DESC:Field of Invention
The present invention is directed to solid forms of Nintedanib Esylate.
The present invention is directed to a substantially amorphous form of Nintedanib Esylate.
The present invention is directed to a crystalline form a of Nintedanib Esylate.
Further the invention also provides a process for preparation of substantially amorphous form and crystalline form a of Nintedanib Esylate as well as pharmaceutical composition comprising the same.
The present complete specification is prepared by cognating the contents provisional patent specification of application numbered 201721016806 dated May 12, 2017 with the contents of the specification of patent application no. 201721021189 dated June 16, 2017. The combined contents of the present specification constitute a single invention within the meaning of the Act.

Background of the invention
Nintedanib Esylate is a triple angiokinase inhibitor (TKI) blocking vascular endothelial growth factor receptors (VEGFR 1-3), fibroblast growth factor receptors (FGFR 1-3) kinase activity and platelet-derived growth factor receptor (PDGFR) a and ß in the low nanomolar range.
Nintedanib Esylate is chemically known as 1H-Indole-6-carboxylic acid, 2,3dihydro-3-[[[4-[methyl[(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene]-2-oxo-,methyl ester, (3Z)-, ethanesulfonate (1:1) and structurally represented by formula (I) as given below.

(I)
U.S. Pat. No. 6,762,180 (US’180) discloses Nintedanib and its pharmaceutically acceptable salts.
U.S. Pat. No. 7,119,093 (US’093) discloses Nintedanib monoethanesulphonate (Esylate) salt in its crystalline hemihydrate form.
IP.com Dis. No. IPCOM000244124D, CN106432042 and WO 2016/178064 describe a dehydrated crystalline form, a monohydrate form A and a crystalline form S of Nintedanib Esylate, respectively.
Polymorphism is a known phenomenon among pharmaceutical substances. A single compound may exist in numerous solid forms having distinct physical properties melting point, solubility, chemical reactivity, etc. This variation in solid forms may be significant and may also appreciably influence pharmaceutical properties such as dissolution rate, bioavailability, stability and other properties.
The inventors of the present invention has surprisingly came across a crystalline form of Nintedanib Esylate, which is anhydrous, or a solvate/hydrate and processes for its preparation, pharmaceutical formulations, and methods of use thereof.
Object of the invention
It is an object of the present invention to provide solid forms of Nintedanib Esylate.
It is an object of the present invention to provide a substantially amorphous form of Nintedanib Esylate.
It is another object of the present invention to provide a crystalline form a of Nintedanib Esylate.
It is another object of the present invention to provide a process for preparation of substantially amorphous form of Nintedanib Esylate.
It is another object of the present invention to provide a process for preparation of crystalline form a of Nintedanib Esylate.
It is yet another object of the present invention to provide a pharmaceutical composition comprising an effective amount of the substantially amorphous form of Nintedanib Esylate.
It is yet another object of the present invention to provide a pharmaceutical composition comprising an effective amount of the crystalline form a of Nintedanib Esylate.
Brief Description of the Drawing
Figure-1: PXRD pattern of the substantially amorphous form of Nintedanib Esylate of the present invention
Figure-2: PXRD pattern of the crystalline form a of Nintedanib Esylate of the present invention
Description of the invention
Accordingly, the present invention is directed to solid forms of Nintedanib Esylate.
Accordingly, the present invention is directed to a substantially amorphous form of Nintedanib Esylate.
In an embodiment, the present invention is directed to a substantially amorphous form of Nintedanib Esylate characterized by powder X-ray diffraction (PXRD).
In another embodiment, the present invention provides a substantially amorphous form of Nintedanib Esylate characterized by a PXRD pattern, substantially as illustrated by Figure-1.
Furthermore the substantially amorphous form of Nintedanib Esylate of the present invention is characterized by thermogravimetry (TGA) and differential scanning calorimetry (DSC).
Accordingly, the present invention is directed to a crystalline form of Nintedanib Esylate, wherein the crystalline form is anhydrous or a solvate/hydrate.
In an embodiment, the present invention is directed to a crystalline form a of Nintedanib Esylate characterized by powder X-ray diffraction (PXRD).
In another embodiment, the present invention provides a crystalline form a of Nintedanib Esylate characterized by a PXRD pattern, substantially as illustrated by Figure-2.
The crystalline Form-a of Nintedanib Esylate is characterized by PXRD pattern having X-ray diffraction peaks at 7.3, 10.93, 14.8, 15.55, 16.51, 17.07, 17.58, 17.87, 18.7, 20.79, 21.37, 21.91, 22.71, 24.6, 25.56 and 27.74 degree 2? ± 0.2 degree 2?.
Furthermore the crystalline form a of Nintedanib Esylate of the present invention is characterized by infrared (IR) spectroscopy, thermogravimetry (TGA) and differential scanning calorimetry (DSC).
In yet another embodiment, the present invention is directed to a process for the preparation of substantially amorphous form of Nintedanib Esylate, wherein the process comprising providing a solution of Nintedanib Esylate in suitable solvent and isolating substantially amorphous form of Nintedanib Esylate.
In yet another embodiment, the present invention is directed to a process for the preparation of crystalline form a of Nintedanib Esylate, wherein the process comprising the steps of:
a) providing Nintedanib in a suitable solvent;
b) adding ethanesulphonic acid; and
c) isolating crystalline form a of Nintedanib Esylate.
The suitable solvent of the present invention is a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof.
Suitable non-polar solvents include, but are not limited to, 1, 4-dioxane, toluene, methyl t-butyl ether (MTBE) and mixtures thereof. Suitable polar aprotic solvents include, but are not limited to, dichloromethane, tetrahydrofuran, ethylacetate, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N- dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), 1 ,2-dimethoxyethane and mixtures thereof. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof.
In an embodiment, water is used as a polar protic solvent for the said process.
In an embodiment, polar aprotic solvent dichloromethane, acetone or a mixture thereof is used as solvent for the said process.
Suitable techniques for solvent removal include using a rotational distillation device such as a Buchi® Rotavapor®, spray drying, agitated thin film drying, freeze drying (lyophilization), and the like, or any other suitable technique known in the art. Other suitable techniques of solvent removal are also included such as decantation, filtration by gravity or suction, centrifugation, or slow solvent evaporation or any other suitable technique known in the art and optionally the isolated solid are washed with a solvent, such as an anti-solvent or the solvent, to reduce the amount of entrained impurities.
According to another embodiment, Nintedanib Esylate used as the starting material which is prepared as per Example-1or the methods reported in the literature i.e. by using a process as per US’180 or US’093 patent, which is incorporated herein as reference, by a novel process or obtained from commercial sources.
The substantially amorphous form or crystalline form a of Nintedanib Esylate of the present invention is stable under stability conditions provided in U.S. Pharmacopeia (USP 40) and is suitable for use in pharmaceutical preparations for therapeutic use.
As used herein the term ‘amorphous,’ unless otherwise specified, is pertinent to a solid form of Nintedanib Esylate with absence of long range crystalline order. As used herein the term ‘substantially amorphous form of Nintedanib Esylate,’ unless otherwise specified, is pertinent to an amorphous form of Nintedanib Esylate wherein the degree of crystallinity is not more than about 25%.
In an embodiment of the present invention, the substantially amorphous form of Nintedanib Esylate prepared according to the present invention is pure having a purity greater than 98.5%, or greater than 99.5 % when determined by high performance liquid chromatography (HPLC). The substantially amorphous form of Nintedanib Esylate produced by the method of the present invention is chemically pure Nintedanib Esylate having purity greater than about 99.5% and contains no single impurity more than 0.15%, by HPLC. The substantially amorphous form of Nintedanib Esylate produced by the method of the present invention is pure and has purity greater than 99.8% and contains no single impurity more than 0.1% by HPLC.
In an embodiment of the present invention, the crystalline form a of Nintedanib Esylate prepared according to the present invention is pure having a purity greater than 98.5%, or greater than 99.5 % when determined by high performance liquid chromatography (HPLC). The crystalline form a of Nintedanib Esylate produced by the method of the present invention is chemically pure Nintedanib Esylate having purity greater than about 99.5% and contains no single impurity more than 0.15%, by HPLC. The crystalline form a of Nintedanib Esylate produced by the method of the present invention is pure and has purity greater than 99.8% and contains no single impurity more than 0.1% by HPLC.
In one more embodiment, the present invention also provides a pharmaceutical composition comprising substantially amorphous form of Nintedanib Esylate along with one or more pharmaceutically acceptable carriers, excipients, or diluents.
The substantially amorphous form of Nintedanib Esylate of the present invention can be used to prepare pharmaceutical composition for the treatment for idiopathic pulmonary fibrosis (IPF). Such pharmaceutical composition can be prepared by the methods known in the literature.
Yet another embodiment of the present invention relates to a solid dispersion or premix of the substantially amorphous form of Nintedanib Esylate with a pharmaceutically acceptable excipient wherein the pharmaceutically acceptable excipient is a diluent, lubricant, disintegrant, stabilizer, glidant or surface active agent or mixtures thereof.
The embodiments of the present invention are further illustrated with the following non-limiting example.
In one more embodiment, the present invention also provides a pharmaceutical composition comprising crystalline form a of Nintedanib Esylate along with one or more pharmaceutically acceptable carriers, excipients, or diluents.
The crystalline form a of Nintedanib Esylate of the present invention can be used to prepare pharmaceutical composition for the treatment for idiopathic pulmonary fibrosis (IPF). Such pharmaceutical composition can be prepared by the methods known in the literature.
Yet another embodiment of the present invention relates to a solid dispersion or premix of the crystalline form a of Nintedanib Esylate with a pharmaceutically acceptable excipient wherein the pharmaceutically acceptable excipient is a diluent, lubricant, disintegrant, stabilizer, glidant or surface active agent or mixtures thereof.
The embodiments of the present invention are further illustrated with the following non-limiting example.
The following Examples describe the present invention in detail, but is not to be construed to be in any way limiting for the present invention.

Example 1:
To 1 gm of Nintedanib dissolved in 40 mL of dichloromethane was added 0.3 mL of ethanesulphonic acid and maintained at room temperature for 30 min. The precipitated solid was filtered and dried to afford 1.2 gm of crystalline form a of Nintedanib Esylate.
Example 2:
To 1 gm of Nintedanib dissolved in 15 mL of dichloromethane was added 0.4 mL of ethanesulphonic acid at 40oC. Thereafter 30 mL acetone was added and the reaction mixture was maintained at 40oC for 30 min. The reaction mixture was cooled to room temperature and maintained for 30 min. The precipitated solid was filtered and dried to afford 1.2 gm of crystalline form a of Nintedanib Esylate.
Example 3:
5 gm of Nintedanib Esylate was dissolved in 315 mL millipore water and the solution was lyophilized at -78 oC to afford 4.8 gm of substantially amorphous Nintedanib Esylate.
,CLAIMS:1. A substantially amorphous form of Nintedanib Esylate.

2. The substantially amorphous form of claim-1 is characterized by a powder X-ray diffraction (PXRD) pattern, substantially as depicted in Figure-1.

3. A crystalline form a of Nintedanib Esylate characterized by a powder X-ray diffraction (PXRD) comprising of peaks, in terms of degrees 2?, at 7.3, 10.93, 14.8, 15.55, 16.51, 17.07, 17.58, 17.87, 18.7, 20.79, 21.37, 21.91, 22.71, 24.6, 25.56 and 27.74 ± 0.2 degree 2?.

4. The crystalline form of claim-3 further characterized by a powder X-ray diffraction (PXRD) pattern, substantially as depicted in Figure-2.

5. A process of preparing Nintedanib Esylate of claim-1, where the process comprises providing a solution of Nintedanib Esylate in suitable solvent and isolating substantially amorphous form of Nintedanib Esylate.

6. The process according to claim-5 where the solvent is a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof.

7. The process according to claim-5 and 6 where the polar protic solvent is water.

8. The process according to claim-5 where the solvent is removed by lyophilized technique.

9. A process of preparing Nintedanib Esylate of claim-3, where the process comprising the steps of:
a) providing Nintedanib in a suitable solvent;
b) adding ethanesulphonic acid; and
c) isolating crystalline form a of Nintedanib Esylate.

10. The process according to claim-9 where the solvent is a polar aprotic solvent which is dichloromethane, acetone or a mixture thereof.