Description:CRYSTALLINE FORM-OS OF ELTROMBOPAG FREE ACID

FIELD OF THE INVENTION

The present invention relates to crystalline Form-OS of Eltrombopag free acid (I). The present invention also relates to a purification process for preparing crystalline Form-OS of Eltrombopag free acid (I).

BACKGROUND OF THE INVENTION

Eltrombopag is a thrombopoietin receptor agonist, which was approved in US under the brand name of Promacta® and Revolade® in most countries outside the US. It is used for the treatment of thrombocytopenia (abnormally low platelet counts) and severe aplastic anemia and is marketed worldwide by Novartis.

Eltrombopag is commercialized in pharmaceutical compositions comprising this active pharmaceutical ingredient in form of Eltrombopag Olamine or ETP Olamine, i.e. a salt of ETP with ethanolamine in 1:2 ratios, also called Eltrombopag bisethanolamine salt of formula (Ia).

Eltrombopag (I) along with pharmaceutically acceptable salts, hydrates, solvates and esters thereof, disclosed first time in US 7160870. US ‘870 patent discloses a process for the preparation of Eltrombopag (I), which comprises 3'-amino-2'-hydroxy-1,1'-biphenyl-3-carboxylic acid (III) with 2-(3,4-dimethylphenyl)-5-methyl-1H-pyrazol-3-(2H)-one (II) in presence of sodium nitrite, hydrochloric acid and ethanol/water to produce Eltrombopag (I).
The above process is schematically shown as below:
Scheme 1
U.S. Pat. No. 7,956,048 B2 discloses different crystalline forms of Eltrombopag free acid as well as process for the preparation of crystalline forms.

U.S. Pat. No. 10,336,706 B2 discloses crystalline Form H1 of Eltrombopag free acid and its process for preparation from dimethyl formamide and alcoholic solvents selected from methanol, ethanol, n-butanol, and isopropanol.

WO 2015111085A2 discloses crystalline Form Z of Eltrombopag free acid and its process for preparation from dimethyl formamide and ethanol.

Many pharmaceutical solids can exist in different physical forms. Polymorphism is often characterized as the ability of drug substance to exist in two or more crystalline phases that have different arrangement and/or conformations of the molecule in the crystal lattice. Polymorphism refers to occurrence of different crystalline form of the same drug substance. The different crystalline forms have different physical properties like melting point, X-ray diffraction pattern,
infrared spectra and solid state NMR spectrum.

The difference in physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules in the bulk solid. Accordingly, the polymorphs are distinct solids sharing the same molecular formulae, yet having different physical properties compared to other crystalline forms of the same compound.

The different polymorphs, pseudo polymorphs or the amorphous form differ in their physical properties such as melting point, solubility etc. and hence may affect pharmaceutical properties such as dissolution rate and bioavailability of the drug substance. Hence, the discovery of new or different polymorphs is essential. Since a new polymorph may aide in the manufacture of the drug product formulation which may prove to be more effective absorption in gastrointestinal tract.

We have found a crystalline Form-OS of Eltrombopag free acid. The crystalline Form-OS of Eltrombopag free acid (I) has been found to be stable over the time and reproducible.

The object of the present invention to prepare crystalline Form-OS of Eltrombopag free acid (I), which it enhances in pharmaceutical composition.

SUMMARY OF THE INVENTION

The present invention relates to crystalline Form-OS of Eltrombopag free acid (I) and also relates to a purification process for preparing crystalline Form-OS of Eltrombopag free acid (I).

In one aspect of the present invention, crystalline Form-OS of Eltrombopag free acid (I) characterized by X-ray powder diffraction pattern according to FIG.-1.

In another aspect of the present invention, provides a crystalline Form-OS of Eltrombopag free acid (I) characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 9.34, 11.97, 13.77, 16.93, 21.86, 25.62, 26.07 and 29.50 ±0.2 degrees 2θ.

In yet another aspect of the present invention, provides a process for the purification of crystalline Form-OS of Eltrombopag free acid (I), comprising:

i. Eltrombopag free acid (I) is dissolved in a solvent,
ii. heating the reaction mixture at suitable temperature,
iii. cooling the reaction mixture,
iv. adding an anti-solvent to the resulting solution, and
v. isolating the pure Eltrombopag free acid (I).

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1: X-ray powder diffraction (PXRD) crystalline Form-OS of Eltrombopag free acid.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to crystalline Form-OS of Eltrombopag free acid and also relates to a purification process for preparing crystalline Form-OS of Eltrombopag free acid.

In one aspect of the present invention, provides a crystalline Form-OS of Eltrombopag free acid characterized by X-ray powder diffraction pattern according to FIG.-1.

In another aspect of the present invention, provides a crystalline Form-OS of Eltrombopag free acid characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 9.34, 11.97, 13.77, 16.93, 21.86, 25.62, 26.07 and 29.50 ±0.2 degrees 2θ.

According to the embodiment of the crystalline Form-OS of Eltrombopag free acid is further characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 9.34, 11.97, 12.41, 12.75, 13.77, 14.64, 15.42, 16.93, 17.63, 17.99, 18.90, 21.86, 25.62, 26.07 and 29.50 ±0.2 degrees 2θ.

In yet another aspect of the present invention provides, a process for the purification of crystalline Form-OS of Eltrombopag free acid (I), comprising:

i. Eltrombopag free acid (I) is dissolved in a solvent,
ii. heating the reaction mixture at suitable temperature,
iii. cooling the reaction mixture,
iv. adding an anti-solvent to the resulting solution, and
v. isolating the pure Eltrombopag free acid (I).

According to the embodiment of the present invention, a process for the purification of Eltrombopag free acid by Eltrombopag (I) is dissolved in a solvent and heating the reaction mass at 60 to 80ºC and cooling the reaction mixture at 25 to 30°C, followed by adding an anti-solvent to the resulting solution and isolating the pure Eltrombopag free acid (I).

According to an embodiment of the present invention. wherein the solvent is selected sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; nitriles such as acetonitrile and propionitrile; ether solvent such as tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and aromatic hydrocarbons such as toluene, heptane and xylene; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; water; cyclohexane and or mixtures thereof.

According to an embodiment of the present invention. wherein the anti-solvent is selected from
methanol, ethanol, isopropyl alcohol, n-butanol and/or mixtures thereof.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
 

EXAMPLES

Example-1: Purification of Eltrombopag (I):
Crude Eltrombopag (100gm) was dissolved in dimethyl sulfoxide (500ml) at room temperature. The reaction mass heated to 70-75°C and stir for 20-30 min at same temperature. The reaction mixture was allowed to cool at 25-30°C, followed by added ethanol (1000 ml) and stir for 60 min. Thus the obtained product was filtered and washed with ethanol (100ml), unload the material. Wet product was dried at 60-65°C to obtained the orange colour material of pure Eltrombopag free acid.
Yield: 95% (95g),
Purity: 99.8% by HPLC.

Example-2: Purification of Eltrombopag (I):
Crude Eltrombopag (50gm) was dissolved in dimethyl sulfoxide (240ml) at room temperature. The reaction mass heated to 70-75°C and stir for 20-30 min at same temperature. The reaction mixture was allowed to cool at 25-30°C, followed by added ethanol (400 ml) and stir for 60 min. Thus the obtained product was filtered and washed with ethanol (20ml), unload the material. Wet product was dried at 60-65°C to obtained the orange colour material of pure Eltrombopag free acid.
Yield: 96% (96g),
Purity: 99.9% by HPLC.

, Claims:WE CLAIM:
1. Crystalline Form-OS of Eltrombopag free acid characterized by

X-ray powder diffraction pattern according to FIG.-1.

2. The crystalline Form-OS of Eltrombopag free acid as claimed in claim 1, wherein the crystalline form has the XRPD peaks at 9.34, 11.97, 13.77, 16.93, 21.86, 25.62, 26.07 and 29.50 ±0.2 degrees 2θ.

3. A process for the purification of crystalline Form-OS of Eltrombopag free acid, which comprising the steps of:

i. Eltrombopag free acid (I) is dissolved in a solvent,
ii. heating the reaction mixture at suitable temperature,
iii. cooling the reaction mixture,
iv. adding an anti-solvent to the resulting solution, and
v. isolating the pure Eltrombopag free acid (I).

4. The process as claimed in claim 3, wherein the solvent is selected from the group consisting of sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; nitriles such as acetonitrile and propionitrile; ether solvent such as tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and aromatic hydrocarbons such as toluene, heptane and xylene; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; water; cyclohexane and or mixtures thereof.
5. The process as claimed in claim 3, wherein the reaction carried at suitable temperature ranges from 60 to 80ºC in step ii.

6. The process as claimed in claim 3, wherein the anti-solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-butanol and/or mixtures thereof