DESC:FIELD OF THE INVENTION
The present invention relates to Ibrutinib methyl vanillate co-crystal and process for preparation thereof. Ibrutinib is represented by the following structural formula (I).

BACKGROUND OF THE INVENTION
Ibrutinib is marketed by Pharmacyclics in US under the trade name Imbruvica® for the treatment of Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, Waldenstrom's Macroglobulinernia and Small lymphocytic lymphoma.

Ibrutinib is chemically known as 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and structurally represented as below.

US patent 7,514,444 discloses process for the preparation of Ibrutinib. The US '444 discloses isolation of Ibrutinib by flash chromatography using dichloromethane and methanol as eluents.

WO2013184572Al application discloses crystalline, solvates and amorphous form of Ibrutinib. In particular, the application discloses polymorphic Forms A, B, C, D, E and F characterized by PXRD, IR, DSC and TGA.

WO2015145415A2 application discloses various solid forms of Ibrutinib designated as Form III, Form IV, Form V, Form VI, Form VII, Form VIII and Form IX.

WO2016079216Al discloses solvates (Anisole, Chlorobenzene, DCM, 1,4-dioxane, Pyridine) of lbrutinib.

WO2016160604A1 discloses co-crystal of Ibrutinib and conformer wherein the conformer is benzoic acid, succinic acid, 3- hydroxybenzoic acid, nicotinamide, 4-aminobenzoic acid, salicylic acid, sorbic acid, fumaric acid, salicylamide, trans-cinnamic acid, 4-hydroxybenzoic acid, 1-hydroxy-naphthoic acid, sulfamic acid, 1,5 -naphthalene disulfonic acid, 2-ethoxybenzamide, 4-aminosalicylic acid, or stearic acid, or a combination thereof.

WO2016156127Al discloses co-crystal of Ibrutinib with carboxylic acid and the carboxylic acid being Benzoic acid, Fumaric acid, Succinic acid.

Due to the described complex polymorphism of ibrutinib base and the significant impact of solid state form on dissolution and solubility, new pharmaceutically applicable forms of ibrutinib might be useful as alternative active pharmaceutical ingredients.

The present invention fulfills the need of the art and provides an improved and industrially applicable process for preparation of Ibrutinib co-crystal which are reproducible and provides Ibrutinib having pharmaceutical grade purity.

Thus, the present invention provides an improved, economical viable and simple process for the preparation of Ibrutinib methyl vanillate co-crystal with high yield and purity.

OBJECTS OF THE INVENTION
The main object of the present invention is to provide Ibrutinib methyl vanillate co-crystal.

Another object of the present invention is to provide process for preparation of Ibrutinib methyl vanillate co-crystal which comprises;
(a) Dissolving Ibrutinib and methyl vanillate in suitable solvent,
(b) Isolating Ibrutinib methyl vanillate co-crystal.

Another object of the present invention is to provide process for preparation of Ibrutinib methyl vanillate co-crystal which comprises;
(a) Dissolving methyl vanillate in suitable solvent,
(b) Adding Ibrutinib to solution obtained in step (a),
(c) Isolating Ibrutinib methyl vanillate co-crystal.

SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide Ibrutinib methyl vanillate co-crystal.

Another aspect of the present invention is to provide process for preparation of Ibrutinib methyl vanillate co-crystal which comprises;
(a) Dissolving Ibrutinib and methyl vanillate in suitable solvent,
(b) Isolating Ibrutinib methyl vanillate co-crystal.

Another aspect of the present invention is to provide process for preparation of Ibrutinib methyl vanillate co-crystal which comprises;
(a) Dissolving methyl vanillate in suitable solvent,
(b) Adding Ibrutinib to solution obtained in step (a)
(c) Isolating Ibrutinib methyl vanillate co-crystal.

DETAILED DESCRIPTION OF THE DRAWINGS
Fig.1 shows an XRPD pattern of Ibrutinib methyl vanillate co-crystal.
Fig.2 shows 1H NMR of Ibrutinib methyl vanillate co-crystal.

DETAILED DESCRIPTION OF THE INVENTION
The main embodiment of the present invention is to provide Ibrutinib methyl vanillate co-crystal.

Another embodiment of the present invention is to provide process for preparation of Ibrutinib methyl vanillate co-crystal which comprises;
(a) Dissolving Ibrutinib and methyl vanillate in suitable solvent,
(b) Isolating Ibrutinib methyl vanillate co-crystal.

Another embodiment of the present invention is to provide process for preparation of Ibrutinib methyl vanillate co-crystal which comprises;
(a) Dissolving methyl vanillate in suitable solvent,
(b) Adding Ibrutinib to solution obtained in step (a),
(c) Isolating Ibrutinib methyl vanillate co-crystal.

Wherein Ibrutinib which is used in step (a) & (b) may be selected from crystalline or amorphous form.

Wherein the suitable solvent which could be employed in step (a) may be selected from group comprising of alcohols such as methanol, ethanol, 1-propanol, 2-propanol, butanol, ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, esters such as ethyl acetate, methyl acetate, propyl acetate, ethers such as diethyl ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, aromatic hydrocarbon such as benzene, toluene, xylene, chlorobenzene, nitrobenzene, aliphatic hydrocarbons hexane, n-heptane, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dialkylformamides selected from dimethyl formamide, dialkylsulfoxides selected from dimethyl sulfoxide, dialkylacetamides selected from N, N-dimethyl acetamide; nitriles selected from acetonitrile and propionitrile; water or mixtures thereof.

Isolation of co-crystal of Ibrutinib and methyl vanillate is carried out by employing any of the techniques, but not limited to cooling, decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, solvent evaporation, solvent-anti solvent system, rotational distillation using a device such as buchi rotavapor, distillation under vacuum, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization), rotary cone vacuum dryer (RVPD), melt crystallization, sieving, grinding, milling, drying and the like.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES
Example 1: Preparation of Ibrutinib methyl vanillate co-crystal
To a solution of Methyl vanillate (3.1 gm) in Methanol (25 ml) was added Ibrutinib (5.0 gm) at 25-30°C, stir reaction mass for 60 to 90 minutes at 25-30°C. Cooled the reaction mass at 0-5°C and stirred for 60 to 90 minutes at the same temperature. Filtered the reaction mass and wash with chilled Methanol (10 ml) and dried material under vacuum at 30-35°C. Yield: 5.1 gm

Example 2: Preparation of Ibrutinib methyl vanillate co-crystal
Methyl vanillate (2.0 gm) and methyl tertiary butyl ether (20 ml) were charged in to the RBF at 25-30°C. Heated the reaction mass at 40-45°C and stirred for 15 minutes. n-Heptane (50 ml) was added to the reaction mass. Cooled the reaction mass to 0-5°C and stirred for 30 to 40 minutes. Ibrutinib (5.0 gm) was charged into the above reaction mass at 0-5°C and stirred for 30 to 40 minutes. Methyl tertiary butyl ether (30 ml) was added to the above reaction mass and stirred for 45 minutes at 0-5°C. Raised the temperature of reaction mass to 25-30°C and stirred the reaction mass for 5 to 6 hrs. Filtered the material and wash with mixture of n-Heptane: Methyl tertiary butyl ether (1:1 10 ml) and dried the material under vacuum at 30-35°C. Yield: 4.8 gm ,CLAIMS:We Claim:
1. Co-Crystal of Ibrutinib and Methyl vanillate.

2. Process for preparation of Ibrutinib methyl vanillate co-crystal which comprises;
(a) Dissolving Ibrutinib and methyl vanillate in suitable solvent,
(b) Isolating Ibrutinib methyl vanillate co-crystal.

3. Process for preparation of Ibrutinib methyl vanillate co-crystal which comprises;
(a) Dissolving methyl vanillate in suitable solvent,
(b) Adding Ibrutinib to solution obtained in step (a)
(c) Isolating Ibrutinib methyl vanillate co-crystal.

4. The process as claimed in claim 2 and 3, wherein the Ibrutinib which is used in step (a) & (b) is selected from crystalline or amorphous form.

5. The process as claimed in claim 2 and 3, Wherein the suitable solvent which could be employed in step (a) is selected from group comprising of alcohols such as methanol, ethanol, 1-propanol, 2-propanol, butanol, ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, esters such as ethyl acetate, methyl acetate, propyl acetate, ethers such as diethyl ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, aromatic hydrocarbon such as benzene, toluene, xylene, chlorobenzene, nitrobenzene, aliphatic hydrocarbons hexane, n-heptane, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dialkylformamides selected from dimethyl formamide, dialkylsulfoxides selected from dimethyl sulfoxide, dialkylacetamides selected from N, N-dimethyl acetamide; nitriles selected from acetonitrile and propionitrile; water or mixtures thereof.

6. The process as claimed in claim 2 and 3, Wherein isolation of co-crystal of Ibrutinib and methyl vanillate is carried out by employing techniques is selected from cooling, decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, solvent evaporation, solvent-anti solvent system, rotational distillation using a device such as buchi rotavapor, distillation under vacuum, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization), rotary cone vacuum dryer (RVPD), melt crystallization, sieving, grinding, milling, drying and the like.