WO2020234817A1 - Polymorphic forms of apalutamide and its preparation thereof - Google Patents

Polymorphic forms of apalutamide and its preparation thereof Download PDF

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Publication number
WO2020234817A1
WO2020234817A1 PCT/IB2020/054815 IB2020054815W WO2020234817A1 WO 2020234817 A1 WO2020234817 A1 WO 2020234817A1 IB 2020054815 W IB2020054815 W IB 2020054815W WO 2020234817 A1 WO2020234817 A1 WO 2020234817A1
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apalutamide
solvent
solution
another embodiment
present
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PCT/IB2020/054815
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French (fr)
Inventor
Ram Thaimattam
Veera Narayana Bandlamudi
Nageswara Rao REGANDLA
Vivek Kumar KUDIRILLA
Chinna Potuluraiah CHIRRA
Rajesh EDUPUGANTI
Ravindra Babu Bollu
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Laurus Labs Limited
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Publication of WO2020234817A1 publication Critical patent/WO2020234817A1/en

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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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 relates to novel crystalline polymorphic forms of apalutamide and its processes for preparation thereof.
  • the present invention also relates to processes for preparation of amorphous form of apalutamide and pharmaceutical composition containing the same.
  • Apalutamide (ARN-509), known as (4-[7-(6-Cyano-5-trifluoromethylpyridin-3-yl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide), has the following structure:
  • Apalutamide is marketed by Janssen Biotech under the trade name ERLEADATM as 60 mg oral tablet in US and EP for the treatment of patients with non-metastatic castration- resistant prostate cancer.
  • U.S. Patent No. 8,445,507 discloses androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases such as apalutamide and process for preparation thereof.
  • The‘507 patent process involves purification of apalutamide by column chromatography using a mixture of dichloromethane and acetone (95:5) to obtain apalutamide as a white powder.
  • the‘507 patent does not disclose any polymorphic information on resulted apalutamide.
  • U.S. Patent No. 9,481,663 (“the‘663 patent”) discloses crystalline forms including solvates of apalutamide such as apalutamide Form A (Isostructural solvate), apalutamide Form B, apalutamide Form C (isopropyl alcohol solvate), apalutamide Form D (tert-butyl methyl ether solvate), apalutamide Form E (dimethylsulfoxide solvate), apalutamide Form F, apalutamide Form G (2-methoxy ethanol solvate), apalutamide Form H, apalutamide Form I, apalutamide Form J (acetone solvate) and its characterization data by PXRD, DSC and TGA.
  • apalutamide Form A Isostructural solvate
  • apalutamide Form B apalutamide Form C (isopropyl alcohol solvate)
  • apalutamide Form D tert-butyl methyl ether solvate
  • apalutamide Form E dimethyl
  • apalutamide Form T1 (mono hydrate), apalutamide Form T2 (2- butanol solvate), apalutamide Form T3 (cyclohexanone solvate), apalutamide Form T4 (acetonitrile- water solvate), apalutamide Form T5 (ethylene glycol solvate), apalutamide Form T6 (isobutanol solvate), apalutamide Form T7 & Form T8 (methyl isobutyl ketone solvate), apalutamide Form T9 (formamide-water solvate), apalutamide Form T10 (methylene dichloride-water solvate), apalutamide Form Ti l (dihydrate), apalutamide Form T12 (dimethyl carbonate solvate), apalutamide Form T13 & Form T14 (E.A solvate), apalutamide Form T15 (methyl acetate solvate), apalutamide Form
  • Indian application No.(S) 201741043701 (“the‘701 publication”), 201841002315 (“the ‘315 publication”), 201841030693 (“the ‘693 publication”) & 201841038834 (“the ‘834 publication”) discloses crystalline solvates of Apalutamide such as acetic acid solvate of Apalutamide (VK1), propionic acid solvate of Apalutamide (VK2), racemic propylene glycol solvate of Apalutamide (VK3), R-propylene glycol solvate of Apalutamide (VK4), S -propylene glycol solvate of Apalutamide (VK5), methyl acetate solvate of Apalutamide (VK6) and crystalline form of apalutamide (VK7), (VK8), (VK9), (VK10), (VK11), (VK12; and apalutamide co-crystal with 2,5-dihydroxy benzoic acid its
  • Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms and solvates, and to determine the stability, dissolution and flow properties of each polymorphic form.
  • Polymorphic forms and solvates of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms and solvates of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.
  • apalutamide is a low aqueous solubility and high intestinal permeability. This low aqueous solubility of active substance is the main challenge in the formulation development and in order to improve the aqueous solubility of the active substance commercial product ERLEADATM utilized amorphous form of apalutamide. However, even though the amorphous form has high aqueous solubility but the stability of the amorphous nature is less which is easily gets converted to less aqueous soluble crystalline form and to improve stability of the product the amorphous form was solid dispersed with excipients.
  • amorphous form of the active substances prone to hold residual quantities of the solvents used in the processes and also possible contamination of the process impurities therefore always getting the amorphous form of the active substances is less pure and highly hygroscopic in nature.
  • complete solvent evaporation methods such as spry drying process is utilized which is not industrially viable method for preparing pure amorphous form.
  • Apalutamide is one of the important drug available in the market for the treatment of non-metastatic castration-resistant prostate cancer. Hence, it’s important to discover new polymorphic forms of apalutamide, which may provide a new opportunity to improve the performance characteristics of a pharmaceutical product. There remains a need for novel polymorphic forms of apalutamide with improved characteristics. Further, there is a need to develop a process for preparing amorphous form of apalutamide where the cumbersome spray drying method is evaded.
  • the main objective of the present invention is to provide novel crystalline form of apalutamide. Further, the present invention also relates to processes for preparation of amorphous form of apalutamide and pharmaceutical composition containing the same.
  • the present invention encompasses novel crystalline polymorphic forms, solvates and hydrates of apalutamide, process for their preparation.
  • the present invention also encompasses processes for the preparation of amorphous form of apalutamide with high product yield and quality, and greater stability.
  • the present invention provides novel crystalline polymorphic forms of apalutamide or its solvates or its hydrates; which are designated herein as apalutamide Form-Ll, apalutamide Form-L2, apalutamide Form-L3, apalutamide Form-L4, apalutamide Form-L5, apalutamide Form-L6, apalutamide Form- L7, apalutamide Form-L8, apalutamide Form-L9, apalutamide Form-LlO, apalutamide Form-Ll 1, apalutamide Form-L12, apalutamide Form-L13 and apalutamide Form-L14.
  • the present invention provides apalutamide Form-Ll.
  • apalutamide Form-Ll of the present invention is an ethyl formate solvate.
  • the present invention provides apalutamide Form-Ll characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 1.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-Ll characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 7.7, 8.1, 10.4, 10.7, 11.1, 11.4, 12.3, 12.5, 14.5, 15.2, 15.5, 16.0, 16.3, 16.9, 17.2, 18.0, 19.0, 19.4, 19.9, 20.7, 20.9, 21.3, 21.8, 22.1, 22.6, 22.7, 23.3, 23.9, 24.5, 25.0, 25.6, 26.2, 26.8, 27.1, 28.4, 28.8, 29.1, 29.7, 29.9, 30.8, 30.9, 31.4, 32.1, 33.0, 33.53, 34.0 and 34.9 ⁇ 0.2° 2Q.
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-Ll, comprising:
  • the present invention provides apalutamide Form-L2.
  • apalutamide Form-L2 of the present invention is a hydrate.
  • the present invention provides apalutamide Form-L2 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 4.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L2 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.8, 8.1, 10.4, 11.4, 12.2, 12.5, 14.2, 15.5, 16.0, 16.3, 16.7, 19.0, 19.3, 19.8, 20.1, 20.7, 21.3, 21.8, 22.6, 23.1, 23.3, 23.7, 24.0, 24.7, 25.0, 25.5, 26.2, 26.5, 26.7, 26.8, 27.6, 28.3, 29.0, 29.4, 29.9, 30.9, 31.1, 31.5, 32.5, 33.1, 33.4, 33.8, 34.7 and 35.1 ⁇ 0.2° 2Q.
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-L2, comprising:
  • step a) suspending apalutamide Form-Ll in ammonia at about 0°C to about 35°C, b) stirred the step a) suspension for about 10 min to about 4 hours and
  • the present invention provides a process for the preparation of apalutamide Form-L2, comprising:
  • step a) suspending apalutamide Form-Ll in ammonia at about 0°C to about 5°C, b) stirred the step a) suspension for about 10 min to about 2 hours and
  • the present invention provides a process for the preparation of apalutamide Form-L2, comprising:
  • step e) suspending apalutamide Form-Ll in ammonia at about 0°C to about 35°C, f) stirred the step e) suspension for about 10 min to about 4 hour, and
  • the present invention provides apalutamide Form-L3.
  • apalutamide Form-L3 of the present invention is a formic acid and n-pentanol solvate.
  • the present invention provides apalutamide Form-L3 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 5.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L3 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.7, 6.9, 7.1, 7.3, 9.4, 10.5, 11.1, 11.3, 11.8, 13.3, 14.1, 14.8, 15.3, 16.3, 16.4, 16.8, 18.4, 18.9, 20.1, 20.7, 21.2, 21.9, 22.9, 23.4, 23.7, 24.0, 24.5, 24.8, 25.2, 25.8, 26.4, 26.8, 27.8, 28.5, 29.9, 30.5, 31.3, 31.8, 32.7 and 33.3 ⁇ 0.2° 2Q.
  • the present invention provides a process for the preparation of apalutamide Form-L3, comprising:
  • the present invention provides apalutamide Form-L4.
  • apalutamide Form-L4 of the present invention is a formic acid and isobutanol solvate.
  • the present invention provides apalutamide Form-L4 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 6.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L4 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.7, 6.8, 7.0, 7.2, 9.4, 10.5, 10.7, 11.3, 11.8, 13.3, 14.1, 14.7, 16.1, 16.3, 16.9, 18.2, 18.8, 20.0, 20.7, 21.3, 21.5, 22.0, 22.7, 23.9, 24.5, 24.7, 25.1, 25.8, 26.7, 27.9 and 29.8 ⁇ 0.2° 2Q.
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-L4, comprising:
  • the present invention provides apalutamide Form-L5.
  • apalutamide Form-L5 of the present invention is a formic acid and cyclohexane solvate.
  • the present invention provides apalutamide Form-L5 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 7.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L5 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.7, 6.7, 7.0, 7.3, 9.3, 10.4, 10.7, 11.0, 11.3, 11.5, 11.8, 13.2, 13.6, 14.0, 14.6,
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-L5, comprising:
  • the present invention provides apalutamide Form-L6.
  • apalutamide Form-L6 of the present invention is formic acid and cyclopentyl methyl ether solvate.
  • the present invention provides apalutamide Form-L6 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 8.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L6 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.8, 6.9, 7.4, 9.5, 10.5, 11.2, 11.9, 13.4, 14.2, 14.7, 15.2, 15.5, 16.2, 16.5, 17.0, 18.3, 18.8, 20.0, 20.4, 21.2, 21.4, 22.1, 22.5, 22.8, 23.5, 23.9, 24.6, 25.3, 25.7, 26.7, 27.0, 27.6, 28.5, 29.7, 31.2, 32.0, 32.7, 33.3 and 34.2 ⁇ 0.2° 2Q.
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-L6, comprising:
  • the present invention provides apalutamide Form-L7.
  • apalutamide Form-L7 of the present invention is a t-pentanol solvate.
  • the present invention provides apalutamide Form-L7 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 9.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L7 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.6, 7.0, 9.1, 10.5, 12.8, 13.7, 14.7, 15.7, 16.0, 16.5, 17.3, 18.0, 18.3, 19.0, 19.7, 20.2, 21.0, 21.2, 21.7, 22.1, 22.7, 22.9, 23.6, 23.9, 24.3, 24.6, 25.3, 25.8, 26.1, 26.7,
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-L7, comprising:
  • the present invention provides apalutamide Form-L8.
  • apalutamide Form-L8 of the present invention is a t-butanol solvate.
  • the present invention provides apalutamide Form-L8 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 10.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L8 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.6, 7.0, 9.2, 10.6, 11.5, 12.8, 13.8, 14.8, 15.8, 16.0, 16.5, 17.4, 18.1, 18.5, 19.2,
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-L8, comprising:
  • the present invention provides apalutamide Form-L9.
  • apalutamide Form-L9 of the present invention is a sulfolane solvate.
  • the present invention provides apalutamide Form-L9 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 11.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L9 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.9, 5.5, 5.8, 8.8, 9.4, 10.0, 10.3, 11.3, 11.7, 12.0, 12.3, 12.8, 13.2, 13.9, 14.1,
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-L9, comprising:
  • step b) adding water to step b) reaction mass
  • the present invention provides apalutamide Form-LlO.
  • apalutamide Form-LlO of the present invention is a trifluoroethanol solvate.
  • the present invention provides apalutamide Form-LlO characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 12.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-LlO characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.6, 7.0, 9.3, 10.7, 11.6, 13.2, 14.0, 14.8, 15.0, 16.1, 16.7, 17.5, 18.5, 18.7, 19.5, 20.0, 20.5, 21.4, 21.6, 21.9, 22.9, 23.5, 24.1, 24.5, 24.8, 25.0, 25.5, 26.3, 27.2,
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-LlO, comprising:
  • the present invention provides apalutamide Form-Ll l.
  • apalutamide Form-Ll l of the present invention is N-methyl-2-pyrrolidone solvate.
  • the present invention provides apalutamide Form-Ll l characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 13.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-Ll l characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.2, 5.0, 6.9, 8.2, 8.5, 9.1, 9.4, 10.4, 10.8, 11.6, 12.0, 12.5, 12.8, 13.3, 14.9,
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-Ll 1, comprising:
  • the present invention provides apalutamide Form-L12.
  • apalutamide Form-L12 of the present invention is N-methyl-2-pyrrolidone solvate.
  • the present invention provides apalutamide Form-Ll 2 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 14.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-Ll 2 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.1, 4.5, 7.7, 8.0, 8.3, 8.8, 9.1, 9.6, 10.4, 11.0, 11.8, 12.4, 13.1, 13.7, 14.4, 14.6,
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-L12, comprising:
  • the present invention provides apalutamide Form-L13.
  • apalutamide Form-L13 of the present invention is N-methyl-2-pyrrolidone solvate.
  • the present invention provides apalutamide Form-L13 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 15.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L13 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 3.9, 4.3, 4.9, 6.4, 7.8, 8.1, 8.6, 9.4, 10.0, 10.7, 12.0, 12.2, 12.9, 13.4, 14.4, 14.8,
  • XRD X-Ray diffraction
  • the present invention provides a process for preparation of apalutamide Form-L13, the process comprising: drying crystalline apalutamide Form LI 3 at a temperature of about 60°C to about 70°C.
  • the present invention provides apalutamide Form-L14.
  • apalutamide Form-L14 of the present invention is N-methyl-2-pyrrolidone solvate.
  • the present invention provides apalutamide Form-L14 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 16.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L14 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 3.9, 4.3, 6.6, 7.6, 7.9, 8.1, 8.7, 9.5, 10.2, 10.8, 11.4, 11.9, 12.3, 13.0, 13.5, 14.2, 14.5, 14.8, 15.2, 15.5, 15.9, 16.3, 17.1, 17.3, 17.6, 17.9, 18.2, 18.6, 19.0, 19.4, 19.7, 20.2, 21.0, 21.7, 22.1, 22.8, 23.8, 24.4, 24.9, 25.5, 25.7, 26.2, 26.3, 26.9, 28.1, 28.4, 28.8, 29.3, 30.0, 30.6, 31.9, 32.6 and 33.8 ⁇ 0.2° 2Q.
  • the present invention provides a process for the preparation of apalutamide Form-L14, comprising:
  • the present invention provides crystalline forms of apalutamide, characterized by X-Ray diffraction (XRD) having one or more peaks selected from the group consisting of:
  • the present invention provides a process for preparation of crystalline form of apalutamide, wherein the crystalline forms selected from Form L3, Form L4, Form L5, Form L6, Form L7, Form L8, Form L9, Form L10, Form LI 1, Form L12 and Form 14, comprising:
  • step b) adding anti-solvent to step b) reaction mass
  • the apalutamide Form L3 is obtained when step a) solvent is a mixture of formic acid and n-pentanol, and step c) anti-solvent is n-pentanol; wherein the apalutamide Form L4 is obtained, when step a) solvent is a mixture of formic acid and isobutanol, and step c) anti-solvent is isobutanol; wherein the apalutamide Form L5 is obtained, when step a) solvent is formic acid, and step c) anti-solvent is cyclohexane; wherein the apalutamide Form L6 is obtained, when step a) solvent is formic acid, and step c) anti-solvent is cyclopentyl methyl ether; wherein the apalutamide Form L7 is obtained, when step a) solvent is a mixture of formic acid and t-pentanol, and step c) anti- solvent is t-pentanol; wherein the apalutamid
  • the present invention provides a process for preparation of amorphous form of apalutamide, comprising:
  • the one or more solvents are selected from the group consisting of ethyl acetate, acetonitrile, methyl ethyl ketone, methanol and mixture thereof.
  • the present invention provides a process for preparation of amorphous form of apalutamide, comprising:
  • the one or more solvents are selected from the group consisting of ethyl acetate, acetonitrile, methyl ethyl ketone, methanol and mixture thereof; and suitable another solvent is non-polar solvent.
  • the present invention provides a process for preparation of amorphous form of apalutamide, comprising: a) providing a solution of apalutamide in one or more solvents, b) adding a suitable anti-solvent to the step a) solution or vice-versa; and c) isolating the amorphous apalutamide.
  • the present invention provides a process for preparation of amorphous form of apalutamide, comprising:
  • step b) adding a suitable anti-solvent to the step a) solution or vice-versa; and c) isolating the amorphous form;
  • the one or more solvents are selected from the group consisting of formic acid, methanol, acetonitrile and mixture thereof; and wherein the suitable anti-solvent is water, ammonia and mixtures thereof.
  • the present invention provides a process for preparation of amorphous form of apalutamide, the process comprising: drying apalutamide in the form of either solvate or hydrates thereof at a suitable temperature.
  • the present invention provides a process for preparation of amorphous form of apalutamide, the process comprising: drying crystalline apalutamide Form LI at a suitable temperature.
  • the present invention provides a process for preparation of amorphous form of apalutamide, the process comprising: drying crystalline apalutamide Form LI at a temperature of about 85°C to about 100°C.
  • the present invention provides a pharmaceutical composition comprising amorphous or novel crystalline forms of apalutamide prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
  • Figure 1 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-Ll.
  • Figure 2 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form obtained according to Example - 2.
  • Figure 3 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form obtained according to Example - 4.
  • Figure 4 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form L2.
  • Figure 5 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-L3.
  • Figure 6 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-L4.
  • Figure 7 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-L5.
  • Figure 8 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-L6.
  • Figure 9 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-L7.
  • Figure 10 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-L8.
  • Figure 11 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-L9.
  • Figure 12 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-LlO.
  • Figure 13 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-Ll 1.
  • Figure 14 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-L12.
  • Figure 15 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-Ll 3.
  • Figure 16 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-L14.
  • Figure 17 is the characteristic powder X-ray diffraction (PXRD) pattern of amorphous apalutamide.
  • Figure 18 is the characteristic powder X-ray diffraction (PXRD) pattern of amorphous apalutamide according to Reference Example. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention provides a process for the preparation of amorphous from of apalutamide and pharmaceutical compositions containing the same.
  • the present invention also relates to novel crystalline polymorphic forms of apalutamide and its processes for preparation thereof and its use an intermediate for preparation of amorphous apalutamide.
  • the amorphous and crystalline apalutamide obtained by process of the present invention are characterized by X-ray powder diffraction (XRPD) pattern, differential scanning calorimetric (DSC) and thermo gravimetric analysis (TGA).
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetric
  • TGA thermo gravimetric analysis
  • the differential scanning calorimetric data reported herein is analyzed in hermitically sealed aluminium pan, with a blank hermitically sealed aluminium pan as the reference and were obtained using DSC (DSC Q200, TA instrumentation, Waters) at a scan rate of 10°C per minute with an Indium standard.
  • thermo gravimetric analysis data reported herein is analyzed using TGA Q500 in platinum pan with a temperature rise of about 10°C/min in the range of about room temperature to about 250°C.
  • the present invention provides novel crystalline polymorphic form of apalutamide; which are designated herein as apalutamide Form-Ll, apalutamide Form-L2, apalutamide Form-L3, apalutamide Form-L4, apalutamide Form-L5, apalutamide Form-L6, apalutamide Form-L7, apalutamide Form-L8, apalutamide Form- L9, apalutamide Form-LlO, apalutamide Form-Ll 1, apalutamide Form-L12, apalutamide Form-Ll 3 and apalutamide Form-Ll 4.
  • apalutamide in the present invention for the preparation of novel polymorphs form LI to L14 is known in the art and can be prepared by any known methods, for example apalutamide may be synthesized as disclosed in U.S. Patent No. 8,445,507.
  • the present invention provides apalutamide Form-Ll.
  • the apalutamide Form-Ll of the present invention is an ethyl formate solvate.
  • the present invention provides apalutamide Form-Ll characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 1.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-Ll characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about
  • the present invention provides a process for the preparation of apalutamide Form-Ll, comprising:
  • the aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in ethyl formate at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution; preferably to about 50°C to about 60°C. If the reaction mass is not clear, then added ethyl formate. Then, the resultant reaction solution can be cooled to below 30°C; preferably to about 10°C to about 20°C.
  • step c) of aforementioned process involves, adding n-heptane to step b) reaction mass at below 30°C; preferably to about 10°C to about 20°C. Then the apalutamide Form-Ll can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration.
  • the resultant product may be further dried at room temperature i.e about 25°C to about 30°C for sufficient period of time; preferably for a period of about 30 min to about 2 hours.
  • the present invention provides apalutamide Form-L2.
  • the apalutamide Form-L2 of the present invention is a hydrate.
  • the present invention provides apalutamide Form-L2 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 4.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L2 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about
  • the present invention provides a process for the preparation of apalutamide Form-L2, comprising:
  • step a) suspending apalutamide Form-Ll in ammonia at about 0°C to about 35°C, b) stirred the step a) suspension for about 10 min to about 4 hour, and
  • the aforementioned process of suspending apalutamide Form-Ll includes first suspending or mixing apalutamide in ammonia at about 0°C to about 35°C; preferably at about 0°C to about 10°C, more preferably at about 0°C to about 5°C. Then, the resultant suspension is allowed to stir for about 10 min to about 4 hour at same temperature; preferably for about 10 min to about 2 hour.
  • the apalutamide Form-L2 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration.
  • the resultant product may be further dried at suitable temperatures i.e. about 35°C to about 55°C for sufficient period of time; preferably for a period of about 5 hours to about 20 hours.
  • the present invention provides a process for the preparation of apalutamide Form-L2, comprising:
  • the aforementioned process involves first preparing the apalutamide Form-Ll as per procedure described as above embodiments and converting the apalutamide Form LI into apalutamide Form L2 as per the procedure described as just above embodiment.
  • the present invention provides apalutamide Form-L3.
  • the apalutamide Form-L3 of the present invention is formic acid and n-pentanol solvate.
  • the present invention provides apalutamide Form-L3 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 5.
  • the present invention provides apalutamide Form-L3 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.7, 6.9, 7.1, 7.3, 9.4, 10.5, 11.1, 11.3, 11.8, 13.3, 14.1, 14.8, 15.3, 16.3, 16.4, 16.8, 18.4, 18.9, 20.1, 20.7, 21.2, 21.9, 22.9, 23.4, 23.7, 24.0, 24.5, 24.8, 25.2, 25.8, 26.4,
  • the present invention provides a process for the preparation of apalutamide Form-L3, comprising:
  • the aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in a mixture of formic acid and n-pentanol at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
  • step c) of aforementioned process involves, adding n-pentanol to step b) reaction mass at below 30°C. Then the apalutamide Form-L3 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 45°C to about 60°C for sufficient period of time; preferably for a period of about 10 to about 20 hours.
  • the present invention provides apalutamide Form-L4.
  • the apalutamide Form-L4 of the present invention is formic acid and isobutanol solvate.
  • the present invention provides apalutamide Form-L4 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 6.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L4 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.7, 6.8, 7.0, 7.2, 9.4, 10.5, 10.7, 11.3, 11.8, 13.3, 14.1, 14.7, 16.1, 16.3, 16.9, 18.2,
  • the present invention provides a process for the preparation of apalutamide Form-L4, comprising: a) providing a solution of apalutamide in a mixture of formic acid and isobutanol at 30°C to reflux temperature,
  • the aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in a mixture of formic acid and isobutanol at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
  • step c) of aforementioned process involves, adding isobutanol to step b) reaction mass at below 30°C. Then the apalutamide Form-L4 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 45°C to about 60°C for sufficient period of time; preferably for a period of about 15 to about 25 hours.
  • the present invention provides apalutamide Form-L5.
  • the apalutamide Form-L5 of the present invention is formic acid and cyclohexane solvate.
  • the present invention provides apalutamide Form-L5 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 7.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L5 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.7, 6.7, 7.0, 7.3, 9.3, 10.4, 10.7, 11.0, 11.3, 11.5, 11.8, 13.2, 13.6, 14.0, 14.6, 15.1, 15.4, 16.1, 16.4, 16.8, 16.9, 17.4, 18.3, 18.8, 19.0, 20.0, 20.8, 21.2, 21.4, 22.1, 22.7, 23.3, 23.9, 24.5, 24.8, 25.2, 25.8, 26.6, 26.9, 27.5, 28.2, 29.6, 30.3, 31.1, 31.8, 32.6, 33.2 and 34.0 ⁇ 0.2° 2Q.
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-L5, comprising:
  • the aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in formic acid at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
  • step c) of aforementioned process involves, adding cyclohexane to step b) reaction mass at below 30°C. Then the apalutamide Form-L5 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 50°C to about 70°C for sufficient period of time; preferably for a period of about 15 to about 25 hours.
  • the present invention provides apalutamide Form-L6.
  • the apalutamide Form-L6 of the present invention is formic acid and cyclopentyl methyl ether solvate.
  • the present invention provides apalutamide Form-L6 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 8.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L6 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about
  • the present invention provides a process for the preparation of apalutamide Form-L6, comprising:
  • the aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in formic acid at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
  • step c) of aforementioned process involves, adding cyclopentyl methyl ether to step b) reaction mass at below 30°C. Then the apalutamide Form-L6 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 45°C to about 60°C for sufficient period of time; preferably for a period of about 10 to about 20 hours.
  • the present invention provides apalutamide Form-L7.
  • the apalutamide Form-L7 of the present invention is t-pentanol solvate.
  • the present invention provides apalutamide Form-L7 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 9.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L7 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.6, 7.0, 9.1, 10.5, 12.8, 13.7, 14.7, 15.7, 16.0, 16.5, 17.3, 18.0, 18.3, 19.0, 19.7, 20.2, 21.0, 21.2, 21.7, 22.1, 22.7, 22.9, 23.6, 23.9, 24.3, 24.6, 25.3, 25.8, 26.1, 26.7, 27.6, 28.1, 29.4, 29.6, 30.2, 30.7, 31.3, 32.0, 32.4, 33.6, 34.1 and 34.4 ⁇ 0.2° 2Q.
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-L7, comprising:
  • the aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in a mixture of formic acid and t-petanol at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
  • step c) of aforementioned process involves, adding t-pentanol to step b) reaction mass at below 30°C. Then the apalutamide Form-L7 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 50°C to about 70°C for sufficient period of time; preferably for a period of about 15 to about 25 hours.
  • the present invention provides apalutamide Form-L8.
  • the apalutamide Form-L8 of the present invention is t-butanol solvate.
  • the present invention provides apalutamide Form-L8 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 10.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L8 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.6, 7.0, 9.2, 10.6, 11.5, 12.8, 13.8, 14.8, 15.8, 16.0, 16.5, 17.4, 18.1, 18.5, 19.2, 19.7,
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-L8, comprising:
  • the aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in a mixture of formic acid and t-butanol at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
  • step c) of aforementioned process involves, adding t-butanol to step b) reaction mass at below 30°C. Then the apalutamide Form-L8 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 50°C to about 70°C for sufficient period of time; preferably for a period of about 15 to about 25 hours.
  • the present invention provides apalutamide Form-L9.
  • the apalutamide Form-L9 of the present invention is sulfolane solvate.
  • the present invention provides apalutamide Form-L9 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 11.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L9 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.9, 5.5, 5.8, 8.8, 9.4, 10.0, 10.3, 11.3, 11.7, 12.0, 12.3, 12.8, 13.2, 13.9, 14.1, 14.9, 15.0, 15.7, 16.1, 16.7, 17.2, 17.7, 18.0, 18.6, 19.0, 19.3, 19.9, 20.1, 20.9, 21.3, 21.7, 22.5, 22.7, 23.1, 23.6, 24.1, 24.4, 24.6, 25.2, 25.8, 26.2, 26.4, 27.1, 27.6, 28.2, 28.8, 29.7, 30.1, 30.7, 30.9, 31.3, 32.1, 32.7, 33.5 and 34.1 ⁇ 0.2° 2Q.
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-L9, comprising:
  • the aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in sulfolane at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
  • step c) of aforementioned process involves, adding water to step b) reaction mass at below 30°C. Then the apalutamide Form-L9 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration.
  • the resultant product may be further dried at suitable temperatures i.e. about 50°C to about 70°C for sufficient period of time; preferably for a period of about 15 to about 25 hours.
  • the present invention provides apalutamide Form-LlO.
  • the apalutamide Form-LlO of the present invention is trifluoroethanol solvate.
  • the present invention provides apalutamide Form-LlO characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 12.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-LlO characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.6, 7.0, 9.3, 10.7, 11.6, 13.2, 14.0, 14.8, 15.0, 16.1, 16.7, 17.5, 18.5, 18.7, 19.5, 20.0, 20.5, 21.4, 21.6, 21.9, 22.9, 23.5, 24.1, 24.5, 24.8, 25.0, 25.5, 26.3, 27.2, 27.8, 28.3, 29.1, 30.3, 31.3, 32.2, 32.6, 33.4 and 34.9 ⁇ 0.2° 2Q.
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-LlO, comprising:
  • the aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in trifluoroethanol at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
  • step c) of aforementioned process involves, adding diisopropylether to step b) reaction mass at below 30°C. Then the apalutamide Form-LlO can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 45 °C to about 60°C for sufficient period of time; preferably for a period of about 15 to about 20 hours.
  • the present invention provides apalutamide Form-Ll 1.
  • the apalutamide Form-Ll 1 of the present invention is N- methyl-2-pyrrolidone solvate.
  • the present invention provides apalutamide Form-Ll 1 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 13.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-Ll 1 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.2, 5.0, 6.9, 8.2, 8.5, 9.1, 9.4, 10.4, 10.8, 11.6, 12.0, 12.5, 12.8, 13.3, 14.9, 15.3, 15.5, 15.7, 16.1, 16.3, 16.6, 16.9, 17.1, 17.4, 18.2, 18.7, 19.2, 19.5, 20.0, 20.5, 20.8, 21.2, 21.9, 22.2, 22.8, 23.2, 23.7, 24.2, 24.9, 25.3, 25.5, 26.4, 27.7, 28.1, 29.1, 29.6, 30.5, 31.0, 32.5, 33.1 and 33.6 ⁇ 0.2° 2Q.
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-Ll 1, comprising:
  • the aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in a mixture of N-methyl-2-pyrrolidone and methyl tert-butyl ether at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
  • step c) of aforementioned process involves, adding methyl tert-butyl ether to step b) reaction mass at below 30°C. Then the apalutamide Form-Ll 1 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 35°C to about 60°C for sufficient period of time; preferably for a period of about 15 to about 20 hours.
  • the present invention provides apalutamide Form-L12.
  • the apalutamide Form-Ll 2 of the present invention is N- methyl-2-pyrrolidone solvate.
  • the present invention provides apalutamide Form-L12 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 14.
  • the present invention provides apalutamide Form-L12 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.1, 4.5, 7.7, 8.0, 8.3, 8.8, 9.1, 9.6, 10.4, 11.0, 11.8, 12.4, 13.1, 13.7, 14.4, 14.6, 15.4,
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-L12, comprising:
  • the aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in N-methyl-2-pyrrolidone at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
  • step c) of aforementioned process involves, adding methyl tert-butyl ether to step b) reaction mass at below 30°C. Then the apalutamide Form-L12 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration and suck dried.
  • the present invention provides apalutamide Form-L13.
  • the apalutamide Form-L13 of the present invention is N- methyl-2-pyrrolidone solvate.
  • the present invention provides apalutamide Form-L13 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 15.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L13 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about
  • the present invention provides a process for preparation of apalutamide Form-L13, the process comprising: drying crystalline apalutamide Form LI 3 at a temperature of about 60°C to about 70°C.
  • the present invention provides apalutamide Form-L14.
  • the apalutamide Form-L14 of the present invention is N- methyl-2-pyrrolidone solvate.
  • the present invention provides apalutamide Form-L14 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 16.
  • PXRD powder X-ray diffraction
  • the present invention provides apalutamide Form-L14 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 3.9, 4.3, 6.6, 7.6, 7.9, 8.1, 8.7, 9.5, 10.2, 10.8, 11.4, 11.9, 12.3, 13.0, 13.5, 14.2, 14.5, 14.8, 15.2, 15.5, 15.9, 16.3, 17.1, 17.3, 17.6, 17.9, 18.2, 18.6, 19.0, 19.4, 19.7, 20.2, 21.0, 21.7, 22.1, 22.8, 23.8, 24.4, 24.9, 25.5, 25.7, 26.2, 26.3, 26.9, 28.1, 28.4, 28.8, 29.3, 30.0, 30.6, 31.9, 32.6 and 33.8 ⁇ 0.2° 2Q.
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of apalutamide Form-L14, comprising:
  • the aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in a mixture of N-methyl-2-pyrrolidone and methyl tert-butyl ether at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
  • step c) of aforementioned process involves, adding methyl tert-butyl ether to step b) reaction mass at below 30°C. Then the apalutamide Form-L14 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried under vacuum at about 25°C to about 30°C for sufficient period of time; preferably for a period of about 15 to about 20 hours.
  • the present invention provides a process for preparation of amorphous form of apalutamide.
  • the present invention provides a process for preparation of amorphous form of apalutamide, comprising: a) providing a solution of apalutamide in one or more solvents, and b) isolating amorphous apalutamide.
  • the one or more solvents are selected from the group consisting of ethyl acetate, acetonitrile, methyl ethyl ketone, methanol and mixture thereof.
  • the present invention provides a process for preparation of amorphous form of apalutamide, comprising:
  • the one or more solvents are selected from the group consisting of ethyl acetate, acetonitrile, methyl ethyl ketone, methanol and mixture thereof; and suitable another solvent is non-polar solvent.
  • the starting apalutamide used herein in step a) may be any crystalline or other form of apalutamide, including various solvates, hydrates, salts and cocrystals as long as amorphous apalutamide is produced during the process of the invention or apalutamide obtaining as existing solution from a previous processing step.
  • Step a) of providing a solution of apalutamide may include dissolving any form of apalutamide in one or more solvents at about 20°C to reflux temperature of the solvent used; preferably at a temperature of about 25°C to about 85°C.
  • the one or more solvents are selected from the group consisting of ethyl acetate, acetonitrile, methyl ethyl ketone, methanol and mixture thereof.
  • Step b) of the aforementioned process involves concentrating the step a) solution under vacuum at a temperature of about 25°C to about 80°C to obtain amorphous apalutamide.
  • suitable another solvent may be added to the amorphous apalutamide to isolate the compound.
  • the suitable another solvent in step c) is selected from the group consisting of n-hexane, n-heptane, cyclohexane and mixture thereof; preferably cyclohexane and n-heptane.
  • the resultant product may optionally be further dried at a temperature of about 35°C to about 85°C for about 2 hours to 30 hours. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven and the like; preferably drying is carried out under vacuum at a temperature of about 50°C to about 85°C for about 2 hours to 20 hours.
  • the present invention provides a process for preparation of amorphous form of apalutamide by solvent and anti-solvent method.
  • the present invention provides a process for preparation of amorphous form of apalutamide, comprising:
  • the present invention provides a process for preparation of amorphous form of apalutamide, comprising:
  • step b) adding a suitable anti-solvent to the step a) solution or vice-versa; and c) isolating the amorphous form;
  • the one or more solvents are selected from the group consisting of formic acid, methanol, acetonitrile and mixture thereof; and wherein the suitable anti-solvent is water, ammonia and mixtures thereof.
  • the starting apalutamide used herein in step a) may be any crystalline or other form of apalutamide, including various solvates, hydrates, salts and cocrystals as long as amorphous apalutamide is produced during the process of the invention or apalutamide obtaining as existing solution from a previous processing step.
  • Step a) of providing a solution of apalutamide may include dissolving any form of apalutamide in one or more solvents at about 20°C to reflux temperature of the solvent used; preferably at a temperature of about 25°C to about 75°C.
  • the one or more solvents are selected from the group consisting of formic acid, methanol, acetonitrile and mixture thereof.
  • Step b) of the aforementioned process involves precipitation of amorphous apalutamide by either addition of suitable anti- solvent to the apalutamide solution of step a) or addition of step a) solution of apalutamide into a suitable anti- solvent.
  • step b) addition of anti-solvent or vice-versa is carried out at a temperature of about -20°C to about 25 °C; preferably at a temperature of about -10°C to about 15°C.
  • the suitable anti- solvent is water, ammonia and mixtures thereof. Then the resultant mass is stirred for sufficient period of time, preferably for a period of about 30 min to 5 hours.
  • the isolation of the resultant product is accomplished by removal of solvent from the solution by, for example, substantially complete evaporation of the solvent, concentrating the solution, cooling to obtain amorphous form and filtering the solid under inert atmosphere.
  • the resultant product may optionally be further dried at a temperature of about 35°C to about 85°C for about 2 hours to 20 hours. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven and the like; preferably drying is carried out under vacuum at a temperature of about 40°C to about 85°C for about 2 hours to 15 hours.
  • the present invention provides a process for preparation of amorphous form of apalutamide, the process comprising: drying apalutamide in the form of either solvate or hydrates thereof at a suitable temperature.
  • the present invention provides a process for preparation of amorphous form of apalutamide, the process comprising: drying crystalline apalutamide Form LI at a suitable temperature.
  • the present invention provides a process for preparation of amorphous form of apalutamide, the process comprising: drying crystalline apalutamide Form LI at a temperature of about 85°C to about 100°C.
  • the present invention provides a process for preparation of amorphous form of apalutamide, the process comprising: drying crystalline apalutamide Form-Ll at a temperature of about 85°C to about 100°C; wherein the apalutamide Form-Ll characterized by an XRPD pattern substantially in accordance with Figure. 1.
  • the present invention provides a pharmaceutical composition comprising amorphous or novel crystalline forms of apalutamide prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
  • Apalutamide (20 gm) and ethyl formate (80 mL) were added in to a round bottom flask at 20-25°C, heated the reaction mass to 50-55°C and stirred for 15 min at same temperature.
  • To the hazy solution was added ethyl formate (10 mL) at 50-55°C and stirred for 15 min. Then the clear solution was allowed to cool to 15-20°C and stirred for 1 hr at same temperature.
  • Apalutamide (10 gm) and ethyl formate (40 mL) were added in to a round bottom flask at 20-25 °C.
  • seed material (55.2 mg) at 20-25 °C and stirred for 1 hr at same temperature.
  • n-heptane 150 mL
  • the solid was filtered and washed with n-heptane (10 mL), suck dried the solid for 15 min and dried the wet material under vacuum at 22-26°C for about 2 hrs. Wt: 9.82 gm.
  • Apalutamide (1 gm), formic acid (1 mL) and n-pentanol (3 mL) were added in to a round bottom flask at 20-25 °C and stirred for 5 min at same temperature, heated the reaction mass to 60-65°C and stirred for 5 min at same temperature. Reaction mass allowed to cool to 40-45°C and was added seed material (20.1 mg) at same temperature. Reaction mass further cool to 20-25°C and was added n-pentanol (10 mL).
  • Apalutamide (1 gm), formic acid (1 mL) and isobutanol (3 mL) were added in to a round bottom flask at 20-25°C and stirred for 5 min at same temperature, heated the reaction mass to 60-65°C and stirred for 5 min at same temperature. Reaction mass allowed to cool to 20-25 °C and was added isobutanol (10 mL) and stirred for 16 hrs at same temperature. Solid was filtered and washed with isobutanol (2 mL), suck dried the solid for 5 min and dried the wet material under vacuum at 50-55°C for about 18 hrs to obtain the title compound. Wt: 556.1 mg.
  • the PXRD is set forth in Figure-6; DSC endotherm peaks at 77.5°C, 123.7°C and 194.3°C; TGA weight loss: 1.0%; Solvent content (%) by NMR- formic acid: 1.6 and n-butanol: 1.9; Moisture Content: 2.8%.
  • Apalutamide (1 gm) and formic acid (1 mL) were added in to a round bottom flask at 20-25°C and stirred for 5 min at same temperature, heated the reaction mass to 60-65°C and stirred for 5 min at same temperature.
  • Reaction mass allowed to cool to 20-25°C and was added cyclohexane (20 mL) and stirred for 16 hrs at same temperature.
  • Solid was filtered and washed with cyclohexane (2 mL), suck dried the solid for 10 min and dried the wet material under vacuum at 60-65°C for about 19 hrs to obtain the title compound.
  • Wt 883.2 mg.
  • the PXRD is set forth in Figure-7; DSC endotherm peaks at 68.6°C, 134.1°C and 167.6°C; TGA weight loss: 1.1%; Solvent content (%) by NMR- formic acid: 1.6 and cyclohexane: 1.5; Moisture Content: 2.1%.
  • Apalutamide (1 gm) and formic acid (1 mL) were added in to a round bottom flask at 20-25°C and stirred for 5 min at same temperature, heated the reaction mass to 60-65°C and stirred for 5 min at same temperature.
  • Reaction mass allowed to cool to 20-25°C and was added cyclopentyl methyl ether (20 mL) and stirred for 16 hrs at same temperature.
  • Solid was filtered and washed with cyclopentyl methyl ether (2 mL), suck dried the solid for 5 min and dried the wet material under vacuum at 50-55°C for about 16 hrs to obtain the title compound.
  • Wt 432.5 mg.
  • the PXRD is set forth in Figure-8; DSC endotherm peaks at 78.6°C, 120.4°C, 163.5°C and 194.5°C; TGA weight loss: 0.65%; Solvent content (%) by NMR- formic acid: 1.2 and cyclopentyl methyl ether: 2.6; Moisture Content: 2.6%.
  • the PXRD is set forth in Figure-9; DSC endotherm peak at 138.4°C; TGA weight loss: No weight loss; Solvent content (%) by NMR- formic acid: Not detected and t-pentanol: 8.6; Moisture Content: 0.3%.
  • Apalutamide (1 gm), formic acid (1.2 mL) and tert-butanol (3 mL) were added in to a round bottom flask at 20-25°C and stirred for 5 min at same temperature, heated the reaction mass to 60-65°C and stirred for 5 min at same temperature. Reaction mass allowed to cool to 20-25°C and was added tert-butanol (10 mL) and stirred for 16 hrs at same temperature. Solid was filtered and washed with tert-butanol (2 mL), suck dried the solid for 10 min and dried the wet material under vacuum at 60-65°C for about 18 hrs to obtain the title compound. Wt: 836.7 mg.
  • the PXRD is set forth in Figure- 10; DSC endotherm peaks at 139.9°C and 194.9°C; TGA weight loss: No weight loss; Solvent content (%) by NMR- formic acid: Not detected and tert-butanol: 7.7; Moisture Content: 0.3%.
  • Apalutamide (1 gm) and sulfolane (2 mL) were added in to a round bottom flask at 20- 25°C and stirred for 5 min at same temperature, heated the reaction mass to 60-65°C and stirred for 5 min at same temperature. Reaction mass allowed to cool to 20-25°C and was added water (20 mL) and stirred for 16 hrs at same temperature. Solid was filtered and washed with water (5 mL), suck dried the solid for 15 min and dried the wet material under vacuum at 60-65°C for about 20 hrs to obtain the title compound. Wt: 985.2 mg.
  • the PXRD is set forth in Figure-11; DSC endotherm peak at 172.2°C; TGA weight loss: No weight loss; Solvent content (%) by NMR- sulfolane: 13.6; Moisture Content: 0.1%.
  • Apalutamide (1 gm) and trifluoroethanol (3 mL) were added in to a round bottom flask at 20-25°C and stirred for 5 min at same temperature, heated the reaction mass to 60- 65°C and stirred for 5 min at same temperature.
  • Reaction mass allowed to cool to 20- 25 °C and was added diisopropyl ether (20 mL) and stirred for 16 hrs at same temperature.
  • Solid was filtered and washed with diisopropyl ether (2 mL), suck dried the solid for 5 min and dried the wet material under vacuum at 50-55°C for about 18 hrs to obtain the title compound.
  • Wt 887.4 mg.
  • Apalutamide (1 gm), N-methyl-2-pyrrolidone (0.45 mL) and methyl tert-butyl ether (4 mL) were added in to a round bottom flask at 20-25 °C and stirred for 5 min at same temperature, heated the reaction mass to 55-60°C and stirred for 5 min at same temperature. Reaction mass allowed to cool to 20-25°C and was added methyl tert-butyl ether (10 mL) and stirred for 40 hrs at same temperature. Solid was filtered and washed with methyl tert-butyl ether (2 mL), suck dried the solid for 5 min and dried the wet material under vacuum at 50-55°C for about 20 hrs to obtain the title compound.
  • Apalutamide Form-L12 from Ex- 14 (740 mg) was dried under vacuum at 60-62°C for about 18 hrs to obtain the title compound. Wt: 447.6 mg.
  • the PXRD is set forth in Figure-15; DSC endotherm peaks at 125.5°C, 160.6°C and 194.7°C; TGA weight loss: No weight loos; Solvent content (%) by NMR- N-methyl-2-pyrrolidone: 8.7 and methyl tert-butyl ether: Not detected.
  • Apalutamide (1 gm), N-methyl-2-pyrrolidone (0.45 mL) and methyl tert-butyl ether (4 mL) were added in to a round bottom flask at 20-25 °C and stirred for 5 min at same temperature, heated the reaction mass to 55-60°C and stirred for 5 min at same temperature. Reaction mass allowed to cool to 30-35°C and was added seed material (15.8 mg) at same temperature. Reaction mass further cool to 20-25°C and was added methyl tert-butyl ether (10 mL) and stirred for 16 hrs at same temperature.
  • EXAMPLE-18 Preparation of amorphous apalutamide Apalutamide Form-Ll (8.51 gm) was dried under vacuum at 90-92°C for about 13 hrs to obtain the title compound. Wt: 7.96 gm.
  • the PXRD is set forth in Figure-17; DSC endotherm peaks at 59.6°C, 103.8°C, 129.4°C and 195.2°C; TGA weight loss: 0.39%;
  • Apalutamide (850 gm) and ethyl formate (3.4 lit) were added in to a round bottom flask at 20-25°C, heated the reaction mass to 50-55°C and stirred for 15 min at same temperature. The solution was filtered and then the clear solution was allowed to cool to 15-20°C and stirred for 1 hr at same temperature. To the reaction mass was added n- heptane (1.2 lit) at 15-20°C. Stirred for about 1 hr at this temperature and the precipitated solid was filtered and washed with n-heptane (1.75 lit), suck dried the solid for 30-45 min. The wet material dried under vacuum at room temperature for about 2 hrs, then at 50°C for 2 hrs and then at 90°C for 15 hrs to obtain the title compound. Wt: 740 gm.
  • the PXRD is set forth in Figure- 17.
  • Apalutamide (1 gm) and ethylacetate (10 mL) were added in to a round bottom flask at 25°C to 35°C and stirred for 5 min at same temperature. Reaction mass was heated to 60-65°C and distilled the solvent completely under vacuum at same temperature to obtaine a foamy solid. The foamy solid was cool to 20-25°C and charged cyclohexane (10 mL), stirred for 1 hr at same temperature. Solid was filtered and washed with cyclohexane (2 mL), suck dried the solid for 10 min and dried the wet material under vacuum at 50-55°C for about 2 hrs and then dried at 70-75°C for about 13 hrs to obtain the title compound. Wt: 790.4 mg.
  • the PXRD is set forth in Figure- 17; DSC endotherm peaks at 106.7°C, 166.5°C and 194.9°C; TGA weight loss: 0.2%;
  • Apalutamide (1 gm) and acetonitrile (10 mL) were added in to a round bottom flask at 25°C to 35°C and stirred for 5 min at same temperature. Reaction mass was heated to 50-55°C and distilled the solvent completely under vacuum at same temperature to obtaine a foamy solid. The foamy solid was co-distilled with cyclohexane (5 mL x 2), then the foamy solid was cool to 20-25°C and charged cyclohexane (10 mL), stirred for 1 hr at same temperature.
  • Apalutamide (1 gm) and methyl ethyl ketone (10 mL) were added in to a round bottom flask at 25°C to 35°C and stirred for 5 min at same temperature. Reaction mass was heated to 60-65°C and distilled the solvent completely under vacuum at same temperature to obtaine a foamy solid. The foamy solid was cool to 20-25°C and charged cyclohexane (10 mL), stirred for 1 hr at same temperature. Solid was filtered and washed with cyclohexane (2 mL), suck dried the solid for 10 min and dried the wet material under vacuum at 50-55°C for about 2 hrs and then dried at 70-75°C for about 13 hrs to obtain the title compound. Wt: 704.2 mg.
  • Apalutamide (500 mg) and methanol (5 mL) were added in to a round bottom flask at 25°C to 35°C and stirred for 5 min at same temperature. Reaction mass was heated to 50-55°C and distilled the solvent completely under vacuum at same temperature to obtaine a foamy solid. After complete evaporation of solvent, raised the temperature to 60-65°C and the foamy solid was maintained for 20 min at same temperature. The foamy solid was cool to 20-25°C and charged n-heptane (10 mL), stirred for 1 hr at same temperature. Solid was filtered and washed with n-heptane (2 mL), suck dried the solid for 10 min and dried the wet material under vacuum at 70-75°C for about 17 hrs to obtain the title compound. Wt: 396.2 mg.
  • Apalutamide (10 gm) and formic acid (15 mL) were added in to a round bottom flask at 20-25°C, heated the reaction mass to 60-65°C to get clear solution.
  • Reaction mass was cool to 20-25°C, and was added to pre cooled ammonia (300 mL) at 3-7°C. Stirred for about 30 min at this temperature and the precipitated solid was filtered and washed with ammonia (10 mL), suck dried the solid for 15 min and dried the wet material under vacuum at room temperature for about 2 hrs and then dried at 45-47°C for about 12 hrs to obtain the title compound.
  • Wt 8.52 gm.
  • Apalutamide (30.1 gm), methanol (45 mL) and acetonitrile (12 mL) were added in to a round bottom flask at 20-25°C, heated the reaction mass to 50-55°C to get clear solution.
  • carbon 3 gm
  • Reaction mass was filtered through celite bed and bed was washed with hot methanol (15 mL). Filterate was cool to 40-45°C, and was added to pre cooled ammonia (300 mL) at -13 to -12°C.
  • Example-26 Stability Study details of crystalline apalutamide Form L2: The following stability study data tables at different storage condition ensure that the crystalline apalutamide Form L2 of the present invention retained the same polymorphic and chemical identity at least up to Six months.
  • Apalutamide Form L2 is packed in a transparent Low density polyethylene (LDPE) bag with a strip seal along with nitrogen filling, which is again kept in a second transparent low density polyethylene bag with strip seal.
  • the LDPE bag is kept in to a triple laminated sunlight barrier with heat seal followed by in a high density polyethylene container and well closed.
  • Example-27 TABLE-II: Impurity profile of crystalline apalutamide Form L2 when stored at 25+2°C / 60+5% RH & 40+2°C / 75+5% RH:
  • apalutamide polymorphic Form L2 shows better solubility when compared to Form A and Form B.
  • Apalutamide Form A and Form B are known in the art and are prepared by the process disclosed in U.S. Patent No. 9,481,663.
  • Amorphous Form obtained according to the reference examples was analyzed by PXRD and is represented according to Fig. 18.

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Abstract

The present invention relates to novel crystalline polymorphic forms of apalutamide. The present invention also relates to processes for preparation of amorphous form of apalutamide and pharmaceutical composition containing the same.

Description

“POLYMORPHIC FORMS OF APALUTAMIDE AND ITS
PREPARATION THEREOF”
PRIORITY:
This application claims the benefit under Indian Provisional Application No. 201941020138 filed on May 21, 2019 entitled“Polymorphic forms of Apalutamide and its preparation thereof’, the content of which is incorporated by reference herein.
FIELD OF THE INVENTION
The present invention relates to novel crystalline polymorphic forms of apalutamide and its processes for preparation thereof. The present invention also relates to processes for preparation of amorphous form of apalutamide and pharmaceutical composition containing the same.
BACKGROUND OF THE INVENTION
Apalutamide (ARN-509), known as (4-[7-(6-Cyano-5-trifluoromethylpyridin-3-yl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide), has the following structure:
Figure imgf000002_0001
Apalutamide is marketed by Janssen Biotech under the trade name ERLEADA™ as 60 mg oral tablet in US and EP for the treatment of patients with non-metastatic castration- resistant prostate cancer.
U.S. Patent No. 8,445,507 (“the‘507 patent”) discloses androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases such as apalutamide and process for preparation thereof. The‘507 patent process involves purification of apalutamide by column chromatography using a mixture of dichloromethane and acetone (95:5) to obtain apalutamide as a white powder. However, the‘507 patent does not disclose any polymorphic information on resulted apalutamide.
U.S. Patent No. 9,481,663 (“the‘663 patent”) discloses crystalline forms including solvates of apalutamide such as apalutamide Form A (Isostructural solvate), apalutamide Form B, apalutamide Form C (isopropyl alcohol solvate), apalutamide Form D (tert-butyl methyl ether solvate), apalutamide Form E (dimethylsulfoxide solvate), apalutamide Form F, apalutamide Form G (2-methoxy ethanol solvate), apalutamide Form H, apalutamide Form I, apalutamide Form J (acetone solvate) and its characterization data by PXRD, DSC and TGA.
PCT publication No. 2016/124149 (“the‘149 publication”) discloses crystalline forms of apalutamide such as apalutamide Form I and apalutamide Form II and its characterization data by PXRD, DSC and TGA.
PCT publication No. 2018/112001 (“the 01 publication”) discloses crystalline forms of apalutamide such as apalutamide Form T1 (mono hydrate), apalutamide Form T2 (2- butanol solvate), apalutamide Form T3 (cyclohexanone solvate), apalutamide Form T4 (acetonitrile- water solvate), apalutamide Form T5 (ethylene glycol solvate), apalutamide Form T6 (isobutanol solvate), apalutamide Form T7 & Form T8 (methyl isobutyl ketone solvate), apalutamide Form T9 (formamide-water solvate), apalutamide Form T10 (methylene dichloride-water solvate), apalutamide Form Ti l (dihydrate), apalutamide Form T12 (dimethyl carbonate solvate), apalutamide Form T13 & Form T14 (E.A solvate), apalutamide Form T15 (methyl acetate solvate), apalutamide Form T16 (methyl ethyl ketone solvate), Form T17 (acetonitrile solvate) and its characterization data by PXRD.
PCT publication No. 2019/016747 (“the ‘747 publication”) discloses process for preparation of amorphous form of apalutamide from acetone, from a mixture of methylene chloride: ethanol, and from a mixture of methylene chloride: acetone. Further,‘747 publication discloses solid dispersion of amorphous apalutamide.
Indian application No.(S) 201741043701 (“the‘701 publication”), 201841002315 (“the ‘315 publication”), 201841030693 (“the ‘693 publication”) & 201841038834 (“the ‘834 publication”) discloses crystalline solvates of Apalutamide such as acetic acid solvate of Apalutamide (VK1), propionic acid solvate of Apalutamide (VK2), racemic propylene glycol solvate of Apalutamide (VK3), R-propylene glycol solvate of Apalutamide (VK4), S -propylene glycol solvate of Apalutamide (VK5), methyl acetate solvate of Apalutamide (VK6) and crystalline form of apalutamide (VK7), (VK8), (VK9), (VK10), (VK11), (VK12; and apalutamide co-crystal with 2,5-dihydroxy benzoic acid its characterization data by PXRD.
PCT publication No. 2019/135254 (“the‘254 publication”) discloses crystalline forms of apalutamide specifically: Form Ml, Form M2, Form M3, Form M4 (DMF hemi solvate), Form M5 (DMF solvate) & Form M6 (2-butanol solvate hydrate) and its characterization data by PXRD.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms and solvates, and to determine the stability, dissolution and flow properties of each polymorphic form.
Polymorphic forms and solvates of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms and solvates of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.
As per European Medicines Agency, apalutamide is a low aqueous solubility and high intestinal permeability. This low aqueous solubility of active substance is the main challenge in the formulation development and in order to improve the aqueous solubility of the active substance commercial product ERLEADA™ utilized amorphous form of apalutamide. However, even though the amorphous form has high aqueous solubility but the stability of the amorphous nature is less which is easily gets converted to less aqueous soluble crystalline form and to improve stability of the product the amorphous form was solid dispersed with excipients.
Further, generally amorphous form of the active substances prone to hold residual quantities of the solvents used in the processes and also possible contamination of the process impurities therefore always getting the amorphous form of the active substances is less pure and highly hygroscopic in nature. In order to minimize the contamination of residual solvents with the amorphous form, complete solvent evaporation methods such as spry drying process is utilized which is not industrially viable method for preparing pure amorphous form.
Apalutamide is one of the important drug available in the market for the treatment of non-metastatic castration-resistant prostate cancer. Hence, it’s important to discover new polymorphic forms of apalutamide, which may provide a new opportunity to improve the performance characteristics of a pharmaceutical product. There remains a need for novel polymorphic forms of apalutamide with improved characteristics. Further, there is a need to develop a process for preparing amorphous form of apalutamide where the cumbersome spray drying method is evaded.
Hence the main objective of the present invention is to provide novel crystalline form of apalutamide. Further, the present invention also relates to processes for preparation of amorphous form of apalutamide and pharmaceutical composition containing the same. SUMMARY OF THE INVENTION
The present invention encompasses novel crystalline polymorphic forms, solvates and hydrates of apalutamide, process for their preparation. The present invention also encompasses processes for the preparation of amorphous form of apalutamide with high product yield and quality, and greater stability.
In accordance with one embodiment, the present invention provides novel crystalline polymorphic forms of apalutamide or its solvates or its hydrates; which are designated herein as apalutamide Form-Ll, apalutamide Form-L2, apalutamide Form-L3, apalutamide Form-L4, apalutamide Form-L5, apalutamide Form-L6, apalutamide Form- L7, apalutamide Form-L8, apalutamide Form-L9, apalutamide Form-LlO, apalutamide Form-Ll 1, apalutamide Form-L12, apalutamide Form-L13 and apalutamide Form-L14.
In accordance with another embodiment, the present invention provides apalutamide Form-Ll.
In accordance with another embodiment, apalutamide Form-Ll of the present invention is an ethyl formate solvate.
In accordance with another embodiment, the present invention provides apalutamide Form-Ll characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 1.
In accordance with another embodiment, the present invention provides apalutamide Form-Ll characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 7.7, 8.1, 10.4, 10.7, 11.1, 11.4, 12.3, 12.5, 14.5, 15.2, 15.5, 16.0, 16.3, 16.9, 17.2, 18.0, 19.0, 19.4, 19.9, 20.7, 20.9, 21.3, 21.8, 22.1, 22.6, 22.7, 23.3, 23.9, 24.5, 25.0, 25.6, 26.2, 26.8, 27.1, 28.4, 28.8, 29.1, 29.7, 29.9, 30.8, 30.9, 31.4, 32.1, 33.0, 33.53, 34.0 and 34.9 ±0.2° 2Q.
In accordance with another embodiment, the present invention provides a process for the preparation of apalutamide Form-Ll, comprising:
a) providing a solution of apalutamide in ethyl formate at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding n-heptane to step b) reaction mass, and
d) isolating apalutamide Form-Ll.
In accordance with another embodiment, the present invention provides apalutamide Form-L2.
In accordance with another embodiment, apalutamide Form-L2 of the present invention is a hydrate. In accordance with another embodiment, the present invention provides apalutamide Form-L2 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 4.
In accordance with another embodiment, the present invention provides apalutamide Form-L2 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.8, 8.1, 10.4, 11.4, 12.2, 12.5, 14.2, 15.5, 16.0, 16.3, 16.7, 19.0, 19.3, 19.8, 20.1, 20.7, 21.3, 21.8, 22.6, 23.1, 23.3, 23.7, 24.0, 24.7, 25.0, 25.5, 26.2, 26.5, 26.7, 26.8, 27.6, 28.3, 29.0, 29.4, 29.9, 30.9, 31.1, 31.5, 32.5, 33.1, 33.4, 33.8, 34.7 and 35.1 ±0.2° 2Q.
In accordance with another embodiment, the present invention provides a process for the preparation of apalutamide Form-L2, comprising:
a) suspending apalutamide Form-Ll in ammonia at about 0°C to about 35°C, b) stirred the step a) suspension for about 10 min to about 4 hours and
c) isolating the apalutamide Form-L2.
In accordance with another embodiment, the present invention provides a process for the preparation of apalutamide Form-L2, comprising:
a) suspending apalutamide Form-Ll in ammonia at about 0°C to about 5°C, b) stirred the step a) suspension for about 10 min to about 2 hours and
c) isolating the apalutamide Form-L2.
In another embodiment, the present invention provides a process for the preparation of apalutamide Form-L2, comprising:
a) providing a solution of apalutamide in ethyl formate at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding n-heptane to step b) reaction mass, and
d) isolating apalutamide Form-Ll,
e) suspending apalutamide Form-Ll in ammonia at about 0°C to about 35°C, f) stirred the step e) suspension for about 10 min to about 4 hour, and
g) isolating apalutamide Form-L2.
In accordance with another embodiment, the present invention provides apalutamide Form-L3.
In accordance with another embodiment, apalutamide Form-L3 of the present invention is a formic acid and n-pentanol solvate.
In accordance with another embodiment, the present invention provides apalutamide Form-L3 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 5. In accordance with another embodiment, the present invention provides apalutamide Form-L3 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.7, 6.9, 7.1, 7.3, 9.4, 10.5, 11.1, 11.3, 11.8, 13.3, 14.1, 14.8, 15.3, 16.3, 16.4, 16.8, 18.4, 18.9, 20.1, 20.7, 21.2, 21.9, 22.9, 23.4, 23.7, 24.0, 24.5, 24.8, 25.2, 25.8, 26.4, 26.8, 27.8, 28.5, 29.9, 30.5, 31.3, 31.8, 32.7 and 33.3 ±0.2° 2Q.
In accordance with another embodiment, the present invention provides a process for the preparation of apalutamide Form-L3, comprising:
a) providing a solution of apalutamide in a mixture of formic acid and n-pentanol at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding n-pentanol to step b) reaction mass, and
d) isolating apalutamide Form- L3.
In accordance with another embodiment, the present invention provides apalutamide Form-L4.
In accordance with another embodiment, apalutamide Form-L4 of the present invention is a formic acid and isobutanol solvate.
In accordance with another embodiment, the present invention provides apalutamide Form-L4 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 6.
In accordance with another embodiment, the present invention provides apalutamide Form-L4 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.7, 6.8, 7.0, 7.2, 9.4, 10.5, 10.7, 11.3, 11.8, 13.3, 14.1, 14.7, 16.1, 16.3, 16.9, 18.2, 18.8, 20.0, 20.7, 21.3, 21.5, 22.0, 22.7, 23.9, 24.5, 24.7, 25.1, 25.8, 26.7, 27.9 and 29.8 ±0.2° 2Q.
In accordance with another embodiment, the present invention provides a process for the preparation of apalutamide Form-L4, comprising:
a) providing a solution of apalutamide in a mixture of formic acid and isobutanol at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding isobutanol to step b) reaction mass, and
d) isolating apalutamide Form-L4.
In accordance with another embodiment, the present invention provides apalutamide Form-L5.
In accordance with another embodiment, apalutamide Form-L5 of the present invention is a formic acid and cyclohexane solvate. In accordance with another embodiment, the present invention provides apalutamide Form-L5 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 7.
In accordance with another embodiment, the present invention provides apalutamide Form-L5 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.7, 6.7, 7.0, 7.3, 9.3, 10.4, 10.7, 11.0, 11.3, 11.5, 11.8, 13.2, 13.6, 14.0, 14.6,
15.1, 15.4, 16.1, 16.4, 16.8, 16.9, 17.4, 18.3, 18.8, 19.0, 20.0, 20.8, 21.2, 21.4, 22.1,
22.7, 23.3, 23.9, 24.5, 24.8, 25.2, 25.8, 26.6, 26.9, 27.5, 28.2, 29.6, 30.3, 31.1, 31.8,
32.6, 33.2 and 34.0 ±0.2° 2Q.
In accordance with another embodiment, the present invention provides a process for the preparation of apalutamide Form-L5, comprising:
a) providing a solution of apalutamide in formic acid at 30°C to reflux temperature, b) cooling the solution to below 30°C,
c) adding cyclohexane to step b) reaction mass, and
d) isolating apalutamide Form-L5.
In accordance with another embodiment, the present invention provides apalutamide Form-L6.
In accordance with another embodiment, apalutamide Form-L6 of the present invention is formic acid and cyclopentyl methyl ether solvate.
In accordance with another embodiment, the present invention provides apalutamide Form-L6 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 8.
In accordance with another embodiment, the present invention provides apalutamide Form-L6 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.8, 6.9, 7.4, 9.5, 10.5, 11.2, 11.9, 13.4, 14.2, 14.7, 15.2, 15.5, 16.2, 16.5, 17.0, 18.3, 18.8, 20.0, 20.4, 21.2, 21.4, 22.1, 22.5, 22.8, 23.5, 23.9, 24.6, 25.3, 25.7, 26.7, 27.0, 27.6, 28.5, 29.7, 31.2, 32.0, 32.7, 33.3 and 34.2 ±0.2° 2Q.
In accordance with another embodiment, the present invention provides a process for the preparation of apalutamide Form-L6, comprising:
a) providing a solution of apalutamide in formic acid at 30°C to reflux temperature, b) cooling the solution to below 30°C,
c) adding cyclopentyl methyl ether to step b) reaction mass, and
d) isolating apalutamide Form-L6.
In accordance with another embodiment, the present invention provides apalutamide Form-L7. In accordance with another embodiment, apalutamide Form-L7 of the present invention is a t-pentanol solvate.
In accordance with another embodiment, the present invention provides apalutamide Form-L7 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 9.
In accordance with another embodiment, the present invention provides apalutamide Form-L7 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.6, 7.0, 9.1, 10.5, 12.8, 13.7, 14.7, 15.7, 16.0, 16.5, 17.3, 18.0, 18.3, 19.0, 19.7, 20.2, 21.0, 21.2, 21.7, 22.1, 22.7, 22.9, 23.6, 23.9, 24.3, 24.6, 25.3, 25.8, 26.1, 26.7,
27.6, 28.1, 29.4, 29.6, 30.2, 30.7, 31.3, 32.0, 32.4, 33.6, 34.1 and 34.4 ±0.2° 2Q.
In accordance with another embodiment, the present invention provides a process for the preparation of apalutamide Form-L7, comprising:
a) providing a solution of apalutamide in a mixture of formic acid and t-pentanol at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding t-pentanol to step b) reaction mass, and
d) isolating apalutamide Form-L7.
In accordance with another embodiment, the present invention provides apalutamide Form-L8.
In accordance with another embodiment, apalutamide Form-L8 of the present invention is a t-butanol solvate.
In accordance with another embodiment, the present invention provides apalutamide Form-L8 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 10.
In accordance with another embodiment, the present invention provides apalutamide Form-L8 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.6, 7.0, 9.2, 10.6, 11.5, 12.8, 13.8, 14.8, 15.8, 16.0, 16.5, 17.4, 18.1, 18.5, 19.2,
19.7, 20.2, 21.1, 21.3, 21.7, 22.2, 22.9, 23.2, 23.8, 24.3, 24.6, 25.5, 25.9, 26.2, 26.9, 27.9, 28.2, 28.4, 29.5, 29.9, 30.5, 31.5, 32.2, 32.6, 33.7 and 34.6 ±0.2° 2Q.
In accordance with another embodiment, the present invention provides a process for the preparation of apalutamide Form-L8, comprising:
a) providing a solution of apalutamide in a mixture of formic acid and t-butanol at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding t-butanol to step b) reaction mass, and
d) isolating apalutamide Form-L8. In accordance with another embodiment, the present invention provides apalutamide Form-L9.
In accordance with another embodiment, apalutamide Form-L9 of the present invention is a sulfolane solvate.
In accordance with another embodiment, the present invention provides apalutamide Form-L9 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 11.
In accordance with another embodiment, the present invention provides apalutamide Form-L9 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.9, 5.5, 5.8, 8.8, 9.4, 10.0, 10.3, 11.3, 11.7, 12.0, 12.3, 12.8, 13.2, 13.9, 14.1,
14.9, 15.0, 15.7, 16.1, 16.7, 17.2, 17.7, 18.0, 18.6, 19.0, 19.3, 19.9, 20.1, 20.9, 21.3,
21.7, 22.5, 22.7, 23.1, 23.6, 24.1, 24.4, 24.6, 25.2, 25.8, 26.2, 26.4, 27.1, 27.6, 28.2,
28.8, 29.7, 30.1, 30.7, 30.9, 31.3, 32.1, 32.7, 33.5 and 34.1 ±0.2° 2Q.
In accordance with another embodiment, the present invention provides a process for the preparation of apalutamide Form-L9, comprising:
a) providing a solution of apalutamide in sulfolane at 30°C to reflux temperature, b) cooling the solution to below 30°C,
c) adding water to step b) reaction mass, and
d) isolating apalutamide Form-L9.
In accordance with another embodiment, the present invention provides apalutamide Form-LlO.
In accordance with another embodiment, apalutamide Form-LlO of the present invention is a trifluoroethanol solvate.
In accordance with another embodiment, the present invention provides apalutamide Form-LlO characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 12.
In accordance with another embodiment, the present invention provides apalutamide Form-LlO characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.6, 7.0, 9.3, 10.7, 11.6, 13.2, 14.0, 14.8, 15.0, 16.1, 16.7, 17.5, 18.5, 18.7, 19.5, 20.0, 20.5, 21.4, 21.6, 21.9, 22.9, 23.5, 24.1, 24.5, 24.8, 25.0, 25.5, 26.3, 27.2,
27.8, 28.3, 29.1, 30.3, 31.3, 32.2, 32.6, 33.4 and 34.9 ±0.2° 2Q.
In accordance with another embodiment, the present invention provides a process for the preparation of apalutamide Form-LlO, comprising:
a) providing a solution of apalutamide in trifluoroethanol at 30°C to reflux temperature,
b) cooling the solution to below 30°C, c) adding diisopropylether to step b) reaction mass, and
d) isolating apalutamide Form-LlO.
In accordance with another embodiment, the present invention provides apalutamide Form-Ll l.
In accordance with another embodiment, apalutamide Form-Ll l of the present invention is N-methyl-2-pyrrolidone solvate.
In accordance with another embodiment, the present invention provides apalutamide Form-Ll l characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 13.
In accordance with another embodiment, the present invention provides apalutamide Form-Ll l characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.2, 5.0, 6.9, 8.2, 8.5, 9.1, 9.4, 10.4, 10.8, 11.6, 12.0, 12.5, 12.8, 13.3, 14.9,
15.3, 15.5, 15.7, 16.1, 16.3, 16.6, 16.9, 17.1, 17.4, 18.2, 18.7, 19.2, 19.5, 20.0, 20.5,
20.8, 21.2, 21.9, 22.2, 22.8, 23.2, 23.7, 24.2, 24.9, 25.3, 25.5, 26.4, 27.7, 28.1, 29.1,
29.6, 30.5, 31.0, 32.5, 33.1 and 33.6 ±0.2° 2Q.
In accordance with another embodiment, the present invention provides a process for the preparation of apalutamide Form-Ll 1, comprising:
a) providing a solution of apalutamide in a mixture of N-methyl-2-pyrrolidone and methyl tert-butyl ether at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding methyl tert-butyl ether to step b) reaction mass, and
d) isolating apalutamide Form-Ll 1.
In accordance with another embodiment, the present invention provides apalutamide Form-L12.
In accordance with another embodiment, apalutamide Form-L12 of the present invention is N-methyl-2-pyrrolidone solvate.
In accordance with another embodiment, the present invention provides apalutamide Form-Ll 2 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 14.
In accordance with another embodiment, the present invention provides apalutamide Form-Ll 2 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.1, 4.5, 7.7, 8.0, 8.3, 8.8, 9.1, 9.6, 10.4, 11.0, 11.8, 12.4, 13.1, 13.7, 14.4, 14.6,
15.4, 15.6, 16.1, 16.5, 17.2, 17.8, 18.0, 18.3, 18.9, 19.9, 20.3, 20.5, 20.7, 21.0, 21.1,
21.4, 22.0, 22.4, 22.9, 23.3, 23.9, 24.5, 25.0, 25.1, 25.6, 26.4, 27.1, 27.9, 28.5, 29.0, 30.1, 30.9, 31.5, 32.7, 33.2, 33.9 and 34.7 ±0.2° 2Q. In accordance with another embodiment, the present invention provides a process for the preparation of apalutamide Form-L12, comprising:
a) providing a solution of apalutamide in N-methyl-2-pyrrolidone at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding methyl tert-butyl ether to step b) reaction mass, and
d) isolating apalutamide Form-L12.
In accordance with another embodiment, the present invention provides apalutamide Form-L13.
In accordance with another embodiment, apalutamide Form-L13 of the present invention is N-methyl-2-pyrrolidone solvate.
In accordance with another embodiment, the present invention provides apalutamide Form-L13 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 15.
In accordance with another embodiment, the present invention provides apalutamide Form-L13 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 3.9, 4.3, 4.9, 6.4, 7.8, 8.1, 8.6, 9.4, 10.0, 10.7, 12.0, 12.2, 12.9, 13.4, 14.4, 14.8,
15.5, 15.7, 16.2, 16.6, 17.2, 17.6, 17.8, 18.6, 18.9, 19.6, 20.1, 20.8, 21.7, 22.0, 22.7,
23.6, 24.6, 24.9, 25.7, 26.1, 26.8, 27.9, 28.7, 29.2, 30.0, 30.6, 32.4, 33.2 and 33.8 ±0.2° 2Q.
In accordance with another embodiment, the present invention provides a process for preparation of apalutamide Form-L13, the process comprising: drying crystalline apalutamide Form LI 3 at a temperature of about 60°C to about 70°C.
In accordance with another embodiment, the present invention provides apalutamide Form-L14.
In accordance with another embodiment, apalutamide Form-L14 of the present invention is N-methyl-2-pyrrolidone solvate.
In accordance with another embodiment, the present invention provides apalutamide Form-L14 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 16.
In accordance with another embodiment, the present invention provides apalutamide Form-L14 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 3.9, 4.3, 6.6, 7.6, 7.9, 8.1, 8.7, 9.5, 10.2, 10.8, 11.4, 11.9, 12.3, 13.0, 13.5, 14.2, 14.5, 14.8, 15.2, 15.5, 15.9, 16.3, 17.1, 17.3, 17.6, 17.9, 18.2, 18.6, 19.0, 19.4, 19.7, 20.2, 21.0, 21.7, 22.1, 22.8, 23.8, 24.4, 24.9, 25.5, 25.7, 26.2, 26.3, 26.9, 28.1, 28.4, 28.8, 29.3, 30.0, 30.6, 31.9, 32.6 and 33.8 ±0.2° 2Q. In accordance with another embodiment, the present invention provides a process for the preparation of apalutamide Form-L14, comprising:
a) providing a solution of apalutamide in a mixture of N-methyl-2-pyrrolidone and methyl tert-butyl ether at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding methyl tert-butyl ether to step b) reaction mass, and
d) isolating apalutamide Form-L14.
In accordance with another embodiment, the present invention provides crystalline forms of apalutamide, characterized by X-Ray diffraction (XRD) having one or more peaks selected from the group consisting of:
4.7, 6.9, 7.1, 7.3, 9.4, 10.5, 11.1, 11.3, 11.8, 13.3, 14.1, 14.8, 15.3, 16.3, 16.4, 16.8,
18.4, 18.9, 20.1, 20.7, 21.2, 21.9, 22.9, 23.4, 23.7, 24.0, 24.5, 24.8, 25.2, 25.8,
26.4, 26.8, 27.8, 28.5, 29.9, 30.5, 31.3, 31.8, 32.7 and 33.3 ±0.2° 2Q (Form L3);
4.7, 6.8, 7.0, 7.2, 9.4, 10.5, 10.7, 11.3, 11.8, 13.3, 14.1, 14.7, 16.1, 16.3, 16.9, 18.2, 18.8, 20.0, 20.7, 21.3, 21.5, 22.0, 22.7, 23.9, 24.5, 24.7, 25.1, 25.8, 26.7, 27.9 and 29.8 ±0.2° 2Q (Form L4);
4.7, 6.7, 7.0, 7.3, 9.3, 10.4, 10.7, 11.0, 11.3, 11.5, 11.8, 13.2, 13.6, 14.0, 14.6, 15.1,
15.4, 16.1, 16.4, 16.8, 16.9, 17.4, 18.3, 18.8, 19.0, 20.0, 20.8, 21.2, 21.4, 22.1,
22.7, 23.3, 23.9, 24.5, 24.8, 25.2, 25.8, 26.6, 26.9, 27.5, 28.2, 29.6, 30.3, 31.1,
31.8, 32.6, 33.2 and 34.0 ±0.2° 2Q (Form L5);
4.8, 6.9, 7.4, 9.5, 10.5, 11.2, 11.9, 13.4, 14.2, 14.7, 15.2, 15.5, 16.2, 16.5, 17.0,
18.3, 18.8, 20.0, 20.4, 21.2, 21.4, 22.1, 22.5, 22.8, 23.5, 23.9, 24.6, 25.3, 25.7,
26.7, 27.0, 27.6, 28.5, 29.7, 31.2, 32.0, 32.7, 33.3 and 34.2 ±0.2° 2Q (Form L6);
4.6, 7.0, 9.1, 10.5, 12.8, 13.7, 14.7, 15.7, 16.0, 16.5, 17.3, 18.0, 18.3, 19.0, 19.7, 20.2, 21.0, 21.2, 21.7, 22.1, 22.7, 22.9, 23.6, 23.9, 24.3, 24.6, 25.3, 25.8, 26.1, 26.7, 27.6, 28.1, 29.4, 29.6, 30.2, 30.7, 31.3, 32.0, 32.4, 33.6, 34.1 and 34.4 ±0.2° 2Q (Form L7);
4.6, 7.0, 9.2, 10.6, 11.5, 12.8, 13.8, 14.8, 15.8, 16.0, 16.5, 17.4, 18.1, 18.5, 19.2, 19.7, 20.2, 21.1, 21.3, 21.7, 22.2, 22.9, 23.2, 23.8, 24.3, 24.6, 25.5, 25.9, 26.2, 26.9, 27.9, 28.2, 28.4, 29.5, 29.9, 30.5, 31.5, 32.2, 32.6, 33.7 and 34.6 ±0.2° 2Q (Form L8);
4.9, 5.5, 5.8, 8.8, 9.4, 10.0, 10.3, 11.3, 11.7, 12.0, 12.3, 12.8, 13.2, 13.9, 14.1, 14.9, 15.0, 15.7, 16.1, 16.7, 17.2, 17.7, 18.0, 18.6, 19.0, 19.3, 19.9, 20.1, 20.9, 21.3, 21.7, 22.5, 22.7, 23.1, 23.6, 24.1, 24.4, 24.6, 25.2, 25.8, 26.2, 26.4, 27.1, 27.6, 28.2, 28.8, 29.7, 30.1, 30.7, 30.9, 31.3, 32.1, 32.7, 33.5 and 34.1 ±0.2° 2Q (Form L9); 4.6, 7.0, 9.3, 10.7, 11.6, 13.2, 14.0, 14.8, 15.0, 16.1, 16.7, 17.5, 18.5, 18.7, 19.5, 20.0, 20.5, 21.4, 21.6, 21.9, 22.9, 23.5, 24.1, 24.5, 24.8, 25.0, 25.5, 26.3, 27.2,
27.8, 28.3, 29.1, 30.3, 31.3, 32.2, 32.6, 33.4 and 34.9 ±0.2° 2Q (Form L10);
4.2, 5.0, 6.9, 8.2, 8.5, 9.1, 9.4, 10.4, 10.8, 11.6, 12.0, 12.5, 12.8, 13.3, 14.9, 15.3, 15.5, 15.7, 16.1, 16.3, 16.6, 16.9, 17.1, 17.4, 18.2, 18.7, 19.2, 19.5, 20.0, 20.5,
20.8, 21.2, 21.9, 22.2, 22.8, 23.2, 23.7, 24.2, 24.9, 25.3, 25.5, 26.4, 27.7, 28.1, 29.1, 29.6, 30.5, 31.0, 32.5, 33.1 and 33.6 ±0.2° 2Q (Form Ll l);
4.1, 4.5, 7.7, 8.0, 8.3, 8.8, 9.1, 9.6, 10.4, 11.0, 11.8, 12.4, 13.1, 13.7, 14.4, 14.6,
15.4, 15.6, 16.1, 16.5, 17.2, 17.8, 18.0, 18.3, 18.9, 19.9, 20.3, 20.5, 20.7, 21.0,
21.1, 21.4, 22.0, 22.4, 22.9, 23.3, 23.9, 24.5, 25.0, 25.1, 25.6, 26.4, 27.1, 27.9,
28.5, 29.0, 30.1, 30.9, 31.5, 32.7, 33.2, 33.9 and 34.7 ±0.2° 2Q (Form L12);
3.9, 4.3, 4.9, 6.4, 7.8, 8.1, 8.6, 9.4, 10.0, 10.7, 12.0, 12.2, 12.9, 13.4, 14.4, 14.8,
15.5, 15.7, 16.2, 16.6, 17.2, 17.6, 17.8, 18.6, 18.9, 19.6, 20.1, 20.8, 21.7, 22.0,
22.7, 23.6, 24.6, 24.9, 25.7, 26.1, 26.8, 27.9, 28.7, 29.2, 30.0, 30.6, 32.4, 33.2 and 33.8 ±0.2° 2Q (Form L13); and
3.9, 4.3, 6.6, 7.6, 7.9, 8.1, 8.7, 9.5, 10.2, 10.8, 11.4, 11.9, 12.3, 13.0, 13.5, 14.2,
14.5, 14.8, 15.2, 15.5, 15.9, 16.3, 17.1, 17.3, 17.6, 17.9, 18.2, 18.6, 19.0, 19.4,
19.7, 20.2, 21.0, 21.7, 22.1, 22.8, 23.8, 24.4, 24.9, 25.5, 25.7, 26.2, 26.3, 26.9,
28.1, 28.4, 28.8, 29.3, 30.0, 30.6, 31.9, 32.6 and 33.8 ±0.2° 2Q (Form L14).
In accordance with another embodiment, the present invention provides a process for preparation of crystalline form of apalutamide, wherein the crystalline forms selected from Form L3, Form L4, Form L5, Form L6, Form L7, Form L8, Form L9, Form L10, Form LI 1, Form L12 and Form 14, comprising:
a) providing a solution of apalutamide in a solvent or a mixture thereof at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding anti-solvent to step b) reaction mass, and
d) isolating crystalline form of apalutamide;
wherein the apalutamide Form L3 is obtained when step a) solvent is a mixture of formic acid and n-pentanol, and step c) anti-solvent is n-pentanol; wherein the apalutamide Form L4 is obtained, when step a) solvent is a mixture of formic acid and isobutanol, and step c) anti-solvent is isobutanol; wherein the apalutamide Form L5 is obtained, when step a) solvent is formic acid, and step c) anti-solvent is cyclohexane; wherein the apalutamide Form L6 is obtained, when step a) solvent is formic acid, and step c) anti-solvent is cyclopentyl methyl ether; wherein the apalutamide Form L7 is obtained, when step a) solvent is a mixture of formic acid and t-pentanol, and step c) anti- solvent is t-pentanol; wherein the apalutamide Form L8 is obtained, when step a) solvent is a mixture of formic acid and t-butanol, and step c) anti-solvent is t-butanol; wherein the apalutamide Form L9 is obtained, when step a) solvent is sulfolane, and step c) anti-solvent is water; wherein the apalutamide Form L10 is obtained, when step a) solvent is trifluoroethanol, and step c) anti-solvent is diisopropylether; wherein the apalutamide Form Ll l is obtained, when step a) solvent is a mixture of N- methyl-2-pyrrolidone and methyl tert-butyl ether, and step c) anti- solvent is methyl tert- butyl ether; wherein the apalutamide Form L12 is obtained, when step a) solvent is N-methyl-2- pyrrolidone, and step c) anti-solvent is methyl tert-butyl ether; and wherein the apalutamide Form L14 is obtained, when step a) solvent is a mixture of N- methyl-2-pyrrolidone and methyl tert-butyl ether, and step c) anti- solvent is methyl tert- butyl ether.
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of apalutamide, comprising:
a) providing a solution of apalutamide in one or more solvents, and
b) isolating amorphous apalutamide.
wherein the one or more solvents are selected from the group consisting of ethyl acetate, acetonitrile, methyl ethyl ketone, methanol and mixture thereof.
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of apalutamide, comprising:
a) providing a solution of apalutamide in one or more solvents,
b) concentrating the step a) solution, and
c) adding suitable another solvent to separating the amorphous apalutamide;
wherein the one or more solvents are selected from the group consisting of ethyl acetate, acetonitrile, methyl ethyl ketone, methanol and mixture thereof; and suitable another solvent is non-polar solvent.
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of apalutamide, comprising: a) providing a solution of apalutamide in one or more solvents, b) adding a suitable anti-solvent to the step a) solution or vice-versa; and c) isolating the amorphous apalutamide.
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of apalutamide, comprising:
a) providing a solution of apalutamide in one or more solvents,
b) adding a suitable anti-solvent to the step a) solution or vice-versa; and c) isolating the amorphous form;
wherein the one or more solvents are selected from the group consisting of formic acid, methanol, acetonitrile and mixture thereof; and wherein the suitable anti-solvent is water, ammonia and mixtures thereof.
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of apalutamide, the process comprising: drying apalutamide in the form of either solvate or hydrates thereof at a suitable temperature.
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of apalutamide, the process comprising: drying crystalline apalutamide Form LI at a suitable temperature.
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of apalutamide, the process comprising: drying crystalline apalutamide Form LI at a temperature of about 85°C to about 100°C.
In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising amorphous or novel crystalline forms of apalutamide prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.
Figure 1 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-Ll.
Figure 2 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form obtained according to Example - 2.
Figure 3 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form obtained according to Example - 4. Figure 4 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form L2.
Figure 5 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-L3.
Figure 6 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-L4.
Figure 7 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-L5.
Figure 8 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-L6.
Figure 9 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-L7.
Figure 10 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-L8.
Figure 11 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-L9.
Figure 12 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-LlO.
Figure 13 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-Ll 1.
Figure 14 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-L12.
Figure 15 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-Ll 3.
Figure 16 is the characteristic powder X-ray diffraction (PXRD) pattern of crystalline apalutamide Form-L14.
Figure 17 is the characteristic powder X-ray diffraction (PXRD) pattern of amorphous apalutamide.
Figure 18 is the characteristic powder X-ray diffraction (PXRD) pattern of amorphous apalutamide according to Reference Example. DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of amorphous from of apalutamide and pharmaceutical compositions containing the same. The present invention also relates to novel crystalline polymorphic forms of apalutamide and its processes for preparation thereof and its use an intermediate for preparation of amorphous apalutamide.
The amorphous and crystalline apalutamide obtained by process of the present invention are characterized by X-ray powder diffraction (XRPD) pattern, differential scanning calorimetric (DSC) and thermo gravimetric analysis (TGA).
The X-Ray powder diffraction data reported herein is analyzed using PANalytical X’ per pro X-ray powder Diffractometer equipped with a Cu-anode ([l] =1.54 Angstrom), X-ray source operated at 45kV, 40 mA. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=3-45°20; step size=0.01°; and Time per step=50 sec.
The differential scanning calorimetric data reported herein is analyzed in hermitically sealed aluminium pan, with a blank hermitically sealed aluminium pan as the reference and were obtained using DSC (DSC Q200, TA instrumentation, Waters) at a scan rate of 10°C per minute with an Indium standard.
The thermo gravimetric analysis data reported herein is analyzed using TGA Q500 in platinum pan with a temperature rise of about 10°C/min in the range of about room temperature to about 250°C.
In one embodiment, the present invention provides novel crystalline polymorphic form of apalutamide; which are designated herein as apalutamide Form-Ll, apalutamide Form-L2, apalutamide Form-L3, apalutamide Form-L4, apalutamide Form-L5, apalutamide Form-L6, apalutamide Form-L7, apalutamide Form-L8, apalutamide Form- L9, apalutamide Form-LlO, apalutamide Form-Ll 1, apalutamide Form-L12, apalutamide Form-Ll 3 and apalutamide Form-Ll 4.
As used herein the starting material apalutamide in the present invention for the preparation of novel polymorphs form LI to L14 is known in the art and can be prepared by any known methods, for example apalutamide may be synthesized as disclosed in U.S. Patent No. 8,445,507.
In another embodiment, the present invention provides apalutamide Form-Ll.
In another embodiment, the apalutamide Form-Ll of the present invention is an ethyl formate solvate. In another embodiment, the present invention provides apalutamide Form-Ll characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 1.
In another embodiment, the present invention provides apalutamide Form-Ll characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about
7.7, 8.1, 10.4, 10.7, 11.1, 11.4, 12.3, 12.5, 14.5, 15.2, 15.5, 16.0, 16.3, 16.9, 17.2, 18.0, 19.0, 19.4, 19.9, 20.7, 20.9, 21.3, 21.8, 22.1, 22.6, 22.7, 23.3, 23.9, 24.5, 25.0, 25.6, 26.2, 26.8, 27.1, 28.4, 28.8, 29.1, 29.7, 29.9, 30.8, 30.9, 31.4, 32.1, 33.0, 33.53, 34.0 and 34.9 ±0.2° 2Q.
In another embodiment, the present invention provides a process for the preparation of apalutamide Form-Ll, comprising:
a) providing a solution of apalutamide in ethyl formate at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding n-heptane to step b) reaction mass, and
d) isolating apalutamide Form-Ll.
The aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in ethyl formate at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution; preferably to about 50°C to about 60°C. If the reaction mass is not clear, then added ethyl formate. Then, the resultant reaction solution can be cooled to below 30°C; preferably to about 10°C to about 20°C.
The step c) of aforementioned process involves, adding n-heptane to step b) reaction mass at below 30°C; preferably to about 10°C to about 20°C. Then the apalutamide Form-Ll can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at room temperature i.e about 25°C to about 30°C for sufficient period of time; preferably for a period of about 30 min to about 2 hours.
In another embodiment, the present invention provides apalutamide Form-L2.
In another embodiment, the apalutamide Form-L2 of the present invention is a hydrate.
In another embodiment, the present invention provides apalutamide Form-L2 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 4.
In another embodiment, the present invention provides apalutamide Form-L2 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about
4.8, 8.1, 10.4, 11.4, 12.2, 12.5, 14.2, 15.5, 16.0, 16.3, 16.7, 19.0, 19.3, 19.8, 20.1, 20.7, 21.3, 21.8, 22.6, 23.1, 23.3, 23.7, 24.0, 24.7, 25.0, 25.5, 26.2, 26.5, 26.7, 26.8, 27.6,
28.3, 29.0, 29.4, 29.9, 30.9, 31.1, 31.5, 32.5, 33.1, 33.4, 33.8, 34.7 and 35.1 ±0.2° 2Q.
In another embodiment, the present invention provides a process for the preparation of apalutamide Form-L2, comprising:
a) suspending apalutamide Form-Ll in ammonia at about 0°C to about 35°C, b) stirred the step a) suspension for about 10 min to about 4 hour, and
c) isolating apalutamide Form-L2.
The aforementioned process of suspending apalutamide Form-Ll includes first suspending or mixing apalutamide in ammonia at about 0°C to about 35°C; preferably at about 0°C to about 10°C, more preferably at about 0°C to about 5°C. Then, the resultant suspension is allowed to stir for about 10 min to about 4 hour at same temperature; preferably for about 10 min to about 2 hour.
Then the apalutamide Form-L2 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 35°C to about 55°C for sufficient period of time; preferably for a period of about 5 hours to about 20 hours.
In another embodiment, the present invention provides a process for the preparation of apalutamide Form-L2, comprising:
h) providing a solution of apalutamide in ethyl formate at 30°C to reflux temperature,
i) cooling the solution to below 30°C,
j) adding n-heptane to step b) reaction mass, and
k) isolating apalutamide Form-Ll,
l) suspending apalutamide Form-Ll in ammonia at about 0°C to about 35°C, m) stirred the step e) suspension for about 10 min to about 4 hour, and
n) isolating apalutamide Form-L2.
The aforementioned process involves first preparing the apalutamide Form-Ll as per procedure described as above embodiments and converting the apalutamide Form LI into apalutamide Form L2 as per the procedure described as just above embodiment.
In another embodiment, the present invention provides apalutamide Form-L3.
In another embodiment, the apalutamide Form-L3 of the present invention is formic acid and n-pentanol solvate.
In another embodiment, the present invention provides apalutamide Form-L3 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 5. In another embodiment, the present invention provides apalutamide Form-L3 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.7, 6.9, 7.1, 7.3, 9.4, 10.5, 11.1, 11.3, 11.8, 13.3, 14.1, 14.8, 15.3, 16.3, 16.4, 16.8, 18.4, 18.9, 20.1, 20.7, 21.2, 21.9, 22.9, 23.4, 23.7, 24.0, 24.5, 24.8, 25.2, 25.8, 26.4,
26.8, 27.8, 28.5, 29.9, 30.5, 31.3, 31.8, 32.7 and 33.3 ±0.2° 2Q.
In another embodiment, the present invention provides a process for the preparation of apalutamide Form-L3, comprising:
a) providing a solution of apalutamide in a mixture of formic acid and n-pentanol at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding n-pentanol to step b) reaction mass, and
d) isolating apalutamide Form- L3.
The aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in a mixture of formic acid and n-pentanol at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
The step c) of aforementioned process involves, adding n-pentanol to step b) reaction mass at below 30°C. Then the apalutamide Form-L3 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 45°C to about 60°C for sufficient period of time; preferably for a period of about 10 to about 20 hours.
In another embodiment, the present invention provides apalutamide Form-L4.
In another embodiment, the apalutamide Form-L4 of the present invention is formic acid and isobutanol solvate.
In another embodiment, the present invention provides apalutamide Form-L4 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 6.
In another embodiment, the present invention provides apalutamide Form-L4 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.7, 6.8, 7.0, 7.2, 9.4, 10.5, 10.7, 11.3, 11.8, 13.3, 14.1, 14.7, 16.1, 16.3, 16.9, 18.2,
18.8, 20.0, 20.7, 21.3, 21.5, 22.0, 22.7, 23.9, 24.5, 24.7, 25.1, 25.8, 26.7, 27.9 and 29.8 ±0.2° 2Q.
In another embodiment, the present invention provides a process for the preparation of apalutamide Form-L4, comprising: a) providing a solution of apalutamide in a mixture of formic acid and isobutanol at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding isobutanol to step b) reaction mass, and
d) isolating apalutamide Form-L4.
The aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in a mixture of formic acid and isobutanol at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
The step c) of aforementioned process involves, adding isobutanol to step b) reaction mass at below 30°C. Then the apalutamide Form-L4 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 45°C to about 60°C for sufficient period of time; preferably for a period of about 15 to about 25 hours.
In another embodiment, the present invention provides apalutamide Form-L5.
In another embodiment, the apalutamide Form-L5 of the present invention is formic acid and cyclohexane solvate.
In another embodiment, the present invention provides apalutamide Form-L5 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 7.
In another embodiment, the present invention provides apalutamide Form-L5 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.7, 6.7, 7.0, 7.3, 9.3, 10.4, 10.7, 11.0, 11.3, 11.5, 11.8, 13.2, 13.6, 14.0, 14.6, 15.1, 15.4, 16.1, 16.4, 16.8, 16.9, 17.4, 18.3, 18.8, 19.0, 20.0, 20.8, 21.2, 21.4, 22.1, 22.7, 23.3, 23.9, 24.5, 24.8, 25.2, 25.8, 26.6, 26.9, 27.5, 28.2, 29.6, 30.3, 31.1, 31.8, 32.6, 33.2 and 34.0 ±0.2° 2Q.
In another embodiment, the present invention provides a process for the preparation of apalutamide Form-L5, comprising:
a) providing a solution of apalutamide in formic acid at 30°C to reflux temperature, b) cooling the solution to below 30°C,
c) adding cyclohexane to step b) reaction mass, and
d) isolating apalutamide Form-L5.
The aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in formic acid at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
The step c) of aforementioned process involves, adding cyclohexane to step b) reaction mass at below 30°C. Then the apalutamide Form-L5 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 50°C to about 70°C for sufficient period of time; preferably for a period of about 15 to about 25 hours.
In another embodiment, the present invention provides apalutamide Form-L6.
In another embodiment, the apalutamide Form-L6 of the present invention is formic acid and cyclopentyl methyl ether solvate.
In another embodiment, the present invention provides apalutamide Form-L6 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 8.
In another embodiment, the present invention provides apalutamide Form-L6 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about
4.8, 6.9, 7.4, 9.5, 10.5, 11.2, 11.9, 13.4, 14.2, 14.7, 15.2, 15.5, 16.2, 16.5, 17.0, 18.3,
18.8, 20.0, 20.4, 21.2, 21.4, 22.1, 22.5, 22.8, 23.5, 23.9, 24.6, 25.3, 25.7, 26.7, 27.0, 27.6, 28.5, 29.7, 31.2, 32.0, 32.7, 33.3 and 34.2 ±0.2° 2Q.
In another embodiment, the present invention provides a process for the preparation of apalutamide Form-L6, comprising:
a) providing a solution of apalutamide in formic acid at 30°C to reflux temperature, b) cooling the solution to below 30°C,
c) adding cyclopentyl methyl ether to step b) reaction mass, and
d) isolating apalutamide Form-L6.
The aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in formic acid at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
The step c) of aforementioned process involves, adding cyclopentyl methyl ether to step b) reaction mass at below 30°C. Then the apalutamide Form-L6 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 45°C to about 60°C for sufficient period of time; preferably for a period of about 10 to about 20 hours.
In another embodiment, the present invention provides apalutamide Form-L7. In another embodiment, the apalutamide Form-L7 of the present invention is t-pentanol solvate.
In another embodiment, the present invention provides apalutamide Form-L7 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 9.
In another embodiment, the present invention provides apalutamide Form-L7 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.6, 7.0, 9.1, 10.5, 12.8, 13.7, 14.7, 15.7, 16.0, 16.5, 17.3, 18.0, 18.3, 19.0, 19.7, 20.2, 21.0, 21.2, 21.7, 22.1, 22.7, 22.9, 23.6, 23.9, 24.3, 24.6, 25.3, 25.8, 26.1, 26.7, 27.6, 28.1, 29.4, 29.6, 30.2, 30.7, 31.3, 32.0, 32.4, 33.6, 34.1 and 34.4 ±0.2° 2Q.
In another embodiment, the present invention provides a process for the preparation of apalutamide Form-L7, comprising:
a) providing a solution of apalutamide in a mixture of formic acid and t-pentanol at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding t-pentanol to step b) reaction mass, and
d) isolating apalutamide Form-L7.
The aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in a mixture of formic acid and t-petanol at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
The step c) of aforementioned process involves, adding t-pentanol to step b) reaction mass at below 30°C. Then the apalutamide Form-L7 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 50°C to about 70°C for sufficient period of time; preferably for a period of about 15 to about 25 hours.
In another embodiment, the present invention provides apalutamide Form-L8.
In another embodiment, the apalutamide Form-L8 of the present invention is t-butanol solvate.
In another embodiment, the present invention provides apalutamide Form-L8 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 10.
In another embodiment, the present invention provides apalutamide Form-L8 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.6, 7.0, 9.2, 10.6, 11.5, 12.8, 13.8, 14.8, 15.8, 16.0, 16.5, 17.4, 18.1, 18.5, 19.2, 19.7,
20.2, 21.1, 21.3, 21.7, 22.2, 22.9, 23.2, 23.8, 24.3, 24.6, 25.5, 25.9, 26.2, 26.9, 27.9,
28.2, 28.4, 29.5, 29.9, 30.5, 31.5, 32.2, 32.6, 33.7 and 34.6 ±0.2° 2Q.
In another embodiment, the present invention provides a process for the preparation of apalutamide Form-L8, comprising:
a) providing a solution of apalutamide in a mixture of formic acid and t-butanol at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding t-butanol to step b) reaction mass, and
d) isolating apalutamide Form-L8.
The aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in a mixture of formic acid and t-butanol at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
The step c) of aforementioned process involves, adding t-butanol to step b) reaction mass at below 30°C. Then the apalutamide Form-L8 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 50°C to about 70°C for sufficient period of time; preferably for a period of about 15 to about 25 hours.
In another embodiment, the present invention provides apalutamide Form-L9.
In another embodiment, the apalutamide Form-L9 of the present invention is sulfolane solvate.
In another embodiment, the present invention provides apalutamide Form-L9 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 11.
In another embodiment, the present invention provides apalutamide Form-L9 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.9, 5.5, 5.8, 8.8, 9.4, 10.0, 10.3, 11.3, 11.7, 12.0, 12.3, 12.8, 13.2, 13.9, 14.1, 14.9, 15.0, 15.7, 16.1, 16.7, 17.2, 17.7, 18.0, 18.6, 19.0, 19.3, 19.9, 20.1, 20.9, 21.3, 21.7, 22.5, 22.7, 23.1, 23.6, 24.1, 24.4, 24.6, 25.2, 25.8, 26.2, 26.4, 27.1, 27.6, 28.2, 28.8, 29.7, 30.1, 30.7, 30.9, 31.3, 32.1, 32.7, 33.5 and 34.1 ±0.2° 2Q.
In another embodiment, the present invention provides a process for the preparation of apalutamide Form-L9, comprising:
a) providing a solution of apalutamide in sulfolane at 30°C to reflux temperature, b) cooling the solution to below 30°C, c) adding water to step b) reaction mass, and
d) isolating apalutamide Form-L9.
The aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in sulfolane at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
The step c) of aforementioned process involves, adding water to step b) reaction mass at below 30°C. Then the apalutamide Form-L9 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 50°C to about 70°C for sufficient period of time; preferably for a period of about 15 to about 25 hours.
In another embodiment, the present invention provides apalutamide Form-LlO.
In another embodiment, the apalutamide Form-LlO of the present invention is trifluoroethanol solvate.
In another embodiment, the present invention provides apalutamide Form-LlO characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 12.
In another embodiment, the present invention provides apalutamide Form-LlO characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.6, 7.0, 9.3, 10.7, 11.6, 13.2, 14.0, 14.8, 15.0, 16.1, 16.7, 17.5, 18.5, 18.7, 19.5, 20.0, 20.5, 21.4, 21.6, 21.9, 22.9, 23.5, 24.1, 24.5, 24.8, 25.0, 25.5, 26.3, 27.2, 27.8, 28.3, 29.1, 30.3, 31.3, 32.2, 32.6, 33.4 and 34.9 ±0.2° 2Q.
In another embodiment, the present invention provides a process for the preparation of apalutamide Form-LlO, comprising:
a) providing a solution of apalutamide in trifluoroethanol at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding diisopropylether to step b) reaction mass, and
d) isolating apalutamide Form-LlO.
The aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in trifluoroethanol at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
The step c) of aforementioned process involves, adding diisopropylether to step b) reaction mass at below 30°C. Then the apalutamide Form-LlO can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 45 °C to about 60°C for sufficient period of time; preferably for a period of about 15 to about 20 hours.
In another embodiment, the present invention provides apalutamide Form-Ll 1.
In another embodiment, the apalutamide Form-Ll 1 of the present invention is N- methyl-2-pyrrolidone solvate.
In another embodiment, the present invention provides apalutamide Form-Ll 1 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 13.
In another embodiment, the present invention provides apalutamide Form-Ll 1 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.2, 5.0, 6.9, 8.2, 8.5, 9.1, 9.4, 10.4, 10.8, 11.6, 12.0, 12.5, 12.8, 13.3, 14.9, 15.3, 15.5, 15.7, 16.1, 16.3, 16.6, 16.9, 17.1, 17.4, 18.2, 18.7, 19.2, 19.5, 20.0, 20.5, 20.8, 21.2, 21.9, 22.2, 22.8, 23.2, 23.7, 24.2, 24.9, 25.3, 25.5, 26.4, 27.7, 28.1, 29.1, 29.6, 30.5, 31.0, 32.5, 33.1 and 33.6 ±0.2° 2Q.
In another embodiment, the present invention provides a process for the preparation of apalutamide Form-Ll 1, comprising:
a) providing a solution of apalutamide in a mixture of N-methyl-2-pyrrolidone and methyl tert-butyl ether at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding methyl tert-butyl ether to step b) reaction mass, and
d) isolating apalutamide Form-Ll 1.
The aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in a mixture of N-methyl-2-pyrrolidone and methyl tert-butyl ether at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
The step c) of aforementioned process involves, adding methyl tert-butyl ether to step b) reaction mass at below 30°C. Then the apalutamide Form-Ll 1 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried at suitable temperatures i.e. about 35°C to about 60°C for sufficient period of time; preferably for a period of about 15 to about 20 hours.
In another embodiment, the present invention provides apalutamide Form-L12.
In another embodiment, the apalutamide Form-Ll 2 of the present invention is N- methyl-2-pyrrolidone solvate. In another embodiment, the present invention provides apalutamide Form-L12 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 14.
In another embodiment, the present invention provides apalutamide Form-L12 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.1, 4.5, 7.7, 8.0, 8.3, 8.8, 9.1, 9.6, 10.4, 11.0, 11.8, 12.4, 13.1, 13.7, 14.4, 14.6, 15.4,
15.6, 16.1, 16.5, 17.2, 17.8, 18.0, 18.3, 18.9, 19.9, 20.3, 20.5, 20.7, 21.0, 21.1, 21.4, 22.0, 22.4, 22.9, 23.3, 23.9, 24.5, 25.0, 25.1, 25.6, 26.4, 27.1, 27.9, 28.5, 29.0, 30.1,
30.9, 31.5, 32.7, 33.2, 33.9 and 34.7 ±0.2° 2Q.
In another embodiment, the present invention provides a process for the preparation of apalutamide Form-L12, comprising:
a) providing a solution of apalutamide in N-methyl-2-pyrrolidone at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding methyl tert-butyl ether to step b) reaction mass, and
d) isolating apalutamide Form-L12.
The aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in N-methyl-2-pyrrolidone at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
The step c) of aforementioned process involves, adding methyl tert-butyl ether to step b) reaction mass at below 30°C. Then the apalutamide Form-L12 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration and suck dried.
In another embodiment, the present invention provides apalutamide Form-L13.
In another embodiment, the apalutamide Form-L13 of the present invention is N- methyl-2-pyrrolidone solvate.
In another embodiment, the present invention provides apalutamide Form-L13 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 15.
In another embodiment, the present invention provides apalutamide Form-L13 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about
3.9, 4.3, 4.9, 6.4, 7.8, 8.1, 8.6, 9.4, 10.0, 10.7, 12.0, 12.2, 12.9, 13.4, 14.4, 14.8, 15.5,
15.7, 16.2, 16.6, 17.2, 17.6, 17.8, 18.6, 18.9, 19.6, 20.1, 20.8, 21.7, 22.0, 22.7, 23.6, 24.6, 24.9, 25.7, 26.1, 26.8, 27.9, 28.7, 29.2, 30.0, 30.6, 32.4, 33.2 and 33.8 ±0.2° 2Q. In another embodiment, the present invention provides a process for preparation of apalutamide Form-L13, the process comprising: drying crystalline apalutamide Form LI 3 at a temperature of about 60°C to about 70°C.
In another embodiment, the present invention provides apalutamide Form-L14.
In another embodiment, the apalutamide Form-L14 of the present invention is N- methyl-2-pyrrolidone solvate.
In another embodiment, the present invention provides apalutamide Form-L14 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 16.
In another embodiment, the present invention provides apalutamide Form-L14 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 3.9, 4.3, 6.6, 7.6, 7.9, 8.1, 8.7, 9.5, 10.2, 10.8, 11.4, 11.9, 12.3, 13.0, 13.5, 14.2, 14.5, 14.8, 15.2, 15.5, 15.9, 16.3, 17.1, 17.3, 17.6, 17.9, 18.2, 18.6, 19.0, 19.4, 19.7, 20.2, 21.0, 21.7, 22.1, 22.8, 23.8, 24.4, 24.9, 25.5, 25.7, 26.2, 26.3, 26.9, 28.1, 28.4, 28.8, 29.3, 30.0, 30.6, 31.9, 32.6 and 33.8 ±0.2° 2Q.
In another embodiment, the present invention provides a process for the preparation of apalutamide Form-L14, comprising:
a) providing a solution of apalutamide in a mixture of N-methyl-2-pyrrolidone and methyl tert-butyl ether at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding methyl tert-butyl ether to step b) reaction mass, and
d) isolating apalutamide Form-L14.
The aforementioned process of providing a solution of apalutamide includes first suspending or mixing apalutamide in a mixture of N-methyl-2-pyrrolidone and methyl tert-butyl ether at about 25°C and then the suspension may be heated to about 50°C to about reflux temperature to obtain a clear solution. Then, the resultant reaction solution can be cooled to below 30°C.
The step c) of aforementioned process involves, adding methyl tert-butyl ether to step b) reaction mass at below 30°C. Then the apalutamide Form-L14 can be recovered by any conventional process not limited to decantation, filtration and etc; preferably by filtration. The resultant product may be further dried under vacuum at about 25°C to about 30°C for sufficient period of time; preferably for a period of about 15 to about 20 hours.
In another embodiment, the present invention provides a process for preparation of amorphous form of apalutamide.
In another embodiment, the present invention provides a process for preparation of amorphous form of apalutamide, comprising: a) providing a solution of apalutamide in one or more solvents, and b) isolating amorphous apalutamide.
wherein the one or more solvents are selected from the group consisting of ethyl acetate, acetonitrile, methyl ethyl ketone, methanol and mixture thereof.
In another embodiment, the present invention provides a process for preparation of amorphous form of apalutamide, comprising:
a) providing a solution of apalutamide in one or more solvents,
b) concentrating the step a) solution, and
c) adding suitable another solvent to isolate the amorphous apalutamide.
wherein the one or more solvents are selected from the group consisting of ethyl acetate, acetonitrile, methyl ethyl ketone, methanol and mixture thereof; and suitable another solvent is non-polar solvent.
The starting apalutamide used herein in step a) may be any crystalline or other form of apalutamide, including various solvates, hydrates, salts and cocrystals as long as amorphous apalutamide is produced during the process of the invention or apalutamide obtaining as existing solution from a previous processing step.
Step a) of providing a solution of apalutamide may include dissolving any form of apalutamide in one or more solvents at about 20°C to reflux temperature of the solvent used; preferably at a temperature of about 25°C to about 85°C. The one or more solvents are selected from the group consisting of ethyl acetate, acetonitrile, methyl ethyl ketone, methanol and mixture thereof.
Step b) of the aforementioned process involves concentrating the step a) solution under vacuum at a temperature of about 25°C to about 80°C to obtain amorphous apalutamide. After concentrating the solvent, suitable another solvent may be added to the amorphous apalutamide to isolate the compound. The suitable another solvent in step c) is selected from the group consisting of n-hexane, n-heptane, cyclohexane and mixture thereof; preferably cyclohexane and n-heptane.
The resultant product may optionally be further dried at a temperature of about 35°C to about 85°C for about 2 hours to 30 hours. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven and the like; preferably drying is carried out under vacuum at a temperature of about 50°C to about 85°C for about 2 hours to 20 hours.
In another embodiment, the present invention provides a process for preparation of amorphous form of apalutamide by solvent and anti-solvent method.
In another embodiment, the present invention provides a process for preparation of amorphous form of apalutamide, comprising:
a) providing a solution of apalutamide in one or more solvents,
b) adding a suitable anti-solvent to the step a) solution or vice-versa; and c) isolating the amorphous apalutamide. In another embodiment, the present invention provides a process for preparation of amorphous form of apalutamide, comprising:
a) providing a solution of apalutamide in one or more solvents,
b) adding a suitable anti-solvent to the step a) solution or vice-versa; and c) isolating the amorphous form;
wherein the one or more solvents are selected from the group consisting of formic acid, methanol, acetonitrile and mixture thereof; and wherein the suitable anti-solvent is water, ammonia and mixtures thereof.
The starting apalutamide used herein in step a) may be any crystalline or other form of apalutamide, including various solvates, hydrates, salts and cocrystals as long as amorphous apalutamide is produced during the process of the invention or apalutamide obtaining as existing solution from a previous processing step.
Step a) of providing a solution of apalutamide may include dissolving any form of apalutamide in one or more solvents at about 20°C to reflux temperature of the solvent used; preferably at a temperature of about 25°C to about 75°C. The one or more solvents are selected from the group consisting of formic acid, methanol, acetonitrile and mixture thereof.
Step b) of the aforementioned process involves precipitation of amorphous apalutamide by either addition of suitable anti- solvent to the apalutamide solution of step a) or addition of step a) solution of apalutamide into a suitable anti- solvent.
The step b) addition of anti-solvent or vice-versa is carried out at a temperature of about -20°C to about 25 °C; preferably at a temperature of about -10°C to about 15°C. The suitable anti- solvent is water, ammonia and mixtures thereof. Then the resultant mass is stirred for sufficient period of time, preferably for a period of about 30 min to 5 hours.
The isolation of the resultant product is accomplished by removal of solvent from the solution by, for example, substantially complete evaporation of the solvent, concentrating the solution, cooling to obtain amorphous form and filtering the solid under inert atmosphere. The resultant product may optionally be further dried at a temperature of about 35°C to about 85°C for about 2 hours to 20 hours. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven and the like; preferably drying is carried out under vacuum at a temperature of about 40°C to about 85°C for about 2 hours to 15 hours.
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of apalutamide, the process comprising: drying apalutamide in the form of either solvate or hydrates thereof at a suitable temperature.
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of apalutamide, the process comprising: drying crystalline apalutamide Form LI at a suitable temperature. In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of apalutamide, the process comprising: drying crystalline apalutamide Form LI at a temperature of about 85°C to about 100°C.
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of apalutamide, the process comprising: drying crystalline apalutamide Form-Ll at a temperature of about 85°C to about 100°C; wherein the apalutamide Form-Ll characterized by an XRPD pattern substantially in accordance with Figure. 1.
In another embodiment, the present invention provides a pharmaceutical composition comprising amorphous or novel crystalline forms of apalutamide prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
EXAMPLES
The following non-limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.
EXAMPLE-1: Preparation of apalutamide Form-Ll
Apalutamide (20 gm) and ethyl formate (80 mL) were added in to a round bottom flask at 20-25°C, heated the reaction mass to 50-55°C and stirred for 15 min at same temperature. To the hazy solution was added ethyl formate (10 mL) at 50-55°C and stirred for 15 min. Then the clear solution was allowed to cool to 15-20°C and stirred for 1 hr at same temperature. To the reaction mass was added n-heptane (300 mL) at 15- 20°C. Stirred for about 1 hr at this temperature and the precipitated solid was filtered and washed with n-heptane (40 mL), suck dried the solid for 15 min and dried the wet material under vacuum at room temperature for about 2 hrs to obtain the title compound. Wt: 18.1 gm. The PXRD is set forth in Figure-1; DSC endotherm peaks at 71.9°C and 93.6°C; TGA weight loss: 2.2%; Solvent content (%) by NMR- Ethyl formate: 6 and heptane: 0.01; Moisture Content: 1.5%.
EXAMPLE-2: Preparation of apalutamide Form-L2
Apalutamide (8.5 gm; from Ex-1) and ammonia (45 mL) were added in to a round bottom flask at 20-25°C. Stirred the heterogeneous reaction mixture for 30 min at same temperature and the solid was filtered and washed with ammonia (10 mL), suck dried the solid for 15 min and dried the wet material under vacuum at room temperature for about 12 hrs to obtain the title compound. Wt: 3.5 gm. The PXRD is set forth in Figure- 2; DSC endotherm peaks at 71.7°C and 114.9°C; TGA weight loss: 2.6%; Solvent content (%) by NMR- Ethyl formate: Not detected; Moisture Content: 2.9%. EXAMPLE-3: Preparation of apalutamide Form-L2
The above material was further dried under vacuum at 40-45 °C for 12 hrs to obtain the title compound. Wt: 2.98 gm. The PXRD is set forth in Figure-4; DSC endotherm peaks at 70.89°C, 114.6°C and 142°C; TGA weight loss: 1.6%; Solvent content (%) by NMR- Ethyl formate: Not detected; Moisture Content: 2.9%.
EXAMPLE-4: Preparation of apalutamide Form-L2
Apalutamide (10 gm) and ethyl formate (40 mL) were added in to a round bottom flask at 20-25 °C. To the clear solution was added seed material (55.2 mg) at 20-25 °C and stirred for 1 hr at same temperature. To the reaction mass was added n-heptane (150 mL) at 20-25°C and stirred for 30 min at same temperature. The solid was filtered and washed with n-heptane (10 mL), suck dried the solid for 15 min and dried the wet material under vacuum at 22-26°C for about 2 hrs. Wt: 9.82 gm.
Above dried material (8.8 gm) and ammonia (45 mL) were added in to a round bottom flask at 20-25°C and stirred for 30 min at same temperature. The solid was filtered and washed with ammonia (9 mL), suck dried the solid for 15 min and dried the wet material under vacuum at 50°C for about 12 hrs to obtain the title compound. Wt: 6 gm. The PXRD is set forth in Figure-3; DSC endotherm peaks at 80.2°C, 112.9°C and 195.2°C; TGA weight loss: 1.2%; Solvent content (%) by NMR- Ethyl formate: Not detected; Moisture Content: 2.0%.
EXAMPLE-5: Preparation of apalutamide Form-L2
Ammonia solution (450 mL) was added in to a round bottom flask and cooled to 0-5 °C and was added apalutamide Form-Ll (100 gm) and allowed to stir for 1-2 hrs at same temperature. The solid was filtered and washed with ammonia (100 mL), suck dried the solid for 15 min and dried the wet material under vacuum at 40-45 °C for about 14 hrs to obtain the title compound. Wt: 95 gm. The PXRD is set forth in Figure-4; DSC endotherm peaks at 67.2°C, 116.8°C and 195.0°C; TGA weight loss: 1.19%; Moisture Content: 1.3%.
EXAMPLE-6: Preparation of apalutamide Form-L3
Apalutamide (1 gm), formic acid (1 mL) and n-pentanol (3 mL) were added in to a round bottom flask at 20-25 °C and stirred for 5 min at same temperature, heated the reaction mass to 60-65°C and stirred for 5 min at same temperature. Reaction mass allowed to cool to 40-45°C and was added seed material (20.1 mg) at same temperature. Reaction mass further cool to 20-25°C and was added n-pentanol (10 mL). Stirred the reaction mass for 16 hr at 20-25°C and the solid was filtered and washed with n- pentanol (2 mL), suck dried the solid for 10 min and dried the wet material under vacuum at 50-55°C for about 16 hrs to obtain the title compound. Wt: 684.8 mg. The PXRD is set forth in Figure-5; DSC endotherm peaks at 81.9°C, 131.7°C and 190.6°C, exotherm peak at 172.5°C; TGA weight loss: 1.1%; Solvent content (%) by NMR- formic acid: 1.3 and n-pentanol: 1.1; Moisture Content: 2.6%.
EXAMPLE-7: Preparation of apalutamide Form-L4
Apalutamide (1 gm), formic acid (1 mL) and isobutanol (3 mL) were added in to a round bottom flask at 20-25°C and stirred for 5 min at same temperature, heated the reaction mass to 60-65°C and stirred for 5 min at same temperature. Reaction mass allowed to cool to 20-25 °C and was added isobutanol (10 mL) and stirred for 16 hrs at same temperature. Solid was filtered and washed with isobutanol (2 mL), suck dried the solid for 5 min and dried the wet material under vacuum at 50-55°C for about 18 hrs to obtain the title compound. Wt: 556.1 mg. The PXRD is set forth in Figure-6; DSC endotherm peaks at 77.5°C, 123.7°C and 194.3°C; TGA weight loss: 1.0%; Solvent content (%) by NMR- formic acid: 1.6 and n-butanol: 1.9; Moisture Content: 2.8%.
EXAMPLE-8: Preparation of apalutamide Form-L5
Apalutamide (1 gm) and formic acid (1 mL) were added in to a round bottom flask at 20-25°C and stirred for 5 min at same temperature, heated the reaction mass to 60-65°C and stirred for 5 min at same temperature. Reaction mass allowed to cool to 20-25°C and was added cyclohexane (20 mL) and stirred for 16 hrs at same temperature. Solid was filtered and washed with cyclohexane (2 mL), suck dried the solid for 10 min and dried the wet material under vacuum at 60-65°C for about 19 hrs to obtain the title compound. Wt: 883.2 mg. The PXRD is set forth in Figure-7; DSC endotherm peaks at 68.6°C, 134.1°C and 167.6°C; TGA weight loss: 1.1%; Solvent content (%) by NMR- formic acid: 1.6 and cyclohexane: 1.5; Moisture Content: 2.1%.
EXAMPLE-9: Preparation of apalutamide Form-L6
Apalutamide (1 gm) and formic acid (1 mL) were added in to a round bottom flask at 20-25°C and stirred for 5 min at same temperature, heated the reaction mass to 60-65°C and stirred for 5 min at same temperature. Reaction mass allowed to cool to 20-25°C and was added cyclopentyl methyl ether (20 mL) and stirred for 16 hrs at same temperature. Solid was filtered and washed with cyclopentyl methyl ether (2 mL), suck dried the solid for 5 min and dried the wet material under vacuum at 50-55°C for about 16 hrs to obtain the title compound. Wt: 432.5 mg. The PXRD is set forth in Figure-8; DSC endotherm peaks at 78.6°C, 120.4°C, 163.5°C and 194.5°C; TGA weight loss: 0.65%; Solvent content (%) by NMR- formic acid: 1.2 and cyclopentyl methyl ether: 2.6; Moisture Content: 2.6%.
EXAMPLE-10: Preparation of apalutamide Form-L7
Apalutamide (1 gm), formic acid (1 mL) and t-pentanol (3 mL) were added in to a round bottom flask at 20-25 °C and stirred for 5 min at same temperature, heated the reaction mass to 60-65°C and stirred for 5 min at same temperature. Reaction mass allowed to cool to 20-25 °C and was added t-pentanol (10 mL) and stirred for 15 hrs at same temperature. Solid was filtered and washed with t-pentanol (2 mL), suck dried the solid for 15 min and dried the wet material under vacuum at 60-65 °C for about 18 hrs to obtain the title compound. Wt: 888.3 mg. The PXRD is set forth in Figure-9; DSC endotherm peak at 138.4°C; TGA weight loss: No weight loss; Solvent content (%) by NMR- formic acid: Not detected and t-pentanol: 8.6; Moisture Content: 0.3%.
EXAMPLE-11: Preparation of apalutamide Form-L8
Apalutamide (1 gm), formic acid (1.2 mL) and tert-butanol (3 mL) were added in to a round bottom flask at 20-25°C and stirred for 5 min at same temperature, heated the reaction mass to 60-65°C and stirred for 5 min at same temperature. Reaction mass allowed to cool to 20-25°C and was added tert-butanol (10 mL) and stirred for 16 hrs at same temperature. Solid was filtered and washed with tert-butanol (2 mL), suck dried the solid for 10 min and dried the wet material under vacuum at 60-65°C for about 18 hrs to obtain the title compound. Wt: 836.7 mg. The PXRD is set forth in Figure- 10; DSC endotherm peaks at 139.9°C and 194.9°C; TGA weight loss: No weight loss; Solvent content (%) by NMR- formic acid: Not detected and tert-butanol: 7.7; Moisture Content: 0.3%.
EXAMPLE-12: Preparation of apalutamide Form-L9
Apalutamide (1 gm) and sulfolane (2 mL) were added in to a round bottom flask at 20- 25°C and stirred for 5 min at same temperature, heated the reaction mass to 60-65°C and stirred for 5 min at same temperature. Reaction mass allowed to cool to 20-25°C and was added water (20 mL) and stirred for 16 hrs at same temperature. Solid was filtered and washed with water (5 mL), suck dried the solid for 15 min and dried the wet material under vacuum at 60-65°C for about 20 hrs to obtain the title compound. Wt: 985.2 mg. The PXRD is set forth in Figure-11; DSC endotherm peak at 172.2°C; TGA weight loss: No weight loss; Solvent content (%) by NMR- sulfolane: 13.6; Moisture Content: 0.1%.
EXAMPLE-13: Preparation of apalutamide Form-LlO
Apalutamide (1 gm) and trifluoroethanol (3 mL) were added in to a round bottom flask at 20-25°C and stirred for 5 min at same temperature, heated the reaction mass to 60- 65°C and stirred for 5 min at same temperature. Reaction mass allowed to cool to 20- 25 °C and was added diisopropyl ether (20 mL) and stirred for 16 hrs at same temperature. Solid was filtered and washed with diisopropyl ether (2 mL), suck dried the solid for 5 min and dried the wet material under vacuum at 50-55°C for about 18 hrs to obtain the title compound. Wt: 887.4 mg. The PXRD is set forth in Figure- 12; DSC endotherm peaks at 140.4°C, 161.8°C and 194.8°C; TGA weight loss: 0.12%; Solvent content (%) by NMR- trifluoroethanol: 9.9 and diisopropyl ether: 0.1; Moisture Content: 0.9%. EXAMPLE-14: Preparation of apalutamide Form-Ll 1
Apalutamide (1 gm), N-methyl-2-pyrrolidone (0.45 mL) and methyl tert-butyl ether (4 mL) were added in to a round bottom flask at 20-25 °C and stirred for 5 min at same temperature, heated the reaction mass to 55-60°C and stirred for 5 min at same temperature. Reaction mass allowed to cool to 20-25°C and was added methyl tert-butyl ether (10 mL) and stirred for 40 hrs at same temperature. Solid was filtered and washed with methyl tert-butyl ether (2 mL), suck dried the solid for 5 min and dried the wet material under vacuum at 50-55°C for about 20 hrs to obtain the title compound. Wt: 643.6 mg. The PXRD is set forth in Figure-13; DSC endotherm peaks at 128.1°C, 153.2°C and 193°C; TGA weight loss: No weight loss; Solvent content (%) by NMR- N-methyl-2-pyrrolidone: 7.3 and methyl tert-butyl ether: 1.4.
EXAMPLE-15: Preparation of apalutamide Form-L12
Apalutamide (1 gm) and N-methyl-2-pyrrolidone (1 mL) were added in to a round bottom flask at 20-25 °C and stirred for 5 min at same temperature, heated the reaction mass to 60-65°C and stirred for 5 min at same temperature. Reaction mass allowed to cool to 20-25°C and was added methyl tert-butyl ether (25 mL) and stirred for 16 hrs at same temperature. Solid was filtered and washed with methyl tert-butyl ether (2 mL), suck dried the solid for 5 min to obtain the title compound. Wt: 740 mg. The PXRD is set forth in Figure-14; Solvent content (%) by NMR- N-methyl-2-pyrrolidone: 13 and methyl tert-butyl ether: Not detected.
EXAMPLE-16: Preparation of apalutamide Form-Ll 3
Apalutamide Form-L12 from Ex- 14 (740 mg) was dried under vacuum at 60-62°C for about 18 hrs to obtain the title compound. Wt: 447.6 mg. The PXRD is set forth in Figure-15; DSC endotherm peaks at 125.5°C, 160.6°C and 194.7°C; TGA weight loss: No weight loos; Solvent content (%) by NMR- N-methyl-2-pyrrolidone: 8.7 and methyl tert-butyl ether: Not detected.
EXAMPLE-17: Preparation of apalutamide Form-L14
Apalutamide (1 gm), N-methyl-2-pyrrolidone (0.45 mL) and methyl tert-butyl ether (4 mL) were added in to a round bottom flask at 20-25 °C and stirred for 5 min at same temperature, heated the reaction mass to 55-60°C and stirred for 5 min at same temperature. Reaction mass allowed to cool to 30-35°C and was added seed material (15.8 mg) at same temperature. Reaction mass further cool to 20-25°C and was added methyl tert-butyl ether (10 mL) and stirred for 16 hrs at same temperature. Solid was filtered and washed with methyl tert-butyl ether (1 mL), suck dried the solid for 5 min and dried the wet material under vacuum at room temperature for about 18 hrs to obtain the title compound. Wt: 740.2 mg. The PXRD is set forth in Figure- 16.
EXAMPLE-18: Preparation of amorphous apalutamide Apalutamide Form-Ll (8.51 gm) was dried under vacuum at 90-92°C for about 13 hrs to obtain the title compound. Wt: 7.96 gm. The PXRD is set forth in Figure-17; DSC endotherm peaks at 59.6°C, 103.8°C, 129.4°C and 195.2°C; TGA weight loss: 0.39%;
EXAMPLE-19: Preparation of amorphous apalutamide
Apalutamide (850 gm) and ethyl formate (3.4 lit) were added in to a round bottom flask at 20-25°C, heated the reaction mass to 50-55°C and stirred for 15 min at same temperature. The solution was filtered and then the clear solution was allowed to cool to 15-20°C and stirred for 1 hr at same temperature. To the reaction mass was added n- heptane (1.2 lit) at 15-20°C. Stirred for about 1 hr at this temperature and the precipitated solid was filtered and washed with n-heptane (1.75 lit), suck dried the solid for 30-45 min. The wet material dried under vacuum at room temperature for about 2 hrs, then at 50°C for 2 hrs and then at 90°C for 15 hrs to obtain the title compound. Wt: 740 gm. The PXRD is set forth in Figure- 17.
EXAMPLE-20: Preparation of amorphous apalutamide
Apalutamide (1 gm) and ethylacetate (10 mL) were added in to a round bottom flask at 25°C to 35°C and stirred for 5 min at same temperature. Reaction mass was heated to 60-65°C and distilled the solvent completely under vacuum at same temperature to obtaine a foamy solid. The foamy solid was cool to 20-25°C and charged cyclohexane (10 mL), stirred for 1 hr at same temperature. Solid was filtered and washed with cyclohexane (2 mL), suck dried the solid for 10 min and dried the wet material under vacuum at 50-55°C for about 2 hrs and then dried at 70-75°C for about 13 hrs to obtain the title compound. Wt: 790.4 mg. The PXRD is set forth in Figure- 17; DSC endotherm peaks at 106.7°C, 166.5°C and 194.9°C; TGA weight loss: 0.2%;
EXAMPLE-21: Preparation of amorphous apalutamide
Apalutamide (1 gm) and acetonitrile (10 mL) were added in to a round bottom flask at 25°C to 35°C and stirred for 5 min at same temperature. Reaction mass was heated to 50-55°C and distilled the solvent completely under vacuum at same temperature to obtaine a foamy solid. The foamy solid was co-distilled with cyclohexane (5 mL x 2), then the foamy solid was cool to 20-25°C and charged cyclohexane (10 mL), stirred for 1 hr at same temperature. Solid was filtered and washed with cyclohexane (5 mL), suck dried the solid for 5 min and dried the wet material under vacuum at room temperature for about 2 hrs and then dried at 70°C for about 16 hrs to obtain the title compound. Wt: 796 mg.
EXAMPLE-22: Preparation of amorphous apalutamide
Apalutamide (1 gm) and methyl ethyl ketone (10 mL) were added in to a round bottom flask at 25°C to 35°C and stirred for 5 min at same temperature. Reaction mass was heated to 60-65°C and distilled the solvent completely under vacuum at same temperature to obtaine a foamy solid. The foamy solid was cool to 20-25°C and charged cyclohexane (10 mL), stirred for 1 hr at same temperature. Solid was filtered and washed with cyclohexane (2 mL), suck dried the solid for 10 min and dried the wet material under vacuum at 50-55°C for about 2 hrs and then dried at 70-75°C for about 13 hrs to obtain the title compound. Wt: 704.2 mg.
EXAMPLE-23: Preparation of amorphous apalutamide
Apalutamide (500 mg) and methanol (5 mL) were added in to a round bottom flask at 25°C to 35°C and stirred for 5 min at same temperature. Reaction mass was heated to 50-55°C and distilled the solvent completely under vacuum at same temperature to obtaine a foamy solid. After complete evaporation of solvent, raised the temperature to 60-65°C and the foamy solid was maintained for 20 min at same temperature. The foamy solid was cool to 20-25°C and charged n-heptane (10 mL), stirred for 1 hr at same temperature. Solid was filtered and washed with n-heptane (2 mL), suck dried the solid for 10 min and dried the wet material under vacuum at 70-75°C for about 17 hrs to obtain the title compound. Wt: 396.2 mg.
EXAMPLE-24: Preparation of amorphous apalutamide
Apalutamide (10 gm) and formic acid (15 mL) were added in to a round bottom flask at 20-25°C, heated the reaction mass to 60-65°C to get clear solution. Reaction mass was cool to 20-25°C, and was added to pre cooled ammonia (300 mL) at 3-7°C. Stirred for about 30 min at this temperature and the precipitated solid was filtered and washed with ammonia (10 mL), suck dried the solid for 15 min and dried the wet material under vacuum at room temperature for about 2 hrs and then dried at 45-47°C for about 12 hrs to obtain the title compound. Wt: 8.52 gm.
EXAMPLE-25: Preparation of amorphous apalutamide
Apalutamide (30.1 gm), methanol (45 mL) and acetonitrile (12 mL) were added in to a round bottom flask at 20-25°C, heated the reaction mass to 50-55°C to get clear solution. To the reaction mass was added carbon (3 gm) at 50-55°C and stirred for 30 min at same temperature. Reaction mass was filtered through celite bed and bed was washed with hot methanol (15 mL). Filterate was cool to 40-45°C, and was added to pre cooled ammonia (300 mL) at -13 to -12°C. Stirred for about 1 hr at this temperature and the precipitated solid was filtered and washed with chilled ammonia (30 mL), suck dried the solid for 60 min and dried the wet material under vacuum at room temperature for about 13 hrs and then dried at 50-52°C for about 9 hrs to obtain the title compound. Wt: 12.42 gm.
Example-26: Stability Study details of crystalline apalutamide Form L2: The following stability study data tables at different storage condition ensure that the crystalline apalutamide Form L2 of the present invention retained the same polymorphic and chemical identity at least up to Six months.
Apalutamide Form L2 is packed in a transparent Low density polyethylene (LDPE) bag with a strip seal along with nitrogen filling, which is again kept in a second transparent low density polyethylene bag with strip seal. The LDPE bag is kept in to a triple laminated sunlight barrier with heat seal followed by in a high density polyethylene container and well closed. TABLE-I: Chemical and polymorphic stability data of Apalutamide Form L2 when stored at 25±2°C / 60+5% RH & 40±2°C / 75+5% RH:
Figure imgf000039_0001
Example-27: TABLE-II: Impurity profile of crystalline apalutamide Form L2 when stored at 25+2°C / 60+5% RH & 40+2°C / 75+5% RH:
Figure imgf000039_0002
Figure imgf000040_0001
Example-28: Solubility studies of crystalline apalutamide Form L2:
Saturation solubility studies were conducted in various mediums for Apalutamide Form L2 of the present invention with Form A and Form B and the values are tabulated as below:
TABLE-III: Summary of aqueous solubility of Form A, Form B and Form L2 in different solvents at~37°C:
Figure imgf000040_0002
TABLE-III: Inference profile of Form A, Form B and Form L2 in different solvents at~ 25°C:
Figure imgf000040_0003
From the above data it is observed that apalutamide polymorphic Form L2 shows better solubility when compared to Form A and Form B. Note: Apalutamide Form A and Form B are known in the art and are prepared by the process disclosed in U.S. Patent No. 9,481,663.
REFERENCE EXAMPLE: The following example was carried out following the teaching of compound-A52 of US 8,445,507 (95% dichlorome thane: 5% acetone) Apalutamide (1 g) was dissolved in a mixture of 95% dichloromethane: 5% acetone (10 mL). The solvent was distilled completely at below 40-45°C under vacuum and maintained for about 30 min after complete evaporation. The obtained solids were dried at 50°C under vacuum for 12 hrs. Wt: 858.4 mg. Further the sample was dried at 70°C under vacuum for 12 hrs. Wt: 370.2 mg.
Amorphous Form obtained according to the reference examples was analyzed by PXRD and is represented according to Fig. 18.
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.

Claims

We Claim:
1. Crystalline apalutamide Form-L2 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.8, 8.1, 10.4, 11.4, 12.2, 12.5, 14.2,
15.5, 16.0, 16.3, 16.7, 19.0, 19.3, 19.8, 20.1, 20.7, 21.3, 21.8, 22.6, 23.1, 23.3,
23.7, 24.0, 24.7, 25.0, 25.5, 26.2, 26.5, 26.7, 26.8, 27.6, 28.3, 29.0, 29.4, 29.9, 30.9, 31.1, 31.5, 32.5, 33.1, 33.4, 33.8, 34.7 and 35.1 ±0.2° 2Q.
2. The crystalline apalutamide Form-L2 as claimed in claim 1, further characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 4.
3. A process for preparation of crystalline apalutamide Form-L2, comprising:
a) suspending apalutamide Form-Ll in ammonia at about 0°C to about 35°C, b) stirred the step a) suspension for about 10 min to about 4 hour, and c) isolating apalutamide Form-L2;
wherein the apalutamide Form-Ll is characterized by X-Ray diffraction pattern having one or more peaks at about 7.7, 8.1, 10.4, 10.7, 11.1, 11.4, 12.3, 12.5,
14.5, 15.2, 15.5, 16.0, 16.3, 16.9, 17.2, 18.0, 19.0, 19.4, 19.9, 20.7, 20.9, 21.3,
21.8, 22.1, 22.6, 22.7, 23.3, 23.9, 24.5, 25.0, 25.6, 26.2, 26.8, 27.1, 28.4, 28.8, 29.1, 29.7, 29.9, 30.8, 30.9, 31.4, 32.1, 33.0, 33.53, 34.0 and 34.9 ±0.2° 2Q.
4. The process as claimed in claim 3, wherein in the step a) is carried out at about 0°C to about 5°C.
5. The process as claimed in claim 3, wherein the step b) is carried out for about 10 min to about 2 hour.
6. A process for the preparation of apalutamide Form-L2, comprising:
a) providing a solution of apalutamide in ethyl formate at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding n-heptane to step b) reaction mass, and
d) isolating apalutamide Form-Ll,
e) suspending apalutamide Form-Ll in ammonia at about 0°C to about 35°C, f) stirred the step e) suspension for about 10 min to about 4 hour, and g) isolating apalutamide Form-L2;
7. The process as claimed in claim 6, wherein in the step a) is carried out at about 50°C to about 60°C.
8. The process as claimed in claim 6, wherein in the step e) is carried out at about 0°C to about 5°C.
9. Crystalline apalutamide Form-Ll characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 7.7, 8.1, 10.4, 10.7, 11.1, 11.4, 12.3, 12.5, 14.5, 15.2, 15.5, 16.0, 16.3, 16.9, 17.2, 18.0, 19.0, 19.4, 19.9, 20.7, 20.9, 21.3, 21.8, 22.1, 22.6, 22.7, 23.3, 23.9, 24.5, 25.0, 25.6, 26.2, 26.8, 27.1, 28.4, 28.8, 29.1, 29.7, 29.9, 30.8, 30.9, 31.4, 32.1, 33.0, 33.53, 34.0 and 34.9 ±0.2° 2Q.
10. The crystalline apalutamide Form-Ll as claimed in claim 9, further characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 1.
11. A process for the preparation of apalutamide Form-Ll, comprising:
a) providing a solution of apalutamide in ethyl formate at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding n-heptane to step b) reaction mass, and
d) isolating apalutamide Form-Ll.
12. The process as claimed in claim 11, wherein in the step a) is carried out at about 50°C to about 60°C.
13. A process for preparation of amorphous form of apalutamide, comprising:
a) providing a solution of apalutamide in one or more solvents,
b) concentrating the step a) solution, and
c) adding suitable another solvent to isolate the amorphous apalutamide; wherein the one or more solvents are selected from the group consisting of ethyl acetate, acetonitrile, methyl ethyl ketone, methanol and mixture thereof; and suitable another solvent is a non-polar solvent selected from the group consisting n- hexane, n-heptane, cyclohexane and mixture thereof.
14. The process as claimed in claim 13, wherein in the step a) is carried out at about 25°C to about 85°C.
15. The process as claimed in claim 13, wherein in the step b) is carried out at about 25°C to about 80°C.
16. A process for preparation of amorphous form of apalutamide, comprising:
a) providing a solution of apalutamide in one or more solvents,
b) adding a suitable anti-solvent to the step a) solution or vice-versa; and c) isolating the amorphous form;
wherein the one or more solvents are selected from the group consisting of formic acid, methanol, acetonitrile and mixture thereof; and wherein the suitable anti-solvent is water, ammonia and mixtures thereof.
17. The process as claimed in claim 16, wherein in the step b) addition of anti solvent is carried out at about -10°C to about 15°C. 18. A process for preparation of amorphous form of apalutamide, comprising: drying crystalline apalutamide Form-Ll at a temperature of about 85°C to about 100°C; wherein the apalutamide Form-Ll is characterized by X-Ray diffraction pattern having one or more peaks at about 7.7, 8.1, 10.4, 10.7, 11.1, 11.4, 12.3,
12.5, 14.5, 15.2, 15.5, 16.0, 16.3, 16.9, 17.2, 18.0, 19.0, 19.4, 19.9, 20.7, 20.9,
21.3, 21.8, 22.1, 22.6, 22.7, 23.3, 23.9, 24.5, 25.0, 25.6, 26.2, 26.8, 27.1, 28.4,
28.8, 29.1, 29.7, 29.9, 30.8, 30.9, 31.4, 32.1, 33.0, 33.53, 34.0 and 34.9 ±0.2° 2Q.
19. Crystalline form of apalutamide, wherein the crystalline form characterized by X-Ray diffraction (XRD) having one or more peaks selected from the group consisting of:
4.7, 6.9, 7.1, 7.3, 9.4, 10.5, 11.1, 11.3, 11.8, 13.3, 14.1, 14.8, 15.3, 16.3, 16.4, 16.8,
18.4, 18.9, 20.1, 20.7, 21.2, 21.9, 22.9, 23.4, 23.7, 24.0, 24.5, 24.8, 25.2, 25.8,
26.4, 26.8, 27.8, 28.5, 29.9, 30.5, 31.3, 31.8, 32.7 and 33.3 ±0.2° 2Q (Form L3);
4.7, 6.8, 7.0, 7.2, 9.4, 10.5, 10.7, 11.3, 11.8, 13.3, 14.1, 14.7, 16.1, 16.3, 16.9, 18.2,
18.8, 20.0, 20.7, 21.3, 21.5, 22.0, 22.7, 23.9, 24.5, 24.7, 25.1, 25.8, 26.7, 27.9 and 29.8 ±0.2° 2Q (Form L4);
4.7, 6.7, 7.0, 7.3, 9.3, 10.4, 10.7, 11.0, 11.3, 11.5, 11.8, 13.2, 13.6, 14.0, 14.6, 15.1,
15.4, 16.1, 16.4, 16.8, 16.9, 17.4, 18.3, 18.8, 19.0, 20.0, 20.8, 21.2, 21.4, 22.1,
22.7, 23.3, 23.9, 24.5, 24.8, 25.2, 25.8, 26.6, 26.9, 27.5, 28.2, 29.6, 30.3, 31.1,
31.8, 32.6, 33.2 and 34.0 ±0.2° 2Q (Form L5);
4.8, 6.9, 7.4, 9.5, 10.5, 11.2, 11.9, 13.4, 14.2, 14.7, 15.2, 15.5, 16.2, 16.5, 17.0,
18.3, 18.8, 20.0, 20.4, 21.2, 21.4, 22.1, 22.5, 22.8, 23.5, 23.9, 24.6, 25.3, 25.7,
26.7, 27.0, 27.6, 28.5, 29.7, 31.2, 32.0, 32.7, 33.3 and 34.2 ±0.2° 2Q (Form L6);
4.6, 7.0, 9.1, 10.5, 12.8, 13.7, 14.7, 15.7, 16.0, 16.5, 17.3, 18.0, 18.3, 19.0, 19.7, 20.2, 21.0, 21.2, 21.7, 22.1, 22.7, 22.9, 23.6, 23.9, 24.3, 24.6, 25.3, 25.8, 26.1,
26.7, 27.6, 28.1, 29.4, 29.6, 30.2, 30.7, 31.3, 32.0, 32.4, 33.6, 34.1 and 34.4 ±0.2° 2Q (Form L7);
4.6, 7.0, 9.2, 10.6, 11.5, 12.8, 13.8, 14.8, 15.8, 16.0, 16.5, 17.4, 18.1, 18.5, 19.2,
19.7, 20.2, 21.1, 21.3, 21.7, 22.2, 22.9, 23.2, 23.8, 24.3, 24.6, 25.5, 25.9, 26.2, 26.9, 27.9, 28.2, 28.4, 29.5, 29.9, 30.5, 31.5, 32.2, 32.6, 33.7 and 34.6 ±0.2° 2Q (Form L8);
4.9, 5.5, 5.8, 8.8, 9.4, 10.0, 10.3, 11.3, 11.7, 12.0, 12.3, 12.8, 13.2, 13.9, 14.1, 14.9, 15.0, 15.7, 16.1, 16.7, 17.2, 17.7, 18.0, 18.6, 19.0, 19.3, 19.9, 20.1, 20.9, 21.3,
21.7, 22.5, 22.7, 23.1, 23.6, 24.1, 24.4, 24.6, 25.2, 25.8, 26.2, 26.4, 27.1, 27.6,
28.2, 28.8, 29.7, 30.1, 30.7, 30.9, 31.3, 32.1, 32.7, 33.5 and 34.1 ±0.2° 2Q (Form L9);
4.6, 7.0, 9.3, 10.7, 11.6, 13.2, 14.0, 14.8, 15.0, 16.1, 16.7, 17.5, 18.5, 18.7, 19.5, 20.0, 20.5, 21.4, 21.6, 21.9, 22.9, 23.5, 24.1, 24.5, 24.8, 25.0, 25.5, 26.3, 27.2,
27.8, 28.3, 29.1, 30.3, 31.3, 32.2, 32.6, 33.4 and 34.9 ±0.2° 2Q (Form L10);
4.2, 5.0, 6.9, 8.2, 8.5, 9.1, 9.4, 10.4, 10.8, 11.6, 12.0, 12.5, 12.8, 13.3, 14.9, 15.3, 15.5, 15.7, 16.1, 16.3, 16.6, 16.9, 17.1, 17.4, 18.2, 18.7, 19.2, 19.5, 20.0, 20.5,
20.8, 21.2, 21.9, 22.2, 22.8, 23.2, 23.7, 24.2, 24.9, 25.3, 25.5, 26.4, 27.7, 28.1, 29.1, 29.6, 30.5, 31.0, 32.5, 33.1 and 33.6 ±0.2° 2Q (Form Ll l);
4.1, 4.5, 7.7, 8.0, 8.3, 8.8, 9.1, 9.6, 10.4, 11.0, 11.8, 12.4, 13.1, 13.7, 14.4, 14.6,
15.4, 15.6, 16.1, 16.5, 17.2, 17.8, 18.0, 18.3, 18.9, 19.9, 20.3, 20.5, 20.7, 21.0,
21.1, 21.4, 22.0, 22.4, 22.9, 23.3, 23.9, 24.5, 25.0, 25.1, 25.6, 26.4, 27.1, 27.9,
28.5, 29.0, 30.1, 30.9, 31.5, 32.7, 33.2, 33.9 and 34.7 ±0.2° 2Q (Form L12);
3.9, 4.3, 4.9, 6.4, 7.8, 8.1, 8.6, 9.4, 10.0, 10.7, 12.0, 12.2, 12.9, 13.4, 14.4, 14.8, 15.5, 15.7, 16.2, 16.6, 17.2, 17.6, 17.8, 18.6, 18.9, 19.6, 20.1, 20.8, 21.7, 22.0, 22.7, 23.6, 24.6, 24.9, 25.7, 26.1, 26.8, 27.9, 28.7, 29.2, 30.0, 30.6, 32.4, 33.2 and 33.8 ±0.2° 2Q (Form L13); and
3.9, 4.3, 6.6, 7.6, 7.9, 8.1, 8.7, 9.5, 10.2, 10.8, 11.4, 11.9, 12.3, 13.0, 13.5, 14.2, 14.5, 14.8, 15.2, 15.5, 15.9, 16.3, 17.1, 17.3, 17.6, 17.9, 18.2, 18.6, 19.0, 19.4, 19.7, 20.2, 21.0, 21.7, 22.1, 22.8, 23.8, 24.4, 24.9, 25.5, 25.7, 26.2, 26.3, 26.9, 28.1, 28.4, 28.8, 29.3, 30.0, 30.6, 31.9, 32.6 and 33.8 ±0.2° 2Q (Form L14).
20. A process for preparation of crystalline form of apalutamide as claimed in claim 19, wherein the crystalline forms selected from Form L3, Form L4, Form L5, Form L6, Form L7, Form L8, Form L9, Form L10, Form Ll l, Form L12 and Form 14, comprising:
a) providing a solution of apalutamide in a solvent or a mixture thereof at 30°C to reflux temperature,
b) cooling the solution to below 30°C,
c) adding anti-solvent to step b) reaction mass, and
d) isolating crystalline form of apalutamide;
wherein the apalutamide Form L3 is obtained when step a) solvent is a mixture of formic acid and n-pentanol, and step c) anti-solvent is n-pentanol; wherein the apalutamide Form L4 is obtained, when step a) solvent is a mixture of formic acid and isobutanol, and step c) anti-solvent is isobutanol; wherein the apalutamide Form L5 is obtained, when step a) solvent is formic acid, and step c) anti-solvent is cyclohexane; wherein the apalutamide Form L6 is obtained, when step a) solvent is formic acid, and step c) anti-solvent is cyclopentyl methyl ether; wherein the apalutamide Form L7 is obtained, when step a) solvent is a mixture of formic acid and t-pentanol, and step c) anti-solvent is t-pentanol; wherein the apalutamide Form L8 is obtained, when step a) solvent is a mixture of formic acid and t-butanol, and step c) anti- solvent is t-butanol; wherein the apalutamide Form L9 is obtained, when step a) solvent is sulfolane, and step c) anti-solvent is water; wherein the apalutamide Form L10 is obtained, when step a) solvent is trifluoroethanol, and step c) anti- solvent is diisoprop ylether; wherein the apalutamide Form LI 1 is obtained, when step a) solvent is a mixture of N-methyl-2-pyrrolidone and methyl tert-butyl ether, and step c) anti-solvent is methyl tert-butyl ether; wherein the apalutamide Form L12 is obtained, when step a) solvent is N- methyl-2-pyrrolidone, and step c) anti-solvent is methyl tert-butyl ether; and wherein the apalutamide Form L14 is obtained, when step a) solvent is a mixture of N-methyl-2-pyrrolidone and methyl tert-butyl ether, and step c) anti-solvent is methyl tert-butyl ether.
21. A pharmaceutical composition comprising amorphous or novel crystalline forms of apalutamide as claimed in claims 1 - 20 and at least one pharmaceutically acceptable excipient.
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