WO2018173071A1 - Novel crystalline forms of ixazomib citrate and its process for preparation thereof - Google Patents

Novel crystalline forms of ixazomib citrate and its process for preparation thereof Download PDF

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WO2018173071A1
WO2018173071A1 PCT/IN2018/050157 IN2018050157W WO2018173071A1 WO 2018173071 A1 WO2018173071 A1 WO 2018173071A1 IN 2018050157 W IN2018050157 W IN 2018050157W WO 2018173071 A1 WO2018173071 A1 WO 2018173071A1
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formula
solvents
ixazomib citrate
crystalline form
compound
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PCT/IN2018/050157
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French (fr)
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Thirumalai Rajan Srinivasan
Eswaraiah Sajja
Rajeshwar Reddy Sagyam
Srinivasulu Rangineni
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Msn Laboratories Private Limited, R&D Center
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Publication of WO2018173071A1 publication Critical patent/WO2018173071A1/en

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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 System
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • 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 pertains to crystalline forms of Ixazomib citrate and its process for preparation thereof.
  • the chemical structure of said compound represented by the following formula-I.
  • Ixazomib citrate The chemical name l,3,2-dioxaborolane-4,4-diacetic acid, 2-[(li?)-l-[[2-[(2,5- dichlorobenzoyl) amino] acetyl] amino] -3-methylbutyl]-5-oxo- or 4-(R,S)-(carboxymethyl)-2- ((R)-l-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-l,3,2-dioxaborinane-4- carboxylic acid are generically known as Ixazomib citrate. Ixazomib citrate is a prodrug, rapidly hydrolyzes under physiological conditions to its biologically active form, boronic acid or Ixazomib which is shown in below chemical structure.
  • Ixazomib belongs to the chemical class of peptide boronic acid derivative compounds and inhibits the chymotrypsin-like subunit (beta 5) of the 20S proteasome reversibly.
  • Ixazomib citrate is a proteasome inhibitor used in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.
  • Ixazomib citrate was approved under the brand name of Ninlaro® by USFDA in November 2015 to Millennium Pharmaceuticals Inc.
  • Ninlaro® capsule was available with dosage strength of 2.3mg, 3mg and 4mg for oral administration.
  • WO 2016/155684 discloses a process for the preparation of Ixazomib citrate and its polymorph Form-3.
  • the process described in WO '684 is treating of the compound of formula-V with boric acid and citric acid to provide the Ixazomib citrate.
  • WO 2016/165677 discloses ethanol and isopropanol solvate forms of Ixazomib citrate.
  • polymorphism occurred because the difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound.
  • the first aspect of the present invention is to provide novel crystalline form of Ixazomib citrate of formula-I ((herein after designated as "crystalline Form-M”) and its process for preparation thereof.
  • the second aspect of the present invention is to provide another novel crystalline form of Ixazomib citrate of formula-I (herein after designated as "crystalline Form-S") and its process for preparation thereof.
  • the third aspect of the present invention is to provide solid dispersion of Ixazomib citrate of formula-I and its process for preparation thereof.
  • the fourth aspect of the present invention is to provide a novel crystalline form of Ixazomib citrate of formula-I (hereinafter referred as "crystalline Form-N") and process for preparation thereof.
  • the fifth aspect of the present invention is to provide a novel crystalline form of Ixazomib citrate of formula-I (hereinafter referred as "crystalline Form-L”) and process for preparation thereof.
  • the sixth aspect of the present invention is to provide a novel crystalline form of Ixazomib citrate of formula-I (hereinafter referred as "crystalline Form-R") and process for preparation thereof.
  • crystalline Form-R novel crystalline form of Ixazomib citrate of formula-I
  • the seventh aspect of the present invention is to provide a process for the preparation of Ixazomib citrate of formula-I.
  • FIG.l Illustrates the Powdered X-Ray Diffraction (PXRD) Pattern of the crystalline Form-M of Ixazomib citrate.
  • FIG.2 Illustrates the PXRD Pattern of the crystalline Form-S of Ixazomib citrate.
  • FIG.3 Illustrates a characteristic Powdered X-Ray Diffraction (PXRD) pattern of crystalline Form-N of Ixazomib citrate.
  • PXRD Powdered X-Ray Diffraction
  • FIG.4 Illustrates a characteristic Powdered X-Ray Diffraction (PXRD) pattern of crystalline Form-L of Ixazomib citrate.
  • PXRD Powdered X-Ray Diffraction
  • FIG.5 Illustrates a characteristic Powdered X-Ray Diffraction (PXRD) pattern of crystalline Form-R of Ixazomib citrate.
  • PXRD Powdered X-Ray Diffraction
  • FIG.6 Illustrates the PXRD Pattern of the solid dispersion of Ixazomib citrate with polyvinylpyrrolidone (PVP K-30).
  • FIG.7 Illustrates the PXRD Pattern of the solid dispersion of Ixazomib citrate with hydroxy propyl methyl cellulose (HPMC) and hydroxy propyl cellulose (HPC).
  • FIG.8 Illustrates the PXRD Pattern of the solid dispersion of Ixazomib citrate with hydroxypropyl beta cyclodextrin.
  • suitable solvent refers to the solvent selected from “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, teri-butanol and isobutanol; “chloro solvents” such as to methylene chloride, chloroform, ethylene dichloride and carbon tetra chloride; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone; “hydrocarbon solvents” such as n-hexane, heptane, cyclohexane, benzene, toluene, cycloheptane, methylcyclohexane, m-, o-, or p- xylene and the like; “nitrile solvents” such as acetonitrile; “ester solvents” such as ethyl acetate
  • suitable base refers to the bases selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; organic bases such as alkali metal alkoxides such as sodium tertiary butoxide, potassium tertiary butoxide; methylamine, ethylamine, isopropylamine, diisopropyl ethylamine, triethylamine / and ammonia or their aqueous solution.
  • alkali metal hydroxides such as sodium hydroxide, potassium hydroxide
  • alkali metal carbonates such as sodium carbonate, potassium carbonate and alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate
  • organic bases such as alkali metal alkoxides such as sodium tertiary butoxide, potassium tertiary butoxide
  • suitable condensing agent or suitable coupling agent refers to ⁇ , ⁇ -dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide(DIC), carbonyldiimidazole (CDI), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), (l-[bis(dimethylamino)methylene]-lH-l ,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluoro phosphate (HATU), alkyl or aryl chloroformates such as ethyl chloroformate, benzylchloroformate, diphenylphosphoryl azide (DPPA), benzotriazol-l-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP)
  • the first aspect of the present invention provides crystalline Form-M of Ixazomib citrate of formula-I and it is characterized by its PXRD pattern substantially in accordance with figure- 1.
  • the further embodiment of the present invention provides a process for the preparation of crystalline Form-M of Ixazomib citrate, comprising:
  • step-a) adding suitable anti-solvent to the reaction mixture obtained in step-a) at a suitable temperature
  • step a) isolating crystalline Form-M of Ixazomib citrate of formula-I.
  • the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, polar aprotic solvents, ether solvents, alcoholic solvents, polar solvents and/or mixtures thereof and the suitable temperature is 0°C to reflux temperature of a solvent used;
  • the suitable anti-solvent is selected from the hydrocarbon solvents such as n- hexane, heptane, benzene, toluene, xylene, cyclohexane and the like and the suitable temperature is 0-5°C; in step-e) isolation may be affected by removing the solvent and then dried for morethan 7 hours.
  • Suitable techniques which may be used for the removal of solvent include filtration, using a rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization), and the like or any other suitable technique.
  • a rotational distillation device such as a Buchi Rotavapor
  • spray drying agitated thin film drying
  • freeze drying lyophilization
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline Form-M of Ixazomib citrate of formula-I, comprising:
  • step-d) isolating the product obtained in step-d) and drying for about 7 hours to get crystalline Form-M of Ixazomib citrate.
  • the second aspect of the present invention provides crystalline Form-S of Ixazomib citrate of formula-I and it is characterized by its PXRD pattern substantially in accordance with figure-2.
  • the further embodiment of the present invention provides a process for the preparation of crystalline Form-S of Ixazomib citrate, comprising:
  • step-a) adding suitable anti-solvent to the reaction mixture obtained in step-a) at a suitable temperature
  • step e) isolating the product obtained in step-d) and then drying for about 5 hours to get crystalline Form-S of Ixazomib citrate of formula-I.
  • the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, polar aprotic solvents, ether solvents, alcoholic solvents, polar solvents and/or mixtures thereof and the suitable temperature is 25°C to reflux temperature of a solvent used
  • step-b) the suitable anti-solvent is selected from the hydrocarbon solvents such as n- hexane, heptane, benzene, toluene, xylene, cyclohexane and the like and the suitable temperature is 0-5°C
  • step-e) isolation may be affected by removing the solvent and then drying for about 5 hours; suitable techniques which may be used for the removal of solvent including filtration, using a rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline Form-S of Ixazomib citrate, comprising the steps of: a) dissolving Ixazomib citrate of formula-I in a mixture of tetrahydrofuran and ethanol at 60-65°C,
  • step-d) isolating the product obtained in step-d) and drying for about 5 hours to get crystalline Form-S of Ixazomib citrate.
  • the third aspect of the present invention provides crystalline Form-N of Ixazomib citrate.
  • Crystalline Form-N of the present invention is characterized by its powder X-ray diffraction (PXRD) pattern having characteristic peaks at about 7.7, 13.1, 14.1, 18.1 and 22.6 ⁇ 0.2 degrees of two-theta.
  • PXRD powder X-ray diffraction
  • the crystalline Form-N of Ixazomib citrate is further characterized by its powder X- ray diffraction (PXRD) pattern having characteristic peaks at about 7.7, 8.4, 11.4, 13.1, 14.1 18.1, 18.8, 21.0, 22.6, 30.2 and 31.3 ⁇ 0.2 degrees of two-theta.
  • PXRD powder X- ray diffraction
  • the crystalline Form-N of Ixazomib citrate is further characterized by its PXRD pattern as illustrated in figure-3.
  • said crystalline Form-N is stable under stress conditions at 60°C for 24 hours, 10 tons of pressure, hygroscopic conditions at 75% RH for 24 hours and under UV light at 254nm for 24 hours.
  • step-a) the suitable organic acid is selected from C1-C5 carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid or mixtures thereof; the suitable temperature is ranges between 25°C to the reflux temperature of the acid which is used; in step-c) the suitable solvent is selected from "ether solvents” such as methyl tert -butyl ether, dimethyl ether, diisopropyl ether, diethyl ether, 1,3-dioxane, 1,4-dioxane tetrahydrofuran; "hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene,
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline Form-N of Ixazomib citrate, comprising:
  • step-c) combining the reaction mixture obtained in step-c) with methyl tert-butyl ether, e) filtering the precipitated solid and drying at about 100°C to provide the crystalline Form-N of Ixazomib citrate.
  • the another embodiment of the present invention provides crystalline Form-N of Ixazomib citrate can be prepared from any other crystalline forms of Ixazomib citrate known in the art or treating the compound of formula-V with isobutyl boronic acid, citric acid and optionally in presence of crystalline Form-N seed crystal.
  • the fourth aspect of the present invention provides crystalline Form-L of Ixazomib citrate.
  • Crystalline Form-L of the present invention is characterized by its powder X-ray diffraction (PXRD) pattern having characteristic peaks at about 7.2, 7.6, 11.1, 16.7, 19.7, 21.6 and 29.8 ⁇ 0.2 degrees of two-theta.
  • the crystalline Form-L of Ixazomib citrate is further characterized by its PXRD pattern as illustrated in figure-4.
  • the other embodiment of the present invention provides a process for the preparation of crystalline Form-L of Ixazomib citrate, comprising:
  • step-b) combining the reaction mixture obtained in step-b) with a suitable solvent at a suitable temperature
  • step-a) the suitable organic acid is selected from C1-C5 carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid or mixtures thereof; the suitable temperature is ranges between 25°C to the reflux temperature of the acid which is used; in step-c) the suitable solvent is selected from "ether solvents" such as methyl tert -butyl ether, dimethyl ether, diisopropyl ether, diethyl ether, 1,3-dioxane, 1,4-dioxane tetrahydrofuran; "hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene; ester solvents such as methyl acetate, ethyl acetate, is
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline Form-L of Ixazomib citrate, comprising:
  • step-c) combining the reaction mixture obtained in step-c) with methyl tert-butyl ether, e) filtering the precipitated solid to provide crystalline Form-L of Ixazomib citrate.
  • the fifth aspect of the present invention provides Ixazomib citrate crystalline Form-R.
  • Crystalline Form-R of the present invention is characterized by its powder X-ray diffraction (PXRD) pattern having characteristic peaks at about 6.0, 10.4 and 14.1 ⁇ 0.2 degrees of two-theta.
  • the crystalline Form-R of Ixazomib citrate is further characterized by its PXRD pattern as illustrated in figure-5.
  • the another embodiment of the present invention provides a process for the preparation of Ixazomib citrate crystalline Form-R, comprising: a) providing Ixazomib citrate in a mixture of benzoyl alcohol, acetic acid and isobutyl acetate at 25-30°C,
  • the sixth aspect of the present invention provides a solid dispersion of Ixazomib citrate of formula-I in combination with one or more pharmaceutically acceptable carrier.
  • the composition of the solid dispersion consist of a ratio of the amount of the compound of formula-I to the amount of the pharmaceutically acceptable carrier therein ranges from about 1 : 0.1 to 1 : 10 (w/w).
  • the composition of Ixazomib citrate with pharmaceutically acceptable carrier preferably microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), hydroxypropylcellulose (HPC), hydroxy propyl beta cyclodextrin, hypromellose acetate succinate (HPMCAS) is about 1 :0.1 to 1: 10 (w/w).
  • the further embodiment of the present invention provides a process for the preparation of a solid dispersion of Ixazomib citrate of formula-I, comprising:
  • the suitable solvent is selected from alcoholic solvents, chloro solvents, ester solvents, polar aprotic solvents, ketone solvents, hydrocarbon solvents and polar solvent like water or mixture thereof;
  • the suitable pharmaceutically acceptable carrier is selected from cellulose derivatives such as cellulose acetate, cellulose nitrate, cellulose xanthate, carboxy methyl cellulose, micro crystalline cellulose, methyl cellulose, ethyl cellulose and hydroxy ethyl cellulose, hydroxy propyl methyl, hydroxy propyl beta cyclodextrin; polyvinylpyrrolidone;
  • the suitable temperature is ranging from 25°C to reflux temperature of the solvent which is used; in step-b) isolation may be affected by removing the solvent; suitable techniques which may be used for the removal of solvent include filtration, using a rotational distillation device such as a Buchi Rotavapor, spray drying,
  • the seventh aspect of the present invention provides a process for the preparation of Ixazomib citrate of the formula-I, comprising: a) reacting the compound of formula-II with glycine in presence of a base in a suitable solvent to provide the compound of formula-Ill,
  • Formula-II Glycine Formula-Ill b) reacting the compound of formula-Ill with the compound of formula-IV in presence of suitable coupling agent, suitable base in a suitable solvent to provide the compound of
  • step-a) step-b) and step-c) the suitable solvent is selected from alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol and isobutanol; chloro solvents such as methylene chloride, chloroform; ketone solvents such as acetone, methyl ethyl ketone; hydrocarbon solvents such as n-hexane, heptane, toluene, benzene; nitrile solvents” such as acetonitrile; "ester solvents” such as ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate and tert -butyl acetate; ether solvents such as tetrahydrofuran, diethyl ether and methyl tert-butyl ether; polar solvents such as water; polar solvents such
  • the preferred embodiment of the present invention provides a process for the preparation of Ixazomib citrate of the formula-I, comprising: a) reacting the compound of formula-II with glycine in presence of sodium hydroxide or its aqueous solution in water and tetrahydrofuran to provide the compound of formula- Ill,
  • Formula-II Glycine Formula-Ill b) reacting the compound of formula-Ill with the compound of formula-IVa in presence of 0-(lH-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), diisopropylethylamine (DIPEA) in dimethylformamide to provide the compound of formula-V,
  • TBTU 0-(lH-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate
  • DIPEA diisopropylethylamine
  • the oral pharmaceutical composition may contain crystalline Form-M, crystalline Form-S, crystalline Form-N, crystalline Form-L, crystalline Form-R and solid dispersion of amorphous Ixazomib citrate obtained by the present invention and one or more additional ex- cipients such as diluents, binders, disintegrants and lubricants.
  • diluents include lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, microcrystalline cellulose, magnesium stearate and mixtures thereof.
  • Exemplary binders are selected from L-hydroxy propyl cellulose, povidone, hydroxypropyl methyl cellulose, hydroxylethyl cellulose and pre- gelatinized starch.
  • Exemplary disintegrants are selected from croscarmellose sodium, cros -povidone, sodium starch glycolate and low substituted hydroxylpropyl cellulose.
  • Exemplary lubricants are selected from sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, glyceryl behenate and colloidal silicon dioxide.
  • Example-2 Preparation of 2,5-dichloro-N-(2-(((R)-3-methyl-l-((3aS,4S,6S,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[d][l,3,2]dioxaborol-2-yl)butyl)amino)-2-oxoethyl )benzamide compound of formula (V).
  • Example-3 Preparation of Ixazomib citrate.
  • the compound of formula- V (10 gms) was added to toluene (150 ml) at 25-30°C.
  • Methanol (50 ml) was added to the reaction mixture at 25-30°C.
  • Isobutyl boronic acid (2.47 gms) and citric acid (4.65 gms) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 70-75 °C and filtered the reaction mixture through hiflow bed, washed with methanol. Stirred the obtained filtrate for 5 hours at 70-75°C. Distilled off the solvent completely from the reaction mixture under reduced pressure, co-distilled with methanol and again co-distilled with ethyl acetate.
  • Example-4 Preparation of Ixazomib citrate.
  • the compound of formula- V (20.0 gms) was added to ethyl acetate (400 ml) at 25- 30°C.
  • Example-5 Preparation of crystalline Form-M of Ixazomib citrate
  • Example-6 Preparation of crystalline Form-S of Ixazomib citrate
  • Ixazomib citrate (1.0 gm) was dissolved in a mixture of tetrahydrofuran/ethanol solution (10 ml, (1: 1)) at 60-65°C.
  • n-Heptane (30 ml) was added to the reaction mixture at 25- 30°C. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at same temperature. Filtered the precipitated solid, washed with n-heptane and then dried for about 5 hours to get the title compound. (Yield: 800 mgs).
  • Example 7 Preparation of crystalline Form-N of Ixazomib citrate.
  • Ixazomib citrate (5 gm) was added to formic acid (75 ml) at 25-30°C and stirred the reaction mixture for 10 min at same temperature. Reaction mixture was cooled to 0-5°C and stirred for 1 hour. Methyl tert-butyl ether (MTBE) (150 ml) was added to the reaction mixture at 0-5°C and stirred for 7 hours at same temperature. Filtered the precipitated solid and dried at 100°C for about 3 hours to afford crystalline Form-N of Ixazomib citrate.
  • MTBE Methyl tert-butyl ether
  • Example 8 Preparation of crystalline Form-L of Ixazomib citrate.
  • Ixazomib citrate (5 gm) was added to formic acid (75 ml) at 25-30°C and stirred the reaction mixture for 10 min at same temperature. Reaction mixture was cooled to 0-5°C and stirred for 1 hour. Methyl tert-butyl ether (MTBE) (150 ml) was added to the reaction mixture at 0-5°C and stirred for 7 hours at same temperature. Filtered the precipitated solid and dried for 15 min to afford crystalline Form-L of Ixazomib citrate.
  • MTBE Methyl tert-butyl ether
  • Ixazomib citrate (1 gr) was added to a mixture of acetic acid, benzoyl alcohol and isobutyl acetate (25 ml, 1: 1: 1) at 25-30°C. Heated the reaction mixture to 75-80°C and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with isobutyl acetate and then dried to afford the title compound. (Yield: 600 mg).
  • Ixazomib citrate 1.0 gms
  • PVP K-30 polyvinylpyrrolidone
  • Example-13 Preparation of solid dispersion of Ixazomib citrate

Abstract

The present invention related to novel crystalline forms of Ixazomib citrate of formula-I and its process for preparation thereof. The chemical structure of said compound represented by the following formula-I. This invention also provides a process for the preparation of Ixazomib citrate of formula-I and also its solid dispersions.

Description

NOVEL CRYSTALLINE FORMS OF IXAZOMIB CITRATE AND ITS PROCESS
FOR PREPARATION THEREOF
Related application
This patent application claims the benefit of priority of our Indian patent application numbers 201741009635 filed on 20th March 2017 and 201741044474 filed on 11th December 2017 which are incorporated herein by reference.
Field of the invention
The present invention pertains to crystalline forms of Ixazomib citrate and its process for preparation thereof. The chemical structure of said compound represented by the following formula-I.
Figure imgf000003_0001
Background of the invention
The chemical name l,3,2-dioxaborolane-4,4-diacetic acid, 2-[(li?)-l-[[2-[(2,5- dichlorobenzoyl) amino] acetyl] amino] -3-methylbutyl]-5-oxo- or 4-(R,S)-(carboxymethyl)-2- ((R)-l-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-l,3,2-dioxaborinane-4- carboxylic acid are generically known as Ixazomib citrate. Ixazomib citrate is a prodrug, rapidly hydrolyzes under physiological conditions to its biologically active form, boronic acid or Ixazomib which is shown in below chemical structure.
Figure imgf000003_0002
Ixazomib Ixazomib belongs to the chemical class of peptide boronic acid derivative compounds and inhibits the chymotrypsin-like subunit (beta 5) of the 20S proteasome reversibly. Ixazomib citrate is a proteasome inhibitor used in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.
Ixazomib citrate was approved under the brand name of Ninlaro® by USFDA in November 2015 to Millennium Pharmaceuticals Inc. Ninlaro® capsule was available with dosage strength of 2.3mg, 3mg and 4mg for oral administration.
US 8546608 (published on October 01, 2013) & US 7442830 (published on October 28, 2008) describes chemical compounds with markush structure that may include Ixazomib. However, there is no any specific process and its characterization reported in the above reference documents.
US 8859504 (Published on October 14, 2014) discloses Form-1 and Form-2 of crystalline Ixazomib citrate.
WO 2016/155684 (Published on October 06, 2016) discloses a process for the preparation of Ixazomib citrate and its polymorph Form-3. The process described in WO '684 is treating of the compound of formula-V with boric acid and citric acid to provide the Ixazomib citrate.
The major disadvantage with above process is partial conversion of starting material formula-V and requires repeated reactions to produce the final product. Hence, this process is tedious and not suitable for industrial scale up.
WO 2016/165677 (Published on October 20, 2016) discloses ethanol and isopropanol solvate forms of Ixazomib citrate.
Polymorphism occurred because the difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound.
The discovery of new crystalline or polymorphic form of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, bioavailability, pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
Hence, there is a significant need in the pharmaceutical industry to develop a novel crystalline forms and improved process for the preparation of Ixazomib citrate of formula-I.
Advantages of the present invention:
• Stable and novel crystalline forms of Ixazomib citrate.
• Use of isobutyl boronic acid and citric acid in a single stage for complete conversion of intermediate compound of formula-V to Ixazomib citrate.
Brief description of the invention
The first aspect of the present invention is to provide novel crystalline form of Ixazomib citrate of formula-I ((herein after designated as "crystalline Form-M") and its process for preparation thereof.
The second aspect of the present invention is to provide another novel crystalline form of Ixazomib citrate of formula-I (herein after designated as "crystalline Form-S") and its process for preparation thereof.
The third aspect of the present invention is to provide solid dispersion of Ixazomib citrate of formula-I and its process for preparation thereof.
The fourth aspect of the present invention is to provide a novel crystalline form of Ixazomib citrate of formula-I (hereinafter referred as "crystalline Form-N") and process for preparation thereof. The fifth aspect of the present invention is to provide a novel crystalline form of Ixazomib citrate of formula-I (hereinafter referred as "crystalline Form-L") and process for preparation thereof.
The sixth aspect of the present invention is to provide a novel crystalline form of Ixazomib citrate of formula-I (hereinafter referred as "crystalline Form-R") and process for preparation thereof.
The seventh aspect of the present invention is to provide a process for the preparation of Ixazomib citrate of formula-I.
Brief description of drawings
FIG.l: Illustrates the Powdered X-Ray Diffraction (PXRD) Pattern of the crystalline Form-M of Ixazomib citrate.
FIG.2: Illustrates the PXRD Pattern of the crystalline Form-S of Ixazomib citrate.
FIG.3: Illustrates a characteristic Powdered X-Ray Diffraction (PXRD) pattern of crystalline Form-N of Ixazomib citrate.
FIG.4: Illustrates a characteristic Powdered X-Ray Diffraction (PXRD) pattern of crystalline Form-L of Ixazomib citrate.
FIG.5: Illustrates a characteristic Powdered X-Ray Diffraction (PXRD) pattern of crystalline Form-R of Ixazomib citrate.
FIG.6: Illustrates the PXRD Pattern of the solid dispersion of Ixazomib citrate with polyvinylpyrrolidone (PVP K-30).
FIG.7: Illustrates the PXRD Pattern of the solid dispersion of Ixazomib citrate with hydroxy propyl methyl cellulose (HPMC) and hydroxy propyl cellulose (HPC).
FIG.8: Illustrates the PXRD Pattern of the solid dispersion of Ixazomib citrate with hydroxypropyl beta cyclodextrin.
Detailed description of the invention
Unless otherwise specified, as used herein the term "suitable solvent" refers to the solvent selected from "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, teri-butanol and isobutanol; "chloro solvents" such as to methylene chloride, chloroform, ethylene dichloride and carbon tetra chloride; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone; "hydrocarbon solvents" such as n-hexane, heptane, cyclohexane, benzene, toluene, cycloheptane, methylcyclohexane, m-, o-, or p- xylene and the like; "nitrile solvents" such as acetonitrile; "ester solvents" such as ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate and tert-butyl acetate; "ether solvents" such as tetrahydrofuran, diethyl ether and methyl tert-butyl ether; "polar solvents" such as water, "polar aprotic solvents" such as dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide.
As used herein the term "suitable base" refers to the bases selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; organic bases such as alkali metal alkoxides such as sodium tertiary butoxide, potassium tertiary butoxide; methylamine, ethylamine, isopropylamine, diisopropyl ethylamine, triethylamine / and ammonia or their aqueous solution.
As used herein the term "suitable condensing agent or suitable coupling agent" refers to Ν,Ν-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide(DIC), carbonyldiimidazole (CDI), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), (l-[bis(dimethylamino)methylene]-lH-l ,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluoro phosphate (HATU), alkyl or aryl chloroformates such as ethyl chloroformate, benzylchloroformate, diphenylphosphoryl azide (DPPA), benzotriazol-l-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP) and the like; optionally in combination with 1- hydroxy-7-azatriazole (HOAt), 1-hydroxybenzotriazole (HOBt), l-hydroxy-lH-l,2,3-triazole- 4-carboxylate (HOCt), 0-(lH-benzotriazol-l-yl)-N,N,N'N'-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu) and N-hydroxysulfosuccinimide.
The first aspect of the present invention provides crystalline Form-M of Ixazomib citrate of formula-I and it is characterized by its PXRD pattern substantially in accordance with figure- 1.
The further embodiment of the present invention provides a process for the preparation of crystalline Form-M of Ixazomib citrate, comprising:
a) dissolving Ixazomib citrate of formula-I in a suitable solvent,
b) adding suitable anti-solvent to the reaction mixture obtained in step-a) at a suitable temperature,
c) cooling the reaction mixture to 0-5°C,
d) stirring the reaction mixture,
e) isolating crystalline Form-M of Ixazomib citrate of formula-I. wherein in step a) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, polar aprotic solvents, ether solvents, alcoholic solvents, polar solvents and/or mixtures thereof and the suitable temperature is 0°C to reflux temperature of a solvent used; in step-b) the suitable anti-solvent is selected from the hydrocarbon solvents such as n- hexane, heptane, benzene, toluene, xylene, cyclohexane and the like and the suitable temperature is 0-5°C; in step-e) isolation may be affected by removing the solvent and then dried for morethan 7 hours. Suitable techniques which may be used for the removal of solvent include filtration, using a rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any other suitable technique.
The preferred embodiment of the present invention provides a process for the preparation of crystalline Form-M of Ixazomib citrate of formula-I, comprising:
a) dissolving Ixazomib citrate of formula-I in a mixture of tetrahydrofuran and etha- nol at 60-65°C,
b) adding n-heptane to the reaction mixture, c) cooling the reaction mixture to 0-5 °C,
d) stirring the reaction mixture,
e) isolating the product obtained in step-d) and drying for about 7 hours to get crystalline Form-M of Ixazomib citrate.
The second aspect of the present invention provides crystalline Form-S of Ixazomib citrate of formula-I and it is characterized by its PXRD pattern substantially in accordance with figure-2.
The further embodiment of the present invention provides a process for the preparation of crystalline Form-S of Ixazomib citrate, comprising:
a) dissolving Ixazomib citrate of formula-I in a suitable solvent,
b) adding suitable anti-solvent to the reaction mixture obtained in step-a) at a suitable temperature,
c) cooling the reaction mixture to 0-5°C
d) stirring the reaction mixture,
e) isolating the product obtained in step-d) and then drying for about 5 hours to get crystalline Form-S of Ixazomib citrate of formula-I. wherein in step a) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, polar aprotic solvents, ether solvents, alcoholic solvents, polar solvents and/or mixtures thereof and the suitable temperature is 25°C to reflux temperature of a solvent used; in step-b) the suitable anti-solvent is selected from the hydrocarbon solvents such as n- hexane, heptane, benzene, toluene, xylene, cyclohexane and the like and the suitable temperature is 0-5°C; in step-e) isolation may be affected by removing the solvent and then drying for about 5 hours; suitable techniques which may be used for the removal of solvent including filtration, using a rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any other suitable technique.
The preferred embodiment of the present invention provides a process for the preparation of crystalline Form-S of Ixazomib citrate, comprising the steps of: a) dissolving Ixazomib citrate of formula-I in a mixture of tetrahydrofuran and ethanol at 60-65°C,
b) adding n-heptane to the reaction mixture,
c) cooling the reaction mixture to 0-5°C,
d) stirring the reaction mixture,
e) isolating the product obtained in step-d) and drying for about 5 hours to get crystalline Form-S of Ixazomib citrate.
The third aspect of the present invention provides crystalline Form-N of Ixazomib citrate.
Crystalline Form-N of the present invention is characterized by its powder X-ray diffraction (PXRD) pattern having characteristic peaks at about 7.7, 13.1, 14.1, 18.1 and 22.6 ± 0.2 degrees of two-theta.
The crystalline Form-N of Ixazomib citrate is further characterized by its powder X- ray diffraction (PXRD) pattern having characteristic peaks at about 7.7, 8.4, 11.4, 13.1, 14.1 18.1, 18.8, 21.0, 22.6, 30.2 and 31.3 ± 0.2 degrees of two-theta.
The crystalline Form-N of Ixazomib citrate is further characterized by its PXRD pattern as illustrated in figure-3.
In yet another embodiment of the present invention said crystalline Form-N is stable under stress conditions at 60°C for 24 hours, 10 tons of pressure, hygroscopic conditions at 75% RH for 24 hours and under UV light at 254nm for 24 hours.
In yet another embodiment of the present invention provides a process for the preparation of crystalline Form-N of Ixazomib citrate, comprising:
a) providing Ixazomib citrate in a suitable organic acid,
b) stirring the reaction mixture at a suitable temperature,
c) combining the reaction mixture obtained in step-b) with a suitable solvent at a suitable temperature, d) filtering the precipitated solid and drying to provide the crystalline form N of Ixazomib citrate. wherein in step-a) the suitable organic acid is selected from C1-C5 carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid or mixtures thereof; the suitable temperature is ranges between 25°C to the reflux temperature of the acid which is used; in step-c) the suitable solvent is selected from "ether solvents" such as methyl tert -butyl ether, dimethyl ether, diisopropyl ether, diethyl ether, 1,3-dioxane, 1,4-dioxane tetrahydrofuran; "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate; "polar aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide; "chloro solvents" such as dichlorome thane, dichloroethane, chloroform, carbon tetrachloride; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, t-butanol; "polar solvents" such as water or mixtures thereof. In this step, the suitable solvent can be added to the reaction mixture or reaction mixture can be added to the suitable solvent.
The preferred embodiment of the present invention provides a process for the preparation of crystalline Form-N of Ixazomib citrate, comprising:
a) providing Ixazomib citrate in a formic acid at 25-30°C,
b) stirring the reaction mixture,
c) cooling the reaction mixture to 0-5°C and stirring,
d) combining the reaction mixture obtained in step-c) with methyl tert-butyl ether, e) filtering the precipitated solid and drying at about 100°C to provide the crystalline Form-N of Ixazomib citrate.
The another embodiment of the present invention provides crystalline Form-N of Ixazomib citrate can be prepared from any other crystalline forms of Ixazomib citrate known in the art or treating the compound of formula-V with isobutyl boronic acid, citric acid and optionally in presence of crystalline Form-N seed crystal.
The fourth aspect of the present invention provides crystalline Form-L of Ixazomib citrate.
Crystalline Form-L of the present invention is characterized by its powder X-ray diffraction (PXRD) pattern having characteristic peaks at about 7.2, 7.6, 11.1, 16.7, 19.7, 21.6 and 29.8 ± 0.2 degrees of two-theta. The crystalline Form-L of Ixazomib citrate is further characterized by its PXRD pattern as illustrated in figure-4.
The other embodiment of the present invention provides a process for the preparation of crystalline Form-L of Ixazomib citrate, comprising:
a) providing Ixazomib citrate in a suitable organic acid at a suitable temperature, b) stirring the reaction mixture at a suitable temperature,
c) combining the reaction mixture obtained in step-b) with a suitable solvent at a suitable temperature,
d) filtering the precipitated solid to provide the crystalline Form L of Ixazomib citrate. wherein in step-a) the suitable organic acid is selected from C1-C5 carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid or mixtures thereof; the suitable temperature is ranges between 25°C to the reflux temperature of the acid which is used; in step-c) the suitable solvent is selected from "ether solvents" such as methyl tert -butyl ether, dimethyl ether, diisopropyl ether, diethyl ether, 1,3-dioxane, 1,4-dioxane tetrahydrofuran; "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate; "polar aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide; "chloro solvents" such as dichlorome thane, dichloroethane, chloroform, carbon tetrachloride; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, t-butanol; "polar solvents" such as water or mixtures thereof. In this step, the suitable solvent can be added to the reaction mixture or reaction mixture can be added to the suitable solvent.
The preferred embodiment of the present invention provides a process for the preparation of crystalline Form-L of Ixazomib citrate, comprising:
a) providing Ixazomib citrate in a formic acid at 25-30°C,
b) stirring the reaction mixture,
c) cooling the reaction mixture to 0-5°C and stirring,
d) combining the reaction mixture obtained in step-c) with methyl tert-butyl ether, e) filtering the precipitated solid to provide crystalline Form-L of Ixazomib citrate.
The fifth aspect of the present invention provides Ixazomib citrate crystalline Form-R.
Crystalline Form-R of the present invention is characterized by its powder X-ray diffraction (PXRD) pattern having characteristic peaks at about 6.0, 10.4 and 14.1 ± 0.2 degrees of two-theta. The crystalline Form-R of Ixazomib citrate is further characterized by its PXRD pattern as illustrated in figure-5.
The another embodiment of the present invention provides a process for the preparation of Ixazomib citrate crystalline Form-R, comprising: a) providing Ixazomib citrate in a mixture of benzoyl alcohol, acetic acid and isobutyl acetate at 25-30°C,
b) heating the reaction mixture to 75-80°C,
c) cooling the reaction mixture to 0-5 °C,
d) filtering the precipitated solid to get crystalline form-R.
The sixth aspect of the present invention provides a solid dispersion of Ixazomib citrate of formula-I in combination with one or more pharmaceutically acceptable carrier.
In the present invention, the composition of the solid dispersion consist of a ratio of the amount of the compound of formula-I to the amount of the pharmaceutically acceptable carrier therein ranges from about 1 : 0.1 to 1 : 10 (w/w). The composition of Ixazomib citrate with pharmaceutically acceptable carrier, preferably microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), hydroxypropylcellulose (HPC), hydroxy propyl beta cyclodextrin, hypromellose acetate succinate (HPMCAS) is about 1 :0.1 to 1: 10 (w/w).
The further embodiment of the present invention provides a process for the preparation of a solid dispersion of Ixazomib citrate of formula-I, comprising:
a) dissolving Ixazomib citrate and pharmaceutically acceptable carrier in a suitable solvent at suitable temperature,
b) isolating the solid dispersion of Ixazomib citrate. wherein in step-a) the suitable solvent is selected from alcoholic solvents, chloro solvents, ester solvents, polar aprotic solvents, ketone solvents, hydrocarbon solvents and polar solvent like water or mixture thereof; the suitable pharmaceutically acceptable carrier is selected from cellulose derivatives such as cellulose acetate, cellulose nitrate, cellulose xanthate, carboxy methyl cellulose, micro crystalline cellulose, methyl cellulose, ethyl cellulose and hydroxy ethyl cellulose, hydroxy propyl methyl, hydroxy propyl beta cyclodextrin; polyvinylpyrrolidone; the suitable temperature is ranging from 25°C to reflux temperature of the solvent which is used; in step-b) isolation may be affected by removing the solvent; suitable techniques which may be used for the removal of solvent include filtration, using a rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any other suitable technique.
The seventh aspect of the present invention provides a process for the preparation of Ixazomib citrate of the formula-I, comprising: a) reacting the compound of formula-II with glycine in presence of a base in a suitable solvent to provide the compound of formula-Ill,
Figure imgf000015_0001
Formula-II Glycine Formula-Ill b) reacting the compound of formula-Ill with the compound of formula-IV in presence of suitable coupling agent, suitable base in a suitable solvent to provide the compound of
Figure imgf000015_0002
c) reacting the compound of formula-V with isobutyl boronic acid in a suitable solvent or mixture of solvents and followed by addition of citric acid to provide the compound of formula-I
Figure imgf000015_0003
wherein in step-a) step-b) and step-c) the suitable solvent is selected from alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol and isobutanol; chloro solvents such as methylene chloride, chloroform; ketone solvents such as acetone, methyl ethyl ketone; hydrocarbon solvents such as n-hexane, heptane, toluene, benzene; nitrile solvents" such as acetonitrile; "ester solvents" such as ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate and tert -butyl acetate; ether solvents such as tetrahydrofuran, diethyl ether and methyl tert-butyl ether; polar solvents such as water; polar aprotic solvents such as dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide or mixtures thereof; the suitable base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; in step-b) the suitable coupling agent is selected from TBTU, HATU, DCC, DIC, CDI, EDC.HC1; the suitable base is selected from organic bases selected from methylamine, ethylamine, isopropylamine, diisopropyl ethylamine, triethylamine and ammonia or their aqueous solution.
The preferred embodiment of the present invention provides a process for the preparation of Ixazomib citrate of the formula-I, comprising: a) reacting the compound of formula-II with glycine in presence of sodium hydroxide or its aqueous solution in water and tetrahydrofuran to provide the compound of formula- Ill,
Figure imgf000016_0001
Formula-II Glycine Formula-Ill b) reacting the compound of formula-Ill with the compound of formula-IVa in presence of 0-(lH-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), diisopropylethylamine (DIPEA) in dimethylformamide to provide the compound of formula-V,
Figure imgf000016_0002
Formula-Ill Formula-IVa Formula-V c) reacting the compound of formula-V with isobutyl boronic acid and citric acid to provide the compound of formula-I
Figure imgf000017_0001
Formula-V Formula-I wherein Z is same as defined hereinbefore.
The oral pharmaceutical composition may contain crystalline Form-M, crystalline Form-S, crystalline Form-N, crystalline Form-L, crystalline Form-R and solid dispersion of amorphous Ixazomib citrate obtained by the present invention and one or more additional ex- cipients such as diluents, binders, disintegrants and lubricants. Exemplary diluents include lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, microcrystalline cellulose, magnesium stearate and mixtures thereof. Exemplary binders are selected from L-hydroxy propyl cellulose, povidone, hydroxypropyl methyl cellulose, hydroxylethyl cellulose and pre- gelatinized starch.
Exemplary disintegrants are selected from croscarmellose sodium, cros -povidone, sodium starch glycolate and low substituted hydroxylpropyl cellulose.
Exemplary lubricants are selected from sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, glyceryl behenate and colloidal silicon dioxide.
PXRD analysis of Ixazomib citrate of present invention was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and at continuous scan speed of 0.03°/min.
The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are for illustrative purposes only and in no way limit the embodiments of the present invention. Examples
Example-1: Preparation of 2,5-[(dichlorobenzoyl)amino]acetic acid of formula (III)
Water (900 ml) was added to glycine (43 gms) at 25-30°C and cooled the reaction mixture temperature to 0-5°C. Aqueous sodium hydroxide solution (24.8 gms dissolved in 300 ml of water) was added to the above reaction mixture at 0-5°C. 2,5-Dichlorobenzoyl chloride (100 gms) in tetrahydrofuran (150 ml) was added to the above reaction mixture at 0- 5°C and stirred for 3 hours at same temperature. Acidified the reaction mixture with 2M HC1 at 0-5°C and stirred for 2 hours at same temperature. Filtered the precipitated solid, washed with water. 20% of Ethyl acetate in cyclohexane solvent mixture was added to the above obtained compound and stirred for 2 hours at 25-30°C. Filtered the precipitated solid, washed with cyclohexane and then dried to afford the title compound. (Yield: 86.0 gms, M.R: 170- 175°C).
Example-2: Preparation of 2,5-dichloro-N-(2-(((R)-3-methyl-l-((3aS,4S,6S,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[d][l,3,2]dioxaborol-2-yl)butyl)amino)-2-oxoethyl )benzamide compound of formula (V).
The compound of formula-Ill (50 gms) was dissolved in DMF (175 ml) at 25-30°C. Cooled the reaction mixture temperature to 0-5°C and added TBTU (71.19 gms) and stirred for 10 minutes at same temperature. (lR)-3-Methyl-l-((3aS,4S,6S)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[d] [ 1 ,3,2]dioxaborol-2-yl)butan- 1 -amine 2,2,2- trifluoroacetate of formula (IV) (76.43 gms) was added to the reaction mixture at 0-5°C and stirred the reaction mixture for 10 min at same temperature. DIPEA (78.15 gm) was slowly added at 0-5 °C and stirred for 2 hours at same temperature. Ethyl acetate (250 ml) was added to the reaction mixture. 5% aqueous NaCl solution was added to the reaction mixture and stirred for 15 min. Separated the both organic, aqueous layers and washed the organic layer with 10% aqueous NaCl solution. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with methanol. Methanol (500 ml) was added to the obtained material and heated the reaction mixture to 55-60°C and stirred for 30 min at same temperature. Water (750 ml) was slowly added to the reaction mixture at 55-60°C and stirred for 30 minutes. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at same temperature. Filtered the material, washed with water and then dried to afford the title compound. (Yield: 74.0 gms).
Example-3: Preparation of Ixazomib citrate.
The compound of formula- V (10 gms) was added to toluene (150 ml) at 25-30°C. Methanol (50 ml) was added to the reaction mixture at 25-30°C. Isobutyl boronic acid (2.47 gms) and citric acid (4.65 gms) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 70-75 °C and filtered the reaction mixture through hiflow bed, washed with methanol. Stirred the obtained filtrate for 5 hours at 70-75°C. Distilled off the solvent completely from the reaction mixture under reduced pressure, co-distilled with methanol and again co-distilled with ethyl acetate. Ethyl acetate (100 ml) was added to the obtained compound at 25-30°C and stirred for 3 hours at same temperature. Filtered the precipitated solid, washed with ethyl acetate and then dried to afford the title compound. (Yield: 5.3 gms).
Example-4: Preparation of Ixazomib citrate.
The compound of formula- V (20.0 gms) was added to ethyl acetate (400 ml) at 25- 30°C. Isobutyl boronic acid (4.94 gms) and citric acid (9.31 gms) were added to the above reaction mixture at 25-30°C. Heated the reaction mixture to 70-75°C. Filtered the reaction mixture through hiflow bed and washed with ethyl acetate. Stirred the obtained filtrate for 4 hours at 70-75°C. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at same temperature. Filtered the precipitated solid, washed with ethyl acetate and then dried to afford the title compound. (Yield: 16.5 gms).
Example-5: Preparation of crystalline Form-M of Ixazomib citrate
Ixazomib citrate (2.0 gms) was dissolved in a mixture of tetrahydrofuran/ethanol solution (20 ml, (1: 1)) at 60-65°C. n-Heptane (50 ml) was added to the reaction mixture at 25- 30°C. Cooled the reaction mixture to 0-5°C and stirred for 2 hours at same temperature. Filtered the precipitated solid, washed with n-heptane and then dried for about 6 hours to get the title compound. (Yield: 1.6 gms).
The PXRD pattern of Form-M was illustrated in FIG.1.
Example-6: Preparation of crystalline Form-S of Ixazomib citrate
Ixazomib citrate (1.0 gm) was dissolved in a mixture of tetrahydrofuran/ethanol solution (10 ml, (1: 1)) at 60-65°C. n-Heptane (30 ml) was added to the reaction mixture at 25- 30°C. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at same temperature. Filtered the precipitated solid, washed with n-heptane and then dried for about 5 hours to get the title compound. (Yield: 800 mgs).
The PXRD pattern of Form-S was illustrated in FIG.2.
Example 7: Preparation of crystalline Form-N of Ixazomib citrate.
Ixazomib citrate (5 gm) was added to formic acid (75 ml) at 25-30°C and stirred the reaction mixture for 10 min at same temperature. Reaction mixture was cooled to 0-5°C and stirred for 1 hour. Methyl tert-butyl ether (MTBE) (150 ml) was added to the reaction mixture at 0-5°C and stirred for 7 hours at same temperature. Filtered the precipitated solid and dried at 100°C for about 3 hours to afford crystalline Form-N of Ixazomib citrate.
The PXRD pattern of the crystalline Form-N of Ixazomib citrate was illustrated in figure-3.
Example 8: Preparation of crystalline Form-L of Ixazomib citrate.
Ixazomib citrate (5 gm) was added to formic acid (75 ml) at 25-30°C and stirred the reaction mixture for 10 min at same temperature. Reaction mixture was cooled to 0-5°C and stirred for 1 hour. Methyl tert-butyl ether (MTBE) (150 ml) was added to the reaction mixture at 0-5°C and stirred for 7 hours at same temperature. Filtered the precipitated solid and dried for 15 min to afford crystalline Form-L of Ixazomib citrate.
The PXRD pattern of the crystalline Form-L of Ixazomib citrate was illustrated in figure-4. Example-9: Preparation of crystalline Form-R of Ixazomib citrate
Ixazomib citrate (1 gr) was added to a mixture of acetic acid, benzoyl alcohol and isobutyl acetate (25 ml, 1: 1: 1) at 25-30°C. Heated the reaction mixture to 75-80°C and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with isobutyl acetate and then dried to afford the title compound. (Yield: 600 mg).
The PXRD pattern of the crystalline Form-R of Ixazomib citrate was illustrated in figure-5. Example-10: Preparation of solid dispersion of Ixazomib citrate
Ixazomib citrate (1.0 gms) and polyvinylpyrrolidone (PVP K-30) (1.0 gms) were dissolved in methanol (30 ml) at 25-30°C. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried to get the title compound. (Yield: 1.2 gms).
The PXRD pattern of the obtained compound was illustrated in FIG.6.
Example- 11: Preparation of solid dispersion of Ixazomib citrate
Ixazomib citrate (1.0 gm) and hydroxy propyl methyl cellulose (HPMC) (1.0 gm) were dissolved in a mixture of methanol (40 ml) and methylene chloride (20 ml) at 25-30°C. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried to get title compound. (Yield: 1.4 gms).
The PXRD pattern of the obtained compound was illustrated in FIG.7.
Example-12: Preparation of solid dispersion of Ixazomib citrate
Ixazomib citrate (1.0 gm) and hydroxy propyl cellulose (HPC) (1.0 gm) were dissolved in methanol (20 ml) at 25-30°C. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried to get title compound. (Yield: 1.4 gms). The PXRD pattern of the obtained compound was similar to PXRD pattern in FIG.7.
Example-13: Preparation of solid dispersion of Ixazomib citrate
Ixazomib citrate (1.0 gm) and hydroxypropyl β-cyclodextrin (HPB-CD) (1.0 gm) were dissolved in methanol (20 ml) at 25-30°C. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried to get title compound. (Yield: 1.3 gms).
The PXRD pattern of the obtained compound was illustrated in FIG.8.

Claims

Claims:
1. Crystalline Form-N of Ixazomib citrate characterized by its powder X-ray diffraction (PXRD) pattern having characteristic peaks at 7.7, 13.1, 14.1, 18.1 and 22.6 ± 0.2 degrees of two-theta.
2. The crystalline Form-N of Ixazomib citrate is further characterized by its powder X-ray diffraction (PXRD) pattern having characteristic peaks at 7.7, 8.4, 11.4, 13.1, 14.1 18.1, 18.8, 21.0, 22.6, 30.2 and 31.3 ± 0.2 degrees of two-theta.
3. The crystalline Form-N according to claim 1 or 2, is further characterized by its PXRD pattern as shown in figure-3.
4. A process for the preparation of crystalline Form-N of Ixazomib citrate, comprising: a) providing Ixazomib citrate in a suitable organic acid,
b) stirring the reaction mixture at a suitable temperature,
c) combining the reaction mixture obtained in step-b) with a suitable solvent at a suitable temperature,
d) filtering the precipitated solid and drying to provide the crystalline form N of Ixazomib citrate.
5. The process according to claim 4, wherein in step-a) the suitable organic acid is C1-C5 carboxylic acid selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid or mixtures thereof; in step-b) the suitable temperature is ranges between 25°C to the reflux temperature of the acid which is used; in step-c) the suitable solvent is selected from ether solvents such as methyl tert-butyl ether, dimethyl ether, diisopropyl ether, diethyl ether, 1,3-dioxane, 1,4-dioxane tetrahydrofuran; hydrocarbon solvents such as n- hexane, n-heptane, cyclohexane, benzene, toluene, xylene; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate; "polar aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide; "chloro solvents" such as dichlorome thane, dichloroethane, chloroform, carbon tetrachloride; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol; "polar solvents" such as water or mixtures thereof.
6. A process for the preparation of crystalline Form-N of Ixazomib citrate, comprising:
a) providing Ixazomib citrate in a formic acid at 25-30°C,
b) stirring the reaction mixture,
c) cooling the reaction mixture to 0-5°C and stirring,
d) combining the reaction mixture obtained in step-c) with methyl tert-butyl ether, e) filtering the precipitated solid and drying at about 100°C to provide the crystalline form N of Ixazomib citrate.
7. Crystalline Form-L of Ixazomib citrate characterized by its powder X-ray diffraction (PXRD) pattern having characteristic peaks at about 7.2, 7.6, 11.1, 16.7, 19.7, 21.6 and 29.8 ± 0.2 degrees of two-theta.
8. The crystalline Form-L according to claim 7, is further characterized by its PXRD pattern as shown in figure-4.
9. A process for the preparation of crystalline Form-L of Ixazomib citrate, comprising:
a) providing Ixazomib citrate in a formic acid at 25-30°C,
b) stirring the reaction mixture,
c) cooling the reaction mixture to 0-5°C and stirring,
d) combining the reaction mixture obtained in step-c) with methyl tert-butyl ether, e) filtering the precipitated solid to provide crystalline Form-L of Ixazomib citrate.
10. Crystalline Form-R of Ixazomib citrate characterized by its powder X-ray diffraction (PXRD) pattern having characteristic peaks at about 6.0, 10.4 and 14.1 ± 0.2 degrees of two-theta.
11. The crystalline Form-R according to claim 10, is further characterized by its PXRD pat- tern as illustrated in figure-5.
12. A process for the preparation of crystalline Form-R of Ixazomib citrate, comprising: a) providing Ixazomib citrate in a mixture of benzoyl alcohol, acetic acid and isobutyl acetate at 25-30°C,
b) heating the reaction mixture to 75-80°C,
c) cooling the reaction mixture to 0-5 °C,
d) filtering the precipitated solid to get crystalline form-R.
13. Solid dispersion of Ixazomib citrate with one or more pharmaceutically acceptable carrier, wherein the solid dispersion consist of a ratio of the amount of the Ixazomib citrate to the amount of the pharmaceutically acceptable carrier selected from microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), hydroxypropylcellulose (HPC), hydroxy propyl beta cyclodextrin, hypromellose acetate succinate (HPMCAS) is about 1: 0.1 to 1 : 10 (w/w).
14. The solid dispersion according to claim 13, further prepared by a process comprising: a) dissolving Ixazomib citrate and pharmaceutically acceptable carrier in a suitable solvent at suitable temperature,
b) isolating the solid dispersion of Ixazomib citrate.
15. A process for the preparation of Ixazomib citrate of the formula-I, comprising: a) reacting the compound of formula-II with glycine in presence of a base in a suitable solvent to provide the compound of formula-Ill,
Figure imgf000025_0001
Formula-II Glycine Formula-Ill b) reacting the compound of formula-Ill with the compound of formula-IV in presence of a suitable coupling agent, suitable base in a suitable solvent to provide the compound
Figure imgf000026_0001
c) reacting the compound of formula-V with isobutyl boronic acid in a suitable solvent or mixture of solvents and followed by addition of citric acid to provide the compound of
Figure imgf000026_0002
16. The process according to claim 15, wherein in step-a), step-b) and step-c) the suitable solvent is selected from alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol and isobutanol; chloro solvents such as methylene chloride, chloroform; ketone solvents such as acetone, methyl ethyl ketone; hydrocarbon solvents such as n-hexane, heptane, toluene, benzene; nitrile solvents" such as acetonitrile; "ester solvents" such as ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate and tert-butyl acetate; ether solvents such as tetrahydrofuran, diethyl ether and methyl tert- butyl ether; polar solvents such as water; polar aprotic solvents such as dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide or mixtures thereof; the suitable base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; in step-b) the suitable coupling agent is selected from TBTU, HATU, DCC, DIC, CDI, EDC.HCl; the suitable base is selected from organic bases selected from methylamine, ethylamine, isopropylamine, diisopropyl ethylamine, triethylamine and ammonia or their aqueous solution.
17. A process for the preparation of Ixazomib citrate of the formula-I, comprising: a) reacting the compound of formula-II with glycine in presence of aqueous sodium hydroxide in water and tetrahydrofuran to provide the compound of formula-Ill,
Figure imgf000027_0001
Formula-II Glycine Formula-Ill b) reacting the compound of formula-Ill with the compound of formula-IVa in presence of 0-(lH-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), diisopropylethylamine (DIPEA) in dimethylformamide to provide the compound of formula-V,
Figure imgf000027_0002
Formula-Ill Formula-IVa Formula-V c) reacting the compound of formula-V with isobutyl boronic acid and citric acid to provide the compound of formula-I.
18. A process for the preparation of Ixazomib citrate of the formula-I, comprising reacting the compound of formula-V with isobutyl boronic acid in a suitable solvent or mixture of solvents and citric acid to provide the compound of formula-I
Figure imgf000028_0001
19. The process according to claim 18, the suitable solvent is alcoholic solvents selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol and isobutanol; chloro solvents selected from methylene chloride, chloroform; ketone solvents selected from acetone, methyl ethyl ketone; hydrocarbon solvents selected from n-hexane, heptane, toluene, benzene; nitrile solvents selected from acetonitrile; ester solvents selected from ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate and tert-butyl acetate; ether solvents selected from tetrahydrofuran, diethyl ether and methyl tert-butyl ether; polar solvents selected from water; polar aprotic solvents selected from dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide or mixtures thereof.
20. Use of crystalline Form-N of Ixazomib citrate for the preparation of pharmaceutical compositions.
21. Use of crystalline Form-L & R in the preparation of pharmaceutical composition or they can be used as intermediates for the preparation of other crystalline polymorphs.
PCT/IN2018/050157 2017-03-20 2018-03-20 Novel crystalline forms of ixazomib citrate and its process for preparation thereof WO2018173071A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009154737A1 (en) * 2008-06-17 2009-12-23 Millennium Pharmaceuticals, Inc. Boronate ester compounds and pharmaceutical compositions thereof
WO2016155684A1 (en) * 2015-04-03 2016-10-06 Zentiva, K.S. A process of preparing ixazomib citrate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009154737A1 (en) * 2008-06-17 2009-12-23 Millennium Pharmaceuticals, Inc. Boronate ester compounds and pharmaceutical compositions thereof
WO2016155684A1 (en) * 2015-04-03 2016-10-06 Zentiva, K.S. A process of preparing ixazomib citrate

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