WO2016178150A1 - Nouveaux polymorphes d'axitinib - Google Patents

Nouveaux polymorphes d'axitinib Download PDF

Info

Publication number
WO2016178150A1
WO2016178150A1 PCT/IB2016/052530 IB2016052530W WO2016178150A1 WO 2016178150 A1 WO2016178150 A1 WO 2016178150A1 IB 2016052530 W IB2016052530 W IB 2016052530W WO 2016178150 A1 WO2016178150 A1 WO 2016178150A1
Authority
WO
WIPO (PCT)
Prior art keywords
axitinib
sab
crystalline form
crystalline
peak
Prior art date
Application number
PCT/IB2016/052530
Other languages
English (en)
Inventor
Bhagat Raj PIPAL
Vinod Kumar Singh
Akshay Kant CHATURVEDI
Original Assignee
Shilpa Medicare Limited
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 Shilpa Medicare Limited filed Critical Shilpa Medicare Limited
Publication of WO2016178150A1 publication Critical patent/WO2016178150A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel stable crystalline polymorphic forms of Axitinib Formula (I).
  • said crystalline forms may be commercially viable and lead to consistently produce as the stable material as per the processes according to the present invention.
  • Axitinib is chemically known as N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH- indazol-6-ylsulf anyl] -benzamide (I) .
  • Axitinib is reported as tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-l, VEGFR-2 and VEGFR-3 in US6,534,524. These receptors are implicated in pathologic angiogenesis, tumour growth, and metastatic progression of cancer.
  • Axitinib has been shown to potently inhibit VEGF-mediated endothelial cell proliferation and survival. Axitinib inhibited the phosphorylation of VEGFR-2 in xenograft tumor vasculature that expressed the target in vivo and produced tumor growth delay, regression, and inhibition of metastases in many experimental models of cancer.
  • Axitinib is weak base, non-hygrospic, classified as Bio pharmaceutics Classification
  • BCS BCS class II (low solubility, high permeability), and exhibits polymorphism.
  • Axitinib was approved by USFDA in 2012 and is marketed under the brand name Inlyta ® , and is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of prior systemic treatment.
  • RRC renal cell carcinoma
  • Axitinib is marketed in a crystalline Form XLI, which is reported by Campeta et al in US8791140.
  • Axitinib is a white to light yellow powder with the empirical formula C 22 His N 4 OS and a molecular weight of 386.47 Daltons.
  • Axitinib is generically and specifically disclosed in US 6, 534,524. The process disclosed for the preparation of Axitinib is delineated below:
  • US patent 7,232,910 further disclosed two more route of synthesis for the preparation of Axitinib.
  • this patent has not disclosed any generalized impurities formed during the process development.
  • This patent also not disclosed exact purity obtained as per this process. It broadly mentioned the purity as > 99 % and does not disclosed the content of total impurities formed in the final active pharmaceutical ingredient (API).
  • Campeta et al in US 2010/0179329 disclosed some more different crystalline forms like crystalline Form XLI, Form XXV, Form IX, Form XII, Form XV and amorphous form of Axitinib. Further, this patent has not disclosed any specific synthesis for the preparation of Axitinib. Specifics for Form- XLI mentioned in this patent requires ethanol solvent to be utilized [as per Example 1(d)] for its preparation. Form-XLI shall essentially contain XRPD peaks at 6.0, 11.5,11.9 and 21.0 +/- 0.1 °2 ⁇ . Further, within large number of reported crystalline forms in the same patent, these essential peaks are also found to be present. E.g.
  • Form VIII and XXV possess peaks at 21.0, Form XVI possess peak at 5.9 and 11.9+/- 0.1 °2 ⁇ . In view of this, it is materially questionable- whether single peak becomes the essential feature for distinguishing a particular crystalline form.
  • Exploring new polymorphic form for developing a stable and pure form of Axitinib, which are amenable to scale up for pharmaceutically active useful compounds in the preparation of Axitinib may thus provide an opportunity to improve the drug performance characteristics of products such as purity and solubility.
  • inventors of the present application report a new polymorphic form, which is a stable and substantially pure form of Axitinib, which may be industrially amenable and usable for preparing the corresponding pharmaceutical compositions.
  • the present invention provides an improved process for the preparation of substantially pure novel crystalline forms of Axitinib, wherein substantially pure material having a purity of greater than 99.5% by HPLC and meeting the quality of ICH guidelines.
  • Axitinib crystalline material obtained by the process of the present invention is chemically stable and has been found with good dissolution properties.
  • the main objective of the invention relates to new stable polymorphic forms of Axitinib.
  • Yet another objective of the invention relates to crystalline forms of Axitinib, which is a stable and substantially pure form of Axitinib, which may be industrially amenable and usable for preparing the corresponding pharmaceutical compositions.
  • Non-solvated Axitinib crystalline Form-SAB-I characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 2 ⁇ 0 peaks selected from 8.3, 9.3, 15.6, 16.5, 17.6, 21.0, 24.1 and 26.0 +0.2 2 ⁇ 0 ; liquid state NMR in DMSO spectrum comprising 13 C chemical shift at 26.1+0.2, 114.7+0.2,
  • This non-solvated Axitinib crystalline Form-SAB-I is further characterized by DSC isotherm comprising two endothermic peaks ranging between- a. Peak -1- Between 213 to 217°C
  • Another aspect of the present invention relates to Axitinib monohydrate crystalline
  • Form-SAB-II characterized by X-ray powder diffraction pattern comprising at least 5characteristic 2 ⁇ 0 peaks selected from 7.5, 8.0, 14.2, 14.7, 15.7, 18.1, 20.1, 24.4, 29.8 and 32.0 +0.2 2 ⁇ 0 .
  • Said Axitinib monohydrate crystalline Form-SAB-II is further characterized by DSC isotherm comprising three endothermic peaks ranging between- a. Peak -1- Between 48 to 86°C
  • step b) stirring the contents of step a) at 25-30 °C;
  • Another aspect of the present invention relates to Axitinib crystalline Form-SAB-III characterized by X-ray powder diffraction pattern comprising at least 4 characteristic 2 ⁇ 0 peaks selected from 10.1, 10.4, 15.3, 18.3, 18.7, 19.7and 24.6 +0.2 2 ⁇ 0 and methanol contents ranging between 1.5 -4.0% w/w (by GC).
  • Said Axitinib crystalline Form-SAB-III is further characterized by DSC isotherm comprising three endothermic peaks ranging between- a. Peak -1- Between 53 to 73 °C
  • Axitinib crystalline Form-SAB-III comprising the steps of:
  • Fig. 1 is an example of X-ray powder diffraction ("XRPD") pattern of Non-solvated Axitinib crystalline Form-SAB-I obtained according the present invention.
  • XRPD X-ray powder diffraction
  • Fig. 2 is an example of liquid state 13 C NMR spectrum of Non-solvated Axitinib crystalline Form-SAB-I obtained according the present invention.
  • Fig. 3 is an example of DSC endotherm of Non-solvated Axitinib crystalline Form-SAB-I obtained according the present invention.
  • Fig. 4 is an example of TGA thermogram of Non-solvated Axitinib crystalline Form-SAB-I obtained according the present invention.
  • Fig. 5 is an example of X-ray powder diffraction ("XRPD") pattern of Axitinib monohydrate crystalline Form-SAB-II obtained according the present invention.
  • Fig. 6 is an example of DSC endotherm of Axitinib monohydrate crystalline Form-SAB-II obtained according the present invention.
  • Fig. 7 is an example of TGA thermogram of Axitinib monohydrate crystalline Form-SAB-II obtained according the present invention.
  • Fig. 8 is an example of X-ray powder diffraction ("XRPD") pattern of Axitinib crystalline Form-SAB-III obtained according the present invention.
  • Fig. 9 is an example of DSC endotherm of Axitinib crystalline Form-SAB-III obtained according the present invention.
  • Fig. 10 is an example of TGA thermogram of Axitinib crystalline Form-SAB-III obtained according the present invention.
  • Fig. His an example of X-ray powder diffraction ("XRPD") pattern of Axitinib crystalline Form obtained according to example- 1.
  • XRPD X-ray powder diffraction
  • Fig. 12 is an example of solid state 13 C NMR spectrum of Non-solvated Axitinib crystalline Form-SAB-I obtained according the present invention.
  • each polymorphic form can be distinguished using several different analytical parameters, alone or in combination, such as, but not limited to, powder X-ray diffraction pattern peaks or combinations of two or more peaks.
  • the present inventors now developed a new stable crystalline polymorphic form, which are different from the prior-art polymorphic forms disclosed in the literature.
  • a novel Non-solvated Axitinib crystalline Form-SAB-I characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 2 ⁇ 0 peaks selected from 8.3, 9.3, 15.6, 16.5, 17.6, 21.0, 24.1 and 26.0 +0.2 2 ⁇ 0 ; liquid state NMR spectrum comprising 13 C chemical shift at 26.1+0.2, 114.7+0.2,
  • Non-solvated Axitinib crystalline Form-SAB-I is further characterized by X-ray powder diffraction pattern comprising at 2 ⁇ 0 peaks selected from 13.7, 16.1, 18.6, 22.6, 23.1, and 23.4 +0.2 2 ⁇ 0 .
  • Non-solvated Axitinib crystalline Form-SAB-I is further characterized by DSC isotherm comprising two endothermic peaks ranging between- a. Peak -1- Between 213 to 217°C
  • the present invention further provides a process for the preparation of Non-solvated Axitinib crystalline Form-SAB-I characterized by X-ray powder diffraction pattern comprising at least 4 characteristic 2 ⁇ 0 peaks selected from 8.3, 9.3, 15.6, 16.5, 17.6, 21.0, 24.1 and 26.0 +0.2 2 ⁇ 0 , comprising the steps of:
  • Non-solvated Axitinib crystalline Form-SAB-I obtained by the above process is anhydrous and having a moisture content of less than 1.0 %.
  • the Axitinib crystalline Form- SAB-I obtained by this process is stable and free of process related impurities.
  • said Non-solvated Axitinib crystalline Form-SAB-I obtained according to the process was found to possess moisture content about 0.44% w/w (By KF).
  • the present inventors analyzed Non-solvated Axitinib crystalline Form-SAB-I for Hygroscopic study. However, the present inventors found that the Non-solvated Axitinib crystalline Form-SAB-I obtained by the present invention is stable at all temperature ranging between 0-80°C.
  • Form-SAB-II also becomes stable as monohydrate form. This form may also be produced consistently at industrial scale quantities. However, due to anticipated degradation in presence of moisture said form may be utilized with caution and further studies of stabilities in preparing any solid oral dosage form.
  • Non-solvated crystalline Axitinib Form-SAB-I obtained by the present invention is free of other polymorphic impurities, wherein said crystalline form is present in a solid form greater than 99.9 %by weight.
  • Non-solvated Axitinib crystalline Form-SAB-I is found to be a very stable crystal lattice which is adequately stable to handle and store for longer time without any significant or measurable change in its morphology and physicochemical characteristics.
  • Non-solvated Axitinib crystalline Form-SAB-I retains its nature even on exposure to uncontrolled environmental conditions. This stable form thus, offers various advantages in terms of storage, shelf life and favorable impurity profile.
  • Non-solvated Axitinib crystalline Form-SAB-I may have one or more advantageous and desirable properties compared to the known Crystalline Axitinib forms, which are not limited to better stability, hygroscopicity, high solubility and high purity leading to improved storage and distribution.
  • the process related impurities, including degradation products and other medium dependent impurities like residual solvent, that appear in the impurity profile of the Axitinib can be substantially removed by the process of the present invention resulting in the formation pure Non-solvated Axitinib crystalline Form-SAB-I.
  • a substantially pure product i.e. Non-solvated Axitinib crystalline Form-SAB-I having purity more than 99.9% (by HPLC) can be obtained in high yield by the process of the present invention.
  • Non-solvated Axitinib crystalline Form-SAB-I described herein may be characterized by X-ray powder diffraction pattern (XRPD) and IR absorption spectra and Thermal techniques such as differential scanning calorimetric (DSC) Analysis and TGA and solid state NMR.
  • XRPD X-ray powder diffraction pattern
  • DSC differential scanning calorimetric
  • the samples of Non-solvated Axitinib crystalline Form-SAB-I were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 A. DSC was done on a Perkin Elmer Pyris 7.0 instrument.
  • Illustrative example of analytical data for the Non-solvated Axitinib crystalline Form-SAB-I obtained in the Examples is set forth in the Figures 1-4 and 12.
  • Axitinib monohydrate crystalline Form-SAB-II characterized by X-ray powder diffraction pattern comprising at least 4 characteristic 2 ⁇ 0 peaks selected from 7.5, 8.0, 14.2, 14.7, 15.7, 18.1, 20.1, 24.4, 29.8 and 32.0 +0.2 2 ⁇ 0 .
  • Axitinib monohydrate crystalline Form-SAB-II is further characterized by X-ray powder diffraction pattern comprising at 2 ⁇ 0 peaks selected from 8.4, 13.3, 13.9, 15.2, 18.6, 20.9, 21.2, 21.9, 22.3, 23.0, 24.0, 25.6 and 28.1 +0.2 2 ⁇ 0 .
  • Axitinib monohydrate crystalline Form-SAB-II is further characterized by DSC isotherm comprising three endothermic peaks ranging between- a. Peak -1- Between 48 to 86°C
  • step b) stirring the contents of step a) at 25-30 °C;
  • Axitinib monohydrate Axitinib monohydrate crystalline Form-SAB-II obtained by the above process appears to be hydrate and having a moisture content of about 4.6 %.
  • the Axitinib monohydrate crystalline Form-SAB-II obtained by this process is stable and free of process related impurities.
  • the present invention provides crystalline Axitinib Form-
  • SAB-II obtained by the present invention is free of other polymorphic impurities, wherein said crystalline form is present in a solid form greater than 99.9 %by weight.
  • Axitinib monohydrate crystalline Form-SAB-II when heated to extreme conditions it loses the water molecule and converted in to Non- solvated Axitinib crystalline Form-SAB-I. It clearly shows that the Axitinib crystalline Form- SAB-II is unstable at extreme conditions.
  • the Axitinib monohydrate crystalline Form-SAB-II is a monohydrate form, which is evident from the moisture content results.
  • a sample of the Axitinib monohydrate crystalline Form-SAB-II prepared by the inventors of this application showed moisture content up to about 4.6 % w/w by KF method, which confirms the monohydrate nature of the compound. While the invention is not limited to any specific theory, it should be understood however that the Axitinib monohydrate crystalline Form-SAB-II may contain additional residual or unbound moisture without losing its character and/or its monohydrate crystalline characteristics. Nevertheless, person having skill in the art should be able to determine whether they are same crystalline forms or not, by looking at the overall shape of the X-ray powder diffraction pattern optionally with help of other thermal data like DSC or TGA.
  • thermo gravimetric analysis of Axitinib monohydrate crystalline Form-SAB-II clearly shows the existence of water molecule and it is about 4.5%, which is depicted in Fig.7
  • the Axitinib monohydrate crystalline Form-SAB-II described herein may be characterized by X-ray powder diffraction pattern (XRPD) and IR absorption spectra and Thermal techniques such as differential scanning calorimetric (DSC) Analysis and TGA.
  • XRPD X-ray powder diffraction pattern
  • DSC differential scanning calorimetric
  • Axitinib monohydrate crystalline Form-SAB-II obtained in the Examples is set forth in the Figures 5-7.
  • Axitinib crystalline Form-SAB-III characterized by X-ray powder diffraction pattern comprising at least 4 characteristic 2 ⁇ 0 peaks selected from 10.1, 10.4, 15.3, 18.3, 18.7, 19.7and 24.6 +0.2 29°and methanol content ranging between 1.5 to 4% w/w..
  • Axitinib crystalline Form-SAB-III is further characterized by X-ray powder diffraction pattern comprising at 2 ⁇ 0 peaks selected from 7.7, 8.2, 8.5, 10.1, 14.9, 15.3, 15.9, 18.3, 18.7, 20.2, 21.0, 21.4, 23.1, 24.6, 30.0 and 32.2 + 0.2 2 ⁇ 0 .
  • Axitinib crystalline Form-SAB-III is further characterized by DSC isotherm comprising three endothermic peaks ranging between- a. Peak -1- Between 53 to 73 °C
  • Axitinib crystalline Form-SAB-III obtained by the above process is having methanol content in the range between 1-4 %.
  • the Axitinib crystalline Form-SAB-III obtained by this process is stable and free of process related impurities.
  • the present inventors analyzed Axitinib crystalline Form-SAB-III for Hygroscopic study. However, the present inventors found that the Axitinib crystalline Form-SAB-III obtained by the present invention is stable at room temperature as well as at 0-5 °C.
  • the Axitinib crystalline Form-SAB-III described herein may be characterized by X- ray powder diffraction pattern (XRPD) and IR absorption spectra and Thermal techniques such as differential scanning calorimetric (DSC) Analysis and TGA.
  • XRPD X- ray powder diffraction pattern
  • DSC differential scanning calorimetric
  • the samples of Axitinib crystalline Form-SAB-III were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 A. DSC was done on a Perkin Elmer Pyris 7.0 instrument.
  • Illustrative example of analytical data for the Axitinib crystalline Form-SAB-III obtained in the Examples is set forth in the Figures 8- 10.
  • the Axitinib of Formula (I) used in the present invention is prepared by comprising the steps of charging2-((3-iodo-lH-indazol-6-yl)thio)-N methylbenzamidewith N- methylpyrrolidonein presence of Palladium (II) acetate and Xantphos at 25-30 °C in nitrogen atmosphere. Diisopropylethylamine was added under stirring. The reaction mixture was heated to 50°C. Acetic anhydride was slowly added and stirred for 2-3 hrs at 50°C. 2- Vinylpyridine was added slowly, raised the temperature of reaction mass to 90-95 °C and maintained for 12 hrs.
  • the crude Axitinib of the compound of the formula (I) obtained from the above stage may be purified by treating the compound of the formula (I) or a reaction mixture or a solvated form thereof is treated with an acid selected from methane sulphonic acid, sulphuric acid, trifluoro-methanesulphonic acid, difluoromethanesulphonic acid, dichloroacetic acid, glucornic acid, gluconic acid, Ferulate, glycols and glycol ethers; to form a salt of the compound of the formula (I) which precipitates from the solution containing the solvated compound of the formula (I), the salt of the compound of the formula (I) is then treated with an aqueous basic solution to precipitate the pure form of compound of the formula (I), preferably at a temperature of from 15° C. to 45° C, most preferably from 25 ° C. to 35° C. If required, repeat again the acidification followed by basification to obtained desired purity, which is greater than 99.5 %.
  • the Axitinib of the compound of the formula (I) is dissolved in a solvent selected from solvent selected from alcohol (Cl-3) or Ketones (C3-6) or organic solvents (Cl-8 alkanes, dimethyl formamide) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof.
  • Axitinib acid salt is dissolved in a solvent selected from solvent selected from alcohol (Cl-4) or Ketones (C3-6) or organic solvents (Cl-8 alkanes, dimethyl formamide, toluene, xylene) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran, Di-isopropyl ether ) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof at a temperature ranging from 25-30°C and stirred for 30min
  • alkaline solution used is prepared using a base selected from organic base such as triethylamine, methylamine, pyridine, imidazole, benzimidazole; or inorganic base selected from carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate; hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, barium hydroxide, magnesium hydroxide, lithium hydroxide, zinc hydroxide; bicarbonates such as sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, calcium bicarbonate, magnesium bicarbonate; in a solvent selected from organic solvent or water.
  • a base selected from organic base such as triethylamine, methylamine, pyridine, imidazole, benzimidazole
  • inorganic base selected from carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate
  • hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammoni
  • reaction mass was stirred for 30 min to 4 hrs depending on the acid used. After completion of the reaction, the reaction mass was cooled to a temperature ranging from 0- 10°C and maintained the reaction mass under stirring for 30min to 4 hrs. The precipitated product was filtered, washed with organic solvent or a mixture of organic solvent or mixture of organic solvent and water to get wet cake, which was dried under vacuum at 50-85°C for 3 hrs to 6hrs to yield pure Axitinib.
  • the obtained pure Axitinib was analyzed, if it is not matching with the desired purity; again repeat the process by treating the Axitinib with acid to prepare the corresponding salt, followed by treating with an alkali solution to obtain substantially pure Axitinib having a purity of greater than 99.5% and meeting the ICH guidelines.
  • Axitinib obtained by this process is substantially pure Axitinib, wherein substantially pure Axitinib contains the process related impurities A, B, C, D, E and F collectively below 0.3% and meeting the ICH guidelines.
  • Another embodiment of the present invention relates to substantially pure crystalline Axitinib having a purity of greater than 99.5 %, wherein substantially pure Axitinib contains the process related impurities A, B, C, D, E and F collectively below 0.3% area percentage by HPLC and meeting the ICH guidelines.
  • the process related impurities that appear in the impurity profile of the Axitinib (I) may be substantially removed by the process of the present invention resulting in the formation of substantially Axitinib (I), which meets the ICH guidelines.
  • the merit of the process according to the present invention resides in that product isolated after drying is stable and having a purity of greater than 99.5% purity by HPLC, which was not disclosed in any of the prior-art.
  • the product obtained as per the present invention is highly pure than the any of the prior-art products obtained.
  • Still now no- publication discloses a purity of greater than 99.5%.
  • Solubility is one of the important parameters to achieve desired concentration of drug in systemic circulation for achieving required pharmacological response. Poorly water soluble drugs often require high doses in order to reach therapeutic plasma concentrations after oral administration.
  • Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as generic formulation development. Most of the drugs are either weakly acidic or weakly basic having poor aqueous solubility.
  • the present invention also relates to a process for the preparation of Axitinib, which is substantially pure having a purity of greater 99.5 % and meeting the ICH guidelines, by limiting the content of each impurity less than 0.3%. Further, the Axitinib obtained as per the present process is found devoid of any other process related impurities and is adequately stable to handle and store for longer time (at least up to more than 6 months) without any significant or measurable change in its morphology and physicochemical characteristics.
  • Drying may be also be performed by any conventional process not limited to spray drying or distillation to remove the solvent. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material.
  • the drying may be performed at a temperature ranging from 50-85°C for a time ranging from 5 to 10 hours depending upon the physical attributes of the end product obtained i.e. Pure Axitinib, which is obtained according to the present invention is having purity greater than 99.5%.
  • the substantially pure Axitinib obtained by the processes of the present application may be taken as such in crystalline form for manufacture of solid dosage forms like tablets, capsules and/or for manufacture of oral liquids.
  • the substantially pure crystalline form of Axitinib obtained by the processes of the present application may be manufactured as the amorphous form by processing with polymers like hydroxypropyl methylcellulose acetate succinate (HPMC-AS).
  • the substantially pure crystalline form of Axitinib obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules.
  • the active product is mixed with one or more pharmaceutically acceptable excipients.
  • the drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.
  • premix comprising one or more pharmaceutically acceptable excipients in the range of 1 to 50% w/w with the substantially pure Axitinibor its acid addition salt, while retaining the crystalline nature of the premix.
  • compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions.
  • a solvent or vehicle propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed.
  • These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents.
  • the sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
  • compositions comprising substantially pure Axitinib or its acid addition salt obtained as per the present application process- include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, di-calcium phosphate, tri-calcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like.
  • diluents such as starch
  • compositions derived from substantially pure Axitinib or its acid addition salt of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
  • Non-solvated Axitinib crystalline Form-SAB-I(about 5 gms) By exposing Non-solvated Axitinib crystalline Form-SAB-I(about 5 gms) at 90% relative humidity in desiccator at 25°C containing saturated potassium chloride solution kept in glass petri-dish and placed it into desiccator.
  • Axitinib crystalline Form-SAB-II is obtained as stable monohydrate form.
  • XRay Po butter Diffraction study reveals that samples after 2 hours resembles in diffraction pattern with no significant variations.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouvelles formes polymorphes cristallines d'axitinib de formule (I). Lesdites formes cristallines peuvent être utiles dans la préparation améliorée de formes galéniques orales pour le traitement du cancer.
PCT/IB2016/052530 2015-05-05 2016-05-04 Nouveaux polymorphes d'axitinib WO2016178150A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2270/CHE/2015 2015-05-05
IN2270CH2015 2015-05-05

Publications (1)

Publication Number Publication Date
WO2016178150A1 true WO2016178150A1 (fr) 2016-11-10

Family

ID=57217616

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2016/052530 WO2016178150A1 (fr) 2015-05-05 2016-05-04 Nouveaux polymorphes d'axitinib

Country Status (1)

Country Link
WO (1) WO2016178150A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111187253A (zh) * 2020-01-09 2020-05-22 鲁南制药集团股份有限公司 一种阿昔替尼新晶型
EP3884929A1 (fr) 2020-03-25 2021-09-29 Ocular Therapeutix, Inc. Implant oculaire contenant un inhibiteur de la tyrosine kinase
CN113943271A (zh) * 2020-07-15 2022-01-18 鲁南制药集团股份有限公司 一种阿昔替尼晶型及其制备方法
CN113943270A (zh) * 2020-07-15 2022-01-18 鲁南制药集团股份有限公司 一种阿昔替尼晶型
CN114685437A (zh) * 2020-12-25 2022-07-01 鲁南制药集团股份有限公司 阿昔替尼与糖精共晶
CN114685433A (zh) * 2020-12-28 2022-07-01 鲁南制药集团股份有限公司 一种阿昔替尼香草酸共晶盐及其制备
CN114685432A (zh) * 2020-12-28 2022-07-01 鲁南制药集团股份有限公司 阿昔替尼盐晶型及其制备方法
CN114685435A (zh) * 2020-12-28 2022-07-01 鲁南制药集团股份有限公司 阿昔替尼马来酸盐晶型及其制备
CN114685431A (zh) * 2020-12-26 2022-07-01 鲁南制药集团股份有限公司 一种阿昔替尼柠檬酸盐晶型

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006048751A1 (fr) * 2004-11-02 2006-05-11 Pfizer Inc. Formes polymorphiques du 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-e-[2-(pyridin-2-yl)ethenyl]indazole
US20100179329A1 (en) * 2007-04-05 2010-07-15 Anthony Michael Campeta Crystalline forms of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-e-[2-(pyridin-2-yl)ethenyl]indazole suitable for the treatment of abnormal cell growth in mammals

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006048751A1 (fr) * 2004-11-02 2006-05-11 Pfizer Inc. Formes polymorphiques du 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-e-[2-(pyridin-2-yl)ethenyl]indazole
US20100179329A1 (en) * 2007-04-05 2010-07-15 Anthony Michael Campeta Crystalline forms of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-e-[2-(pyridin-2-yl)ethenyl]indazole suitable for the treatment of abnormal cell growth in mammals

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111187253A (zh) * 2020-01-09 2020-05-22 鲁南制药集团股份有限公司 一种阿昔替尼新晶型
CN111187253B (zh) * 2020-01-09 2023-05-09 鲁南制药集团股份有限公司 一种阿昔替尼新晶型
EP3884929A1 (fr) 2020-03-25 2021-09-29 Ocular Therapeutix, Inc. Implant oculaire contenant un inhibiteur de la tyrosine kinase
WO2021195163A1 (fr) 2020-03-25 2021-09-30 Ocular Therapeutix, Inc. Implant oculaire contenant un inhibiteur de tyrosine kinase
EP4252725A2 (fr) 2020-03-25 2023-10-04 Ocular Therapeutix, Inc. Implant oculaire contenant un inhibiteur de la tyrosine kinase
CN113943271A (zh) * 2020-07-15 2022-01-18 鲁南制药集团股份有限公司 一种阿昔替尼晶型及其制备方法
CN113943270A (zh) * 2020-07-15 2022-01-18 鲁南制药集团股份有限公司 一种阿昔替尼晶型
CN113943271B (zh) * 2020-07-15 2023-11-14 鲁南制药集团股份有限公司 一种阿昔替尼晶型及其制备方法
CN113943270B (zh) * 2020-07-15 2023-05-09 鲁南制药集团股份有限公司 一种阿昔替尼晶型
CN114685437A (zh) * 2020-12-25 2022-07-01 鲁南制药集团股份有限公司 阿昔替尼与糖精共晶
CN114685437B (zh) * 2020-12-25 2022-12-09 鲁南制药集团股份有限公司 阿昔替尼与糖精共晶
CN114685431B (zh) * 2020-12-26 2022-11-29 鲁南制药集团股份有限公司 一种阿昔替尼柠檬酸盐晶型
CN114685431A (zh) * 2020-12-26 2022-07-01 鲁南制药集团股份有限公司 一种阿昔替尼柠檬酸盐晶型
CN114685433B (zh) * 2020-12-28 2022-11-25 鲁南制药集团股份有限公司 一种阿昔替尼香草酸共晶盐及其制备
CN114685432B (zh) * 2020-12-28 2022-11-25 鲁南制药集团股份有限公司 阿昔替尼盐晶型及其制备方法
CN114685435B (zh) * 2020-12-28 2023-01-31 鲁南制药集团股份有限公司 阿昔替尼马来酸盐晶型及其制备
CN114685435A (zh) * 2020-12-28 2022-07-01 鲁南制药集团股份有限公司 阿昔替尼马来酸盐晶型及其制备
CN114685432A (zh) * 2020-12-28 2022-07-01 鲁南制药集团股份有限公司 阿昔替尼盐晶型及其制备方法
CN114685433A (zh) * 2020-12-28 2022-07-01 鲁南制药集团股份有限公司 一种阿昔替尼香草酸共晶盐及其制备

Similar Documents

Publication Publication Date Title
WO2016178150A1 (fr) Nouveaux polymorphes d'axitinib
US20100016590A1 (en) Nilotinib intermediates and preparation thereof
US20040010151A1 (en) Lansoprazole polymorphs and processes for preparation thereof
US11332467B2 (en) Solid state forms of palbociclib dimesylate
US9902698B2 (en) 2-[[[2-[(Hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzenesulfonate, crystal of same, crystal polymorph thereof, and methods for production thereof
JP2019523273A (ja) ベリノスタットの多形形態、およびその調製のためのプロセス
WO2016005874A1 (fr) Procédé pour la préparation du régorafénib et ses formes cristallines
WO2016108106A1 (fr) Procédé amélioré de préparation d'axitinib
AU2018234306B2 (en) Salts of antiviral phosphonate analogues and process for preparation thereof
CA2762307C (fr) Formes cristallines de la 6-(1h-imidazol-1-yl)-2-phenylquinazoline et sels associes.
WO2015049698A2 (fr) Procédé pour le régorafénib
US11111250B2 (en) Polymorphs of Ribociclib mono succinate
KR20080090661A (ko) 결정형의 베포타스틴 금속염 수화물, 이의 제조방법 및이를 포함하는 약학 조성물
WO2020053795A2 (fr) Procédé de préparation d'acalabrutinib et de ses intermédiaires
WO2012090221A1 (fr) Nouveaux sels d'imatinib
US20240010632A1 (en) Solid state forms of erdafitinib salts and processes for preparation of erdafitinib
US20050245578A1 (en) Polymorphs of pantoprazole sodium salt and process for the preparation thereof
KR20200014924A (ko) 메푸파리브 히드로클로라이드 다결정형 물질 및 이의 제조방법과 응용
WO2018078383A1 (fr) Composition pharmaceutique comprenant du selexipag amorphe
KR102323090B1 (ko) 페닐 피리미돈 화합물의 염, 다형체 및 이의 약학 조성물 및 용도
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
WO2015104602A2 (fr) Procédé de préparation d'anagliptine et de ses intermédiaires
EP3512854A1 (fr) Procédé de préparation de la forme 3 du potassium de raltégravir cristalline pure et stable
EP3397618A1 (fr) Procédé de fabrication d'une forme cristalline a de géfitinib
KR101307712B1 (ko) 결정형의 베포타스틴 금속염 수화물, 이의 제조방법 및 이를 포함하는 약학 조성물

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: 16789388

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: 16789388

Country of ref document: EP

Kind code of ref document: A1