WO2020044364A1 - Formes polymorphes de maléate d'avatrombopag - Google Patents

Formes polymorphes de maléate d'avatrombopag Download PDF

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Publication number
WO2020044364A1
WO2020044364A1 PCT/IN2019/050609 IN2019050609W WO2020044364A1 WO 2020044364 A1 WO2020044364 A1 WO 2020044364A1 IN 2019050609 W IN2019050609 W IN 2019050609W WO 2020044364 A1 WO2020044364 A1 WO 2020044364A1
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Prior art keywords
avatrombopag
maleate
crystalline form
amorphous
solvent
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PCT/IN2019/050609
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English (en)
Inventor
Ramakoteswara Rao Jetti
Narasimha Murthy PILLI
Bhaskar Rao PADALA
Yogesh SANGVIKAR
Sureshbabu JAYACHANDRA
Daveedu BHATRAJU
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Mylan Laboratories Limited
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Publication of WO2020044364A1 publication Critical patent/WO2020044364A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates generally to pharmaceutically active compounds and more specifically to crystalline Form M1 of Avatrombopag, crystalline Form M2 of Avatrombopag, crystalline Form M3 of Avatrombopag , crystalline Form M4 of Avatrombopag, crystalline Form M5 of Avatrombopag, crystalline Form M1 of Avatrombopag maleate, crystalline Form M2 of Avatrombopag maleate, crystalline Form M3 of Avatrombopag maleate, amorphous Avatrombopag, amorphous Avatrombopag maleate, amorphous solid dispersions of
  • Avatrombopag is first disclosed in U.S Patent No. 7,638,536.
  • Avatrombopag is chemically known as 1 -[3-Chloro-5-[[[4-(4-chloro-2-thienyl)-5-(4-cyclohexyl-1 -piperazinyl)-2- thiazolyl]amino]carbonyl]-2-pyridinyl]-4-piperidinecarboxylic acid, having the below structure:
  • Avatrombopag maleate is specifically disclosed in W02004029049A1.
  • WO2013018362A1 patent publication discloses crystalline forms A, B and C of Avatrombopag maleate, wherein Form C and Form B are commercially suitable for industrial scaleup, but Form B has inferior oral absorption compared to Form C and Form A.
  • the inventors of the invention disclosed herein have developed The present invention relates generally to pharmaceutically active compounds and more specifically to crystalline Form M1 of Avatrombopag, crystalline Form M2 of Avatrombopag, crystalline Form M3 of Avatrombopag , crystalline Form M4 of Avatrombopag, crystalline Form M5 of Avatrombopag, crystalline Form M1 of Avatrombopag maleate, crystalline Form M2 of Avatrombopag maleate, crystalline Form M3 of Avatrombopag maleate, amorphous Avatrombopag, amorphous Avatrombopag maleate, amorphous solid dispersions of Avatrombopag maleate and processes for the preparation thereof.
  • a first aspect of the present invention is to provide amorphous Avatrombopag maleate.
  • the present invention is to provide amorphous Avatrombopag maleate is characterized by powdered X-ray diffraction pattern as shown in Figure 10.
  • Another aspect of the present invention is to provide a process for the preparation of amorphous Avatrombopag maleate which comprises: a) dissolving Avatrombopag maleate in a mixture of organic solvent or organic solvent and water at elevated temperature,
  • Another aspect of the present invention is to provide a process for the preparation of amorphous Avatrombopag maleate, which comprises: a) dissolving Avatrombopag maleate in organic solvent,
  • Another aspect of the present invention is to provide a novel crystalline Form M1 of Avatrombopag maleate.
  • the present invention is to provide a novel crystalline Form M1 of Avatrombopag maleate, having significant peaks at 2Q angle positions of about 1 1 .48, 17.67,18.85, 22.00 and 23.55 ⁇ 0.2°.
  • the present invention is to provide a novel crystalline Form M1 of Avatrombopag maleate is characterized by powdered X-ray diffraction pattern as shown in Figure 6.
  • Another aspect of the present invention is to provide a process for the preparation of crystalline Form M1 of Avatrombopag maleate, which comprises:
  • Another aspect of the present invention is to provide novel crystalline Form M3 of Avatrombopag maleate.
  • the present disclosure is to provide a novel crystalline Form M3 of Avatrombopag maleate, having significant peaks at 2Q angle positions of about 4.94, 8.47, 9.75 and 17.95 ⁇ 0.2°.
  • crystalline Form M3 of Avatrombopag maleate is characterized by powder X-ray diffraction pattern as shown in Figure 8.
  • Another aspect of the present invention is to provide a process for the preparation of crystalline Form M3 of Avatrombopag maleate, which comprises:
  • Figure 1 is an X-ray powder diffractogram of crystalline Form M1 of Avatrombopag.
  • Figure 2 is an X-ray powder diffractogram of crystalline Form M2 of Avatrombopag.
  • Figure 3 is an X-ray powder diffractogram of crystalline Form M3 of Avatrombopag.
  • Figure 4 is an X-ray powder diffractogram of crystalline Form M4 of Avatrombopag.
  • Figure 5 is an X-ray powder diffractogram of crystalline Form M5 of Avatrombopag.
  • Figure 6 is an X-ray powder diffractogram of crystalline Form M1 of Avatrombopag maleate.
  • Figure 7 is an X-ray powder diffractogram of crystalline Form M2 of Avatrombopag maleate.
  • Figure 8 is an X-ray powder diffractogram of crystalline Form M3 of Avatrombopag maleate.
  • Figure 9 is an X-ray powder diffractogram of amorphous Avatrombopag.
  • Figure 10 is an X-ray powder diffractogram of amorphous Avatrombopag maleate.
  • Figure 1 1 is an X-ray powder diffractogram of amorphous solid dispersions of Avatrombopag maleate.
  • the present disclosure relates generally to pharmaceutically active compounds and more specifically to crystalline Form M1 of Avatrombopag, crystalline Form M2 of Avatrombopag, crystalline Form M3 of Avatrombopag , crystalline Form M4 of Avatrombopag, crystalline Form M5 of Avatrombopag, crystalline Form M1 of Avatrombopag maleate, crystalline Form M2 of Avatrombopag maleate, crystalline Form M3 of Avatrombopag maleate, amorphous Avatrombopag, amorphous Avatrombopag maleate, amorphous solid dispersions of Avatrombopag maleate and processes for the preparation thereof.
  • the term“about” when modifying a temperature measurement is meant to mean the recited temperature plus or minus five degrees.
  • the term “about” when modifying an absolute measurement, such as time, mass, or volume means the recited value plus or minus 10% of the value.
  • the term “elevated temperature” means the temperature above 25°C and it is depending on the solvent ratio and the concentration of Avatrombopag maleate.
  • the polymorphs of the present disclosure are characterized by its X-ray powder diffraction pattern.
  • the X-ray diffraction patterns of the polymorphs of the disclosure were measured on BRUKER D-8 Discover powder diffractometer equipped with goniometer of Q/2Q configuration and Lynx Eye detector.
  • the Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2Q range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.
  • the present invention is to provide a novel crystalline Form M1 of Avatrombopag.
  • the present disclosure is to provide a novel crystalline Form M1 of Avatrombopag, having significant peaks at 2Q angle positions of about 5.37, 9.02, 10.98, 13.85, 14.98, 15.48, 17.70, 18.49, 19.49, 20.48, 21 .33, 22.71 , 24.89, 26.16, 27.51 and 30.1 1 ⁇ 0.2°.
  • the present disclosure is to provide a novel crystalline Form M1 of Avatrombopag that is characterized by powdered X-ray diffraction pattern as shown in Figure 1 .
  • the present invention is to provide a process for the preparation of crystalline Form M1 of Avatrombopag, which comprises:
  • Avatrombopag maleate is dissolved in pyridine at elevated temperature.
  • Avatrombopag maleate may be dissolved at elevated temperature of about 60°C to about 95°C.
  • Avatrombopag maleate may be dissolved at about 85°C.
  • Avatrombopag maleate may be dissolved in mixture of pyridine and water at about 60°C to about 95°C.
  • Avatrombopag maleate may be dissolved in mixture of pyridine and water at about 85°C.
  • the portion of slow solvent evaporation is about 14 to 16 hours at room temperature.
  • the portion of solvent may be 30% to 95% of initial solvent volume. In particular useful embodiments of the present invention 95% of the solvent is evaporated.
  • the anti-solvent employed for this embodiment is water.
  • the product is isolated by filtration, evaporation, centrifuge and distillation.
  • Yet another embodiment of the present invention is to provide a process for the preparation of crystalline Form M1 of Avatrombopag, which comprises:
  • Avatrombopag maleate is dissolved in a mixture of an organic solvents at elevated temperature.
  • the organic solvent employed may include 2-methoxy ethanol, dimethylsulfoxide (DMSO), formamide, and dimethyl formamide (DMF).
  • solvent employed is mixture of 2-methoxy ethanol, 1 ,4-dioxane and dimethylsulfoxide or mixture of Formamide, dimethyl formamide and dimethylsulfoxide.
  • Avatrombopag maleate may be dissolved at elevated temperature about 60°C to about 95°C. In particular useful embodiments of the present disclosure Avatrombopag maleate may be dissolved at about 85°C.
  • the portion of slow solvent evaporation is about 14 to 16 hours at room temperature.
  • the portion of solvent may be 30% to 95% of initial solvent volume. In particular useful embodiments of the present disclosure 95% of the solvent is evaporated.
  • the product is isolated by filtration, evaporation and distillation.
  • the present disclosure is to provide a novel crystalline Form M2 of Avatrombopag.
  • the present disclosure is to provide a novel crystalline Form M2 of Avatrombopag, having significant peaks at 2Q angle positions of about 5.49, 9.05, 11.02, 1 1 .73, 13.97, 14.98, 15.49, 18.18, 20.47, 20.84, 21 .41 , 22.10, 22.81 , 23.52, 26.02, 27.65, 29.22 and 42.40 ⁇ 0.2°.
  • the present disclosure is to provide a novel crystalline Form M2 of Avatrombopag that is characterized by powdered X-ray diffraction pattern as shown in Figure 2.
  • In another embodiment of the present invention is to provide a process for the preparation of crystalline Form M2 of Avatrombopag, which comprises:
  • Avatrombopag maleate is dissolved in a mixture of acetonitrile, dimethylformamide and water at elevated temperature.
  • Avatrombopag maleate may be dissolved at elevated temperature of about 60°C to about 95°C.
  • Avatrombopag maleate may be dissolved at about 85°C.
  • the compound is isolated by solvent removal using any techniques in the art such as filtration, centrifugation, slow evaporation, distillation, agitated thin film drier (ATFD), lyophilization and spray-drying.
  • the solvent is removed by lyophilization.
  • the present invention is to provide a novel crystalline Form M3 of Avatrombopag.
  • the present disclosure is to provide a novel crystalline Form M3 of Avatrombopag, having significant peaks at 2Q angle positions of about 7.61 , 10.37, 1 1.72, 13.52, 14.74, 15.29, 17.10, 17.91 , 18.90, 20.81 , 23.03, 24.00, 24.79, 28.54, 33.43, 34.26, 34.63 and 37.92 ⁇ 0.2°.
  • the present disclosure is to provide a novel crystalline Form M3 of Avatrombopag is characterized by powdered X-ray diffraction pattern as shown in Figure 3.
  • Another embodiment of the present invention is to provide a process for the preparation of crystalline Form M3 of Avatrombopag, which comprises:
  • Avatrombopag maleate in a mixture morpholine and isobutyl acetate at elevated temperature.
  • Avatrombopag maleate may be dissolved in mixture of morpholine and isobutyl acetate at elevated temperature of about 60°C to about 95°C.
  • Avatrombopag maleate may be dissolved in mixture of morpholine and isobutyl acetate at about 85°C.
  • the product is isolated by filtration, evaporation and distillation.
  • the present invention is to provide a provide novel crystalline Form M4 of Avatrombopag.
  • the present disclosure is to provide a novel crystalline Form M4 of Avatrombopag, having significant peaks at 2Q angle positions of about 3.17, 8.78, 10.15,
  • the present disclosure is to provide a novel crystalline Form M4 of Avatrombopag that is characterized by powdered X-ray diffraction pattern as shown in Figure 4.
  • Another embodiment of the present invention is to provide a process for the preparation of crystalline Form M4 of Avatrombopag, which comprises:
  • crystalline Form M1 of Avatrombopag is heating at a temperature about 20°C to about 400°C.
  • crystalline Form M1 of Avatrombopag may be heated at about 30°C to 240°C.
  • slow cooling about 25°C to about 35°C temperature. In particular useful embodiments of the present invention it is cooled to about 30°C.
  • the present invention is to provide a novel crystalline Form M5 of Avatrombopag.
  • the present disclosure is to provide a novel crystalline Form M5 of Avatrombopag, having significant peaks at 2Q angle positions of about 3.59, 7.52, 7.89, 8.93, 10.37, 1 1 .87, 13.47, 14.64, 15.28, 15.75, 16.94, 19.98, 20.59, 21.12, 21 .92, 22.72, 24.41 , 25.21 , 29.25 and 42.58 ⁇ 0.2°.
  • the present disclosure is to provide a novel crystalline Form M5 of Avatrombopag is characterized by powdered X-ray diffraction pattern as shown in Figure 5.
  • Another embodiment of the present invention is to provide a process for the preparation of crystalline Form M5 of Avatrombopag, which comprises:
  • crystalline Form M2 of Avatrombopag is heating at a temperature about 20°C to about 400°C.
  • crystalline Form M2 of Avatrombopag may be heated at about 30°C to 240°C.
  • slow cooling about 25°C to about 35°C temperature. In particular useful embodiments of the present invention it is cooled to about 30°C.
  • the present invention provides a novel crystalline Form M1 of Avatrombopag maleate.
  • the present invention is to provide a novel crystalline Form M1 of Avatrombopag maleate, having significant peaks at 2Q angle positions of about 1 1.48, 17.67,18.85, 22.00 and 23.55 ⁇ 0.2°.
  • crystalline Form M1 of Avatrombopag maleate having significant peaks at 2Q angle positions of about 5.14, 8.01 , 8.46, 8.91 , 9.67, 10.32,
  • the present disclosure is to provide a novel crystalline Form M1 of Avatrombopag maleate is characterized by powdered X-ray diffraction pattern as shown in Figure 6.
  • Another aspect of the present invention is to provide a process for the preparation of crystalline Form M1 of Avatrombopag maleate, which comprises:
  • Avatrombopag maleate may be dissolved in dimethyl sulfoxide at a temperature about 60°C to about 95°C.
  • Avatrombopag maleate may be dissolved in dimethyl sulfoxide (DMSO) at about 85°C.
  • the solution is added to an anti-solvent at room temperature.
  • the anti-solvent employed may include water and methyl tertiary-butyl ether.
  • the solution is added to an anti-solvent at room temperature containing a seed of avatrombopag maleate crystalline form M1 .
  • the present invention is to provide novel crystalline Form M2 of Avatrombopag maleate.
  • the present disclosure is to provide a novel crystalline Form M2 of Avatrombopag maleate, having significant peaks at 2Q angle positions of about 6.90, 7.69, 8.69, 1 1 .33, 1 1 .69, 12.63, 13.65, 15.31 , 17.55, 18.49, 19.50, 20.68, 21 .76, 22.43, 22.85, 23.35, 25.74, 28.03, 28.82, 30.63, 32.65 and 40.38 ⁇ 0.2°.
  • the present disclosure is to provide a novel crystalline Form M2 of Avatrombopag maleate is characterized by powder X-ray diffraction pattern as shown in Figure 7.
  • the present invention is to provide a process for the preparation of crystalline Form M2 of Avatrombopag maleate, which comprises:
  • step (b) adding an anti-solvent to the solution of step (b) or vice-versa;
  • Avatrombopag maleate is dissolved in dimethylsulfoxide at elevated temperature.
  • Avatrombopag maleate may be dissolved at elevated temperature about 60°C to about 95°C.
  • Avatrombopag maleate may be dissolved at about 85°C.
  • solution of Avatrombopag maleate may be treated with an anti-solvent or vice-versa at room temperature to obtain crystalline form M2 of Avatrombopag maleate.
  • the anti-solvent employed for this embodiment may include ethyl acetate.
  • the product is isolated by filtration, evaporation, centrifuge, suck drying and distillation.
  • the present invention is to provide novel crystalline Form M3 of Avatrombopag maleate.
  • the present disclosure is to provide a novel crystalline Form M3 of Avatrombopag maleate, having significant peaks at 2Q angle positions of about 4.94, 8.47, 9.75 and 17.95 ⁇ 0.2°.
  • crystalline Form M3 of Avatrombopag maleate having significant peaks at 2Q angle positions of about 4.94, 8.47, 9.75, 9.72, 10.13, 1 1.02, 12.82, 13.08, 13.35, 14.59, 15.91 , 16.07, 16.51 , 17.08, 17.52, 17.95, 18.68, 18.95, 19.28, 19.85, 20.21 , 20.65, 21 .09, 21 .74, 22.49, 23.31 , 23.76, 24.10, 24.30, 24.85, 25.33, 26.50, 27.45, 28.29, 29.42, 30.72, 31 .66, 32.45, 33.60, 34.24, 36.1 1 ,37.14, 38.30, 39.72, 40.85, and 41 46 ⁇ 0.2°.
  • the present disclosure is to provide a novel crystalline Form M3 of Avatrombopag maleate is characterized by powder X-ray diffraction pattern as shown in Figure 8.
  • Another aspect of the present invention is to provide a process for the preparation of crystalline Form M3 of Avatrombopag maleate, which comprises:
  • Avatrombopag maleate is dissolved in dimethyl acetamide and 2-ethoxy ethanol or mixture thereof.
  • Avatrombopag maleate may be dissolved at elevated temperature about 60°C to about 95°C. In particular useful embodiments of the present invention Avatrombopag maleate may be dissolved at about 85°C.
  • the product is isolated by filtration, evaporation, centrifuge, suck drying and distillation.
  • solution of Avatrombopag maleate may be treated with an anti-solvent or vice-versa at room temperature to obtain crystalline form M3 of Avatrombopag maleate.
  • the anti-solvent employed for this embodiment may include isobutyl acetate, ethyl acetate, anisole, methyl isobutyl ketone, 2-butanol, 2-propanol and 2-methyl-1 - propanol.
  • the product is isolated by filtration, evaporation, centrifuge, suck drying and distillation.
  • the present invention is to provide amorphous Avatrombopag.
  • the present disclosure is to provide amorphous Avatrombopag is characterized by powdered X-ray diffraction pattern as shown in Figure 9.
  • Another embodiment of the present invention is to provide a process for the preparation of amorphous Avatrombopag, which comprises drying Avatrombopag crystalline form M3 at about 80°C to about 120°C under reduced pressure.
  • crystalline Form M3 of Avatrombopag may be dried at about 100°C.
  • In another aspect of the present invention is to provide amorphous Avatrombopag maleate.
  • the present disclosure is to provide amorphous Avatrombopag maleate is characterized by powdered X-ray diffraction pattern as shown in Figure 10.
  • Another aspect of the present invention is to provide a process for the preparation of amorphous Avatrombopag maleate, which comprises: a) dissolving Avatrombopag maleate in a mixture of organic solvent or organic solvent and water at elevated temperature,
  • the solvent employed may include, ether solvents such as 1 ,4-dioxane and tetrahydrofuran (TFIF) and nitrile solvents such as acetonitrile, dimethyl sulfoxide (DMSO), anisole, methanol, ethanol, isopropyl alcohol, acetone, acetonitrile and dimethylformamide.
  • solvent employed is a mixture of 1 ,4-dioxane/ water, tetrahydrofuran/water and dimethyl sulfoxide/anisole.
  • Avatrombopag maleate may be dissolved in mixture of tetrahydrofuran (THF) and water at about 85°C.
  • Avatrombopag maleate may be dissolved in mixture of mixture of 1 ,4- dioxane and water at about 60°C to about 95°C.
  • Avatrombopag maleate may be dissolved in mixture of 1 ,4-dioxane and water at about 85°C.
  • removing of solvent can be done using any techniques in the art such as, decantation, filtration by gravity or suction, centrifugation, slow evaporation, distillation, ATFD, lyophilization and spray-drying.
  • the solvent is removed by lyophilization and spray-drying.
  • Another aspect of the present invention is to provide a process for the preparation of amorphous Avatrombopag maleate, which comprises: a) dissolving Avatrombopag maleate in organic solvent,
  • Avatrombopag maleate is dissolved in dimethyl sulfoxide (DMSO).
  • Avatrombopag maleate may be dissolved in mixture of dimethyl sulfoxide (DMSO) at elevated temperature about 60°C to about 95°C.
  • DMSO dimethyl sulfoxide
  • Avatrombopag maleate may be dissolved in dimethyl sulfoxide at about 80°C.
  • solution of Avatrombopag maleate may be combined with an anti- solvent at room temperature to obtain amorphous product.
  • Suitable anti-solvent employed for this embodiment is water.
  • removing of solvent can be done using any techniques in the art such as, decantation, filtration by gravity or suction, centrifugation, slow evaporation, distillation, ATFD, lyophilization and spray-drying.
  • the solvent is removed by spray-drying.
  • Yet another embodiment of the present invention is to provide amorphous solid dispersion of avatrombopag maleate with pharmaceutically acceptable carriers.
  • the present disclosure is to provide amorphous solid dispersion of Avatrombopag maleate is characterized by powdered X-ray diffraction pattern as shown in Figure 1 1 .
  • Another embodiment of the present invention is to provide a process for the preparation of amorphous solid dispersion of Avatrombopag maleate with pharmaceutically acceptable carriers, which comprises:
  • step (b) adding pharmaceutically acceptable carrier to the solution obtained in step (b), d) removing the solvent and isolating the amorphous solid dispersion of Avatrombopag maleate.
  • solvent employed may include, ether solvents such as tetrahydrofuran (THF) and 1 ,4-dioxane and nitrile solvents such as acetonitrile.
  • solvent employed is a mixture of tetrahydrofuran (TFIF), and water.
  • Avatrombopag maleate may be dissolved in mixture of tetrahydrofuran (TFIF) and water at elevated temperature about 60°C to about 95°C.
  • TFIF tetrahydrofuran
  • Avatrombopag maleate may be dissolved in mixture of tetrahydrofuran (TFIF) and water at about 85°C.
  • removing of solvent can be done using any techniques in the art such as, decantation, filtration by gravity or suction, centrifugation, slow evaporation, distillation, ATFD, lyophilization and spray-drying.
  • the solvent is removed by lyophilization.
  • pharmaceutically acceptable carrier employed may include, PLASDONETM S-630, polyvinyl pyrrolidine K-30 (PVP-K30), silicon dioxide, microcrystalline cellulose, lactose monohydrate, HPMC or mixtures thereof.
  • pharmaceutically acceptable carrier selected is silicon dioxide or polyvinyl pyrrolidine K-30 (PVP-K30).
  • Avatrombopag maleate with pharmaceutically acceptable carrier employed in the ratio of 1 :99 to 99:1 , preferably 1 :1 ratio.
  • the present invention is to provide amorphous solid dispersion of Avatrombopag maleate.
  • the present disclosure is to provide amorphous solid dispersion of Avatrombopag maleate is characterized by powdered X-ray diffraction pattern as shown in Figure 10.
  • Another embodiment of the present invention is to provide a process for the preparation of amorphous solid dispersion of Avatrombopag maleate with pharmaceutically acceptable carriers, which comprises:
  • Avatrombopag maleate is dissolved in a mixture of organic solvent and water.
  • the solvent employed may include tetrahydrofuran (THF) and 1 ,4-dioxane.
  • solvent employed is a mixture of tetrahydrofuran (TFIF) and water.
  • Avatrombopag maleate may be dissolved in solvent at elevated temperature about 60°C to about 95°C.
  • Avatrombopag maleate may be dissolved at about 85°C.
  • pharmaceutically acceptable carrier employed may include, PLASDONETM S-630, polyvinyl pyrrolidine K-30 (PVP-K30), silicon dioxide, microcrystalline cellulose (MCC), lactose monohydrate, HPMC or mixtures thereof.
  • pharmaceutically acceptable carrier selected is microcrystalline cellulose (MCC).
  • Avatrombopag maleate with pharmaceutically acceptable carrier employed in the ratio of 1 :99 to 99:1 , preferably 1 :1 ratio.
  • the solvent is removed by lyophilization, spray-drying, evaporation and filtration.
  • Another embodiment of the present invention is to provide a process for the preparation of amorphous solid dispersion of Avatrombopag maleate with pharmaceutically acceptable carrier, which comprises:
  • Avatrombopag maleate and pharmaceutically acceptable carrier is dissolved in a mixture of organic solvent and water.
  • the solvent employed may include ether solvents such as tetrahydrofuran (THF) and 1 ,4-dioxane.
  • solvent employed is a mixture of tetrahydrofuran (THF) and water.
  • pharmaceutically acceptable carrier employed may include, PLASDONE S-630, polyvinyl pyrrolidine K-30 (PVP-K30), silicon dioxide, microcrystalline cellulose (MCC), lactose monohydrate, HPMC or mixtures thereof.
  • pharmaceutically acceptable carrier selected is PLASDONE S-630 or lactose monohydrate.
  • Avatrombopag maleate and pharmaceutical carrier may be dissolved in mixture of tetrahydrofuran (THF) and water at a temperature about 60°C to about 95°C. In particular useful embodiments it may be dissolved at about 85°C.
  • THF tetrahydrofuran
  • the solvent is removed by lyophilization, spray-drying, evaporation and filtration.
  • the indicative stability data shows Avatrombopag maleate Amorphous, Form M1 and Form M3 are physically stable and shows no change in PXRD pattern when stored at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions for 6 months, 1 month and 1 month respectively.
  • Example 1 Preparation of crystalline Form M1 of Avatrombopag.
  • Avatrombopag maleate (50mg) was dissolved in pyridine (2mL) at 80 ⁇ 5°C. The resulting clear solution was cooled to 25 ⁇ 5°C and allowed for slow solvent evaporation for 15h at 25 ⁇ 5°C. Then added water (2mL) and stirred for 30min. The solid obtained was filtered, suck-dried and identified as crystalline Form M1 of Avatrombopag.
  • Example 2 Preparation of crystalline Form M1 of Avatrombopag.
  • Avatrombopag maleate (0.5g) was dissolved in a mixture of pyridine (5mL) and water (3mL) at 80 ⁇ 5°C. The resulting clear solution was cooled to 25 ⁇ 5°C, added seeds of Form M1 and maintained under stirring for 15h at 25 ⁇ 5°C. The solid obtained was filtered, suck-dried and identified as crystalline Form M1 of Avatrombopag.
  • Example 3 Preparation of crystalline Form M1 of Avatrombopag.
  • Avatrombopag maleate (50mg) was dissolved in a mixture of 2-methoxy ethanol (2mL), 1 ,4- dioxane (1 mL) and DMSO (0.5mL) at 80 ⁇ 5°C. The resulting clear solution was cooled to 25 ⁇ 5°C and allowed for slow solvent evaporation for 15h at 25 ⁇ 5°C. The solid obtained was filtered, suck-dried and identified as crystalline Form M1 of Avatrombopag.
  • Example 4 Preparation of crystalline Form M1 of Avatrombopag.
  • Avatrombopag maleate (50mg) was dissolved in a mixture of Formamide (2mL), DMF (2mL) and DMSO (0.5mL) at 80 ⁇ 5°C. The resulting clear solution was cooled to 25 ⁇ 5°C and allowed for slow solvent evaporation for 15h at 25 ⁇ 5°C. The solid obtained was filtered, suck-dried and identified as crystalline Form M1 of Avatrombopag.
  • Example 5 Preparation of crystalline Form M1 of Avatrombopag.
  • Avatrombopag maleate 50mg was dissolved in DMF (2mL) at 80 ⁇ 5°C. The resulting clear solution was cooled to 25 ⁇ 5°C and allowed for slow solvent evaporation for 15h at 25 ⁇ 5°C. The solid obtained was filtered, suck-dried and identified as crystalline Form M1 of Avatrombopag.
  • Example 6 Preparation of crystalline Form M2 of Avatrombopag.
  • Avatrombopag maleate (200mg) was dissolved in a mixture of acetonitrile (1 OmL), water (3mL) and DMF (2.5mL) at 80 ⁇ 5°C. The resulting clear solution was filtered to remove any undissolved particulate and subjected to Lyophilization using Labocon lyophilizer (Model: LFD-BT-104) to yield crystalline Form M2 of Avatrombopag.
  • Example 7 Preparation of crystalline Form M3 of Avatrombopag.
  • Avatrombopag maleate 50mg was dissolved in a mixture of morpholine (2.5mL) and isobutyl acetate (3mL) at 80 ⁇ 5°C. The resulting clear solution was cooled to 25 ⁇ 5°C and maintained under stirring for 5h at 25 ⁇ 5°C. The solid obtained was filtered, suck-dried and identified as crystalline Form M3 of Avatrombopag.
  • Example 8 Preparation of crystalline Form M4 of Avatrombopag.
  • Avatrombopag crystalline Form M1 (200mg) was heated using variable temperature powder XRD tool on Bruker D8 X-Ray Diffractometer from 30-240°C and followed by slow cooling to 30°C. The resulting solid was identified as crystalline Form M4 of Avatrombopag.
  • Example 9 Preparation of crystalline Form M5 of Avatrombopag.
  • Avatrombopag Form M2 (200mg) was heated using variable temperature powder XRD tool on Bruker D8 X-Ray Diffractometer from 30-240°C and followed by slow cooling to 30°C. The resulting solid was identified as crystalline Form M5 of Avatrombopag.
  • Example 10 Preparation of crystalline Form M1 of Avatrombopag maleate.
  • Avatrombopag maleate (1 g) was dissolved in DMSO (3mL) at 80 ⁇ 5°C. The resulting clear solution was filtered to remove any undissolved particulate, added to water (16mL) at 25 ⁇ 5°C and maintained for 4h at 25 ⁇ 5°C. The solid precipitated was filtered, washed with 4mL of water and dried the material at 70 ⁇ 5°C under vacuum for 2h. The solid obtained is identified as crystalline Form M1 of Avatrombopag maleate.
  • Example 11 Preparation of crystalline Form M1 of Avatrombopag maleate.
  • Avatrombopag maleate (100mg) was dissolved in DMSO (0.3mL) at 80 ⁇ 5°C. The resulting clear solution was filtered to remove any undissolved particulate and then added to MTBE solution (3mL) maintained at 25 ⁇ 5°C containing seeds of Avatrombopag maleate Form M1 . The reaction mass was maintained for 4h under stirring at 25 ⁇ 5°C, filtered and washed with MTBE (1 ml_). The solid obtained is identified as crystalline Form M1 of Avatrombopag maleate.
  • Example 12 Preparation of crystalline Form M2 of Avatrombopag maleate.
  • Avatrombopag maleate 500mg was dissolved in DMSO (2mL) at 80 ⁇ 5°C, cooled to 25 ⁇ 5°C and filtered using hyflo to remove any undissolved particulate matter. The resulting clear solution was added to Ethyl acetate (1 OmL) at 25 ⁇ 5°C and the suspension was maintained for 4h at 25 ⁇ 5°C. The resulting reaction mass was filtered, suck-dried for 30min and further dried under vacuum at 80 ⁇ 5°C for 15h. The solid obtained was identified as crystalline Form M2 of Avatrombopag maleate.
  • Example 13 Preparation of crystalline Form M3 of Avatrombopag maleate.
  • Avatrombopag maleate (1 g) was dissolved in a mixture of Dimethyl acetamide (2.5mL) and 2- Ethoxy ethanol (5mL) at 80 ⁇ 5°C and filtered at same temperature to remove any undissolved particulate. The resulting clear solution was slowly cooled to 25 ⁇ 5°C and maintained under stirring at same temperature for 15h. The solid precipitated was filtered and suck dried under vacuum for 30min. The solid obtained is identified as crystalline Form M3 of Avatrombopag maleate.
  • Example 14 Preparation of crystalline Form M3 of Avatrombopag maleate.
  • Avatrombopag maleate (0.2g) was dissolved in Dimethyl acetamide (0.5mL) at 60 ⁇ 5°C and allowed to cool to 25 ⁇ 5°C. The clear solution was slowly added to isobutyl acetate (2m L) at 25 ⁇ 5°C and the reaction mass was stirred for 15h at 25 ⁇ 5°C. The solid precipitated was filtered and suck dried under vacuum for 30min. The solid obtained is identified as crystalline Form M3 of Avatrombopag maleate.
  • Example 15 Preparation of crystalline Form M3 of Avatrombopag maleate.
  • Avatrombopag maleate (0.2g) was dissolved in Dimethyl acetamide (0.5mL) at 60 ⁇ 5°C and allowed to cool to 25 ⁇ 5°C. The clear solution was slowly added to ethyl acetate (2m L) at 25 ⁇ 5°C and the reaction mass was stirred for 15h at 25 ⁇ 5°C. The solid precipitated was filtered and suck dried under vacuum for 30min. The solid obtained is identified as crystalline Form M3 of Avatrombopag maleate.
  • Example 16 Preparation of crystalline Form M3 of Avatrombopag maleate.
  • Avatrombopag maleate (0.2g) was dissolved in Dimethyl acetamide (0.5mL) at 60 ⁇ 5°C and allowed to cool to 25 ⁇ 5°C. The clear solution was slowly added to anisole (2mL) at 25 ⁇ 5°C and the reaction mass was stirred for 15h at 25 ⁇ 5°C. The solid precipitated was filtered and suck dried under vacuum for 30min. The solid obtained is identified as crystalline Form M3 of Avatrombopag maleate.
  • Example 17 Preparation of crystalline Form M3 of Avatrombopag maleate.
  • Avatrombopag maleate (0.2g) was dissolved in Dimethyl acetamide (0.5mL) at 60 ⁇ 5°C and allowed to cool to 25 ⁇ 5°C. The clear solution was slowly added to methyl isobutyl ketone (2mL) at 25 ⁇ 5°C and the reaction mass was stirred for 15h at 25 ⁇ 5°C. The solid precipitated was filtered and suck dried under vacuum for 30min. The solid obtained is identified as crystalline Form M3 of Avatrombopag maleate.
  • Example 18 Preparation of crystalline Form M3 of Avatrombopag maleate.
  • Avatrombopag maleate (0.2g) was dissolved in Dimethyl acetamide (0.5mL) at 60 ⁇ 5°C and allowed to cool to 25 ⁇ 5°C. The clear solution was slowly added to 2-butanol (2m L) at 25 ⁇ 5°C and the reaction mass was stirred for 15h at 25 ⁇ 5°C. The solid precipitated was filtered and suck dried under vacuum for 30min. The solid obtained is identified as crystalline Form M3 of Avatrombopag maleate.
  • Example19 Preparation of crystalline Form M3 of Avatrombopag maleate.
  • Avatrombopag maleate (0.2g) was dissolved in Dimethyl acetamide (0.5mL) at 60 ⁇ 5°C and allowed to cool to 25 ⁇ 5°C. The clear solution was slowly added to 2-Propanol (2mL) at 25 ⁇ 5°C and the reaction mass was stirred for 15h at 25 ⁇ 5°C. The solid precipitated was filtered and suck dried under vacuum for 30min. The solid obtained is identified as crystalline Form M3 of Avatrombopag maleate.
  • Example 20 Preparation of crystalline Form M3 of Avatrombopag maleate.
  • Avatrombopag maleate (0.2g) was dissolved in Dimethyl acetamide (0.5mL) at 60 ⁇ 5°C and allowed to cool to 25 ⁇ 5°C. The clear solution was slowly added to 2-methyl-1 -propanol (2mL) at 27 ⁇ 2°C and the reaction mass was stirred for 15h at 27 ⁇ 2°C. The solid precipitated was filtered and suck dried under vacuum for 30min. The solid obtained is identified as crystalline Form M3 of Avatrombopag maleate.
  • Example 21 Preparation of Amorphous Avatrombopag.
  • Avatrombopag crystalline Form M3 was heated at 100°C under vacuum for 4h, the resulting solid was identified as Amorphous Avatrombopag
  • Avatrombopag maleate (0.2g) was dissolved in a mixture of tetrahydrofuran (12mL) and water (3mL) at 85 ⁇ 5°C. The resulting clear solution was filtered to remove any undissolved particulates and subjected to lyophilization using labocon lyophilizer (Model: LFD-BT104) to yield Avatrombopag maleate amorphous form.
  • Avatrombopag maleate (0.2g) was dissolved in a mixture of 1 ,4-dioxane (15mL) and water (3mL) at 85 ⁇ 5°C. The resulting clear solution was filtered to remove any undissolved particulates and subjected to lyophilization using labocon lyophilizer (Model: LFD-BT104) to yield Avatrombopag maleate amorphous form.
  • Example 24 Preparation of amorphous Avatrombopag maleate
  • Avatrombopag maleate (5g) was dissolved in a mixture of tetrahydrofuran (300 ml.) and water (75 ml) at 85 ⁇ 5°C. Filtered the clear solution through hyflo to remove any undissolved particulate. The clear solution was cooled to 25 ⁇ 5°C, then subjected to spray-drying in a laboratory spray-dryer (Model: Buchi B-290) with feed rate of solution 5ml/min and inlet temperature at 80°C with 100% aspiration to yield Avatrombopag maleate amorphous form.
  • Example 25 Preparation of amorphous Avatrombopag maleate
  • Avatrombopag maleate (0.5g) was dissolved in dimethyl sulfoxide (1 5mL) at 80 ⁇ 5°C and cooled to 25 ⁇ 5°C. The resulting clear solution was added to water (6mL) at 25 ⁇ 5°C and the reaction mass was maintained under stirring at 25 ⁇ 5°C for 4h. The solid obtained was filtered, washed with water (4 ml_), suck-dried for 4h. The product obtained is identified as Avatrombopag maleate amorphous form.
  • Avatrombopag maleate (1 Og) was dissolved in a mixture of DMSO (30 ml.) and Anisole (100 ml.) at 65 ⁇ 5°C. Filtered the clear solution through hyflo to remove any undissolved particulate, then subjected to spray-drying in a laboratory spray-dryer (Model: Buchi B-290) with feed rate of solution 5ml/min and inlet temperature at 140°C with 100% aspiration to yield Avatrombopag maleate amorphous form.
  • Avatrombopag maleate (2g) was dissolved in a mixture of DMSO (4 ml.) and Anisole (20 ml.) at 65 ⁇ 5°C. Filtered the clear solution through hyflo to remove any undissolved particulate, then subjected to spray-drying in a laboratory spray-dryer (Model: Buchi B-290) with feed rate of solution 5ml/min and inlet temperature at 120°C with 100% aspiration to yield Avatrombopag maleate amorphous form.
  • Example 28 Preparation of amorphous solid dispersion of Avatrombopag maleate:
  • Avatrombopag maleate (0.5g) was dissolved in a mixture of tetrahydrofuran (30mL) and water (7.5mL) at 85 ⁇ 5°C. The resulting clear solution was filtered to remove any undissolved particulates and added silicon dioxide (0.5g) and subjected to lyophilization using labocon lyophilizer (Model: FD-BT-104) to yield amorphous solid dispersion of Avatrombopag maleate.
  • Example 29 Preparation of amorphous solid dispersion of Avatrombopag maleate:
  • Avatrombopag maleate (0.5g) was dissolved in a mixture of tetrahydrofuran (30mL) and water (7.5mL) at 85 ⁇ 5°C. The resulting clear solution was filtered to remove any undissolved particulates and added PVP-K-30 (0.5g) and subjected to lyophilization using labocon lyophilizer (Model: FD-BT-104) to yield amorphous solid dispersion of Avatrombopag maleate.
  • Example 30 Preparation of amorphous solid dispersions of Avatrombopag maleate.
  • Avatrombopag maleate (0.5g) and Plasdone S-630 (0.5g) were dissolved in a mixture of tetrahydrofuran (30mL) and water (9.5mL) at 85 ⁇ 5°C. The resulting clear solution was filtered to remove any undissolved particulate and subjected to Lyophilization using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous solid dispersion of Avatrombopag maleate.
  • Example 31 Preparation of amorphous solid dispersions of Avatrombopag maleate.
  • Avatrombopag maleate (0.5g) was dissolved in a mixture of tetrahydrofuran (30mL) and water (7.5mL) at 85 ⁇ 5°C. The resulting clear solution was filtered to remove any undissolved particulate and added Microcrystalline cellulose (MCC, 0.5g) and subjected to Lyophilization using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous solid dispersion of Avatrombopag maleate.
  • Example 32 Preparation of amorphous solid dispersions of Avatrombopag maleate.
  • Avatrombopag maleate (0.5g) and Lactose monohydrate (0.5g) were dissolved in a mixture of tetrahydrofuran (30mL) and water (9.5mL) at 85 ⁇ 5°C.
  • the resulting clear solution was filtered to remove any undissolved particulates and subjected to Lyophilization using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous solid dispersion of Avatrombopag maleate.

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

Abstract

La présente invention concerne de manière générale des composés pharmaceutiquement actifs et plus spécifiquement la forme cristalline M1 de l'avatrombopag, la forme cristalline M2 de l'avatrombopag, la forme cristalline M3 de l'avatrombopag, la forme cristalline M4 de l'avatrombopag, la forme cristalline M5 de l'avatrombopag, forme cristalline M1 de maléate d'avatrombopag, la forme cristalline M2 de maléate d'avatrombopag, forme cristalline M3 de maléate d'avatrombopag, l'avatrombopag amorphe, maléate d'avatrombopag amorphe, dispersions solides amorphes de maléate d'avatrombopag et leurs procédés de préparation.
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