DESC:SOLID STATE FORMS OF IBRUTINIB
INTRODUCTION
The present invention provides co-crystal of Ibrutinib, process for the preparation of co-crystals of Ibrutinib and pharmaceutical composition comprising said co-crystals of Ibrutinib. The present invention also provides crystalline forms of Ibrutinib, processes for their preparation and pharmaceutical composition comprising said crystalline forms.

BACKGROUND OF THE INVENTION
The drug compound having the adopted name “Ibrutinib”, has a chemical name l-{3R-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)}prop-2-en-l-one, and is represented by the structure of formula as below;

Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK) and is approved in US for the treatment of patients with mantle cell lymphoma and chronic lymphocytic leukemia who have received at least one prior therapy.
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.
WO2013184572A1 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. The WO ‘572 application discloses process for the preparation of amorphous form of Ibrutinib by dissolving Form A in dichloromethane. The solvent dichloromethane was removed under rotary evaporation to provide amorphous Ibrutinib.
CN103694241A discloses crystal form A of Ibrutinib characterized by PXRD. CN103923084A discloses crystal forms II, III, IV, V, VI, VII and VIII of Ibrutinib, characterized by PXRD pattern.
WO 2015145415A2 application discloses various solid forms of Ibrutinib designated as Form III, Form IV, Form V, Form VI, Form VII, Form VIII and Form IX. WO 2016022942A1 application discloses solid dispersions of ibrutinib. WO 2016025720A1 application discloses crystalline forms of Ibrutinib designated as Form G, Form J and Form K. WO2016139588A1 discloses crystalline forms of Ibrutinib designated as Form D1 to D13. WO2016079216A1 discloses solvates (Anisole, Chlorobenzene, DCM, 1,4-dioxane, Pyridine) of Ibrutinib. WO2016160598A1 discloses solvates (butyronitrile, 1,2-dimethoxy ethane, hexafluorobenzene, acetophenone, chlorobenzene, dimethylacetamide, benzyl acetate, or 1,1,2-trichloroethane) of Ibrutinib. WO2017029586A1 discloses crystalline forms of Ibrutinib designated as Form S1 to S4. EP3243824A1 discloses crystalline forms of Ibrutinib designated as Form a, ß, ?, d, e and ?. WO2018000250A1 discloses crystalline form of Ibrutinib designated as Form III. US2018153895A1 discloses crystalline forms of Ibrutinib designated as APO-I as anhydrous form, methyl benzoate solvate (APO II) and methyl salicylate solvate (APO IV). Some other Chinese patent applications discloses crystalline forms and solvates of Ibrutinib.
WO2016160604A1 discloses co-crystal of Ibrutinib and a co-former with co-former being 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-hydroxys- naphthoic acid, sulfamic acid, 1,5 -naphthalene disulfonic acid, 2-ethoxybenzamide, 4-aminosalicylic acid, or stearic acid.
WO2016156127A1 discloses co-crystal of Ibrutinib with carboxylic acid and the carboxylic acid being Benzoic acid, Fumaric acid, Succinic acid.
The existence and possible numbers of polymorphic forms for a given compound cannot be predicted, and there are no "standard" procedures that can be used to prepare polymorphic forms of a substance. This is well-known in the art, as reported, for example, by A. Goho, "Tricky Business," Science News, Vol. 166(8), August 2004.
Despite of various crystalline forms of Ibrutinib, there remains a need for alternate solid forms of Ibrutinib and processes for preparing them.
The present invention describes solvates of Ibrutinib and processes for their preparation, pharmaceutical compositions comprising these solvate forms.
The present invention also describes co-crystal, obtained from Ibrutinib and a neutral conformer, where both are solids at room temperature.
The obtained solvates and co-crystals have a constant quality and have improved physicochemical properties, such as a higher solubility and dissolution rate, enhanced flow properties and enhanced stability.

SUMMARY
The present invention provides co-crystal of Ibrutinib and palmitic acid, process of preparing said co-crystal and pharmaceutical composition comprising said co-crystal.
The present invention also provides crystalline forms of Ibrutinib and process for preparing said crystalline forms and pharmaceutical composition comprising said crystalline forms.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D14.
Figure 2 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D15.
Figure 3 illustrates a characteristic PXRD pattern of co-crystal of Ibrutinib and Palmitic acid referred to as Form D16.

DETAILED DESCRIPTION
In an aspect, the present invention provides co-crystal of Ibrutinib and Palmitic acid. In another aspect, the present invention provides co-crystal of Ibrutinib and Palmitic acid, characterized by an x-ray powder diffraction pattern having peaks at about 3.35 and 6.69 ± 0.20 degrees 2-theta, and also having peaks at about 10.03, 11.98, 13.38, 22.29 and 23.61 ± 0.20 degrees 2-theta. In another aspect, the present invention provides co-crystal of Ibrutinib and Palmitic acid designated as Form D16, characterized by an X-ray powder diffraction pattern as illustrated in Figure 3.
In another aspect, the present invention provides process for the preparation of co-crystal of Ibrutinib and Palmitic acid, comprising the steps of:
a) mixing Ibrutinib, Palmitic acid and a solvent or mixture of solvents;
b) obtaining a solution of the above contents;
c) crystallizing the solution to obtain the co-crystal.
The solvent or a mixture of two or more is/are selected from among aprotic solvents, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, t-butanol, ethylene glycol, propylene glycol, acetone, methyl isobutyl ketone, methyl ethyl ketone, 1,4-dioxane, tetrahydrofuran, dimethylacetamide, dimethylformamide, dimethyl sulfoxide, acetonitrile or water. In an embodiment, the solvent is methanol.
Crystallization can be accomplished under cold conditions at a temperature of about 0~10°C, or by evaporating the solvent from the solution, the evaporation can be at 25-30oC or at any other suitable temperature depending upon the solvent system, thereby obtaining the co-crystal.
The obtained co-crystal may optionally be dried and drying may be done using any equipment such as a gravity oven, tray dryer, vacuum oven, Rotavapor®, air tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like.
The drying may be carried out at atmospheric pressure or under reduced pressure. In an embodiment, the drying may be carried out at a temperature of about 60 °C, at a temperature of about 50 °C, at a temperature of about 40°C or at a temperature of about 30°C. The drying may be carried out for any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours, or longer.
In an aspect, the present invention provides a crystalline form of Ibrutinib designated as Form D14. In an aspect, the crystalline form of Ibrutinib designated as Form D14 is benzyl alcohol solvate. In another aspect, the present invention provides a crystalline form of Ibrutinib designated as Form D14, characterized by X-ray powder diffraction pattern having peaks at about 7.71, 12.79 and 25.32 ± 0.20 degrees 2-theta and also having peaks at about 9.46, 8.74, 19.60 and 24.66 ± 0.20 degrees 2-theta. In another aspect, the present invention provides crystalline form of Ibrutinib designated as Form D14, characterized by an X-ray powder diffraction pattern as illustrated in Figure 1.
In another aspect, the present invention provides a process for the preparation of crystalline form of Ibrutinib designated as Form D14, comprising the steps of:
a) mixing Ibrutinib and benzyl alcohol;
b) mixing an anti-solvent with content of step a); and
c) isolating the benzyl alcohol solvate of Ibrutinib.
The step a) may be performed at a temperature of about 10°C to about the boiling point of the solvent. In a preferred embodiment, the step a) is performed at 20-80oC. In a more preferred embodiment, the step a) is performed at 20-40oC.
Step b) involves mixing with a suitable anti-solvent. The anti-solvent used is selected from methyl tert-butyl ether; aliphatic or alicyclic hydrocarbons such as hexane, heptane, pentane, cyclohexane, methyl cyclohexane, or the like. In an embodiment, the anti-solvent used is a mixture of methyl tert-butyl ether and n-heptane. The ratio of first anti-solvent to second anti-solvent in the mixture of anti-solvents may vary from about 1:1 to 1:10 by volume. Preferably the ratio is about 1:4 to 1:10 by volume.
In step b) the mixing of anti-solvent with contents of step a) may be performed at about 2-30oC. In a more preferred embodiment, the step b) is performed at 2-10oC.
Isolation in step c) may involve one or more methods including removal of solvent by techniques known in the art e.g. evaporation, distillation, filtration of precipitated solid and the like, cooling, concentrating the reaction mass, and the like. Stirring or other alternate methods such as shaking, agitation, and the like, may also be employed for the isolation. Isolation may be performed at a temperature of about 20-60oC. More preferably, the isolation is at temperature of about 20-40oC.
Drying may be done using any equipment such as a gravity oven, tray dryer, vacuum oven, Rotavapor®, air tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. In an embodiment, the drying may be carried out at atmospheric pressure or under reduced pressure. In an embodiment, the drying may be carried out at a temperature of about 60 °C, at a temperature of about 50 °C, at a temperature of about 40°C or at a temperature of about 30°C. The drying may be carried out for any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours, or longer.
In an aspect, the present invention provides a crystalline form of Ibrutinib designated as Form D15. In an aspect, the crystalline form of Ibrutinib designated as Form D15 is benzyl alcohol solvate. In another aspect, the present invention provides a crystalline form of Ibrutinib designated as Form D15, characterized by X-ray powder diffraction pattern having peaks at about 9.58 and 25.23 ± 0.20 degrees 2-theta and also having peaks at about 5.54, 11.33 and 17.86 ± 0.20 degrees 2-theta. In another aspect, the present invention provides crystalline form of Ibrutinib designated as Form D15, characterized by an X-ray powder diffraction pattern as illustrated in Figure 2.
In another aspect, the present invention provides a process for the preparation of crystalline form of Ibrutinib designated as Form D15, comprising the steps of:
a) mixing Ibrutinib and benzyl alcohol;
b) mixing an anti-solvent with content of step a); and
c) isolating the benzyl alcohol solvate of Ibrutinib.
The step a) may be performed at a temperature of about 10°C to about the boiling point of the solvent. In a preferred embodiment, the step a) is performed at 20-80oC. In a more preferred embodiment, the step a) is performed at 20-40oC.
Step b) involves mixing with a suitable anti-solvent. The anti-solvent used is methyl tert-butyl ether, aliphatic or alicyclic hydrocarbons such as hexane, heptane, pentane, cyclohexane, methyl cyclohexane, or the like; or mixtures thereof. In an embodiment, the anti-solvent used is a mixture of methyl tert-butyl ether and n-heptane. The ratio of first anti-solvent to second anti-solvent in the mixture of anti-solvents may vary from about 1:1 to 1:10 by volume. Preferably the ratio is about 1:4 to 1:10 by volume.
In step b) the mixing of anti-solvent with contents of step a) may be performed at about 2-30oC. In a more preferred embodiment, the step b) is performed at 2-10oC.
Isolation in step c) may involve one or more methods including removal of solvent by techniques known in the art e.g. evaporation, distillation, filtration of precipitated solid and the like, cooling, concentrating the reaction mass, and the like. Stirring or other alternate methods such as shaking, agitation, and the like, may also be employed for the isolation. Isolation may be performed at a temperature of about 20-60oC. More preferably, the isolation is at temperature of about 20-40oC.
Drying may be done using any equipment such as a gravity oven, tray dryer, vacuum oven, Rotavapor®, air tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. In an embodiment, the drying may be carried out at atmospheric pressure or under reduced pressure. In an embodiment, the drying may be carried out at a temperature of about 60 °C, at a temperature of about 50 °C, at a temperature of about 40°C or at a temperature of about 30°C. The drying may be carried out for any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours, or longer.
Any particular form of Ibrutinib may be used as input material for preparing Ibrutinib form D14, Form D15 and Form D16.
In one embodiment, the present invention provides pharmaceutical composition comprising a therapeutically effective amount of crystalline form of Ibrutinib Form D14, D15 and D16 as mentioned above along with one or more suitable pharmaceutically acceptable carriers/excipients.
Further, the pharmaceutical composition of the invention may be any pharmaceutical form which contains crystalline forms of the invention. The pharmaceutical composition may be solid form such as tablets, powders, capsule, liquid suspension or an injectable composition along with any suitable carrier well known in the prior art. The dosage forms can also be prepared as sustained, controlled, modified and immediate release dosage forms. Suitable excipients and the amounts to use may be radially determined by the standard procedures and reference works in the field, e.g. the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents, disintegrates etc.
All PXRD data reported herein are obtained using a PANalytical X-ray Diffractometer, with copper Ka radiation.
Instrumental parameters.
Model & Detector
Model PANalytical & X’Pert PRO
Detector X’Celerator
Instrument Setting
Goniometer Theta/Theta
Mode of Collection Reflection
Measuring circle 240 mm
Radiation Cu K-alpha (Wave length = 1.5406 Å)
Scan Parameters
Voltage (kV) and Current (mA) 45 kV and 40 mA
Scan range (°2?) 3-40
Step size (°2?) 0.017
Scan Step Time (s) 194.9450
Run Time (min) 60 min
Scan mode Continuous
Divergent slit (°) 0.5
Anti-scattering slit (mm) 5.5 mm
Rotation/min On

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms "about," the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms "comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
The term "optional" or "optionally" is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
The term "anti-solvent" may be taken to mean a solvent in which Ibrutinib have low solubility.
"Co-crystal" is a crystal formed by two or more non-identical molecules, in which the starting components are solid at room conditions when they are in their pure form, and wherein the two or more co-crystal components form aggregates that are characterized by being linked by intermolecular interactions—such as the Van der Waals forces, p-stacking, hydrogen bonding or electrostatic interactions—but without forming covalent bonds.
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the present application in any manner.

EXAMPLES
Example 1: Preparation of crystalline ibrutinib Form D14
10.0g of ibrutinib and 40 mL of benzyl alcohol were taken together and stirred at 25oC. The contents were cooled to 3oC and 240 mL of n-heptane and 160 mL of methyl tert-butyl ether were added and stirred for 22-23 hours at 3oC. The contents were filtered at 25oC and dried in vacuum tray drier at 40oC for 18-20 hours to afford the title compound.
Result: Form D14; PXRD pattern: Figure 1

Example 2: Preparation of crystalline ibrutinib Form D15
2.5g of ibrutinib and 10 mL of benzyl alcohol were taken together and stirred at 25oC. The contents were heated to 50oC and then cooled to 5oC. To the cooled contents were added 60 mL of n-heptane and 40 mL of methyl tert-butyl ether and stirred for 17-18 hours at 5oC. The contents were filtered at 25oC and dried in vacuum tray drier at 40oC to afford the title compound.
Result: Form D15; PXRD pattern: Figure 2

Example 3: Preparation of co-crystal of Ibrutinib and Palmitic acid (Form D16)
4.14g of Ibrutinib, 2.56g of Palmitic acid and 200 mL of methanol was taken together and stirred at 25oC. The contents were heated to 50oC for one hour and cooled to 25oC. The contents were stirred at 25oC for two hours and filtered using 0.45µ syringe filter. The filtrate was dried in open atmosphere at 25oC for about 3 days to afford the title compound.
Result: Form D16; PXRD pattern: Figure 3
,CLAIMS:We Claim:
1. Co-crystal of Ibrutinib and Palmitic acid.
2. Co-crystal of Ibrutinib and Palmitic acid as claimed in claim 1, having characteristic X-ray powder diffraction peaks at 3.35, 6.69, 10.03, 11.98, 13.38, 22.29 and 23.61 ± 0.20 degrees 2-theta.
3. A process of preparing a co-crystal of Ibrutinib and Palmitic acid comprising the steps of;
a) mixing Ibrutinib, Palmitic acid and a solvent or mixture of solvents;
b) obtaining a solution of the above contents;
c) crystallizing the solution to obtain the co-crystal.
4. Benzyl alcohol solvate of Ibrutinib.
5. Benzyl alcohol solvate of Ibrutinib as claimed in claim 4, having characteristic X-ray powder diffraction peaks at 7.71, 12.79 and 25.32 ± 0.20 degrees 2-theta.
6. Benzyl alcohol solvate of Ibrutinib as claimed in claim 4, having characteristic X-ray powder diffraction peaks at 9.58 and 25.23 ± 0.20 degrees 2-theta.
7. Benzyl alcohol solvate of Ibrutinib as claimed in claim 6, further characterized by having characteristic X-ray powder diffraction peaks at 5.54, 11.33 and 17.86 ± 0.20 degrees 2-theta.
8. A process of preparing Benzyl alcohol solvate of Ibrutinib comprising the steps of;
a) mixing Ibrutinib and benzyl alcohol;
b) mixing an anti-solvent with content of step a); and
c) isolating the benzyl alcohol solvate of Ibrutinib.
9. Pharmaceutical composition comprising co-crystal of Ibrutinib and Palmitic acid as claimed in claims 1 to 3 and a pharmaceutically acceptable excipient.
10. Pharmaceutical composition comprising Benzyl alcohol solvate of Ibrutinib as claimed in any of claims 4 to 8 and a pharmaceutically acceptable excipient.