WO2023152773A1 - Formes solides de sels de momélotinib et procédés améliorés pour la préparation de momélotinib - Google Patents

Formes solides de sels de momélotinib et procédés améliorés pour la préparation de momélotinib Download PDF

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WO2023152773A1
WO2023152773A1 PCT/IN2023/050151 IN2023050151W WO2023152773A1 WO 2023152773 A1 WO2023152773 A1 WO 2023152773A1 IN 2023050151 W IN2023050151 W IN 2023050151W WO 2023152773 A1 WO2023152773 A1 WO 2023152773A1
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momelotinib
salt
xrpd pattern
free base
peaks
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PCT/IN2023/050151
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English (en)
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Dr. Srinivas ORUGANTI
Dr. Neti SRINIVASAN
Mr. Kottur Mohan KUMAR
Dr. Saikat SEN
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Dr. Reddy's Institute Of Life Sciences
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/06—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing halogen atoms, or nitro or nitroso groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to the Amorphous Solid Dispersions (ASDs) of Momelotinib di-hydrochloride and processes for preparation thereof. Also, it relates to the processes of preparing Momelotinib salts and their use as means to purify the free base.
  • Amorphous Solid Dispersions ASDs
  • Momelotinib di-hydrochloride Amorphous Solid Dispersions of Momelotinib di-hydrochloride
  • processes for preparation thereof relates to the processes of preparing Momelotinib salts and their use as means to purify the free base.
  • Momelotinib is N-(Cyanomethyl)-4- ⁇ 2-[4- (morpholin-4-yl)anilino]pyrimidin-4-yl ⁇ benzamide, and is represented by the structure of formula below:
  • Momelotinib is a potent, selective, and orally bioavailable JAK1, JAK2 & ACVR1 inhibitor which is being developed by Sierra Oncology, Inc. as a therapeutic agent in the treatment of myelofibrosis.
  • US 9809559 B2 discloses the PXRD and thermal characterization data for two forms of the di-hydrochloride salt (anhydrous Form I and monohydrate Form II) and two forms of the mono-hydrochloride salt (anhydrous Forms I and III).
  • crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. It is also well known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and, in some cases, different bioavailability patterns as compared to the crystalline form (Chem. Pharm. Bull. 1990, 38, 2003). For some therapeutic indications, one bioavailability pattern may be favored over another. Amorphous form of Cefuroxime axetil, Venetoclax and Apalutamide are good examples that exhibit higher bioavailability than the crystalline form. Therefore, it is desirable to have amorphous forms of drugs with high purity to meet the needs of regulatory agencies and also have highly reproducible processes for their preparation.
  • Amorphous solid dispersions of drugs are known to generally improve the stability and solubility of drug products.
  • dispersions are generally unstable over time.
  • Amorphous solid dispersions of drugs tend to convert to crystalline forms over time, which can lead to improper dosing due to differences of the solubility of crystalline drug material compared to amorphous drug material.
  • the present invention provides stable amorphous dispersions of Momelotinib di-hydrochloride.
  • the present invention provides solid dispersions of Momelotinib di-hydrochloride which may be reproduced easily and is amenable for processing into a dosage form.
  • Momelotinib free base exhibits low to extremely low solubility in common organic solvents (such as methanol, ethyl acetate, isopropanol, ethanol, acetonitrile and dichloromethane) and is quite resistant to purification via usually employed techniques such as re-crystallization, trituration and column chromatography.
  • US 8486941B2 describes the synthesis and NMR characterization of Momelotinib free base and its hydrochloride, sulfate and methanesulfonate salts.
  • the present inventors have observed that the process of preparation of Momelotinib free base via the neutralization of certain salt forms (e.g., hydrochloride, di -hydrochloride, besylate) of Momelotinib improves the chemical purity.
  • certain salt forms e.g., hydrochloride, di -hydrochloride, besylate
  • An aspect of the present invention provides an amorphous solid dispersion of di-hydrochloride salt of Momelotinib together with at least one pharmaceutically acceptable excipient.
  • Another aspect of the present invention provides a stable amorphous premix comprising an amorphous solid dispersion of di-hydrochloride salt of Momelotinib together with at least one pharmaceutically acceptable excipient and Syloid.
  • Another aspect of the present invention provides a process for the preparation of amorphous solid dispersion of di-hydrochloride salt of Momelotinib, comprising the steps of providing a solution of di-hydrochloride salt of Momelotinib together with at least one pharmaceutically acceptable excipient in a solvent and removing the solvent.
  • Yet another aspect of the present invention provides a process for the preparation of Momelotinib, comprising the step of releasing Momelotinib free base from its salt by neutralization.
  • Yet another aspect of the present invention provides the salt form of Momelotinib selected from the group consisting of -toluenesulfonate (tosylate), benzenesulfonate (besylate) and trifluoromethanesulfonate (triflate) salts of Momelotinib.
  • Yet another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising Momelotinib or its di-hydrochloride salt, obtained according to the processes of above aspects and at least one pharmaceutically acceptable excipient.
  • Figure 1 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Momelotinib di -hydrochloride and PVP K-30 prepared by the method of Example No. 2(a).
  • Figure 2 is an illustrative X-ray powder diffraction pattern of premix of amorphous solid dispersion of Momelotinib di -hydrochloride and PVP K-30 with Syloid prepared by the method of Example No. 2(b).
  • Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Momelotinib di-hydrochloride and Copovidone prepared by the method of Example No. 2(c).
  • Figure 4 is an illustrative X-ray powder diffraction pattern of premix of amorphous solid dispersion of Momelotinib di-hydrochloride and Copovidone with Syloid prepared by the method of Example No. 2(d).
  • Figure 5 is an illustrative X-ray powder diffraction pattern of Momelotinib dihydrochloride prepared by the method of Example No. 3(a).
  • Figure 6 is an illustrative X-ray powder diffraction pattern of Momelotinib mesylate prepared by the method of Example No. 3(b).
  • Figure 7 is an illustrative X-ray powder diffraction pattern of Momelotinib tosylate prepared by the method of Example No. 3(c).
  • Figure 8 is an illustrative X-ray powder diffraction pattern of Momelotinib besylate prepared by the method of Example No. 3(d).
  • Figure 9 is an illustrative X-ray powder diffraction pattern of Momelotinib triflate prepared by the method of Example No. 3(e).
  • Figure 10 is an illustrative X-ray powder diffraction pattern of Momelotinib sulfate prepared by the method of Example No. 3(f).
  • Figure 11 is an illustrative X-ray powder diffraction pattern of Momelotinib hydrochloride prepared by the method of Example No. 3(g).
  • Figure 12 is an illustrative X-ray powder diffraction pattern of Momelotinib free base prepared by the method of Example No. 4(h). DETAILED DESCRIPTION OF THE INVENTION
  • An aspect of the present invention provides an acid addition salt of Momelotinib, wherein salt is selected from a group comprising tosylate, besylate and triflate.
  • Another aspect of the present invention provides an acid addition salt of Momelotinib, wherein salt is selected from a group consisting tosylate, besylate and triflate.
  • Yet another aspect of the present invention provides a tosylate salt of Momelotinib, characterized by X-ray powder diffraction (XRPD) pattern comprising peaks at 4.46°, 10.38°, 13.90°, 14.74°, 16.53°, 23.07°, 20.33°, 23.92°, 26.34° and 27.78° ⁇ 0.2° 20 or an XRPD pattern as depicted in Figure 7.
  • XRPD X-ray powder diffraction
  • Yet another aspect of the present invention provides the tosylate salt, wherein an XRPD pattern comprising peaks at 8.90°, 9.47°, 11.44°, 13.32°, 15.27°, 16.20°, 17.36°, 19.07°, 19.63°, 20.80° and 22.26° ⁇ 0.2° 20.
  • Yet another aspect of the present invention provides the tosylate salt, wherein an XRPD pattern comprising peaks at 22.67°, 24.41°, 24.93°, 25.87°, 28.88°, 29.84°, 31.03°, 33.63°, 34.40°, 35.39°, 36.66° and 38.89° ⁇ 0.2° 20.
  • Yet another aspect of the present invention provides a besylate salt of Momelotinib, characterized by an XRPD pattern comprising peaks at 4.77°, 14.61°, 15.15°, 16.09°, 17.54°, 18.11°, 19.19°, 23.10°, 23.70°, and 24.49° ⁇ 0.2° 20 or an XRPD pattern as depicted in Figure 8.
  • Yet another aspect of the present invention provides the besylate salt, wherein an XRPD pattern comprising peaks at 8.29°, 9.55°, 10.31°, 10.87°, 11.62°, 13.16°, 13.85°, 14.12°, 18.93°, 19.86°, 20.72°, 21.85°, 22.54°, 23.38° and 24.85° ⁇ 0.2° 20.
  • Yet another aspect of the present invention provides the besylate salt, wherein an XRPD pattern comprising peaks at 25.78°, 26.35°, 27.22°, 28.06°, 28.80°, 29.92°, 31.08°, 31.60°, 33.05°, 33.63°, 34.70°, 34.87°, 35.55°, 36.88°, 37.28°, 38.37° and 39.02° ⁇ 0.2° 20.
  • Yet another aspect of the present invention provides a triflate salt of Momelotinib, characterized by an XRPD pattern comprising peaks at 15.13°, 18.09°, 19.09°, 20.24°, 21.29°, 21.71°, 22.89°, 24.10°, 27.77° and 30.32° ⁇ 0.2° 20 or an XRPD pattern as depicted in Figure 9.
  • Yet another aspect of the present invention provides the triflate salt, wherein an XRPD pattern comprising peaks at 5.38°, 8.40°, 9.89°, 10.14°, 10.58°, 10.88°, 11.59°, 13.56°, 13.91°, 15.33°, 15.80°, 16.30°, 17.35°, 18.52° and 19.73° ⁇ 0.2° 20.
  • Yet another aspect of the present invention provides the triflate salt, wherein an XRPD pattern comprising peaks at 23.51°, 25.23°, 25.64°, 26.60°, 27.33°, 28.12°, 28.56°, 30.74°, 31.38°, 32.17°, 35.16°, 36.34°, 37.86°, 38.25° and 38.85° ⁇ 0.2° 20.
  • Yet another aspect of the present invention provides the salt, wherein the salt is crystalline.
  • Yet another aspect of the present invention provides a solid dispersion comprising momelotinib di-hydrochloride and at least one pharmaceutically acceptable excipient.
  • Yet another aspect of the present invention provides the solid dispersion, wherein the solid dispersion is amorphous solid dispersion.
  • Yet another aspect of the present invention provides the solid dispersion, wherein the pharmaceutically acceptable excipient is selected from a group comprising polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone, vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene-polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol, monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose phthalate, hydroxyprop
  • Yet another aspect of the present invention provides the process for preparation of solid dispersion comprising the step of combining momelotinib di-hydrochloride with at least one pharmaceutically acceptable excipient in the presence of a suitable solvent.
  • Yet another aspect of the present invention provides the process, wherein the solvent is selected from a group comprising methanol, ethanol, 2-propanol, 1 -butanol, 2-butanol, 1 -pentanol, 2-pentanol, 3 -pentanol, tetrahydrofuran, 2-methyl- tetrahydrofuran, 1-4-di oxane, acetone, acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, water, and mixtures thereof.
  • the solvent is selected from a group comprising methanol, ethanol, 2-propanol, 1 -butanol, 2-butanol, 1 -pentanol, 2-pentanol, 3 -pentanol,
  • Yet another aspect of the present invention provides a process for the preparation of momelotinib free base, comprising preparing momelotinib salt and converting the momelotinib salt to momelotinib free base.
  • Yet another aspect of the present invention provides the process, wherein the salt is an acid addition salt.
  • Yet another aspect of the present invention provides the process, wherein the acid addition salt is selected from a group comprising hydrochloride, di-hydrochloride, bromide, sulfate, phosphate, perchlorate, formate, oxalate, trifluoroacetate, trichloroacetate, mesylate, tosylate, besylate, triflate, napsylate, camphorsulfonate and p-nitrobenzenesulfonate.
  • the acid addition salt of Momelotinib is selected from a group comprising tosylate, besylate, hydrochloride, di-hydrochloride or triflate.
  • Yet another aspect of the present invention provides the process, wherein the final momelotinib free base has a purity of more than about 98.5% by HPLC.
  • Yet another aspect of the present invention provides the process, wherein converting the momelotinib salt to momelotinib free base comprises neutralizing the momelotinib salt with a base.
  • the base is an inorganic base selected from a group comprising a hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, and a combination thereof, or an organic base selected from a group comprising tri ethylamine, diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and a combination thereof.
  • a solvent selected from a group comprising ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, MTBE, dioxane, and dimethoxy ethane; alcohols, such as methanol, ethanol, ethylene glycol, 1 -propanol, 2- propanol, 2-methoxy ethanol, 1 -butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, glycerol, and Ci-Ce alcohols; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, and chlorobenzene; aromatic hydrocarbons, such as toluene; aliphatic hydrocarbons such as hexane and heptane; nitriles such as acetonitrile; esters such as ethylenes, diethyl ether, diisopropyl ether,
  • Yet another aspect of the present invention provides the process, wherein the solvent is water.
  • momelotinib is crystalline.
  • Yet another aspect of the present invention provides a solid form of momelotinib free base characterized by an XRPD pattern comprising peaks at 4.21, 12.76, 15.26, 17.45, 20.01, 20.75, 21.72, 23.53, 26.13 and 28.02° ⁇ 0.2° 20 or an XRPD pattern as depicted in Figure 12.
  • Yet another aspect of the present invention provides the solid form, wherein an XRPD pattern comprising peaks at 8.36°, 10.15°, 11.13°, 11.96°, 13.96°, 15.99°, 16.37°, 18.69°, 24.12°, 24.53°, 25.53°, 27.11° and 29.30° ⁇ 0.2° 20.
  • Yet another aspect of the present invention provides the solid form, wherein an XRPD pattern comprising peaks at 29.84°, 30.88°, 31.47°, 32.87°, 33.39°, 34.07°, 34.54°, 35.11°, 35.78°, 37.23°, 38.06° and 39.07° ⁇ 0.2° 20.
  • Yet another aspect of the present invention provides the free base, wherein the free base is crystalline.
  • Yet another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an acid addition salt, or a solid dispersion, or a solid form, or a free base and optionally a pharmaceutically acceptable excipient.
  • Yet another aspect of the present invention provides a method of preventing or treating a condition or a disorder or a disease in a subject, comprising administering to the subject an effective amount of an acid addition salt, or a solid dispersion, or a solid form, or a free base or a pharmaceutical composition, wherein the condition or disorder or disease can be ameliorated with Janus kinase (JAK) inhibition.
  • JNK Janus kinase
  • Yet another aspect of the present invention provides an acid addition salt, or a solid dispersion, or a solid form, or a free base or a pharmaceutical composition, used for the condition or disorder or disease that can be ameliorated with Janus kinase (JAK) inhibition.
  • JK Janus kinase
  • compositions or a solid form or a free base or a process wherein at least one pharmaceutically acceptable excipient may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene-polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropy
  • Solid dispersions of the present application also include the solid dispersions obtained by combining di-hydrochloride salt of Momelotinib with a suitable non-polymeric excipient by employing techniques known in the art or procedures described or exemplified in any aspect of the present invention.
  • Another aspect of the present invention provides a stable amorphous premix comprising an amorphous solid dispersion of di-hydrochloride salt of Momelotinib together with at least one pharmaceutically acceptable excipient and Syloid.
  • Syloid may be Syloid 244 FP.
  • the amorphous solid dispersion of dihydrochloride salt of Momelotinib may be combined with Syloid or any other suitable additional pharmaceutically acceptable excipient to obtain premix of this aspect.
  • the amorphous solid dispersion of di-hydrochloride salt of Momelotinib may be combined with Syloid or any other suitable additional excipient using a technique known in art or according to the previous aspects of the present invention such as grinding together in mortar-pestle.
  • Yet another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising amorphous solid dispersion of di-hydrochloride salt of Momelotinib or premix thereof.
  • Yet another aspect of the present invention provides a process for the preparation of amorphous solid dispersion of di-hydrochloride salt of Momelotinib, comprising the step of providing a solution of di-hydrochloride salt of Momelotinib together with at least one pharmaceutically acceptable excipient in a solvent and removing the solvent.
  • the process produces amorphous solid dispersion of di-hydrochloride salt of Momelotinib.
  • the solvent may be selected from the group consisting of methanol, ethanol, 2-propanol, 1 -butanol, 2-butanol, 1 -pentanol, 2- pentanol, 3 -pentanol, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1-4-dioxane, acetone, acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, water, and mixtures thereof.
  • providing a solution may be carried out by dissolving di-hydrochloride salt of Momelotinib and at least one pharmaceutically acceptable excipient simultaneously or separately in same or different solvents.
  • a solution of di-hydrochloride salt of Momelotinib and the excipient may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
  • a solution of di-hydrochloride salt of Momelotinib and the excipient may be filtered to make it clear and free of unwanted particles.
  • the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
  • an adsorbent material such as carbon and/or hydrose
  • removal of solvent may be carried out by methods known in the art or any procedure disclosed in the present inventio.
  • removal of solvent may include, but not limited to solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Biichi® Rotavapor®, spray drying, freeze drying, agitated thin film drying and the like.
  • the solvent may be removed under reduced pressures, at temperatures of less than about 100 °C, less than about 80 °C, less than about 40 °C, less than about 20 °C, less than about 0 °C, less than about -20 °C, less than about -40 °C, less than about -60 °C, less than about -80 °C, or any other suitable temperatures.
  • the isolation of an amorphous solid dispersion of di-hydrochloride salt of Momelotinib with excipient involves recovering the solid obtained.
  • the solid may be recovered using techniques such as by scraping, or by shaking the container, or triturating with a solvent to make slurry followed by filtration, or other techniques specific to the equipment used.
  • the amorphous solid dispersion of di-hydrochloride salt of Momelotinib and excipient obtained may be optionally dried before or after isolating.
  • Yet another aspect of the present invention provides a process for the preparation of Momelotinib, comprising the step of releasing Momelotinib free base from its salt by neutralization.
  • Suitable bases may include, but are not limited to hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, or the like; alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkali metal bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, or the like; organic bases, such as triethylamine, diisopropylethylamine, pyridine, 2,6-dimethylpyridine or the like.
  • hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, or the like
  • alkali metal carbonates such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like
  • alkali metal bicarbonates such as, for example, sodium bicarbonate, potassium bicarbonate, or the like
  • organic bases such as triethylamine, diisoprop
  • neutralization may be carried out at a suitable temperature of about 0 °C or above.
  • the salt may be treated with a base at a suitable temperature of about 0 °C or above.
  • Momelotinib may be obtained as solid directly on neutralization of the salt of Momelotinib.
  • solid may be precipitated by cooling or addition of anti-solvent to the reaction mixture containing Momelotinib.
  • the solid Momelotinib obtained according to the process of this aspect may be separated according suitable techniques such as filtration or centrifugation.
  • the solid Momelotinib may be dried under suitable drying conditions such as suitable temperature and pressure.
  • the solid form of Momelotinib obtained according to the process of this aspect may be in amorphous state.
  • the solid form of Momelotinib obtained according to the process of this aspect may be any crystalline form reported in the literature.
  • the inventors have identified that the process of preparation of Momelotinib through the neutralization of certain salt forms of Momelotinib surprisingly improves the chemical purity significantly as illustrated below. % (NH40Hwas used for neutralization)
  • Yet another aspect of the present invention provides Momelotinib obtained according to the processes of the present invention, having a chemical purity of at least 99% or at least 99.5 or at least 99.9%, by HPLC.
  • Momelotinib or its pharmaceutically acceptable salt or free base may be prepared according to any of the methods known in the art (J. Heterocycl. Chem., 2017, 54, 2902-2905 and J. Chem. Res., 2016, 40, 511- 513).
  • ASDs of Momelotinib salt is used for the treatment of cancer such as myelofibrosis.
  • inert solvent when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ⁇ 10%, preferably within a range of ⁇ 5%, more preferably within a range of ⁇ 2%, still more preferably within a range of ⁇ 1 % of its value.
  • inert solvent when used in the present application is a solvent that does not react with the reactants or reagents under conditions that cause the chemical reaction indicated to take place.
  • amorphous amorphous denotes that 90 %, preferably 95 % or 99 %, more preferably all of the di-hydrochloride salt of Momelotinib being present in the solid dispersion, on the adsorbate or in the pharmaceutical composition is amorphous.
  • an "amorphous" Momelotinib di-hydrochloride salt composition denotes a Momelotinib di-hydrochloride salt-containing composition, which does not contain substantial amounts, preferably does not contain noticeable amounts, of crystalline portions of Momelotinib di-hydrochloride salt e.g., measurable upon X-ray powder diffraction analysis.
  • solid dispersion when used in the present application, denotes a state where most of the di -hydrochloride salt of Momelotinib, preferably 90%, 95% or all of the di-hydrochloride salt of Momelotinib of the solid dispersion, is homogeneously molecularly dispersed in a solid polymer matrix.
  • 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 components form a homogeneous one- phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size.
  • no chemical bonds can be detected between the API and the polymer.
  • it is required to have a substantial amount of API dissolved in a suitable solvent at least at one time point during preparation of said solid dispersion.
  • Momelotinib may be prepared according to any of the methods known in the art such as Heterocycl. Chem., 2017, 54, 2902-2905 and J. Chem. Res., 2016, 40, 511-513 (Scheme 1).
  • Example 2 Preparation of amorphous solid dispersion (ASD) of Momelotinib dihydrochloride (a): Preparation of ASD with PVP K-30.

Abstract

La présente invention concerne les dispersions solides amorphes (ASD) de di-chlorhydrate de momélotinib et leurs procédés de préparation. Par rapport à une forme cristalline, une forme amorphe stable de di-chlorhydrate de momélotinib améliore la solubilité du médicament. Les dispersions solides amorphes stables de di-chlorhydrate de momélotinib selon l'invention peuvent être facilement reproduites et se prêtent à une transformation en forme posologique. La présente invention concerne en outre des procédés de préparation de sels de momélotinib et leur utilisation en tant que moyen de purification de la base libre. En outre, le procédé de préparation de la base libre de momélotinib par neutralisation de certaines formes de sels de momélotinib améliore significativement la pureté chimique de la base libre.
PCT/IN2023/050151 2022-02-14 2023-02-14 Formes solides de sels de momélotinib et procédés améliorés pour la préparation de momélotinib WO2023152773A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101861313A (zh) * 2007-03-12 2010-10-13 西托匹亚研究有限公司 苯基氨基嘧啶化合物及其用途
WO2015191846A1 (fr) * 2014-06-12 2015-12-17 Gilead Sciences, Inc. Sels de chlorhydrate de n-(cyanométhyl)-4-(2-(4-morpholinophénylamino)pyrimidin-4-yl)benzamide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101861313A (zh) * 2007-03-12 2010-10-13 西托匹亚研究有限公司 苯基氨基嘧啶化合物及其用途
WO2015191846A1 (fr) * 2014-06-12 2015-12-17 Gilead Sciences, Inc. Sels de chlorhydrate de n-(cyanométhyl)-4-(2-(4-morpholinophénylamino)pyrimidin-4-yl)benzamide

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