WO2011069053A1 - Procede de preparation de pazopanip hcl et formes cristallines de pazopanib hcl - Google Patents

Procede de preparation de pazopanip hcl et formes cristallines de pazopanib hcl Download PDF

Info

Publication number
WO2011069053A1
WO2011069053A1 PCT/US2010/058867 US2010058867W WO2011069053A1 WO 2011069053 A1 WO2011069053 A1 WO 2011069053A1 US 2010058867 W US2010058867 W US 2010058867W WO 2011069053 A1 WO2011069053 A1 WO 2011069053A1
Authority
WO
WIPO (PCT)
Prior art keywords
pazopanib
hci
hcl
pzp
stirring
Prior art date
Application number
PCT/US2010/058867
Other languages
English (en)
Inventor
Jacob Rendell
Ana Kwokal
Original Assignee
Teva Pharmaceutical Industries Ltd.
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 Pharmaceutical Industries Ltd., Teva Pharmaceuticals Usa, Inc. filed Critical Teva Pharmaceutical Industries Ltd.
Publication of WO2011069053A1 publication Critical patent/WO2011069053A1/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention encompasses crystalline forms of 5-[[4-[(2, 3- dimethyl-2H-indazol-6-yl) methylamino]-2-pyrimidinyl] amino]-2-methyl- benzolsulfonamide HCI, the preparation thereof and pharmaceutical compositions thereof.
  • Pazopanib is administered as an HCI salt and is marketed by GSK in the US under the name Votrient®.
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single molecule like Pazopanib, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviours (e.g. measured by thermogravimetric analysis - "TGA”, or differential scanning calorimetry - “DSC”), X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum.
  • TGA thermogravimetric analysis -
  • DSC differential scanning calorimetry -
  • Discovering new polymorphic 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 polymorphic forms.
  • New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional polymorphs of Pazopanib.
  • the present invention provides solid state forms of Pazopanib.
  • the present invention further encompasses a pharmaceutical composition comprising the above described polymorphs of Pazopanib
  • the present invention encompasses the use of the above described crystalline forms of pazopanib HC1 for the preparation of formulations.
  • Figure 1 provides a characteristic X-ray powder diffractogram of crystalline Pazopanib di-HCl Form I.
  • Figure 2 provides a characteristic X-ray powder diffractogram of crystalline Pazopanib HCl Form II.
  • Figure 3 provides a characteristic X-ray powder diffractogram of crystalline Pazopanib HCl Form III.
  • Figure 4 provides a characteristic X-ray powder diffractogram of crystalline Pazopanib HCl Form IV.
  • Figure 5 provides a characteristic X-ray powder diffractogram of crystalline Pazopanib HCl Form V.
  • Figure 6 provides a characteristic X-ray powder diffractogram of crystalline Pazopanib HCl Form VI.
  • Figure 7 provides a characteristic X-ray powder diffractogram of crystalline Pazopanib HCl Form VIII.
  • Figure 8 provides DSC curve of crystalline Pazopanib HCl Form VIII.
  • Figure 9 provides a characteristic X-ray powder diffractogram of crystalline Pazopanib HCl Form IX.
  • Figure 10 provides DSC curve of crystalline Pazopanib HCl Form IX.
  • Figure 1 1 provides a characteristic X-ray powder diffractogram of crystalline Pazopanib HCl Form X.
  • Figure 12 provides DSC curve of crystalline Pazopanib HCl Form X.
  • Figure 13 provides a characteristic X-ray powder diffractogram of crystalline Pazopanib HCl Form G.
  • Figure 14 provides DSC curve of crystalline Pazopanib HCl Form G.
  • Figure 15 provides a characteristic X-ray powder diffractogram of crystal line Pazopanib HCl Form A, prepared according to example 1 .
  • Figure 16 provides DSC and TGA curve of crystalline Pazopanib HCl
  • Figure 17 provides a characteristic X-ray powder diffractogram of crystalline Pazopanib HCl Form A, prepared according to example 2.
  • Figure 18 provides a characteristic X-ray powder diffractogram of crystalline Pazopanib HC1 Form XII.
  • Figure 19 provides a characteristic X-ray powder diffractogram of crystalline Pazopanib HC1 Form XI.
  • Figure 20 provides a characteristic X-ray powder diffractogram of crystalline Pazopanib HC1 Form XIII.
  • Figure 21 provides a characteristic X-ray powder diffractogram of crystalline Pazopanib di-HCl Form XIV.
  • Figure 22 provides a characteristic X-ray powder diffractogram of crystalline Pazopanib di-HCl Form XV.
  • Figure 23 provides a characteristic X-ray powder diffractogram of crystalline Pazopanib base.
  • the present invention provides solid state physical properties of Pazopanib HCI.
  • a crystal form may be referred to herein as being characterized by graphical data "as shown in,” or “as depicted in” a Figure.
  • Such data include, for example, powder X-ray diffractograms and solid state NMR spectra.
  • 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. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form, and confirm whether the two sets of data are characterizing the same crystal form or two different crystal forms.
  • a crystal form referred to herein as being characterized by graphical data "as shown in,” or “as depicted in” a Figure includes the crystal form characterized by the data shown in the Figure or the data shown in the Figure with any of the small variations known to the skilled person.
  • pure or “polymorphically pure.” This terminology refers to the subject polymorph containing less than about 20% (w/w) of other polymorphic forms.
  • a crystal form according to the invention when referred to as pure of polymorphically pure, it will contain less than 10%, less than 5%, less than 2%, less than 1 % or even less than Patent Application
  • the polymorphs of Pazopanib according to the invention may contain from 1 % to 20% (w/w), from 5% to 20% (w/w), or from 5% to 10% (w/w) of one or more other polymorphic forms of Pazopanib.
  • the term "substantially pure” refers to a compound, such as pazopanib HCI, having a purity of 99.0% area by HPLC or more.
  • the pazopanib HCI has a purity of about 99.5% area by HPLC or more, more preferably, about 99.9% area by HPLC or more.
  • 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 means milliliters per gram, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent.
  • essentially free from CPMI refers to pazopanib HCI containing less than about 0.05% area by HPLC of CPMI.
  • pazopanib HCI contains less than about 100 ppm of CPMI as measured by a suitable HPLC method as described herein, more preferably pazopanib HCI containing between 20 to 75 ppm of CPMI, less than 75 ppm of CPMI, or an undetectable amount of CPMI as measured by a suitable HPLC method.
  • pazopanib HCI contains less than about 0.1 % area by HPLC of PZP-PDMI, more preferably pazopanib HCI containing less than about 0.05% area by HPLC of PZP-PDMI, most preferably, pazopanib HCI containing an undetectable amount of PZP-PDMI as measured by HPLC.
  • the term "essentially free from AMBS" refers to pazopanib HCI containing less than about 0.1 5% area by HPLC of AMBS. In preferred
  • pazopanib HCI contains less than about 0.1 % area by HPLC of AMBS, more preferably, pazopanib HCI containing less than about 0.05% area by HPLC of AMBS, most preferably, pazopanib HCI containing an undetectable amount of AMBS as measured by HPLC.
  • pazopanib di-HCl salt refers to pazopanib HC1 having about 1 .7 to about 2.3 moles equivalent of HCI per 1 mole of pazopanib. More preferably, having about 2 moles equivalent of HCI per 1 mole of pazopanib.
  • room temperature or “ambient temperature” refers to a temperature of about 15°C to about 30°C, more preferably, to a temperature of about 20°C to about 25°C.
  • vacuum or “reduced pressure” refers to a pressure of about to 2 mmHg to about 100 mmHg.
  • the present invention encompasses crystalline Pazopanib HCI, designated herein as Form I I.
  • Form II can be characterized by data selected from: an X-ray powder diffraction pattern having peaks at 6.5, 16.9, 19.0, 19.6 and 24.1 ⁇ 0.2 degrees 2-Theta; an X-ray powder diffraction pattern substantially as depicted in figure 2; and combinations thereof.
  • Pazopanib HCI Form II can be further characterized by additional X-ray powder diffraction peaks at 13.0, 15.0, 23.6 and 30.1 ⁇ 0.2 degrees 2-Theta.
  • the present invention encompasses crystalline
  • Pazopanib HCI designated herein as Form I II.
  • Form I II can be characterized by data selected from: an X-ray powder diffraction pattern having peaks at 9.8, 14.7, 18.8, 19.8 and 24.0 ⁇ 0.2 degrees 2-Theta; an X-ray powder diffraction pattern substantially as depicted in figure 3; and combinations thereof.
  • Pazopanib HCI Form III can be further characterized by additional X-ray powder diffraction peaks at 16.7, 18.3, 26.1 and 30.1 ⁇ 0.2 degrees 2-Theta.
  • the present invention encompasses crystalline
  • Pazopanib HCI designated herein as Form V.
  • Form V can be characterized by data selected from : an X-ray powder diffraction pattern having peaks at: 6.6, 17.4, 19.0, 19.9, 21 .3and 27.1 ⁇ 0.2 degrees 2-Theta; an X-ray powder diffraction pattern substantially as depicted in figure 5; and combinations thereof.
  • Pazopanib HCI Form V can be further characterized by additional X-ray powder diffraction peaks at 9.4, 1 2.9, 16.3, 1.8 and 25.9 ⁇ 0.2 degrees 2-Theta.
  • the present invention encompasses crystalline Pazopanib HCI, designated herein as Form VI.
  • Form VI can be characterized by data selected from: an X-ray powder diffraction pattern having peaks at: 10.1 , 14.7, 19.0, 19.5, 22.3 and 24.3 ⁇ 0.2 degrees 2-Theta; an X-ray powder diffraction pattern substantially as Patent Application
  • Pazopanib HCI Form VI can be further characterized by additional X-ray powder diffraction peaks at 12.7, 16.8, 18.2, 20.0 and 25.9 ⁇ 0.2 degrees 2-Theta.
  • the present invention encompasses crystalline Pazopanib HCI, designated herein as Form VIII.
  • Form VII can be characterized by data selected from : an X-ray powder diffraction pattern having peaks at 10.7, 1 5.4, 16.6, 23.4 and 23.9 ⁇ 0.2 degrees 2-Theta; an X-ray powder diffraction pattern substantially as depicted in figure 7; and combinations thereof.
  • Pazopanib HCI Form VIII can be further characterized by additional X-ray powder diffraction peaks at 13.9, 14.6, 19.7 and 27.6 ⁇ 0.2 degrees 2-Theta and by the differential scanning calorimetry ("DSC”) thermogram substantially as depicted in Figure 8.
  • DSC differential scanning calorimetry
  • the present invention encompasses crystalline Pazopanib HCI, designated herein as Form IX.
  • Form IX can be characterized by data selected from: an X-ray powder diffraction pattern having peaks at 6.2, 12.3, 16.7, 21 .3 and 24.0 ⁇ 0.2 degrees 2-Theta; an X-ray powder diffraction pattern substantially as depicted in figure 9; and combinations thereof.
  • Pazopanib HCI Form IX can be further characterized by additional X-ray powder diffraction peaks at 13.7, 14.6, 17.4, 1 8.3, 19.2 and 25.1 ⁇ 0.2 degrees 2-Theta and by the DSC thermogram substantially as depicted in Figure 10.
  • the present invention encompasses crystalline
  • Pazopanib HCI designated herein as Form X.
  • Form X can be characterized by data selected from: an X-ray powder diffraction pattern having peaks at 7.2, 14.5, 17.1 and 23.0 ⁇ 0.2 degrees 2-Theta; an X-ray powder diffraction pattern substantially as depicted in Figure 1 1 ; and combinations thereof.
  • Pazopanib HCI Form X can be further characterized by additional X-ray powder diffraction peaks at 19.0, 20.9 and 26.8 ⁇ 0.2 degrees 2-Theta and by the DSC thermogram substantially as depicted in Figure 12.
  • the present invention encompasses crystalline
  • Pazopanib HCI designated herein as Form XII.
  • Form XII can be characterized by data selected from : an X-ray powder diffraction pattern having peaks at 8.9, 9.8, 17.0, 1 8.9, 19.3 and 21 .5 ⁇ 0.2 degrees 2-Theta; an X-ray powder diffraction pattern substantially as depicted in Figure 1 8; and combinations thereof.
  • Pazopanib HCI Form XII can be further characterized by additional X-ray powder diffraction peaks at 14.0, 14.4, 17.8, 20.5 and 26.9 ⁇ 0.2 degrees 2-Theta.
  • the present invention encompasses crystalline Pazopanib HCl, designated herein as Form G.
  • Form G can be characterized by data selected from : an X-ray powder diffraction pattern having peaks at 9.6, 16.8, 19.6, 24.7 and 26.2 ⁇ 0.2 degrees 2-Theta; an X-ray powder diffraction pattern substantially as depicted in figure 13; and combinations thereof.
  • Pazopanib HCl Form G can be further characterized by additional X-ray powder diffraction peaks at 1 1 .8, 14.6, 15.3, 18.4, 20.3 and 23.6 ⁇ 0.2 degrees 2-Theta and by the DSC thermogram substantially as depicted in figure 14.
  • the present invention encompasses crystalline Pazopanib HCl, designated herein as Form XI.
  • Form XI can be characterized by data selected from : an X-ray powder diffraction pattern having peaks at 6.7, 1 1 .9, 15.1 , 15.6 and 24.3 ⁇ 0.2 degrees 2-Theta; an X-ray powder diffraction pattern substantially as depicted in figure 19; and combinations thereof.
  • Pazopanib HCl Form XI can be further characterized by additional X-ray powder diffraction peaks at 19.7, 20.9, 25.1 and 27.3 ⁇ 0.2 degrees 2-Theta.
  • the present invention encompasses crystalline Pazopanib HCl, designated herein as Form XIII.
  • Form XIII can be characterized by data selected from: an X-ray powder diffraction pattern having peaks at 1 5.1 , 16.6, 19.9 and 23.8 ⁇ 0.2 degrees 2-Theta; an X-ray powder diffraction pattern substantially as depicted in figure 20; and combinations thereof.
  • Pazopanib HCl Form XI II can be further characterized by additional X-ray powder diffraction peaks at 10.4, 14.4, 15.4 and 24.5 ⁇ 0.2 degrees 2-Theta.
  • form XIII is an acetic acid solvate.
  • the present invention encompasses crystalline
  • Pazopanib di-HCl designated herein as Form XIV.
  • Form XIV can be characterized by data selected from : an X-ray powder diffraction pattern having peaks at 7.8, 12.4, 22.9, 23.6 and 26.9 ⁇ 0.2 degrees 2-Theta; an X-ray powder diffraction pattern substantially as depicted in figure 21 ; and combinations thereof.
  • Pazopanib di-HCl Form XIV can be further characterized by additional X-ray powder diffraction peaks at 14.8, 17.5, 19.0, 25.3 and 27.4 ⁇ 0.2 degrees 2-Theta.
  • the present invention encompasses crystalline Pazopanib di-HCl, designated herein as Form XV.
  • Form XV can be characterized by data selected from : an X-ray powder diffraction pattern having peaks at 6.9, 12.1 , 23.6, 26.8 and 27.4 ⁇ 0.2 degrees 2-Theta; an X-ray powder diffraction pattern substantially as Patent Application
  • Pazopanib di-HCl Form XV can be further characterized by additional X-ray powder diffraction peaks at 15.7, 19.4, 23.3 and 25.7 ⁇ 0.2 degrees 2-Theta.
  • the present invention encompasses crystalline Pazopanib base, characterized by data selected from: an X-ray powder diffraction pattern having peaks at 7.3, 13.2, 14.7, 18.6 and 21 .7 ⁇ 0.2 degrees 2-Theta; an X-ray powder diffraction pattern substantially as depicted in figure 23; and combinations thereof.
  • Pazopanib base can be further characterized by additional X-ray powder diffraction peaks at 12.3, 13.7, 16.1 , 24.7 and 26.7 ⁇ 0.2 degrees 2-Theta.
  • the present invention further provides crystalline Pazopanib di-HCl, designated herein as Form I.
  • Form I can be characterized by data selected from: an X-ray powder diffraction pattern having peaks at 6.7, 7.4, 12.0, 14.8 and 23.6 ⁇ 0.2 degrees 2- Theta; an X-ray powder diffraction pattern substantially as depicted in figure 1 ; and combinations thereof.
  • Pazopanib di-HCl Form I can be further characterized by additional X-ray powder diffraction peaks at 13.3, 14.8, 19.0 and 26.6 ⁇ 0.2 degrees 2-Theta.
  • the present invention further provides crystalline Pazopanib HCI, designated herein as Form IV.
  • Form IV can be characterized by data selected from: an X- ray powder diffraction pattern having peaks at 1 1.5, 1 1 .9, 15.5, 17.2 and 20.9 ⁇ 0.2 degrees 2-Theta; an X-ray powder diffraction pattern substantially as depicted in figure 4; and combinations thereof.
  • Pazopanib HCI Form IV can be further characterized by additional X-ray powder diffraction peaks at 18.2, 18.7, 25.7 and 27.1 ⁇ 0.2 degrees 2- Theta.
  • form IV is a hydrate.
  • the present invention further provides crystalline Pazopanib HCI, designated herein as form A.
  • Form A can be characterized by data selected from: an X- ray powder diffraction pattern having peaks at 5.6, 15.5, 16.4, 24.0 and 24.3 ⁇ 0.2 degrees 2-Theta; an X-ray powder diffraction pattern substantially as depicted in figure 15, 1 7 or 18; and combinations thereof.
  • Pazopanib HCI form A can be further characterized by data selected from: additional X-ray powder diffraction peaks at 10.5, 16.8, 17.9, 26.4 and 32.9 ⁇ 0.2 degrees 2-Theta; a DSC thermogram substantially as depicted in figure 16; and thermogravimetric analysis ("TGA”) substantially as depicted in figure 16.
  • Form A is an anhydrous form containing less than about 1 % water as measured by the Karl-Fisher method.
  • the present invention encompasses a process for preparing Pazopanib HCI comprising reacting N-(2-chloropyrimidin-4-yl)-2,3-dimethyl- 2H-indazol-6-amine (CPMI) and 5-amino-2-methylbenzenesulfonamide (AMBS) with acetic acid or alternatively in a mixture of water and acetic acid.
  • CPMI N-(2-chloropyrimidin-4-yl)-2,3-dimethyl- 2H-indazol-6-amine
  • AMBS 5-amino-2-methylbenzenesulfonamide
  • the CPMI and AMBS are combined with acetic acid or with a mixture of water and acetic acid to provide a solution.
  • the solution is then cooled to obtain a suspension comprising Pazopanib HCI.
  • the reaction can be carried out at a temperature of about 80°C to about 120°C, or at a temperature of about 90°C to about 100°C, for example at a temperature of about 95°C.
  • the reaction mixture may be cooled, for example to about ambient temperature. The reaction mixture can be further maintained following the cooling, for a period of about 1 hour to provide a suspension comprising Pazopanib HCI form XIII.
  • the obtained pazopanib HCI may be recovered from the suspension by any suitable technique, for example by precipitation, filtering and washing the precipitate and drying. Washing can be done with acetic acid. Drying can be done for example, by heating at a temperature of about 50-70°C, for a period of about 48-72 hours, e.g., about 62 hours.
  • the reaction When the reaction is done with a mixture of acetic acid and water, the reaction can be carried out at a temperature of about 65°C. The solution can be further heated to a temperature of about 100°C for a period of about 1 hour. When the reaction is complete, the reaction mixture may be cooled, for example to about 0°C. The cooling can be accompanied by addition of ethanol to form a suspension comprising Pazopanib HCI form A.
  • the obtained pazopanib HCI may be recovered from the suspension by any suitable technique, for example by precipitation, filtering and washing the precipitate and drying. Washing can be done with ethanol. Drying can be done for example, under vacuum e.g., at less than about 200 mbar, at a temperature of about 50-60°C for a period of about 1 2- 1 7 hours.
  • the pazopanib HCI obtained according to the above process using acetic acid or a mixture of acetic acid and water is substantially pure.
  • the process provides pazopanib HCl essentially free of the starting material CPMI.
  • CPMI can be prepared according to example 52 or 54. During its preparation several impurities, described herein, can be formed.
  • Des-Me-DMAD can be prepared for example according to the procedure described in example 49.
  • the obtained Des-Me-DMAD is crystalline.
  • DMND 2,3-dimethyl-6-nitro-2H- indazole
  • DMND can be prepared for example according to the procedure described in example 50.
  • the obtained DMND is crystalline.
  • N-(4-chloropyrimidin-2-yl)-2, 3-dimethyl-2H-indazol-6-amine "4-CPDMI" is N-(4-chloropyrimidin-2-yl)-2, 3-dimethyl-2H-indazol-6-amine "4-CPDMI"
  • Bis-PDM I can be prepared for example according to the procedure described in example 48.
  • the obtained bis-PDMI is crystalline.
  • pazopanib HC1 which is essentially free of 5-((4-((2,3-dimethyl-2H-indazol-6-yl)(methyl)amino)pyrimidin-2- yl)(4-(2,3-dimethyl-2H-indazol-6-ylamino)pyrimidin-2-yl)amino)-2-methylbenzene- sulfonamide (“PZP-PDMI”), an impurity which is formed during the preparation of pazopanib HC1, which has the followin formula:
  • PZP-PDMI can be isolated from the reaction mixture, where it is formed.
  • the separation can be done by filtering the precipitated PZP-PDMI or by isolating it from the reaction mixture using column chromatography on silica.
  • NMBS 2-methyl-5-benzenesulfonamide
  • Des-Me-PZP can be prepared for example according to the procedure described in example 43.
  • the obtained Des-Me-PZP is crystalline.
  • Pazopanib HCl can be also prepared by a process comprising: reacting N-
  • CPMI and AMBS are combined with water to form a reaction mixture, and HCl is then added to the reaction mixture to form a suspension comprising the crystalline form.
  • the reaction mixture may be heated before the HCl addition or after it. Preferably, this heating is to about the reflux temperature.
  • the heating step may be followed by a maintaining step.
  • the heated mixture is maintained at the temperature achieved in the heating step.
  • the heated mixture is maintained at that temperature until the amount of CPMI of less than about 1 %, more preferably, less Patent Application
  • Atty Docket No. 14669.0172 WOU1 than about 0.5%, most preferably, less than about 0.1 %, as measured by HPLC.
  • the process may further comprise a cooling step, e.g., to about ambient temperature, such as about 25°C.
  • Pazopanib HC1 form IV is a hydrate, having a water content of about 5% as measured by the Karl-Fisher method.
  • Crystalline pazopanib HC1 form IV may further be recovered from the suspension, for example, by filtering the suspension comprising pazopanib HC1 form IV, washing the filtered mater, e.g., with water, and then drying it. Drying may be done by heating, e.g., in a vacuum oven at a temperature of about 40-60°C, preferably, for a period of about 8-24 hours.
  • the above crystalline forms can be prepared by a process comprising crystallizing pazopanib HC1 from a polar aprotic solvent selected from:
  • a protic solvent selected from: a Ci- C4 alcohol, such as methanol or ethanol; a C1-C4 halogenated alcohol, such as trifluoroethanol (TFE), formic acid, acetic acid, triflouroacetic acid and mixtures thereof, to form a precipitate.
  • a Ci- C4 alcohol such as methanol or ethanol
  • a C1-C4 halogenated alcohol such as trifluoroethanol (TFE), formic acid, acetic acid, triflouroacetic acid and mixtures thereof, to form a precipitate.
  • the crystallization comprises providing a solution of pazopanib HCI in the polar aprotic solvent and cooling the solution, e.g., to a temperature from about 0°C to about 10° C, to obtain a suspension comprising the above crystalline forms.
  • the solvent is DMSO
  • the process is preferably done at about ambient temperature, more preferably, at about 25°C to about 20°C.
  • a maintaining step is performed.
  • the cooled DMSO suspension is maintained at the reduced temperature for about 12 to about 24 hours, more preferably, for about 15 hours to about 17 hours.
  • the heating is to a temperature of about
  • the heating is for about 5 minutes to about 30 minutes, more preferably, for about 15 minutes.
  • the cooling is preferably to about ambient temperature, more preferably, from about 25°C to about 20°C. .
  • the process may further comprise a maintaining step.
  • the cooled mixture is maintained for about 10 minutes to about 3 hours, more preferably, for about 2 Patent Application
  • the obtained Pazopanib HCl may further be recovered, e.g., by filtering; and then drying. Drying is preferably done at reduced pressure, preferably, at a temperature of about 40°C to about 60°C, more preferably, at about 35. mbar and about 45°C. Preferably, the drying is done for about 12 hours to about 90 hours, more preferably, for about 24 hours to about 72 hours.
  • the process preferably comprises heating to a temperature of about 120°C to about 140°C, more preferably, to about 125°C to about 130°C.
  • the heating is preferably to reflux temperature.
  • the cooling is preferably to about ambient temperature, more preferably, to about 25°C to about 20°C.
  • a maintaining step is performed.
  • the heated mixture is maintained at the heated temperature for about 10 minutes to about 3 hours, more preferably, for about 1 5 minutes to about 2 hours.
  • the maintaining step is done for about 1 day to about 5 days, more preferably, for about 3 days.
  • the obtained Pazopanib HCl may further be recovered, e.g., by techniques such as filtering, centrifugation or solvent decantation; and then drying.
  • the solvent is NMP
  • the recovery is preferably done by centrifugation or solvent decantation, and then drying.
  • the solvent is DMF, pazopanib HCl form II is obtained, and when the solvent is DMA or NMP, form I I I is obtained.
  • the heating is preferably to a temperature of about 1 10°C to about 1 20°C, more preferably, to about 1 17°C to about 1 18°C, and the cooling is preferably to about ambient temperature, more preferably, to about 25°C to about 20°C.
  • additional acetic acid is added prior to the cooling step.
  • the addition is done dropwise until complete dissolution is obtained.
  • the process when acetic acid is the solvent may further comprise a maintaining step.
  • the acetic acid mixture is maintained at the cooled temperature for an interval of about 30 minutes to about 2 hours, more preferably, for about 1 hour.
  • the obtained Pazopanib HCl may further be recovered, for example, by filtering;
  • drying is done at reduced pressure, e.g., from about Patent Application
  • washing is preferably done with acetic acid.
  • the invention further encompasses a precipitation process for preparing pazopanib HC1 comprising: dissolving pazopanib HC1 in formic acid, DMSO or TFE and adding an anti-solvent selected from: acetone, acetonitrile, methyl tert-butyl ether (MTBE), ethyl-acetate (EtOAc), toluene, and ethanol.
  • an anti-solvent selected from: acetone, acetonitrile, methyl tert-butyl ether (MTBE), ethyl-acetate (EtOAc), toluene, and ethanol.
  • the anti-solvent is added over a period of about 5 minutes to about 10 minutes.
  • the solvent are used in suitable amounts.
  • DMSO is preferably used in about 10 vol. to about 15 vol
  • formic acid is used in about 2.0 vol. to about 3 vol.
  • the anti-solvent is preferably used in about 30 vol. to about 35 vol.
  • a heating step is performed prior to the addition of anti solvent.
  • the heating is to a temperature of about 40°C to about 60°C, more preferably about 40°C, most preferably, until dissolution is obtained.
  • a cooling step is performed following the heating step.
  • cooling is to about ambient temperature, more preferably, from about 25°C to about 20°C.
  • the product may further be recovered, e.g., by filtration.
  • the filtered product may further be dried. Drying is preferably done under vacuum at a temperature of about 45°C to about 80°C, more preferably, at about 60°C, and for about 20 hours to about 30 hours.
  • a washing step is performed, preferably, using the anti- solvent used in the process. Washing may be repeated.
  • the invention further encompasses a process for preparing pazopanib HC1 comprising: slurrying pazopanib HC1 in acetone or DMF.
  • This slurry process is preferably done at about ambient temperature, more preferably, at about 25°C to about 20°C.
  • the slurry process is also preferably done with stirring, e.g., for about 10 hours to Patent Application
  • Atty Docket No. 14669.0172 WOU 1 about 27 hours, more preferably, for about 10 to about 17 hours.
  • the slurry process may further comprise a recovery step, e.g., by filtering.
  • the recovery step further comprises drying, preferably, at a temperature of about 55°C to about 85°C , more preferably from about 65°C to about 75°C, most preferably, at 70°C.
  • drying is preferably done, e.g., with acetone, and optionally may be repeated.
  • the invention further encompasses a process for preparing pazopanib HCI comprising: dissolving pazopanib HCI in TFE and rapidly evaporating the TFE.
  • a heating step is performed, e.g., to about 80°C to about 120°C, more preferably, about 100°C to about 1 10°C, most preferably, about 1 10°C.
  • a purging step is performed.
  • the purge is done in the presence of nitrogen, and under vacuum, preferably, at a pressure of about 6 mbar to about 10 mbar.
  • this process comprises rapidly evaporating the solvent while adding solution of Pazopanib HCI and TFE under reduced pressure.
  • the addition is done in portions, more preferably, drop-wise.
  • the Pazopanib HCI obtained using this process is amorphous.
  • the above process may further comprise a recovery step.
  • the recovery step may comprise drying; and cooling.
  • drying is done under vacuum, more preferably, at the same pressure used in the process. Cooling is preferably to about ambient temperature, more preferably, to about 25°C to about 20°C. Preferably, said cooling is done under nitrogen.
  • the compounds may be characterized by high performance liquid chromatography (HPLC) using Agilent 1200 HPLC system equipped with a diode array detector or Waters Acquity UPLC system with a photo diode array (PDA) detector.
  • HPLC high performance liquid chromatography
  • PDA photo diode array
  • One analytical column used here is the Zorbax Eclipse XDB-C8 150x 4.6mm (3.5 ⁇ particle size) from Agilent Technology.
  • some analyses were done using a Acquity UPLC BEH C I 8, 2.1 100mm ( 1.7 ⁇ particle size) from Waters Corp.
  • HPLC method 2 determination of CPMI by UPLC
  • the detection limit for CPMI is 20 ppm and the quantification limit is 40 ppm.
  • Atty Docket No. 14669.0172WOU 1 positions were determined by using silicon powder as internal standard in an admixture with the sample measured.
  • the position of the silicon (1 1 1 ) peak was corrected to be 28.45 degrees two theta.
  • the positions of the peaks were corrected respectively (no corrections were performed on the presented diffractograms in the figures).
  • the scanning parameters were: range: 2-40 degrees two-theta; scan mode: continuous scan; step size: 0.01 67°; and scan rate: 0.05 degrees/sec.
  • the silicon powder as internal standard was present as an admixture within the samples.
  • the position of the silicon ( 1 1 1 ) peak was 28.45 degrees two theta. No corrections were performed on the presented diffractograms in the figures and peak list.
  • PZP.HC1 (form A, 0.1 54 g) was suspended in NMP (30V) and heated to 130°C for 30 min until dissolution, and subsequently cooled to ambient temperature. Stirring was continued for 3 days leading to precipitation. The resulting precipitate was separated by centrifugation, the solvent was decanted and the solid (form III) was dried at 70 °C (25 mbar) for 66 h to give polymorphic form III.
  • Atty Docket No. 14669.0172WOU 1 heated to reflux for 10 mins resulting in dissolution. The solution was then gradually cooled to ambient temperature over 40 min and stirring was continued at the same temperature for 2 h leading to precipitation. The solid was filtered and dried under vacuum (25 mbar) at 60°C for 18 h to give Pazopanib HC1. (>99.99% purity, AMBS, CPMI and PZP-PDM1 not detected by HPLC method 1)
  • Pazopanib HCI (229 mg, form A) and DMSO (2.5 mL, 1 I V). The mixture was stirred at ambient temperature for about 10 min resulting in dissolution. To the solution was added ethanol (4.8 mL, 30V) drop-wise over 5 min leading to precipitation. Stirring was continued at ambient temperature for 17 h. The solid was filtered, washed with ethanol (2x2 mL) (polymorph G) and dried under vacuum (26 mbar) at 60°C for 22 h to give Pazopanib HCI form G .
  • Pazopanib HCI (98.6% purity and containing 0.92% CPMI) (210 mg, form A) and DMSO (2.3 mL, 1 1 V). The mixture was stirred at ambient temperature for about 10 min resulting in dissolution. To the solution was added MTBE (6.1 mL, 29V) dropwise over 5 min leading to precipitation. Stirring was continued at ambient temperature for 20 h. The solid was filtered, washed with MTBE (2x2 mL) (polymorph G) and dried under vacuum (25 mbar) at 60 °C for 39 h to give Pazopanib HCI (59% yield, >99.9% purity, AMBS not detected, CPMI 0.04%, PZP-PDMI 0.03%) form G .
  • Atty Docket No. 14669.0172 WOU 1 was isolated by vacuum filtration and dried in a vacuum oven (25 mbar) at 70°C for about 16 h to give form VIII.
  • PZP.HC1 (form A, 100 mg) was suspended in 2,2,2-trifluoroethanol (3 mL, 3V). The mixture was heated to reflux resulting in dissolution with mixing. The resulting clear solution was cooled to ambient temperature and stirred over night leading to precipitation. The precipitate was filtered and dried at 70 °C (25 mbar) for 72 h to give polymorphic form X. The wet form was a mixture of form IX and X.
  • Example 36 Process for preparation of form XI
  • Example 40 Process for preparation of forms XIV and XV (di-HCl salt from PZP free base)
  • PZP.HC1 500 mg, form A was slurried with a 10% aqueous solution of sodium carbonate ( 10 mL) at ambient temperature. To the slurry was added chloroform ( 15 mL) with stirring. Stirring was continued and then the slurry was filtered and the filter cake was washed with water and dried in a vacuum oven at 35°C. Titration of the material indicated that all HCl had been removed to below detection limit.
  • PZP.HC1 (14.6 g, form A) was slurried with a 5% aq solution of sodium carbonate ( 1 25 mL) at ambient temperature with stirring. After 30 min the solid was filtered and slurried again a 5% aq solution of sodium carbonate (125 mL) at ambient temperature. This operation was repeated again and the resulting solid was isolated by filtration. CI titration indicated a small presence of HC1 so the material was slurried in sodium carbonate (10% aq. soln) over night at room temperature. The solid was filtered, washed with water ( 120 mL) and dried at room temperature under nitrogen stream for 16 h to give PZP free base ( 13.2 g, 97.1 % assay, chloride content not detectable).
  • PZP.HC1 ( 1 g, form A) was slurried with sodium carbonate ( 10% aq. soln) (9.0 g, 8 eq) and MeOH (9.0 g) at ambient temperature. Stirring was continued for 5 h before the solid was filtered and dried in a vacuum oven (35mbar) at 40 °C for 1 7 h to give PZP free base (0.92 g, 97% yield, chloride content not detectable)
  • Example 50 Process for preparation of DMND
  • Example 51 Process for preparation of des-Me-PZP
  • Example 52 Process for preparation of CP I
  • a 1 L reactor equipped with a mechanical stirrer was charged with CPDMI (80 g, 0.29 mol), dimethylcarbonate ( 131 .6 g, 1 .46 mol, 5 eq), potassium carbonate ( 10.1 g, 0.073 mol, 0.25 mol eq) and DMF (266 mL, 3.3V) and the resulting mixture was stirred and heated to 1 18°C. Stirring was continued at this temperature for 7.5 h and then the reaction mixture was cooled to 65°C and subsequently water (800 mL, 10V) was added over a period of 20 min, keeping the temperature at 54-56°C during this time.
  • CPDMI 80 g, 0.29 mol
  • dimethylcarbonate 131 .6 g, 1 .46 mol, 5 eq
  • potassium carbonate 10.1 g, 0.073 mol, 0.25 mol eq
  • DMF 266 mL, 3.3V
  • the filter cake was added to the reactor and slurried with ethyl acetate twice (2x850 mL, 2x3 V) at 10°C.
  • the solid was filtered and the filter cake was slurried with tap water twice (2x4083 mL, 2x 15V) at 25°C.
  • Example 54 Process for preparation of CPMI Patent Application
  • Atty Docket No. 14669.0172WOU 1 was then cooled to 0°C over a period of 4 h and stirring was then continued at the same temperature for 16 h.
  • the solids were isolated by filtration and the filter cake was washed with EtOH abs (4x 13.5 mL, 4x3 V) at room temperature.
  • the cake was dried in a vacuum oven (35 mbar) at 60 °C for 48 h to give pure PZP.HCI (4.09 g, 90.9% yield, 99.5% assay, CPMI ⁇ 20 ppm) as a white powder.
  • Example 61 Process for the preparation of PZP.HC1 form XII
  • PZP.HC1 form A (0.181 g) was dissolved at reflux in MeOH (75 V) with stirring over a period of 10 min. The resulting clear solution was subsequently cooled to room temperature over 2h, and then stirring was continued for 3 days at this temperature. The resulting precipitate was filtered and the filter cake was dried in a vacuum oven (35 mbar) at 45°C for 70 h to give PZP.HC1 form XII as determined by XRD
  • Example 62 Process for the preparation of PZP.HCI form XII
  • PZP.HCI form A (0.620 g) was suspended in MeOH (6.2 mL, 10V). The resulting slurry was stirred at room temperature for 21 h and then the solids were isolated by filtration to give polymorphic form XII.
  • Example 63 Process for the preparation of PZP.HCI form XII
  • PZP.HCI form A (0.500 g) was suspended in MeOH (5.0 mL, 10V). The resulting slurry was stirred at room temperature for 90 h and then the solids were isolated by filtration to give polymorphic form XII.

Abstract

L'invention concerne la préparation de formes cristallines variées de Pazopanib HCl. Dans des modes de réalisation préférés, le Pazopanib HCl obtenu est essentiellement exempt de CPMI.
PCT/US2010/058867 2009-12-04 2010-12-03 Procede de preparation de pazopanip hcl et formes cristallines de pazopanib hcl WO2011069053A1 (fr)

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
US26682709P 2009-12-04 2009-12-04
US61/266,827 2009-12-04
US29016509P 2009-12-24 2009-12-24
US61/290,165 2009-12-24
US30461910P 2010-02-15 2010-02-15
US61/304,619 2010-02-15
US34601610P 2010-05-18 2010-05-18
US61/346,016 2010-05-18
US35417610P 2010-06-11 2010-06-11
US61/354,176 2010-06-11
US35440210P 2010-06-14 2010-06-14
US61/354,402 2010-06-14

Publications (1)

Publication Number Publication Date
WO2011069053A1 true WO2011069053A1 (fr) 2011-06-09

Family

ID=43628877

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/058867 WO2011069053A1 (fr) 2009-12-04 2010-12-03 Procede de preparation de pazopanip hcl et formes cristallines de pazopanib hcl

Country Status (1)

Country Link
WO (1) WO2011069053A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103232443A (zh) * 2013-02-01 2013-08-07 天津药物研究院 一种吲唑衍生物的晶型及其制备和用途
WO2014097152A1 (fr) 2012-12-17 2014-06-26 Ranbaxy Laboratories Limited Procédé de préparation du pazopanib ou de ses sels
CN104557881A (zh) * 2014-12-30 2015-04-29 山东博迈康药物研究有限公司 一种盐酸帕唑帕尼晶型的制备方法
US9474756B2 (en) 2014-08-08 2016-10-25 Forsight Vision4, Inc. Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof
US9802923B2 (en) 2012-12-17 2017-10-31 Sun Pharmaceutical Industries Limited Process for the preparation of pazopanib or salts thereof
CN107991398A (zh) * 2016-10-26 2018-05-04 齐鲁制药有限公司 盐酸帕唑帕尼中间体相关杂质的分析测定方法
US9968603B2 (en) 2013-03-14 2018-05-15 Forsight Vision4, Inc. Systems for sustained intraocular delivery of low solubility compounds from a port delivery system implant
US10166142B2 (en) 2010-01-29 2019-01-01 Forsight Vision4, Inc. Small molecule delivery with implantable therapeutic device
CN109212042A (zh) * 2017-06-30 2019-01-15 齐鲁制药有限公司 一种采用液质联用法测定盐酸培唑帕尼基因毒性杂质的分析方法
US10626110B2 (en) 2018-08-07 2020-04-21 Formosa Laboratories, Inc. Polymorph of pazopanib hydrochloride and preparation process thereof
US10730859B2 (en) 2013-11-05 2020-08-04 Laurus Labs Limited Process for the preparation of pazopanib or a pharmaceutically acceptable salt thereof
US10874548B2 (en) 2010-11-19 2020-12-29 Forsight Vision4, Inc. Therapeutic agent formulations for implanted devices
US11129900B2 (en) 2014-12-25 2021-09-28 Kyoto University Cytophilic peptide-fused high-density lipoprotein, and delivery of drug to posterior segment of eye by ocular installation of said fusion

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002059110A1 (fr) 2000-12-21 2002-08-01 Glaxo Group Limited Composes chimiques
WO2003106416A2 (fr) 2002-06-17 2003-12-24 Smithkline Beecham Corporation Processus chimique
WO2005105094A2 (fr) 2004-04-16 2005-11-10 Smithkline Beecham Corporation Methode de traitement du cancer
WO2006020564A1 (fr) 2004-08-09 2006-02-23 Smithkline Beecham Corporation Derives de pyrimidine pour le traitement du myelome multiple
WO2007064753A2 (fr) 2005-11-29 2007-06-07 Smithkline Beecham Corporation Procede de traitement du cancer
WO2007143483A2 (fr) 2006-06-01 2007-12-13 Smithkline Beecham Corporation Procédé de traitement du cancer
US20080293691A1 (en) 2005-11-29 2008-11-27 Smithkline Beecham Corporation Treatment Method

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002059110A1 (fr) 2000-12-21 2002-08-01 Glaxo Group Limited Composes chimiques
US7105530B2 (en) 2000-12-21 2006-09-12 Smithkline Beecham Corporation Pyrimidineamines as angiogenesis modulators
US7262203B2 (en) 2000-12-21 2007-08-28 Smithkline Beecham Corporation Pyrimidineamines as angiogenesis modulators
WO2003106416A2 (fr) 2002-06-17 2003-12-24 Smithkline Beecham Corporation Processus chimique
US20060252943A1 (en) 2002-06-17 2006-11-09 Amogh Boloor Chemical process
WO2005105094A2 (fr) 2004-04-16 2005-11-10 Smithkline Beecham Corporation Methode de traitement du cancer
WO2006020564A1 (fr) 2004-08-09 2006-02-23 Smithkline Beecham Corporation Derives de pyrimidine pour le traitement du myelome multiple
WO2007064753A2 (fr) 2005-11-29 2007-06-07 Smithkline Beecham Corporation Procede de traitement du cancer
US20080293691A1 (en) 2005-11-29 2008-11-27 Smithkline Beecham Corporation Treatment Method
WO2007143483A2 (fr) 2006-06-01 2007-12-13 Smithkline Beecham Corporation Procédé de traitement du cancer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
THE JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, vol. 50, 2009, pages 144 - 150

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10166142B2 (en) 2010-01-29 2019-01-01 Forsight Vision4, Inc. Small molecule delivery with implantable therapeutic device
US11065151B2 (en) 2010-11-19 2021-07-20 Forsight Vision4, Inc. Therapeutic agent formulations for implanted devices
US10874548B2 (en) 2010-11-19 2020-12-29 Forsight Vision4, Inc. Therapeutic agent formulations for implanted devices
WO2014097152A1 (fr) 2012-12-17 2014-06-26 Ranbaxy Laboratories Limited Procédé de préparation du pazopanib ou de ses sels
US9802923B2 (en) 2012-12-17 2017-10-31 Sun Pharmaceutical Industries Limited Process for the preparation of pazopanib or salts thereof
CN103232443A (zh) * 2013-02-01 2013-08-07 天津药物研究院 一种吲唑衍生物的晶型及其制备和用途
US9968603B2 (en) 2013-03-14 2018-05-15 Forsight Vision4, Inc. Systems for sustained intraocular delivery of low solubility compounds from a port delivery system implant
US11427570B2 (en) 2013-11-05 2022-08-30 Laurus Labs Limited Process for the preparation of pazopanib or a pharmaceutically acceptable salt thereof
US11299477B2 (en) 2013-11-05 2022-04-12 Laurus Labs Limited Process for the preparation of Pazopanib or a pharmaceutically acceptable salt thereof
US10730859B2 (en) 2013-11-05 2020-08-04 Laurus Labs Limited Process for the preparation of pazopanib or a pharmaceutically acceptable salt thereof
CN107106551A (zh) * 2014-08-08 2017-08-29 弗赛特影像4股份有限公司 受体酪氨酸激酶抑制剂的稳定且可溶的制剂和其制备方法
US10363255B2 (en) 2014-08-08 2019-07-30 Forsight Vision4, Inc. Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof
US10765677B2 (en) 2014-08-08 2020-09-08 Forsight Vision4, Inc. Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof
US9895369B2 (en) 2014-08-08 2018-02-20 Forsight Vision4, Inc Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof
US9474756B2 (en) 2014-08-08 2016-10-25 Forsight Vision4, Inc. Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof
US11129900B2 (en) 2014-12-25 2021-09-28 Kyoto University Cytophilic peptide-fused high-density lipoprotein, and delivery of drug to posterior segment of eye by ocular installation of said fusion
CN104557881B (zh) * 2014-12-30 2017-08-11 山东博迈康药物研究有限公司 一种盐酸帕唑帕尼晶型的制备方法
CN104557881A (zh) * 2014-12-30 2015-04-29 山东博迈康药物研究有限公司 一种盐酸帕唑帕尼晶型的制备方法
CN107991398A (zh) * 2016-10-26 2018-05-04 齐鲁制药有限公司 盐酸帕唑帕尼中间体相关杂质的分析测定方法
CN109212042A (zh) * 2017-06-30 2019-01-15 齐鲁制药有限公司 一种采用液质联用法测定盐酸培唑帕尼基因毒性杂质的分析方法
US10626110B2 (en) 2018-08-07 2020-04-21 Formosa Laboratories, Inc. Polymorph of pazopanib hydrochloride and preparation process thereof

Similar Documents

Publication Publication Date Title
WO2011069053A1 (fr) Procede de preparation de pazopanip hcl et formes cristallines de pazopanib hcl
KR102325775B1 (ko) 5-클로로-ｎ2-(2-이소프로폭시-5-메틸-4-피페리딘-4-일-페닐)-ｎ4[2-(프로판-2-술포닐)-페닐]-피리미딘-2,4-디아민의 결정질 형태
US9090598B2 (en) Nilotinib salts and crystalline forms thereof
US20100016590A1 (en) Nilotinib intermediates and preparation thereof
CN111269186A (zh) 激酶抑制剂及其盐的晶型
JP5689875B2 (ja) トランス−４−［［（５ｓ）−５−［［［３，５−ビス（トリフルオロメチル）フェニル］メチル］（２−メチル−２ｈ−テトラゾール−５−イル）アミノ］−２，３，４，５−テトラヒドロ−７，９−ジメチル−１ｈ−１−ベンゾアゼピン−１−イル］メチル］−シクロヘキサンカルボン酸
CA2866857A1 (fr) Sels d'inhibiteur de kinases du recepteur de facteur de croissance epidermique
US8598341B2 (en) Process for etravirine intermediate and polymorphs of etravirine
WO2012015999A2 (fr) Procédé de préparation de mésylate d'imatinib
US8772483B2 (en) Solid forms of (S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid
WO2010140139A2 (fr) Formes cristallines de la 6-(1h-imidazol-1-yl)-2-phénylquinazoline et sels associés
WO2012090221A1 (fr) Nouveaux sels d'imatinib
US20150119398A1 (en) Form 2 polymorph of 7-(tert-butyl-d9)-3-(2,5-difluorophenyl)-6-((1-methyl-1h-1,2,4-triazol-5-yl)methoxy)-[1,2,4]triazolo[4,3-b]pyridazine
CA2957498C (fr) Procede de production a grande echelle d'oxalate de 1-isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]-oxadiazol-2-yl}-1h-indazole
US20050222134A1 (en) Crystalline forms of 5, 11-dihydro-11-ethyl-5-methyl-8-{2-{(1-oxido-4-quinolinyl)oxy}ethyl}-6H-dipyrido[3,2-b:2',3'-e] [1,4]diazepin-6-one
AU2019240721A1 (en) Crystalline forms of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide mono hydrochloride
US20150158870A1 (en) Polymorphs of 7-(tert-butyl-d9)-3-(2,5-difluorophenyl)-6-((1-methyl-1h-1,2,4-triazol-5-yl)methoxy)-[1,2,4]triazolo[4,3-b]pyridazine

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: 10807570

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: 10807570

Country of ref document: EP

Kind code of ref document: A1