WO2017163190A1 - Citrate d'ixazomib amorphe et dispersion solide de celui-ci - Google Patents

Citrate d'ixazomib amorphe et dispersion solide de celui-ci Download PDF

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Publication number
WO2017163190A1
WO2017163190A1 PCT/IB2017/051646 IB2017051646W WO2017163190A1 WO 2017163190 A1 WO2017163190 A1 WO 2017163190A1 IB 2017051646 W IB2017051646 W IB 2017051646W WO 2017163190 A1 WO2017163190 A1 WO 2017163190A1
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WO
WIPO (PCT)
Prior art keywords
ixazomib citrate
amorphous
solvent
solid dispersion
citrate
Prior art date
Application number
PCT/IB2017/051646
Other languages
English (en)
Inventor
Subba Reddy Peddi Reddy
Ajit Prabhakar WALKE
Original Assignee
Dr. Reddy’S Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Dr. Reddy’S Laboratories Limited filed Critical Dr. Reddy’S Laboratories Limited
Publication of WO2017163190A1 publication Critical patent/WO2017163190A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/04—Esters of boric acids

Definitions

  • the present invention provides amorphous Ixazomib citrate, solid dispersion thereof and processes for their preparation.
  • Ixazomib citrate is approved by US FDA under the brand name of Ninlaro . It is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. Ixazomib citrate is a prodrug which rapidly hydrolyzes under physiological conditions to its biologically active form, ixazomib.
  • US patent number 8859504 B2 describes crystalline Form 1 and Form 2 of Ixazomib citrate and processes for its preparation.
  • API active pharmaceutical ingredient
  • Processability of the API during manufacture of the pharmaceutical composition and characteristics of the finished dosage form, such as storage stability under difficult environmental conditions, such as high relative humidity and/or high temperature, can still be improved or optimized.
  • the presence of the high energy form of the API in a pharmaceutical composition (amorphous form) usually improves the dissolution rate.
  • An object of the present invention is to provide a pharmaceutical composition comprising ixazomib citrate in a solid form, wherein the physicochemical stability and the dissolution characteristics of the solid form is improved, and wherein ixazomib citrate is rendered more suitable for use in a pharmaceutical composition.
  • the present invention provides amorphous Ixazomib citrate.
  • the present invention provides a process for the preparation of amorphous Ixazomib citrate, comprising the steps; a) providing a solution of Ixazomib citrate in a solvent and,
  • the present invention provides a solid dispersion comprising amorphous Ixzomib citrate and one or more pharmaceutically acceptable carriers.
  • the present invention provides a process for the preparation of solid dispersion comprising amorphous Ixazomib citrate and one or more pharmaceutically acceptable carriers, comprising the steps: a) providing a solution comprising ixazomib citrate and one or more pharmaceutically acceptable carriers in a solvent, b) removing the solvent from the solution obtained in step (a) and, c) recovering a solid dispersion comprising amorphous Ixazomib citrate and one or more pharmaceutically acceptable carriers.
  • Fig. 1 illustrates the PXRD pattern of amorphous Ixazomib citrate, obtained by the procedure of Example 1 .
  • Fig. 2 illustrates the PXRD pattern of solid dispersion comprising amorphous Ixazomib citrate with PVP K-30 excipient, obtained by the procedure of Example 2.
  • Fig. 3 illustrates the PXRD pattern of solid dispersion comprising amorphous Ixazomib citrate with PVP K-30 & syloid 244 FP-NW excipients, obtained by the procedure of Example 2.
  • Fig. 4 illustrates the PXRD pattern of solid dispersion comprising amorphous Ixazomib citrate with Copovidone, obtained by the procedure of Example 3.
  • Fig. 5 illustrates the PXRD pattern of solid dispersion comprising amorphous Ixazomib citrate with Microcrystalline cellulose and Copovidone, obtained by the procedure of Example 3.
  • Fig. 6 illustrates the PXRD pattern of amorphous Ixazomib citrate, obtained by the procedure of Example 4.
  • Fig. 7 illustrates the PXRD pattern of solid dispersion comprising amorphous Ixazomib citrate with syloid 244 FP-NW, obtained by the procedure of Example 4.
  • Fig. 8 illustrates the PXRD pattern of solid dispersion comprising amorphous Ixazomib citrate with HPC excipient, obtained by the procedure of Example 5.
  • Fig. 9 illustrates the PXRD pattern of solid dispersion comprising amorphous Ixazomib citrate with Eudragit excipient, obtained by the procedure of Example 6.
  • Fig. 10 illustrates the PXRD pattern of solid dispersion comprising amorphous Ixazomib citrate with Methyl Cellulose excipient, obtained by the procedure of Example 7.
  • Fig. 1 1 illustrates the PXRD pattern of amorphous Ixazomib citrate, obtained by the procedure of Example 8.
  • Fig. 12 illustrates the PXRD pattern of solid dispersion comprising amorphous Ixazomib citrate with Methyl Cellulose excipient, obtained by the procedure of Example 8.
  • the present invention provides amorphous Ixazomib citrate.
  • the amorphous Ixazomib citrate characterized by PXRD pattern provided in Fig.1 , Fig.6 and Fig.1 1 .
  • the present invention provides a process for the preparation of amorphous Ixazomib citrate, comprising the steps; c) providing a solution of Ixazomib citrate in a solvent and,
  • Providing a solution of Ixazomib citrate in step a) includes: i) direct use of a reaction mixture containing Ixazomib citrate that is obtained in the course of its synthesis; or ii) dissolving Ixazomib citrate in a solvent.
  • any physical form of Ixazomib citrate may be utilized for providing the solution of Ixazomib citrate in step a).
  • the dissolution temperatures may range from about 0 °C to about the reflux temperature of the solvent, or less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of Ixazomib citrate is obtained without affecting its quality.
  • the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material.
  • the solution obtained above may be filtered to remove any insoluble particles.
  • the insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure.
  • the solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow.
  • the filtration apparatus may need to be preheated to avoid premature crystallization.
  • Ixazomib citrate can be dissolved in the following solvents.
  • the solvents comprises alcohols, such as methanol, ethanol, 1 -propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1 -butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t- pentyl alcohol, diethylene glycol monomethyl ether, cyclohexanol, glycerol, or C1 -C6 alcohols and the like; nitriles, such as acetonitrile or propionitrile; amides, such as formamide, ⁇ , ⁇ -dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or hexamethyl phosphoric triamide and the like
  • the quantity of solvent used for dissolution depends on the solvent and the dissolution temperature adopted.
  • the concentration of Ixazomib citrate in the solution may generally range from about 0.1 to about 10 g/ml in the solvent.
  • Step b) involves isolating amorphous Ixazomib citrate from the solution obtained in step a).
  • Isolation of amorphous Ixazomib citrate in step b) may involve methods including removal of solvent, cooling, crash cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, fast solvent evaporation, rotational drying, spray drying, thin-film drying, agitated thin film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, rotary vacuum paddle dryer, adding anti-solvent or the like.
  • Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
  • the amorphous Ixazomib citrate as isolated may carry some amount of occluded mother liquor and may have higher than desired levels of impurities. If desired, this amorphous form may be washed with a solvent or a mixture of solvents to wash out the impurities.
  • Suitable temperatures for isolation may be less than about 120 °C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.
  • the recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the Ixazomib citrate is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.
  • the present invention provides a solid dispersion comprising amorphous Ixzomib citrate and one or more pharmaceutically acceptable carriers.
  • solid dispersion defines a system in a solid state wherein one component is dispersed more or less evenly throughout the other component or components, e.g. in the context of the present invention amorphous ixazomib citrate within the polymer.
  • the absence of peaks on the X-ray powder diffractogram of the solid dispersion of the invention suggests that, in the solid dispersion of the present invention ixazomib citrate is amorphous.
  • the solid dispersion of the present invention is obtainable as a solid dispersion that is stable and pure with regard to the physical form of amorphous ixazomib citrate therein, and that is obtainable in an easy and reliable manner, e.g. even in large scale.
  • the present invention further describes processes for the preparation of the solid dispersion.
  • the present invention provides a process for the preparation of solid dispersion comprising amorphous Ixazomib citrate and one or more pharmaceutically acceptable carriers, comprising the steps: a) providing a solution comprising ixazomib citrate and one or more pharmaceutically acceptable carriers in a solvent b) removing the solvent from the solution obtained in step (a) and c) recovering the solid dispersion comprising amorphous Ixazomib citrate and one or more pharmaceutically acceptable carriers.
  • Step a) involves providing a solution of Ixazomib citrate and at least one pharmaceutically acceptable carrier in a solvent;
  • Step a) may involve forming a solution of Ixazomib citrate and one or more pharmaceutically acceptable carriers.
  • the carrier enhances stability of the amorphous solid upon removal of solvent.
  • Providing the solution in step a) includes: i) direct use of a reaction mixture containing Ixazomib citrate that is obtained in the course of its manufacture, if desired, after addition of one or more pharmaceutically acceptable carriers; or ii) dissolution of Ixazomib citrate in a solvent, either alone or in combination with one or more pharmaceutically acceptable carriers.
  • the quantity of solvent used for dissolution depends on the solvent and the dissolution temperature adopted.
  • the concentration of Ixazomib citrate in the solution may generally range from about 0.1 to about 10 g/ml in the solvent.
  • Ixazomib citrate Any physical form of Ixazomib citrate, such as crystalline, amorphous or their mixtures may be utilized for providing a solution in step a).
  • Pharmaceutically acceptable carriers that may be used in step a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones (PVP), PVP K-30, copovidone, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like
  • Ixazomib citrate and the pharmaceutically acceptable carrier may be dissolved either in the same solvent or they may be dissolved in different solvents and then combined to form a mixture.
  • the solid dispersion described herein comprises amorphous Ixazomib citrate and the carrier present in weight ratios ranging from about 5:95 to about 95:5; for example the ratio is about 50:50.
  • the dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of Ixazomib citrate is obtained without affecting its quality.
  • the solution may optionally be treated with carbon, flux- calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material.
  • the solution obtained above may be filtered to remove any insoluble particles.
  • the insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure.
  • the solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow.
  • the filtration apparatus may need to be preheated to avoid premature crystallization.
  • the solvents that may be used in step a) include but are not limited to: alcohols, such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1 -butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, cyclohexanol, or CrC 6 alcohols and the like; nitriles, such as acetonitrile or propionitrile; amides, such as formamide, ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone, or hexamethyl phosphoric triamide and the like; sulfoxides, such as dimethylsulfoxide and the like.
  • Step b) involves removal of the solvent from the solution comprising ixazomib citrate and one or more pharmaceutically acceptable carriers.
  • the solvent can be removed using the techniques such as evaporation, spray drying and other conventional techniques.
  • Step c) involves recovering the solid dispersion comprising amorphous Ixazomib citrate and one or more pharmaceutically acceptable carriers.
  • a solid dispersion comprising amorphous Ixazomib citrate and one or more pharmaceutically acceptable carriers may be isolated from a solution comprising ixazomib citrate and one or more pharmaceutically acceptable carriers in a solvent by using the conventional methods.
  • the methods includes but not limited to cooling, crash cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, fast solvent evaporation, rotational drying, spray drying, thin-film drying, agitated thin- film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
  • the amorphous Ixazomib citrate as isolated may carry some amount of occluded mother liquor and may have higher than desired levels of impurities. If desired, this amorphous form may be washed with a solvent or a mixture of solvents to wash out the impurities.
  • the recovered solid dispersion may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the Ixazomib citrate is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes.
  • Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.
  • the present invention also provides a pharmaceutical composition comprising the solid dispersion as described above.
  • the pharmaceutical composition of the present invention may be formulated in accordance with conventional methods, and may be prepared in the form of oral formulations such as tablets, pills, powders, capsules, syrups, emulsions, micro emulsions, and others, or formulation for parenteral injection, e.g., intramuscular, intravenous, or subcutaneous administration.
  • the pharmaceutical composition of the present invention may comprise the inventive solid dispersion, and any possible carrier and excipient

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

Abstract

La présente invention concerne un citrate d'ixazomib amorphe et un procédé de préparation de celui-ci. La présente invention concerne en outre une dispersion solide de citrate d'ixazomib amorphe et son procédé de préparation.
PCT/IB2017/051646 2016-03-23 2017-03-22 Citrate d'ixazomib amorphe et dispersion solide de celui-ci WO2017163190A1 (fr)

Applications Claiming Priority (2)

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IN201641010201 2016-03-23
IN201641010201 2016-03-23

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WO2017163190A1 true WO2017163190A1 (fr) 2017-09-28

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018158697A1 (fr) * 2017-03-03 2018-09-07 Fresenius Kabi Oncology Limited Procédé de préparation de citrate d'ixazomib
CN117964650A (zh) * 2024-03-28 2024-05-03 成都硕德药业有限公司 一种枸橼酸伊沙佐米的制备方法
WO2024097905A1 (fr) 2022-11-02 2024-05-10 Celgene Corporation Méthodes de traitement au moyen d'une thérapie par lymphocytes t et d'une thérapie d'entretien par agent immunomodulateur

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009154737A1 (fr) * 2008-06-17 2009-12-23 Millennium Pharmaceuticals, Inc. Composés de borates esters et compositions pharmaceutiques contenant des composés
WO2016165677A1 (fr) * 2015-04-15 2016-10-20 Zentiva, K.S. Nouvelles formes du citrate d'ixazomib
WO2017046815A1 (fr) * 2015-09-16 2017-03-23 Mylan Laboratories Limited Polymorphes de citrate d'ixazomib et leurs procédés de préparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009154737A1 (fr) * 2008-06-17 2009-12-23 Millennium Pharmaceuticals, Inc. Composés de borates esters et compositions pharmaceutiques contenant des composés
WO2016165677A1 (fr) * 2015-04-15 2016-10-20 Zentiva, K.S. Nouvelles formes du citrate d'ixazomib
WO2017046815A1 (fr) * 2015-09-16 2017-03-23 Mylan Laboratories Limited Polymorphes de citrate d'ixazomib et leurs procédés de préparation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018158697A1 (fr) * 2017-03-03 2018-09-07 Fresenius Kabi Oncology Limited Procédé de préparation de citrate d'ixazomib
WO2024097905A1 (fr) 2022-11-02 2024-05-10 Celgene Corporation Méthodes de traitement au moyen d'une thérapie par lymphocytes t et d'une thérapie d'entretien par agent immunomodulateur
CN117964650A (zh) * 2024-03-28 2024-05-03 成都硕德药业有限公司 一种枸橼酸伊沙佐米的制备方法
CN117964650B (zh) * 2024-03-28 2024-06-07 成都硕德药业有限公司 一种枸橼酸伊沙佐米的制备方法

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