DESC:The following specification particularly describes the invention and the manner in which it is to be performed.

MULTI-COMPONENT SOLID FORMS OF IBRUTINIB

INTRODUCTION
The present invention provides multi-component solid forms of Ibrutinib, processes for their preparation and pharmaceutical composition comprising said crystalline forms.
BACKGROUND OF THE INVENTION
l-{3R-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)}prop-2-en-l-one, known as Ibrutinib is structurally represented 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.

SUMMARY
The present invention also provides multi-component solid 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 D23.
Figure 2 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D24.
Figure 3 ORTEP of Ibrutinib-Palmitic acid Co-crystal (Form-D16). Displacement ellipsoids were drawn at the 30% probability level for non-hydrogen atoms. Hydrogen atoms are shown as small spheres of arbitrary radii. Dashed line indicates hydrogen bonds.

DETAILED DESCRIPTION
In an aspect, the present invention provides a crystalline form of Ibrutinib designated as Form D23. In an aspect, the crystalline form of Ibrutinib designated as Form D23 is nonanoic acid solvate.
In another aspect, the present invention provides a crystalline form of Ibrutinib designated as Form D23, characterized by X-ray powder diffraction pattern having peaks at about 4.1, 8.14 and 12.18 ± 0.20 degrees 2-theta and also having peaks at about 16.81, 21.89 and 23.48 ± 0.20 degrees 2-theta.
In another aspect, the present invention provides crystalline form of Ibrutinib designated as Form D23, 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 D23, comprising the steps of:
a) mixing Ibrutinib and Nonanoic acid;
b) mixing anti-solvent with content of step a); and
c) isolating the Nonanoic acid solvate of Ibrutinib.
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, diisopropyl ether, pet ether or the like; aliphatic or alicyclic hydrocarbons such as hexane, heptane, pentane, cyclohexane, methyl cyclohexane, or the like; esters such as ethyl acetate, isopropyl acetate or the like. In an embodiment, the anti-solvent used is a mixture of methyl tert-butyl ether and n-heptane. In an embodiment, the anti-solvent used is ethyl acetate. 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 1:1 to 1:7 by volume.
In step b) the mixing of anti-solvent with contents of step a) may be performed at about 20-60oC. In a more preferred embodiment, the step b) is performed at about 20-50oC.
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 0-50oC. More preferably, the isolation is at temperature of about 0-40oC.
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 20°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 D24. In an aspect, the crystalline form of Ibrutinib designated as Form D24 is Heptanoic acid solvate.
In another aspect, the present invention provides a crystalline form of Ibrutinib designated as Form D24, characterized by X-ray powder diffraction pattern having peaks at about 4.31, 8.61 and 12.92 ± 0.20 degrees 2-theta and also having peaks at about 14.32, 17.26, 21.02, 22.64 and 24.37 ± 0.20 degrees 2-theta.
In another aspect, the present invention provides crystalline form of Ibrutinib designated as Form D24, 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 D24, comprising the steps of:
a) mixing Ibrutinib and Heptanoic acid;
b) mixing anti-solvent with content of step a); and
c) isolating the Heptanoic acid solvate of Ibrutinib.
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 10-60oC. In a more preferred embodiment, the step a) is performed at 10-50oC.
Step b) involves mixing with a suitable anti-solvent. The anti-solvent used is methyl tert-butyl ether, diisopropyl ether, pet ether or the like; aliphatic or alicyclic hydrocarbons such as hexane, heptane, pentane, cyclohexane, methyl cyclohexane, or the like; water; or mixtures thereof. In an embodiment, the anti-solvent used is a mixture of methyl tert-butyl ether and n-pentane. In another embodiment, the anti-solvent used is a mixture of water and n-hexane. 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.
In step b) the mixing of anti-solvent with contents of step a) may be performed at about 10-60oC. In a more preferred embodiment, the step b) is performed at 10-50oC.
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 0-60oC. More preferably, the isolation is at temperature of about 0-40oC.
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 20°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 embodiment, the invention provides solvates and/or co-crystals of Ibrutinib with C4-C16 carboxylic acid.
Any particular form of Ibrutinib may be used as input material for preparing Ibrutinib Form D23 and D24 as described in this patent application.
In one embodiment, the present invention provides pharmaceutical composition comprising a therapeutically effective amount of crystalline form of Ibrutinib Form D23 and D24 as mentioned above along with one or more suitable pharmaceutically acceptable carriers/excipients.
The co-pending application IN201841000955 discloses a co-crystal of Ibrutinib and Palmitic acid.
Single crystal X-ray structure of Ibrutinib and Palmitic acid reveals that the asymmetric unit consists of one molecule of Ibrutinib and one molecule of Palmitic acid. It is a 1:1 stoichiometric anhydrous co-crystal. Carboxylic acid functional group of Palmitic acid is forming robust ‘Carboxylic acid? Aminopyridine’ Supramolecular heterosynthon with amino-pyrimidine group of Ibrutinib through strong O-H…N and N-H…O hydrogen bonds as shown in Figure 3. Such units are connected through (Amine) N-H…O=C(Amide) hydrogen bonds and forming a linear tape.
Crystal data and structure refinement of Ibrutinib and Palmitic acid 1:1 Co-crystal.
Empirical formula C25H24N6O2, C16 H32 O2
Formula weight 696.91
Temperature 294 (2) K
Wavelength 0.71073 Å
Crystal system Orthorhombic
Space group P212121
Unit cell dimensions a=7.685 (2) Å, a=90°
b=9.764(3) Å, ß=90°
c=52.921(16) Å, ?=90°
Volume 3971 (2) Å3
Z 4
Density 1.166 mg/m3
Absorption coefficient 0.076 mm-1
F(000) 1504
Crystal size 0.20x0.18x0.10 mm3
Theta range for data collection 2.223 to 24.995°
Indexing ranges -9<=h<=5, -10<=k<=11, -62<=l<=62
Reflections collected 21363
Independent reflections 6975 [ R(int)=0.0593]
Completeness to ?=25° 99.9%
Refinement method Full matrix least-squares on F2
Data/restraints/parameters 6975/0/473
Goodness of fit on F2 1.041
Final R indices [I>2?s(I)] R1=0.0599, wR2=0.1209
R indices (all data) R1=0.1070, wR2=0.1385
Absolute structure parameter -0.2 (8)
Extinction coefficient 0.0048 (6)
Largest dif. Peak and hole 0.254 and -0.164 e.Å-3
Measurement Bruker D8 QUEST PHOTON-100 Detector
Software used SHELXTL-PLUS

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, disintegrants 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) 64.77
Run Time (min) 20 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.
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 D23
4.0 g of Ibrutinib and 25 mL of Nonanoic acid were taken together and stirred at 25oC for 50 minutes and filtered the solution to make particle free. 25 mL of methyl tert-butyl ether followed by 150 mL of n-heptane were added and stirred for 28 hours at 25oC. The contents were filtered at 25oC and dried in vacuum tray drier at 40oC for 24-48 hours to afford the title compound.
Result: Form D23

Example 2: Preparation of crystalline Ibrutinib Form D24
4.0 g of Ibrutinib was dissolved in 25 mL of Heptanoic acid at 40°C. The above clear solution was charged in a 250 mL round bottom flask. Water (100 mL) was added to the above clear solution. Cooled it down to 10°C and after 24 hours added 100 mL of n-Hexane to it at 25°C. The reaction was maintained for four days. The contents were filtered at 25oC and dried in vacuum tray drier at 40oC for 20-24 hours to afford the title compound.
Result: Form D24

Example 3: Preparation of crystalline Ibrutinib Form D24
2.5 g of Ibrutinib was dissolved in 6 mL of Heptanoic acid under stirring at 25oC. 6 mL of methyl tert-butyl ether followed by 30 mL of n-pentane were added and stirred for 1 hour at 25oC. The contents were cooled to 5oC and maintained for 4 days. The contents were filtered at 25oC to afford the title compound.
Result: Form D24
,CLAIMS:We Claim:
1. Crystalline Form D23 (Nonanoic acid solvate) of Ibrutinib characterized by an X-ray powder diffraction pattern comprising the peak at about 4.1, 8.14 and 12.18 ± 0.20 degrees 2-theta.
2. Crystalline Form D23 of Ibrutinib of claim 1, further characterized by PXRD pattern having additional peaks at about 16.81, 21.89 and 23.48 ± 0.20 degrees 2-theta.
3. A process for preparing crystalline Form D23 of Ibrutinib, comprising the steps of;
a) mixing Ibrutinib and Nonanoic acid;
b) mixing an anti-solvent with content of step a); and
c) isolating the Octanoic acid solvate of Ibrutinib.
4. The process of claim 3 wherein, the anti-solvent is mixture of methyl tert-butyl ether and n-heptane.
5. Crystalline Form D24 (Heptanoic acid solvate) of Ibrutinib characterized by an X-ray powder diffraction pattern comprising the peak at 4.31, 8.61 and 12.92 ± 0.20 degrees 2-theta.
6. Crystalline Form D24 of Ibrutinib of claim 5, further characterized by PXRD pattern having additional peaks at about 14.32, 17.26, 21.02, 22.64 and 24.37 ± 0.20 degrees 2-theta.
7. A process for preparing crystalline Form D24 of Ibrutinib, comprising the steps of;
d) mixing Ibrutinib and Heptanoic acid;
e) mixing an anti-solvent with content of step a); and
f) isolating the Heptanoic acid solvate of Ibrutinib.
8. The process of claim 7 wherein, the anti-solvent is mixture of methyl tert-butyl ether and n-heptane or n-hexane or n-pentane.
9. A pharmaceutical composition comprising crystalline Ibrutinib Form D23 and pharmaceutically acceptable excipients.
10. A pharmaceutical composition comprising crystalline Ibrutinib Form D24 and pharmaceutically acceptable excipients.