven drying, drying under nitrogen flow, etc.
  • anhydrous in relation to crystalline Cediranib maleate relates to crystalline Cediranib maleate which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form does not contain more than about 1% (w/w) of either water or organic solvents as measured for example by TGA.
  • 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 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 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 MTBE (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of MTBE was added.
  • non-hygroscopic in relation to crystalline Cediranib maleate refers to less than about 0.2% (w/w) absorption of water at about 25°C and about 80% relative humidity (RH) by the crystalline Cediranib maleate as determined for example by TGA.
  • Water can be for example atmospheric water.
  • reduced pressure refers to a pressure of about 10 mbar to about 50 mbar.
  • Cediranib free base which is prepared according to the process described in US' 570, may be characterized as providing an X-ray powder diffraction pattern as in Figure 6. The ten most prominent XRPD peaks of said crystalline form of Cediranib base are shown in the table below:
  • the present disclosure comprises a crystalline form of Cediranib maleate designated as Form D.
  • the crystalline Form D of Cediranib maleate can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 7.8, 8.1, 9.9, 20.3 and
  • Crystalline Form D of Cediranib maleate may be further characterized by data selected from one or more of the following: the XRPD pattern having peaks at 7.8, 8.1, 9.9,
  • Crystalline Form D of Cediranib maleate may be further characterized by one or more of the following: XRPD pattern having maxima of the characteristic peaks, optionally with the intensities, as listed in the following table:
  • Crystalline Form D of Cediranib maleate may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 7.8, 8.1, 9.9, 20.3 and 26.2 degrees 2-theta ⁇ 0.2 degrees 2-theta and an XRPD pattern as depicted in Figure 1
  • Form D of Cediranib maleate may have advantageous properties selected from at least one of:
  • the increased solubility of Form D of Cediranib maleate is particularly advantageous, as Cediranib malate forms A and B are practically insoluble in such a medium.
  • the increased solubility of form D of Cediranib maleate may enhance bioavailability of the API.
  • the present disclosure comprises a crystalline form of Cediranib maleate designated as Form E.
  • the crystalline Form E of Cediranib maleate can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 13.4, 14.0, 14.8, 16.1 and 18.6 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 2; and combinations of these data.
  • Crystalline Form E of Cediranib maleate may be further characterized by the XRPD pattern having peaks at 13.4, 14.0, 14.8, 16.1 and 18.6 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having one, two, three, four or five additional peaks selected from 9.9, 16.7, 18.3, 21.4 and 23.1 degrees two theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form E of Cediranib maleate may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 13.4,
  • the present disclosure comprises a crystalline form of Cediranib maleate
  • Crystalline Form C of Cediranib maleate can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 7.7, 9.6, 11.1, 19.5 and 24.5 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 3; and combinations of these data.
  • Crystalline Form C of Cediranib maleate may be further characterized by the XRPD pattern having peaks at 7.7, 9.6, 11.1, 19.5 and 24.5 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having one, two, three, four or five additional peaks selected from 6.2, 9.1, 13.4, 20.3, and 26.7 degrees two theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form C of Cediranib maleate may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 7.7, 9.6,
  • the present disclosure further comprises a crystalline form of Cediranib maleate designated as Form F.
  • the crystalline Form F of Cediranib maleate can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 9.6, 14.1, 14.7, 18.3 and 23.4 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 4; and combinations of these data.
  • Crystalline Form F of Cediranib maleate may be further characterized by data selected from one or more of the following: the XRPD pattern having peaks at 9.6, 14.1, 14.7, 18.3 and 23.4 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks selected from 5.6, 13.4, 14.0, 19.3 and 20.8 degrees two theta ⁇ 0.2 degrees 2- theta; Raman spectmm having peaks at 2947, 1421, 1382, 1316 and 941 cm “1 ⁇ 4 cm “1 ; Raman spectmm as depicted in figure 8; and combinations of these data.
  • Crystalline Form F of Cediranib maleate may be further characterized by one or more of the following: XRPD pattern having maxima of the characteristic peaks optionally with the intensities as listed in the following table:
  • 459 talline Form F of Cediranib maleate may be a hydrate.
  • Crystalline Form F of Cediranib maleate may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 9.6, 14.1, 14.7, 18.3 and 23.4 degrees 2-theta ⁇ 0.2 degrees 2-theta and an XRPD pattern as depicted in Figure 4.
  • Form F of Cediranib maleate may have advantageous properties selected from at least one of:
  • the increased solubility of Form F of Cediranib maleate is particularly advantageous, as Cediranib malate forms A and B are practically insoluble in such a medium.
  • the increased solubility of form F of Cediranib maleate may enhance bioavailability of the API.
  • the present disclosure further comprises an amorphous form of Cediranib maleate.
  • the amorphous form of Cediranib maleate may be characterized by an XRPD pattern as depicted in Figure 5.
  • the present disclosure also provides the use of any one or a combination of the solid state forms of Cediranib maleate for preparing other solid state forms of Cediranib maleate, Cediranib base or other salts and solid state forms thereof.
  • the present disclosure also provides any one or a combination of the solid state forms of Cediranib maleate of the present disclosure for use in the preparation of other solid state forms of Cediranib maleate, Cediranib and/or other Cediranib salts and solid state forms thereof.
  • the present disclosure further encompasses processes for preparing Cediranib base or solid state forms thereof.
  • the process comprises preparing any one or combination of the solid state forms of the present disclosure, and converting it to Cediranib base.
  • the conversion can be done, for example, by processes comprising reacting the obtained Cediranib maleate with an appropriate base to obtain Cediranib base.
  • the present disclosure further encompasses processes for preparing other salts of Cediranib or solid state forms thereof.
  • the processes comprise preparing any one or combination of the solid state forms of Cediranib maleate by the processes of the present disclosure, and converting that salt to said other Cediranib salt.
  • the conversion can be done, for example, by processes comprising basifying the above described Cediranib maleate salt or solid state forms thereof, and reacting the obtained Cediranib base with an appropriate acid, to obtain the corresponding salt.
  • the conversion can be done by salt switching, i.e., reacting Cediranib maleate or solid state forms thereof, with an acid having a pKa which is lower than the pKa of maleic acid.
  • the present disclosure encompasses any one or a combination of the above described solid state forms of Cediranib maleate and/or combinations thereof for use in the preparation of pharmaceutical compositions and/or formulations, optionally for the treatment of cancer.
  • the present disclosure encompasses the use of any of the above described solid state forms of Cediranib maleate and/or combinations thereof for the preparation of pharmaceutical compositions and/or formulations.
  • the present disclosure encompasses pharmaceutical formulations comprising any one of the above described solid state forms of Cediranib maleate and/or combinations thereof and optionally at least one pharmaceutically acceptable excipient.
  • the present disclosure encompasses processes to prepare said formulations of Cediranib maleate comprising combining any one of the above solid state forms and/or
  • any one of the solid state forms as defined herein and/or combinations thereof, as well as the pharmaceutical compositions or formulations 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 any one of the solid state forms of the present disclosure and/or combinations thereof, 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 the use of any one of the solid state forms of the present disclosure and/or combinations thereof, or at least one of the above pharmaceutical compositions or formulations for the manufacture of a medicament for treating cancer.
  • Raman spectra were acquired on a Nicolet 6700 interferometer, equipped with an NXR FT-Raman modul.
  • Nd-YAG laser (1064 nm, 500 mW) was used to excite the sample.
  • the spectrometer utilizes a CaF2 beamsplitter and a liquid nitrogen cooled Ge detector. The spectra were recorded at resolution of 4 cm "1 .
  • Cediranib base starting material may be prepared according to the process described in US'570 or alternatively according to the following process:
  • Cediranib base 500 mg was suspended in a mixture of acetonitrile (3.5 ml) and water (0.184 ml) at 20-25 °C. The suspension was cooled down to 0-5 °C and maleic acid solution (132 mg dissolved in 3.0 ml acetonitrile) was added drop-wise during 9 minutes. The suspension was stirred at 0-5 °C for 2 hours. Crystals of Cediranib maleate were filtered off and dried at 60 °C and 10 mbar for 10 hours. The XRPD of the obtained product is shown in Figure 1.
  • Cediranib base 500 mg was suspended in acetonitrile (3.5 ml) at 20-25 °C. The suspension was cooled down to 0-5 °C and maleic acid solution (132 mg dissolved in 3.0 ml acetonitrile) was added drop-wise during 5 minutes. The suspension was stirred at 0-5 °C for 4 hours. Crystals of Cediranib maleate were filtered off and dried at 60 °C, under vacuum for 10 hours.
  • Cediranib base 500 mg was suspended in acetonitrile (3.5 ml) at 20-25 °C. The suspension was cooled down to 0-5 °C and maleic acid solution (132 mg dissolved in 3.0 ml acetonitrile) was added drop-wise during 8 minutes. The suspension was stirred at 0-5 °C for 4 hours. Crystals of Cediranib maleate were filtered off and dried at 40 °C and 10 mbar for 10 hours. Crystals are additionally dried at 55 °C and 10 mbar for 20 hours.
  • Cediranib base 300 mg was suspended in ethyl acetate (4.2 ml) at 20-25 °C. The suspension was cooled down to 0-5 °C and maleic acid solution (79 mg dissolved in 3.0 ml ethyl acetate) was added drop-wise during 2 minutes. The suspension was stirred at 0-5 °C for 15 minutes. Crystals of Cediranib maleate were filtered off and dried at 50 °C and 10 mbar for 5 hours. The XRPD of the obtained product is shown in Figure 2.
  • Cediranib base 300 mg was suspended in mixture of acetonitrile (2.1 ml) and water (0.11 ml) at 20-25 °C. The suspension was cooled down to 0-5 °C and maleic acid solution (79 mg dissolved in 1.8 ml acetonitrile) was added drop-wise during 5 minutes. The suspension was stirred at 0-5 °C for 2 hours. Crystals of Cediranib maleate were filtered off and air dried. The XRPD of the obtained product is shown in Figure 3.
  • Cediranib base 500 mg was suspended in acetonitrile (3.5 ml) at 20-25 °C. The suspension was cooled down to 0-5 °C and maleic acid solution (132 mg dissolved in 3.0 ml acetonitrile) was added drop-wise during 5 minutes. The suspension was stirred at 0-5 °C for 4 hours. Crystals of Cediranib maleate were filtered off.
  • Cediranib base 300 mg was suspended in a mixture of ethyl acetate (4.2 ml) and water (0.13 ml) at 20-25 °C. The suspension was cooled down to 0-5 °C and maleic acid solution (79 mg dissolved in 3.0 ml ethyl acetate) was added drop-wise during 5 minutes. The suspension was stirred at 0-5 °C for 15 minutes. Crystals of Cediranib maleate were filtered off and dried at 50 °C and 10 mbar for 5h. The XRPD of the obtained product is shown in Figure 4.
  • Cediranib maleate (503 mg) was dissolved in mixture of tert-butanol: water 1 : 1 (10 ml). The solution was filtered and freeze dried. Amorphous Cediranib maleate (503 mg) was obtained. The XRPD of the obtained product is shown in Figure 5.
  • Cediranib base (5 g) was suspended in acetonitrile/water (19: 1; 36.8 mL) at
  • Example 10 Preparation of Cediranib maleate form F [0088] Cediranib base (5 g ) was suspended in ethyl acetate/water (32: 1; 72,2 mL) at 0°C. A solution of maleic acid (1.32 g) in 30 mL of ethyl acetate was added drop-wisely. The obtained suspension was stirred for additional 15 minutes at RT and filtered. The wet crystals were dried in vacuum drier at 50°C and 10 mbar for 5 hours to provide crystalline form F of Cediranib maleate as confirmed by XRPD.

Abstract

La présente invention concerne des formes à l'état solide de maléate de Cédiranib, des procédés pour leur préparation et des compositions pharmaceutiques associées.
PCT/US2016/048251 2015-08-24 2016-08-24 Formes à l'état solide de maléate de cédiranib WO2017035170A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005061488A1 (fr) * 2003-12-24 2005-07-07 Astrazeneca Ab Sels de maleate d'un derive de quinazoline utile comme agent antianiogenique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005061488A1 (fr) * 2003-12-24 2005-07-07 Astrazeneca Ab Sels de maleate d'un derive de quinazoline utile comme agent antianiogenique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CAIRA: "Crystalline Polymorphism of Organic Compounds", TOPICS IN CURRENT CHEMISTRY, SPRINGER, BERLIN, DE, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP008166276, ISSN: 0340-1022 *
HILFIKER R (EDITOR) ED - HILFIKER R: "Polymorphism in the Pharmaceutical Industry", 1 January 2006, 20060101, PAGE(S) 1 - 19, ISBN: 978-3-527-31146-0, XP002528052 *

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