ELTROMBOPAG NOVEL SALTS

Technical Field

The present invention relates to novel salts of eltrombopag, namely eltrombopag sesquiethanolamine, eltrombopag sesquicholine, and processes for the preparation thereof. The invention also relates to solid state forms of eltrombopag sesquiethanolamine and processes for the preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

Background Art

Eltrombopag is chemically known as (Z)-3'-(2-(l-(3,4-dimethylphenyl)-3-methyl-5-oxo-l/Z- pyrazol-4(5//)-ylidene)hydrazinyl)-2'-hydroxy- [1,1 '-biphenyl] -3-carboxylic acid and represented by the following chemical structure:

Eltrombopag

Eltrombopag is a small molecule and non-peptide thrombopoietin (TPO) receptor agonist that stimulates the growth and development of platelets in the bone marrow. It is used for patients with low platelet levels who also have the condition of aplastic anemia, primary immune thrombocytopenia (ITP), or chronic hepatitis C virus (HCV) infection associated thrombocytopenia.

Duffy et al. in EP 1294378 Bl provided the first disclosure of the (Z)-3'-(2-(l-(3,4- dimethylphenyl)-3-methyl-5-oxo-l/Z-pyrazol-4(5//)-ylidene)hy drazinyl)-2'-hydroxy-[l,r- biphenyl]- 3 -carboxylic acid (eltrombopag free base) and pharmaceutically acceptable salts, hydrates, and solvates thereof.

It has generally been observed that different salts of the base compound have improved physical and chemical properties without affecting the pharmacological action of the drug and hence provide an opportunity to improve the drug performance characteristics of such product.

Eltrombopag is marketed as bis-(monoethanolamine) salt, which formed by two molecules of 2-aminoethanol for one molecule of eltrombopag. It is marketed by Novartis in USA under trade name Promacta® and under trade name Revolade® in Europe. The structure of eltrombopag olamine corresponds to the following formula:

Eltrombopag olamine (Eltrombopag bis-(monoethanolamine))

EP1534390B1 discloses bis-(monoethanolamine) salt of eltrombopag and its process for preparation.

EP2152237B1 discloses tablet composition comprising eltrombopag bis-(monoethanolamine) salt.

Besides bis-(monoethanolamine) salt of eltrombopag, there are few disclosures of other salt forms of eltrombopag.

PCT application WO2013/072921A2 discloses ammonium salt of eltrombopag and its preparation. IP.com journal, volume 9, issue 12A, 2009 discloses tert-butylamine salt and meglumine salt of eltrombopag.

PCT application W02017/081014 Al discloses novel salts of eltrombopag, namely eltrombopag ethylamine salt and eltrombopag diisopropylamine salt. It also reports use of said novel salts of eltrombopag in preparation of eltrombopag olamine.

Indian patent application IN2018/41008924 A discloses eltrombopag N-methylethanolamine salt and its process for preparation.

Different salts of an active pharmaceutical ingredient may also give rise to a variety of polymorphs, which may in turn provide additional opportunities for providing an improved drug substance and product. Different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates.

WO2010/114943 Al reports new polymorphs of eltrombopag and eltrombopag ethanolamine salt.

Shafakat Ali et al. in PCT application WO2017/042839 Al described tromethamine salt of eltrombopag and crystalline form thereof.

Hariprasad et al. in PCT application WO2019/071111 Al described solid state form of eltrombopag choline.

PCT application W02020/025444 Al discloses polymorphs of eltrombopag monoethanolamine salt and eltrombopag ammonium salt.

Besides the aforementioned disclosures, still there appears to be need for new salts of eltrombopag and polymorphs of these new salts having further improved physical and/or chemical properties. Hence it was thought worthwhile by the inventors of the present application to explore pharmaceutically acceptable novel salts of eltrombopag, which may further improve the characteristics of eltrombopag finished medicinal product.

Summary of the invention

The object of the present invention is to provide pharmaceutically acceptable salts of eltrombopag.

Another object of the present invention is to provide processes for preparing pharmaceutically acceptable salts of eltrombopag.

Yet another object of the present invention is to provide solid state forms of eltrombopag sesquiethanolamine salt.

Technical Problem

Active pharmaceutical ingredients (APIs) are individual components that are used as a part of a finished pharmaceutical drug or medicinal product, where they provide the pharmacological activity.

Research and development projects in the pharmaceutical industry mainly aim to investigate different possible salts, polymorphs and processes to produce these APIs.

Salt formation in general is vitally important in drug substance synthesis as well as overall pharmaceutical development and manufacture. Salt forms of drug substances have significant effects on physicochemical properties of the drug influencing its quality, safety, and performance.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties. 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.

The relationship between polymorphic forms of pharmaceutically active substance and pharmaceutical product is well known in the pharmaceutical industry. Pharmaceutical formulation is affected by polymorphic form of the pharmaceutically active substance.

Discovery of new salts and polymorphic forms of an active pharmaceutical ingredient provides a new opportunity to improve the performance characteristics of pharmaceutical finished product, therefore, development of new salts and polymorphic forms are always encouraged.

According to the need, studies have been done to develop novel salts of eltrombopag and additional polymorphs thereof having advantageous properties which are useful and suitable for the preparation of various pharmaceutical compositions.

Solution to Problem

In an embodiment invention relates to novel pharmaceutically acceptable salts and solid forms of eltrombopag.

These new salts of eltrombopag, besides being stable, meet the pharmaceutical requirements such as storage, shelf life, solubility and high purity.

Description of embodiments

The present invention relates to novel salts of eltrombopag, namely eltrombopag sesquiethanolamine and eltrombopag sesquicholine.

A method for preparing eltrombopag sesquiethanolamine and eltrombopag sesquicholine is outlined as following:

In an embodiment, the present invention relates to eltrombopag sesquicholine salt.

In another embodiment, the invention provides a process for preparation of eltrombopag sesquicholine salt comprising addition of choline chloride in a suitable solvent into a suspension of eltrombopag base and isolating eltrombopag as sesquicholine salt.

In an embodiment, the present invention relates to sesquiethanolamine salt of eltrombopag.

In one embodiment, the invention provides a process for preparation of eltrombopag sesquiethanolamine salt comprising addition of ethanolamine to a solution of eltrombopag free base in a suitable solvent and isolating eltrombopag as sesquiethanolamine salt.

Molar ratio of eltrombopag base to ethanolamine is between 1:1.1 - 1:1.9, preferably 1:1.2 - 1:1.8, more preferably 1:3.1 - 1:1.7).

In one embodiment, invention relates to eltrombopag sesquiethanolamine form A characterized with an XRPD pattern showing at least one characteristic peak (2theta ± 0.2°) at 6.8, 16.9 and 26.5; and further characterized by having XRPD peaks (2theta ± 0.2°) at 7.4, 8.2, 11.3, 16.1, 20.7, 22.1, 22.7, 23.3, 24.6, 25.7, 27.7, 28.3, 31.0 and 37.7. Eltrombopag sesquiethanolamine form A alternatively characterized by an XPRD pattern having 2 theta values as shown in Fig. 1.

In one embodiment, invention relates to eltrombopag sesquiethanolamine form B characterized with an XRPD pattern showing at least one characteristic peak (2theta ± 0.2°) at

7.4, 16.9 and 26.5; and further characterized by having XRPD peaks (2theta ± 0.2°) at 8.2,

11.1, 12.3, 12.7, 13.8, 14.3, 15.5, 18.8, 19.5, 19.8, 20.7, 22.1, 22.8, 23.3, 24.6, 25.5, 27.8, 28.3, 28.8, 31.0 and 37.7. Eltrombopag sesquiethanolamine form B alternatively characterized by an XPRD pattern having 2 theta values as shown in Fig. 2.

In one embodiment, invention relates to eltrombopag sesquiethanolamine form C characterized with an XRPD pattern showing at least one characteristic peak (2theta ± 0.2°) at

7.5, 17.1 and 25.6; and further characterized by having XRPD peaks (2theta ± 0.2°) at 6.5, 7.0, 8.3, 11.0, 12.4, 12.8, 13.9, 14.4, 15.0, 15.6, 16.3, 18.9, 19.6, 19.9 20.8, 21.5, 22.2, 23.5,

24.1, 28.8 and 31.1. Eltrombopag sesquiethanolamine form C alternatively characterized by an XPRD pattern having 2 theta values as shown in Fig. 3.

In one embodiment, invention relates to eltrombopag sesquiethanolamine form D characterized with an XRPD pattern showing at least one characteristic peak (2theta ± 0.2°) at 7.7, 17.0 and 24.1; and further characterized by having XRPD peaks (2theta ± 0.2°) at 5.3, 7.0, 8.4, 11.2, 12.3, 13.8, 15.8, 19.0, 20.8, 21.5, 22.2, 23.4, 24.1, 27.9 and 37.7. Eltrombopag sesquiethanolamine form D alternatively characterized by an XPRD pattern having 2 theta values as shown in Fig. 4.

In one embodiment, the invention provides a process for preparation of crystalline forms of eltrombopag sesquiethanolamine comprises; a) providing a reaction solution by addition of ethanolamine into a suspension of eltrombopag base in presence of a suitable solvent; b) then stirring the reaction solution for a suitable time, c) filtering the crystals; and d) washing the crystals with solvent, and e) finally drying the crystals in vacuo.

Wherein suitable solvent is selected from water, methanol, ethanol, 2-propanol, 1 -propanol, 1- butanol, 2-butanol, tert-butyl alcohol, 1 -pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3 -pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, toluene, xylene, chloroform, dichloromethane, carbontetrachloride, ethylene dichloride, chlorobenzene, acetonitrile, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran (THF), 1,4-dioxane, 2-methoxyethanol, N,N- dimethylformamide (DMF), N, 7V-dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), pyridine, dimethylsulfoxide (DMSO), sulfolane, formamide, acetamide, propanamide, pyridine, formic acid, acetic acid, propionic acid, hexane, heptane, cyclohexane, cycloheptane and cyclooctane or mixtures thereof.

The suitable temperature used in present invention is selected from room temperature to reflux temperature of the solvent used.

The suitable time used in stirring the reaction solution in step (b) is between 1 - 16 hours.

Eltrombopag sesquiethanolamine salt is also characterized by ATR-FTIR (Attenuated Total Reflectance Fourier Transform Infrared) spectra as depicted in Fig. 5.

Eltrombopag sesquicholine salt is also characterized by ATR-FTIR spectra as depicted in Fig. 6.

Eltrombopag sesquiethanolamine salt is alternatively characterized in that it has a ^-Nuclear Magnetic Resonance ( H-NMR) spectrum as depicted in Fig. 10 and a C-Nuclear Magnetic Resonance ( C-NMR) spectrum as depicted in Fig. 15.

Eltrombopag sesquicholine salt is alternatively characterized in that it has a ^-Nuclear Magnetic Resonance spectrum ( H-NMR) as depicted in Fig. 11 and a C-Nuclear Magnetic Resonance spectrum ( C-NMR) as depicted in Fig. 16.

The degree of purity of the active ingredient and the resulting possible changes of the efficacy, further important properties for the pharmaceutical processing can be affected in an adverse manner, e.g. the capability to be pressed to tablets by an impairment of the pourability or flow rate of the crystalline form.

In a general aspect, there is provided sesquiethanolamine and sesquicholine salts of eltrombopag having purity greater than about 99% by area percentage of HPLC.

In another general aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of crystalline eltrombopag sesquiethanolamine and one or more pharmaceutically acceptable carriers, excipients or diluents, wherein crystalline eltrombopag sesquiethanolamine is characterized by having X-ray powder diffraction pattern substantially as depicted in Fig. 1, Fig. 2, Fig.3 and Fig.4.

In one general aspect, there is provided use of sesquiethanolamine and sesquicholine salts of eltrombopag for the treatment of patients with low platelet levels who also have the condition of aplastic anemia, primary immune thrombocytopenia (ITP), or chronic hepatitis C vims (HCV) infection associated thrombocytopenia.

Brief description of the drawings:

Fig. 1 shows the X-Ray Powder Diffraction (XRPD) pattern of crystalline eltrombopag sesquiethanolamine form A

Fig. 2 shows the X-Ray Powder Diffraction (XRPD) pattern of crystalline eltrombopag sesquiethanolamine form B

Fig. 3 shows the X-Ray Powder Diffraction (XRPD) pattern of crystalline eltrombopag sesquiethanolamine form C

Fig. 4 shows the X-Ray Powder Diffraction (XRPD) pattern of crystalline eltrombopag sesquiethanolamine form D

Fig. 5 shows the Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectra of crystalline eltrombopag sesquiethanolamine

Fig 6 shows the Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectra of the eltrombopag sesquicholine

Fig. 7 shows the Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectra of eltrombopag free base

Fig. 8 shows the Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectra of eltrombopag choline

Fig. 9 shows the Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectra of eltrombopag olamine

Fig. 10 shows the ^-Nuclear Magnetic Resonance ^H-NMR) spectrum of eltrombopag sesquiethanolamine

Fig. 11 shows the ^-Nuclear Magnetic Resonance ^H-NMR) spectrum of eltrombopag sesquicholine Fig. 12 shows the ^-Nuclear Magnetic Resonance ( ^X H-NMR) spectrum of eltrombopag free base

Fig. 13 shows the ^-Nuclear Magnetic Resonance ( ^X H-NMR) spectrum of eltrombopag choline

Fig. 14 shows the ^-Nuclear Magnetic Resonance ( ^X H-NMR) spectrum of eltrombopag olamine

Fig. 15 shows the C-Nuclear Magnetic Resonance ( C-NMR) spectrum of eltrombopag sesquiethanolamine

Fig. 16 shows the C-Nuclear Magnetic Resonance ( C-NMR) spectrum of eltrombopag sesquicholine

13 13

Fig. 17 shows the C-Nuclear Magnetic Resonance ( C-NMR) spectrum of eltrombopag free base

13 13

Fig. 18 shows the C-Nuclear Magnetic Resonance ( C-NMR) spectrum of eltrombopag choline

Fig. 19 shows the C-Nuclear Magnetic Resonance ( C-NMR) spectrum of eltrombopag olamine

Instrumental parameters:

1 1

H-NMR and C-NMR experiments were performed on a 400 MHz NMR spectrometer (JEOL Ltd., Tokyo, Japan) using deuterated dimethylsulfoxide (DMSO-df,) as a solvent.

Samples were measured as neat by ATR (Attenuated Total Reflectance) on Shimadzu FTIR Spectrometer IR Prestige-21 (Shimadzu Corporation, Kyoto, Japan) in the range of 600 - 4000 cm ^-1 with 20 scans and 4 cm ^-1 resolution.

X-Ray powder diffractograms were measured using a Shimadzu LabX XRD-6100 X-ray diffractometer (Shimadzu Corporation, Japan) by using the following instrument parameters;

The measurement conditions were as follows:

Radiation: Cu (1.5406 A)

Filter for Kp : Nickel

Voltage: 40.0 kV

Current: 30.0 mA

Auto slit: not used

Divergence slit: 1.0°

Scatter slit: 1.0° Receiving slit: 0.30 mm with a Graphite monochromator

Drive axis: Theta-2Theta

Scan range: 3.00 - 40.00°

Scan mode: continuous scan

Scan speed: 1.07min

Sampling pitch: 0.02°

Following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.

EXAMPLES

Example 1: Preparation of eltrombopag sesquicholine (eltrombopag/choline ratio: 1/1.5)

Aqueous solution of sodium hydroxide (1.8 g, 45 mmol, 4.0 equiv.; dissolved in 10 mL of water) is added into a methanol (100 mL) solution of choline chloride (6.31 g, 45 mmol, 4.0 equiv.). This mixture is added into a suspension of eltrombopag base (5 g, 11.3 mmol, 1.0 equiv.) in acetone (100 mL) at room temperature (20 - 30 °C) and stirred for 12 - 16 h. After that, the mixture is evaporated in vacuo to remove the solvents and then acetonitrile (250 mL) is added onto the residue. The mixture is cooled to 0 - 5 °C and stirred 1 - 3 h for crystallization. The product crystals are filtered, washed with acetonitrile and dried in vacuo to afford a brownish -black colored solid eltrombopag sesquicholine (6.7 g, 99.5%, HPLC purity: 99.4%).

Preparation of eltrombopag sesquiethanolamine (eltrombopag/ethanolamine ratio: 1/1.5)

General procedure: 2-Aminoethanol is added into a suspension of eltrombopag base in an organic solvent at room temperature (20 - 30 °C) and stirred for 2 - 16 h. After that, the product crystals are filtered, washed with an organic solvent and dried in vacuo to afford a brownish-claret red colored solid eltrombopag sesquiethanolamine.

Example 2: Preparation of crystalline eltrombopag sesquiethanolamine (Form A)

2-Aminoethanol (1.02 mL, 16.88 mmol, 1.5 equiv.) is added into a suspension of eltrombopag base (5 g, 11.3 mmol, 1.0 equiv.) in dichloromethane (100 mL) at room temperature (20 - 30 °C) and stirred for 3 h. After that, the product crystals are filtered, washed with dichloromethane and dried in vacuo to afford a brownish-claret red colored solid eltrombopag sesquiethanolamine (5.9 g, 97.76%, HPLC purity: 99.89%; form A).

Example 3: Preparation of crystalline eltrombopag sesquiethanolamine (Form A)

2-Aminoethanol (1.02 mL, 16.88 mmol, 1.5 equiv.) is added into a suspension of eltrombopag base (5 g, 11.3 mmol, 1.0 equiv.) in ethyl acetate (100 mL) at room temperature (20 - 30 °C) and stirred for 15-16 h. After that, the product crystals are filtered, washed with ethyl acetate and dried in vacuo to afford a brownish-claret red colored solid eltrombopag sesquiethanolamine (5.7 g, 94.44%, HPLC purity: 99.83%; form A).

Example 4: Preparation of crystalline eltrombopag sesquiethanolamine (Form A)

2-Aminoethanol (1.09 mL, 18 mmol, 1.6 equiv.) is added into a suspension of eltrombopag base (5 g, 11.3 mmol, 1.0 equiv.) in tetrahydrofuran (100 mL) at room temperature (20 - 30 °C) and stirred for 3 - 4 h. After that, the product crystals are filtered and dried in vacuo to afford a brownish-claret red colored solid eltrombopag sesquiethanolamine (5.3 g, 87.89%, HPLC purity: 99.95%; form A).

Example 5: Preparation of crystalline eltrombopag sesquiethanolamine (Form B)

2-Aminoethanol (3.8 mL, 62.83 mmol, 5.7 equiv.) is added into a suspension of eltrombopag base (5 g, 11.3 mmol, 1.0 equiv.) in acetone (100 mL) at room temperature (20 - 30 °C) and stirred for 2 h. After that, the product crystals are filtered, washed with acetone and dried in vacuo to afford a brownish-claret red colored solid eltrombopag sesquiethanolamine (5.7 g, 94.44%, HPLC purity: 99.50%; form B).

Example 6: Preparation of crystalline eltrombopag sesquiethanolamine (Form B)

2-Aminoethanol (2.72 mL, 45 mmol, 4.0 equiv.) is added into a suspension of eltrombopag base (5 g, 11.3 mmol, 1.0 equiv.) in acetone (100 mL) at room temperature (20 - 30 °C) and stirred for 2 h. After that, the product crystals are filtered, washed with acetone and dried in vacuo to afford a brownish-claret red colored solid eltrombopag sesquiethanolamine (5.9 g, 97.76%, HPLC purity: 99.78%; form B).

Example 7: Preparation of crystalline eltrombopag sesquiethanolamine (Form B)

2-Aminoethanol (3.07 mL, 50 mmol, 4.5 equiv.) is added into a suspension of eltrombopag base (5 g, 11.3 mmol, 1.0 equiv.) in acetone (140 mL) and methanol (15 mL) at room temperature (20 - 30 °C) and stirred for 4 h. After that, the product crystals are filtered, washed with acetone and dried in vacuo to afford a brownish-claret red colored solid eltrombopag sesquiethanolamine (5.7 g, 94.44%, HPLC purity: 99.58%; form B). Example 8: Preparation of crystalline eltrombopag sesquiethanolamine (Form B)

2-Aminoethanol (1.09 mL, 18 mmol, 1.6 equiv.) is added into a suspension of eltrombopag base (5 g, 11.3 mmol, 1.0 equiv.) in 2-propanol (100 mL) at room temperature (20 - 30 °C) and stirred for 3 - 4 h. After that, the product crystals are filtered and dried in vacuo to afford a brownish-claret red colored solid eltrombopag sesquiethanolamine (5.7 g, 94.52%; form B).

Example 9: Preparation of crystalline eltrombopag sesquiethanolamine (Form C)

2-Aminoethanol (3.07 mL, 50 mmol, 4.5 equiv.) is added into a suspension of eltrombopag base (5 g, 11.3 mmol, 1.0 equiv.) in acetone (100 mL) at room temperature (20 - 30 °C) and stirred for 12 - 16 h. After that, the product crystals are filtered, washed with acetone and dried in vacuo to afford a brownish-claret red colored solid eltrombopag sesquiethanolamine (6.0 g, 99.42%, HPLC purity: 99.46%).

Example 10: Preparation of crystalline eltrombopag sesquiethanolamine (Form C)

2-Aminoethanol (1.09 mL, 18 mmol, 1.6 equiv.) is added into a suspension of eltrombopag base (5 g, 11.3 mmol, 1.0 equiv.) in ethanol (100 mL) at room temperature (20 - 30 °C) and stirred for 3 - 4 h. After that, the product crystals are filtered and dried in vacuo to afford a brownish-claret red colored solid eltrombopag sesquiethanolamine (5.6 g, 92.86%; form C).

Example 11: Preparation of crystalline eltrombopag sesquiethanolamine (Form C)

2-Aminoethanol (1.09 mL, 18 mmol, 1.6 equiv.) is added into a suspension of eltrombopag base (5 g, 11.3 mmol, 1.0 equiv.) in methanol (100 mL) at room temperature (20 - 30 °C) and stirred for 12 - 16 h. After that, the product crystals are filtered and dried in vacuo to afford a brownish-claret red colored solid eltrombopag sesquiethanolamine (4.8 g, 79.60%; form C).

Example 12: Preparation of crystalline eltrombopag sesquiethanolamine (Form D)

2-Aminoethanol (1.31 mL, 21.6 mmol, 1.6 equiv.) is added into a suspension of eltrombopag base (6 g, 13.5 mmol, 1.0 equiv.) in acetonitrile (100 mL) at room temperature (20 - 30 °C) and stirred for 12 - 16 h. After that, the product crystals are filtered and dried in vacuo to afford a brownish-claret red colored solid eltrombopag sesquiethanolamine (5.3 g, 73.20%; form D).

Example 13: Preparation of eltrombopag olamine (eltrombopag/ethanolamine ratio: 1/2)

2-Aminoethanol (3.07 mL, 50 mmol, 4.5 equiv.) is added into a suspension of eltrombopag base (5 g, 11.3 mmol, 1.0 equiv.) in acetonitrile (100 mL) at room temperature (20 - 30 °C) and stirred for 2 - 3 h. After that, the product crystals are filtered, washed with dichloromethane and dried in vacuo to afford a claret red colored solid eltrombopag olamine (6.3 g, 98.75%, HPLC purity: 99.25%).

Example 14: Preparation of eltrombopag choline (eltrombopag/choline ratio: 1/1)

A solution of choline chloride (6.94 g, 49.7 mmol, 4.0 equiv.) in methanol (100 mL) and N,N- diisopropylamine (2 mL) are added into a suspension of eltrombopag base (5.5 g, 12.4 mmol, 1.0 equiv.) in acetone (100 mL). The mixture is stirred for 16 h at room temperature (20 - 30 °C) and then filtered and dried to afford orange solid eltrombopag choline (5.4 g, 79.62%).