Claims:1. A process for preparation of polymorph form 1 of Eltrombopag ethanolamine with high purity and yields comprising,
a) reacting Form I of Eltrombopag free base with Ethanolamine in the presence of aliphatic ether solvents at temperature range of 25°C to 80°C for sufficient period of time;
b) isolating the product followed by drying the product at a temperature of 50 to 80° C to affect the formation of Form I of Eltrombopag bisethanolamine salt.
2. The process according to claim 1, wherein, the aliphatic ether solvents are selected from methyl tert. butyl ether and cyclopropylmethylether.
3. The process according to claim 2, wherein, the process comprises;
a) reacting Form I of Eltrombopag free base with Ethanolamine in the presence of methyl tert. butyl ether (MTBE) at temperature range of 25°C to 60°C for sufficient period of time;
b) cooling the reaction mass to room temperature to isolate the solid; and
c) drying the obtained solid at 50-55° C using vacuum to obtain polymorphic Form 1 of Eltrombopag bisethanolamine salt.
4. The process according to claim 2, wherein, the process comprises;
a) reacting Form I of Eltrombopag free base with Ethanolamine in the presence of cyclopropylmethylether (CPME) at temperature range of 25°C to 80°C for sufficient period of time;
d) cooling the reaction mass to room temperature to isolate the solid; and
e) drying the obtained solid at 70-75° C using vacuum to obtain polymorphic Form 1 of Eltrombopag bisethanolamine salt.
5. The process according to claim 1, wherein, the polymorphic form 1 of Eltrombopag ethanolamine contains residual solvents within the prescribed limits of ICH guidelines.
6. The process according to claim 1, wherein, the polymorphic form 1 of Eltrombopag ethanolamine is substantially free of other polymorphic forms.
7. A pharmaceutical composition comprising polymorphic form 1 of Eltrombopag ethanolamine prepared according to the claim 1 together with one or more pharmaceutical excipients.
, Description:Technical filed:
This invention relates to an industrial process for preparation of Eltrombopag Polymorph I. More specially, the invention relates to process for preparation of Eltrombopag Polymorph I from aliphatic ether solvents.

Background and prior art:
Eltrombopag is chemically known as (Z)-3'-(2-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)hydrazinyl)-2'-hydroxybiphenyl-3-carboxylic acid. Eltrombopag is marketed under the trade name Promacta® by GlaxoSmithKline and Ligand Pharmaceuticals as a bisethanolamine salt having the following formula I.

Eltrombopag is a small-molecule, non-peptide thrombopoitin (TPO) receptor agonist that stimulates the proliferation and differentiation of megakaryocytes. Eltrombopag has been developed for certain conditions that lead to thrombocytopenia.

Eltrombopag is first disclosed in US7332481 and US7160870. Bisethanolamine salt of the Eltrombopag is disclosed in US 2006/0178518. Different polymers of the API and bisethanolamine salt are disclosed in US2010256212.

US20170275255 discloses a process for the preparation of crystalline Form 1 of Eltrombopag Olamine, from polymorphic form H1 in polar aprotic solvent selected from tetrahydrofuran, ethyl acetate, acetone, dimethyl sulfoxide, dimethyl formamide, acetonitrile and alcoholic solvents is selected from the group comprising of methanol, ethanol, n-butanol, isopropanol.

US2010256212 discloses process for preparation of polymorphic form II of Eltrombopag bisethanolamine salt by grinding amorphous Eltrombopag bisethanolamine salt in the presence of methyl tert-butyl ether (MTBE) and Form 1 is prepared from THF and alcohols such as methanol.

However, the inventors have observed that it is difficult to dry the Form I of bisethanolamine salt prepared using THF and alcohols as per the procedure disclosed in US2010256212 and the presence of solvent is always observed in spite of high temperature and/or high vacuum drying of the Form 1.

Therefore, it is the objective of the invention to provide an improved process for preparation of Eltrombopag polymorphic Form 1, where the residual solvents in the isolated polymorphic Form 1 of Eltrombopag bisethanolamine salt are controlled to well below ICH guidelines.

Description of drawings:
Fig. 1 PXRD Form I of Bisethanolamine salt of Eltrombopag according to the examples 1 and 2.

Summary of the invention:
The present invention provides a process for preparation of polymorph form 1 of Eltrombopag ethanolamine salt in high chemical purity and yields. The polymorph form 1 of Eltrombopag ethanolamine salt is prepared using aliphatic ether solvents. The aliphatic ether solvents are selected from methyl tert. butyl ether, cyclopropylmethylether, etc.
The preparation of the polymorph form 1 of Eltrombopag ethanolamine salt can be achieved with high degree of purity, yield and consistency when reproduced using these solvents.

Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The present invention provides a process for preparation of polymorph form 1 of Eltrombopag ethanolamine salt in high chemical purity and yields.

Accordingly, the process for preparation of polymorph form 1 of Eltrombopag ethanolamine salt which process comprises, the reaction of Form I of Eltrombopag free base with Ethanolamine in the presence of aliphatic ether solvents at temperature range of 25°C to 80°C for sufficient period of time followed by isolating the product and drying at a temperature of 50 to 80° C to affect the formation of Form I of Eltrombopag bisethanolamine salt. According to the present invention, drying the solid at a temperature of 50 to 80° C under vacuum is another important aspect to eliminate the residual solvents and to meet the ICH guidelines.

In an aspect, the polymorph form 1 of Eltrombopag ethanolamine salt is prepared using aliphatic ether solvents. The aliphatic ether solvents are selected from methyl tert. butyl ether, cyclopropylmethylether, etc.

US2010256212 discloses process for preparation of polymorphic form II of Eltrombopag bisethanolamine salt by grinding amorphous Eltrombopag bisethanolamine salt in the presence of methyl tert-butyl ether (MTBE). Contrary to the teachings of US’212, the present invention employs methyl tert-butyl ether (MTBE) for the preparation of Form I in a reproducible manner. It is clear from above embodiments that the same solvent gives two different crystalline forms under different experimental conditions.

The Form I prepared in accordance with the invention is subjected to PXRD and observed that the PXRD peaks are corresponding to the Form I reported in US20100256212.

Accordingly, the present invention provides a process for preparation of polymorphic Form 1 of Eltrombopag bisethanolamine salt which process comprises;
a) reacting Form I of Eltrombopag free base with Ethanolamine in the presence of methyl tert. butyl ether (MTBE) at temperature range of 25°C to 60°C for sufficient period of time;
b) cooling the reaction mass to room temperature to isolate the solid; and
c) drying the obtained solid at 50-55° C using vacuum to obtain polymorphic Form 1 of Eltrombopag bisethanolamine salt.

The PXRD spectra of the obtained Eltrombopag bisethanolamine salt is corresponding to Form I, as depicted in figure 1.

In another process variant, the invention provides process for preparation of polymorphic Form 1 of Eltrombopag bisethanolamine salt which process comprises;
a) reacting Form I of Eltrombopag free base with Ethanolamine in the presence of cyclopropylmethylether at temperature range of 25°C to 80°C for sufficient period of time;
b) cooling the reaction mass to room temperature to isolate the solid; and
c) drying the salt obtained at 70-75° C under vacuum to obtain polymorphic Form 1 of Eltrombopag bisethanolamine salt.

The PXRD spectra of the obtained Eltrombopag bisethanolamine salt is corresponding to Form I, as depicted in figure 1.

The process of the present invention enables consistency and re-produsability of the process in terms of yields and purity. Also the polymorphic form 1 obtained according to the process of the present invention is observed to be stable for a storage period of 12 months without any inter conversion of polymorphic forms.

Accordingly, in another aspect, the polymorphic form 1 obtained according to the process of the present invention is substantially free of any other polymorphic forms. The phrase “substantially free” as referred herein refers to polymorphic form I that contains any other polymorphic forms in less than 5%; more preferably 2%; still more preferably, less than 1%.

According to another aspect, the polymorph form 1 of Eltrombopag ethanolamine obtained according to the process of the invention is completely devoid of residual solvents and is much lesser than the ICH guidelines.

In yet another aspect, the invention provides pharmaceutical compositions comprising the polymorphic form 1 of Eltrombopag ethanolamine along with one or more pharmaceutical excipients.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples
Example 1
Preparation of Form I of bisethanolamine salt of Eltrombopag using MTBE:
Ethanolamine (34.46g) was added to the suspension of Eltrombopag Form I (50g) in MTBE (1000mL) at room temperature and then heated the reaction mass to 50-55° C for about 1Hr. The reaction mass was then cooled to room temperature and filtered the solid. The solid thus obtained was dried at 50-55° C under vacuum for about 1Hr to get 61.8gm of the crystalline bisethanolamine salt of Eltrombopag.
Yield: 96.8%
Purity: >99.5% Presence of MTBE is observed to be much lesser than ICH guidelines
PXRD spectra of the crystalline bisethanolamine salt of Eltrombopag obtained according to this example matches with Form I, reported in US20100256212.

Example 2:
Preparation of Form I of bisethanolamine salt of Eltrombopag using CPME:
Ethanolamine (34.46g) was added to the suspension of Eltrombopag Form I (50g) in CPME (1000mL) at room temperature and then heated the reaction mass to 70-75° C for about 1Hr. The reaction mass was then cooled to room temperature and filtered the solid. The solid thus obtained was dried at 70-75° C under vacuum for about 1Hr to get 62gm of the crystalline bisethanolamine salt of Eltrombopag.
Yield: 97.1%
Purity: Purity: >99.5% Presence of CPME is observed to be much lesser than ICH guideline
PXRD spectra of the crystalline bisethanolamine salt of Eltrombopag obtained according to this example matches with Form I, reported in US20100256212.

Example 3:
Preparation of Form I of bisethanolamine salt of Eltrombopag using CPME:
Ethanolamine (17.23g) was added to the suspension of Eltrombopag Form I (25g) in CPME (500mL) at room temperature and then heated the reaction mass to 70-75° C for about 1Hr. The reaction mass was then cooled to room temperature and filtered the solid. The solid thus obtained was dried at 70-75° C under vacuum for about 1Hr to get 31gm of the crystalline bisethanolamine salt of Eltrombopag.
Yield: 97%
Purity: Purity: >99.5% Presence of CPME is observed to be much lesser than ICH guideline
PXRD spectra of the crystalline bisethanolamine salt of Eltrombopag obtained according to this example matches with Form I, reported in US20100256212.

Example 4:
Preparation of Form I of bisethanolamine salt of Eltrombopag using CPME:
Ethanolamine (8.61g) was added to the suspension of Eltrombopag Form I (12.5g) in CPME (250mL) at room temperature and then heated the reaction mass to 70-75° C for about 1Hr. The reaction mass was then cooled to room temperature and filtered the solid. The solid thus obtained was dried at 70-75° C under vacuum for about 1Hr to get 15.5gm of the crystalline bisethanolamine salt of Eltrombopag.
Yield: 97.1%
Purity: Purity: >99.5% Presence of CPME is observed to be much lesser than ICH guideline
PXRD spectra of the crystalline bisethanolamine salt of Eltrombopag obtained according to this example matches with Form I, reported in US20100256212.