WO2023195018A1 - Dispersions solides de 3-(2,6-difluoro-3,5-diméthoxyphényl)-1-éthyl-8-(morpholin-4-ylméthyl)-1,3,4,7-tétrahydro-h-pyrrolo[3',2:5,6]pyrido[4,3-d]pyrimidin-2-one - Google Patents

Dispersions solides de 3-(2,6-difluoro-3,5-diméthoxyphényl)-1-éthyl-8-(morpholin-4-ylméthyl)-1,3,4,7-tétrahydro-h-pyrrolo[3',2:5,6]pyrido[4,3-d]pyrimidin-2-one Download PDF

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Publication number
WO2023195018A1
WO2023195018A1 PCT/IN2023/050294 IN2023050294W WO2023195018A1 WO 2023195018 A1 WO2023195018 A1 WO 2023195018A1 IN 2023050294 W IN2023050294 W IN 2023050294W WO 2023195018 A1 WO2023195018 A1 WO 2023195018A1
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WO
WIPO (PCT)
Prior art keywords
pemigatinib
solid dispersion
cellulose
hpmc
pharmaceutically acceptable
Prior art date
Application number
PCT/IN2023/050294
Other languages
English (en)
Inventor
Thirumalai Rajan Srinivasan
Eswaraiah Sajja
Vijayavitthal T MATHAD
Venkata Narasayya SALADI
Bal Raju Kammari
Narendar KAMMARI
Original Assignee
Msn Laboratories Private Limited, R&D Center
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Msn Laboratories Private Limited, R&D Center filed Critical Msn Laboratories Private Limited, R&D Center
Publication of WO2023195018A1 publication Critical patent/WO2023195018A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the present invention relates to a solid dispersion of 3-(2,6-difluoro-3,5- dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-l,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6] pyrido[4,3-d]pyrimidin-2-one and process for its preparation thereof.
  • Pemigatinib is chemically known as 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8- (morpholin-4-ylmethyl)-l,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, represented by the following structural formula.
  • Pemigatinib is a small molecule tyrosine kinase inhibitor of fibroblast growth factor receptor family (FGFR1, FGFR2, FGFR3 and FGFR4). Pemigatinib inhibits FGFR phosphorylation and signalling and decreases cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions or rearrangements.
  • Pemigatinib is approved in the USFDA and Europe for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.
  • Pemigatinib is being marketed by Incyte under the brand name Pemazyre.
  • US’267 discloses process for the preparation of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l- ethyl-8-(morpholin-4-ylmethyl)-l,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin- 2-one.
  • 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 to determine the stability, dissolution and flow properties of each polymorphic form.
  • Polymorphic forms 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 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.
  • the present invention relates to a solid dispersion of Pemigatinib.
  • the present invention also relates to a process for the preparation of solid dispersion of Pemigatinib. Brief description of Drawings:
  • Figure-1 Illustrates the PXRD pattern of solid dispersion of Pemigatinib with HPMC-E5.
  • solvent used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, nitromethane and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl t-butyl ether, 1,2- dimethoxy ethane, anisole and the like; “ester solvents” such as methyl formate
  • solid dispersion refers to dispersion of drug in a solid matrix where the matrix is either a small molecule or polymer.
  • solid dispersion relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way.
  • the two or more components form a homogeneous one -phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size.
  • excipient refers to play a significant role in stabilizing solid dispersions, maximizing bioavailability, and overcoming absorption issues associated with poorly soluble drugs.
  • solid dispersion and premix are used interchangeably to describe solid states disclosed herein.
  • the present invention provides a solid dispersion of Pemigatinib of formula- 1 with one or more pharmaceutically acceptable excipients.
  • the suitable pharmaceutically acceptable excipient is selected from but not limited to syloid, polyvinylpyrrolidone (povidone or PVP; PVP of different grades like K-15, K-30, K-60, K-90 and K-120 may be used), co-povidone, crospolyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), cros-copovidone, Eudragit, polyethylene glycol (macro gol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethylcellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropy
  • the present invention provides a process for the preparation of solid dispersion of Pemigatinib of formula- 1 with one or more pharmaceutically acceptable excipients, which comprises: a) providing a solution of Pemigatinib of formula- 1 , b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step-a), and c) isolating the solid dispersion of Pemigatinib of formula- 1 with one or more pharmaceutically acceptable excipients.
  • providing a solution of Pemigatinib of formula- 1 in step-a) comprises dissolving Pemigatinib of formula- 1 in a suitable solvent or a mixture of solvents at a suitable temperature of about 25 °C and above.
  • the solution can be filtered to make it particle free.
  • the suitable solvent used in step-a) is selected from alcohol solvent and chloro solvent.
  • the suitable pharmaceutically acceptable excipient used in step-b) is same as defined in the first embodiment.
  • the present invention provides a process for the preparation of solid dispersion of Pemigatinib of formula- 1 with HPMC-E5, which comprises: a) providing a solution of Pemigatinib of formula- 1 , b) adding HPMC-E5 to the solution obtained in step-a), and c) isolating the solid dispersion of Pemigatinib of formula- 1 with HPMC-E5.
  • providing a solution of Pemigatinib of formula- 1 in step-a) comprises dissolving Pemigatinib of formula- 1 in methanol and dichloromethane at a suitable temperature of about 25°C and above.
  • the solution can be filtered to make it particle free.
  • the solid dispersion of Pemigatinib of formula- 1 with HPMC-E5 is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure- 1.
  • isolating involves removal of solvent is carrying out by suitable techniques which includes but not limited to decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as buchi rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration by gravity or suction, thin film drying, centrifugation or by any other suitable techniques known in the art.
  • suitable techniques which includes but not limited to decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as buchi rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the clear solution to
  • drying solid dispersion of Pemigatinib of formula- 1 by a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
  • the drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
  • the drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
  • Solid dispersion of Pemigatinib prepared according to the present invention can be further micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • the starting material of Pemigatinib of formula- 1 can be used in the form of amorphous or crystalline or any other physical form which is prepared from any of the processes known in the art.
  • pharmaceutically acceptable excipient used for the preparation of solid dispersion can be amorphous, crystalline or any other physical form.
  • the resulting, solid dispersion of Pemigatinib can be amorphous, crystalline or a mixture thereof. It is an object of the present invention to provide storage stable solid dispersions of Pemigatinib.
  • the stability of solid dispersion of Pemigatinib is determined by storing the samples at 2°C to 8°C temperature for about 12 months. The samples were analyzed by X-ray powder diffraction pattern (XRPD). The solid dispersion of Pemigatinib is found to be stable at 2°C to 8°C temperature for about 12 months.
  • the objective of the present invention is achieved through the preparation of storage stable solid dispersion of Pemigatinib.
  • composition comprising solid dispersion of Pemigatinib of formula- 1 and one or more pharmaceutically acceptable excipients is formulated in a manner suitable for the route of administration to be used.
  • compositions include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • PXRD analysis of solid dispersion of Pemigatinib was carried out by using BRUKER/D8 ADVANCE diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
  • Example-1 Preparation of solid dispersion of Pemigatinib with HPMC-E5.

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

Abstract

La présente invention concerne des dispersions solides de 3-(2,6-difluoro-3,5-diméthoxyphényl)-1-éthyl-8-(morpholin-4-ylméthyl)-1,3,4,7-tétrahydro-2H-pyrrolo [3',2':5,6]pyrido[4,3-d]pyrimidin-2-one. La présente invention concerne des dispersions solides de 3-(2,6-difluoro-3,5-diméthoxyphényl)-1-éthyl-8-(morpholin-4-ylméthyl)-1,3,4,7-tétrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one représentées par la formule structurale suivante.
PCT/IN2023/050294 2022-04-05 2023-03-28 Dispersions solides de 3-(2,6-difluoro-3,5-diméthoxyphényl)-1-éthyl-8-(morpholin-4-ylméthyl)-1,3,4,7-tétrahydro-h-pyrrolo[3',2:5,6]pyrido[4,3-d]pyrimidin-2-one WO2023195018A1 (fr)

Applications Claiming Priority (2)

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IN202241020537 2022-04-05
IN202241020537 2022-04-05

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PCT/IN2023/050294 WO2023195018A1 (fr) 2022-04-05 2023-03-28 Dispersions solides de 3-(2,6-difluoro-3,5-diméthoxyphényl)-1-éthyl-8-(morpholin-4-ylméthyl)-1,3,4,7-tétrahydro-h-pyrrolo[3',2:5,6]pyrido[4,3-d]pyrimidin-2-one

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130338134A1 (en) * 2012-06-13 2013-12-19 Incyte Corporation Substituted tricyclic compounds as fgfr inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130338134A1 (en) * 2012-06-13 2013-12-19 Incyte Corporation Substituted tricyclic compounds as fgfr inhibitors

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
REDDY M. R., SHIVA GUBBIYAPPA KUMAR: "A Comprehensive Review On Supersaturable Self-Nanoemulsifying Drug Delivery System", ASIAN J PHARM CLIN RES, vol. 14, no. 8, 1 January 2021 (2021-01-01), pages 40 - 44, XP093101196, DOI: 10.22159/ajpcr.2021v14i8.41987 *
SHIN, YU, LEE, JI, JOUNG, HAN, YOO, KANG: "A Hydroxypropyl Methylcellulose-Based Solid Dispersion of Curcumin with Enhanced Bioavailability and its Hepatoprotective Activity", BIOMOLECULES, vol. 9, no. 7, pages 1 - 15, XP093101255, DOI: 10.3390/biom9070281 *
YING CHEN, CHEN CHEN, JIANLING ZHENG, ZHIYU CHEN, QIONGZHI SHI, HONG LIU: "Development of a solid supersaturatable self-emulsifying drug delivery system of docetaxel with improved dissolution and bioavailability", BIOLOGICAL & PHARMACEUTICAL BULLETIN, vol. 34, no. 2, 1 February 2011 (2011-02-01), JP , pages 278 - 286, XP002663906, ISSN: 0918-6158, DOI: 10.1248/bpb.34.278 *

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