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

SOLID STATE FORMS OF IBRUTINIB

INTRODUCTION
The present invention provides crystalline forms of Ibrutinib, processes for their preparation and pharmaceutical composition comprising said crystalline forms. Also, the invention provides co-crystal of Ibrutinib, process for the preparation of co-crystals of Ibrutinib and pharmaceutical composition comprising said co-crystals of Ibrutinib.
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.
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 a co-crystal of Ibrutinib and Decanoic 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 co-crystal of Ibrutinib and Decanoic acid referred to as Form D17.
Figure 2 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D18.
Figure 3 illustrates a characteristic DSC thermogram of crystalline Ibrutinib Form D18
Figure 4 illustrates a characteristic TGA thermogram of crystalline Ibrutinib Form D18.
Figure 5 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D19.
Figure 6 illustrates a characteristic DSC thermogram of crystalline Ibrutinib Form D19
Figure 7 illustrates a characteristic TGA thermogram of crystalline Ibrutinib Form D19.
Figure 8 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D20a.
Figure 9 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D20.
Figure 10 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D21.
Figure 11 illustrates a characteristic PXRD pattern of crystalline Ibrutinib Form D22.

DETAILED DESCRIPTION
In an aspect, the present invention provides co-crystal of Ibrutinib and Decanoic acid. In an aspect, the present invention provides co-crystal of Ibrutinib and Decanoic acid in the 1:1 mole ratio.
In another aspect, the present invention provides co-crystal of Ibrutinib and Decanoic acid, characterized by an X-ray powder diffraction pattern having peaks at about 3.94 and 11.84 ± 0.20 degrees 2-theta, and also having peaks at about 7.86, 14.55, 16.49, 18.04 and 24.59 ± 0.20 degrees 2-theta.
In another aspect, the present invention provides co-crystal of Ibrutinib and Decanoic acid, characterized by an X-ray powder diffraction pattern as illustrated in Figure 1.
In another aspect, the present invention provides process for the preparation of co-crystal of Ibrutinib and Decanoic acid, comprising the steps of:
a) mixing Ibrutinib, Decanoic 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, acetone, methyl isobutyl ketone, methyl ethyl ketone. In an embodiment, the solvent is acetone.
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 tray dryer, 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 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 D18. In an aspect, the crystalline form of Ibrutinib designated as Form D18 is Octanoic acid solvate.
In another aspect, the present invention provides a crystalline form of Ibrutinib designated as Form D18, characterized by X-ray powder diffraction pattern having peaks at about 4.23, 8.43 and 12.65 ± 0.20 degrees 2-theta and also having peaks at about 16.89, 17.33, 18.70, 21.13 and 24.05 ± 0.20 degrees 2-theta.
In another aspect, the present invention provides crystalline form of Ibrutinib designated as Form D18, characterized by an X-ray powder diffraction pattern as illustrated in Figure 2.
The crystalline Form D18 has a differential scanning calorimetric thermogram substantially as shown in Figure. 3, which exhibits an endothermic peak at about 87.09° C.
The crystalline Form D18 has a thermal gravimetric analysis thermogram substantially as shown in Figure. 4.
In another aspect, the present invention provides a process for the preparation of crystalline form of Ibrutinib designated as Form D18, comprising the steps of:
a) mixing Ibrutinib and Octanoic acid;
b) mixing an anti-solvent with content of step a); and
c) isolating the Octanoic acid 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, 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 1:5 by volume.
In step b) the mixing of anti-solvent with contents of step a) may be performed at about 2-60oC. 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 2-60oC. More preferably, the isolation is at temperature of about 5-25oC.
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 D19. In an aspect, the crystalline form of Ibrutinib designated as Form D19 is Hexanoic acid solvate.
In another aspect, the present invention provides a crystalline form of Ibrutinib designated as Form D19, characterized by X-ray powder diffraction pattern having peaks at about 4.48, 8.97 and 12.25 ± 0.20 degrees 2-theta and also having peaks at about 18.05, 19.90, 21.49 and 23.26 ± 0.20 degrees 2-theta.
In another aspect, the present invention provides crystalline form of Ibrutinib designated as Form D19, characterized by an X-ray powder diffraction pattern as illustrated in Figure 5.
The crystalline Form D19 has a differential scanning calorimetric thermogram substantially as shown in Figure. 6, which exhibits an endothermic peak at about 91.45° C.
The crystalline Form D19 has a thermal gravimetric analysis thermogram substantially as shown in Figure.7.
In another aspect, the present invention provides a process for the preparation of crystalline form of Ibrutinib designated as Form D19, comprising the steps of:
a) mixing Ibrutinib and Hexanoic acid;
b) mixing an anti-solvent with content of step a); and
c) isolating the Hexanoic acid 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 2-60oC. In a more preferred embodiment, the step a) is performed at 20-50oC.
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; or mixtures thereof. In an embodiment, the anti-solvent used is a mixture of methyl tert-butyl ether and n-heptane. In another embodiment, the anti-solvent used is a mixture of methyl tert-butyl ether 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 1:20 by volume.
In step b) the mixing of anti-solvent with contents of step a) may be performed at about 2-60oC. In a more preferred embodiment, the step b) is performed at 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 0-60oC. 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.
Both the Form D18 (Octanoic acid solvate) and Form D19 (Hexanoic acid solvate) of the present applications are non-hygroscopic, chemically and physically stable and suitable for pharmaceutical formulation. The following tables provides the stability data of both Form D18 and Form D19.

Stability data of Form D18 (Octanoic acid solvate)
Storage condition Time Period Description %Water content %Total Impurities Octanoic acid content (%) PXRD
40°C±2°C 75%RH ± 5RH Initial White colored solid 0.13 0.38 25.24 Crystalline
1 Month White colored solid 0.16 0.45 24.70 Matches with Initial
3 Months White colored solid 0.29 0.45 24.99 Matches with Initial

25°C±2°C 60%RH ± 5RH Initial White colored solid 0.13 0.38 25.24 Crystalline
1 Month White colored solid 0.10 0.46 24.70 Matches with Initial
3 Months White colored solid 0.19 0.39 25.57 Matches with Initial

Stability data of Form D19 (Hexanoic acid acid solvate)
Storage condition Time Period Description %Water content %Total Impurities Hexanoic acid content (%) PXRD
40°C±2°C 75%RH ± 5RH Initial Off-White colored solid 0.19 0.41 23.13 Crystalline
1 Month Off-White colored solid 0.13 0.49 21.48 Matches with Initial
3 Months Off-White coloured solid 0.11 0.50 20.79 Matches with Initial

25°C±2°C 60%RH ± 5RH Initial Off-White colored solid 0.19 0.41 23.13 Crystalline
1 Month Off-White colored solid 0.20 0.42 21.73 Matches with Initial
3 Months Off-White colored solid 0.09 0.42 21.24 Matches with Initial

Form D18 and Form D19 can be micronized to get the desired particle size suitable for pharmaceutical formulation.
In an aspect, the present invention provides a crystalline form of Ibrutinib designated as Form D20a. In an aspect, the crystalline form of Ibrutinib designated as Form D20a is Butyric acid solvate.
In another aspect, the present invention provides a crystalline form of Ibrutinib designated as Form D20a, characterized by X-ray powder diffraction pattern having peaks at about 4.69, 9.38, 11.39, 14.90 and 16.82 ± 0.20 degrees 2-theta and also having peaks at about 18.07, 20.43, 21.06, 22.23 and 24.11 ± 0.20 degrees 2-theta.
In another aspect, the present invention provides crystalline form of Ibrutinib designated as Form D20a, characterized by an X-ray powder diffraction pattern as illustrated in Figure 8.
In another aspect, the present invention provides a process for the preparation of crystalline form of Ibrutinib designated as Form D20a, comprising the steps of:
a) mixing Ibrutinib and Butyric acid;
b) mixing an anti-solvent with content of step a); and
c) isolating the Butyric 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 1:5 by volume.
In step b) the mixing of anti-solvent with contents of step a) may be performed at about 2-60oC. 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 2-60oC. More preferably, the isolation is at temperature of about 5-25oC.
In another aspect, Form D20a is dried to obtain Form D20.
In an aspect, the crystalline form of Ibrutinib designated as Form D20 is Butyric acid solvate. In another aspect, the present invention provides a crystalline form of Ibrutinib designated as Form D20, characterized by X-ray powder diffraction pattern having peaks at about 4.52, 9.03, 9.52 and 12.32 ± 0.20 degrees 2-theta and also having peaks at about 18.05, 19.96, 20.49 and 21.55 ± 0.20 degrees 2-theta.
In another aspect, the present invention provides crystalline form of Ibrutinib designated as Form D20, characterized by an X-ray powder diffraction pattern as illustrated in Figure 9.
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 embodiment, Form D20a is dried at 25oC in vacuum oven for about 12-72 hours to obtain Form D20.
In an aspect, the present invention provides a crystalline form of Ibrutinib designated as Form D21. In an aspect, the crystalline form of Ibrutinib designated as Form D21 is Pentanoic acid solvate.
In another aspect, the present invention provides a crystalline form of Ibrutinib designated as Form D21, characterized by X-ray powder diffraction pattern having peaks at about 6.80, 10.57, 13.60 and 16.95 ± 0.20 degrees 2-theta and also having peaks at about 17.70, 19.86, 21.24, 21.89, 22.87, 23.63 and 25.11 ± 0.20 degrees 2-theta.
In another aspect, the present invention provides crystalline form of Ibrutinib designated as Form D21, characterized by an X-ray powder diffraction pattern as illustrated in Figure 10.
In another aspect, the present invention provides a process for the preparation of crystalline form of Ibrutinib designated as Form D21, comprising the steps of:
a) mixing Ibrutinib and Pentanoic acid;
b) mixing an anti-solvent with content of step a); and
c) isolating the Pentanoic acid solvate of Ibrutinib.
The step a) may be performed at a temperature of about 20°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 1:5 by volume.
In step b) the mixing of anti-solvent with contents of step a) may be performed at about 2-60oC. 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 20-50oC. More preferably, the isolation is at temperature of about 20-30oC.
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 D22. In an aspect, the crystalline form of Ibrutinib designated as Form D22 is Pentanoic acid solvate.
In another aspect, the present invention provides a crystalline form of Ibrutinib designated as Form D22, characterized by X-ray powder diffraction pattern having peaks at about 4.61, 9.23, 11.34, 12.33 and 14.71 ± 0.20 degrees 2-theta and also having peaks at about 18.03, 18.56, 20.17, 21.83 and 25.57 ± 0.20 degrees 2-theta.
In another aspect, the present invention provides crystalline form of Ibrutinib designated as Form D22, characterized by an X-ray powder diffraction pattern as illustrated in Figure 11.
In another aspect, the present invention provides a process for the preparation of crystalline form of Ibrutinib designated as Form D22, comprising the steps of:
a) mixing Ibrutinib and Pentanoic acid;
b) mixing an anti-solvent with content of step a); and
c) isolating the Pentanoic acid solvate of Ibrutinib.
Step a) may be performed at a temperature of about 20°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 1:5 by volume.
In step b) the mixing of anti-solvent with contents of step a) may be performed at about 2-8oC. In a more preferred embodiment, the step b) is performed at about 3-6oC.
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 2-25oC. More preferably, the isolation is at temperature of about 5-20oC.
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 D17, D18, D19, D20a, D20, D21 and D22 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 D17, D18, D19, D20a, D20, D21 and D22 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, 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) 194.9450
Run Time (min) 60 min
Scan mode Continuous
Divergent slit (°) 0.5
Anti-scattering slit (mm) 5.5 mm
Rotation/min On

Differential Scanning Calorimetry (DSC)
Analytical Instrument: TA Instruments Discovery (DSC)
Heating rate: 10° C per minute.
Purge gas: nitrogen
Thermal Gravimetric Analysis (TGA)
Analytical Instrument: TA Instruments Q500 (TGA)
Heating rate: 10° C. per minute.
Purge gas: nitrogen.
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 co-crystal of Ibrutinib and Decanoic acid (Form D17)
4.41g of Ibrutinib, 2.73 g of Decanoic acid and 80 mL of acetone was taken together and stirred at 25oC. The contents were heated to 40oC and then cooled to 25oC. The contents were taken in a beaker and covered with pin holed aluminum foil. The solvent was allowed to evaporate for 6 days at 25oC to afford solid compound. The isolated solid was dried in vacuum tray drier at 25oC for about 30 hours followed by drying at 40oC for 24 hours to afford the title compound 18-20 hours to afford the title compound.
Result: Form D17.
Example 2: Preparation of crystalline ibrutinib Form D18
32.0 g of Ibrutinib and 150 mL of Octanoic acid were taken together and stirred at 25oC. The contents were heated to 50oC and then cooled to 25oC. 200 mL of n-heptane and 150 mL of methyl tert-butyl ether were added and stirred for 1-2 hours at 5oC. 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 D18
Example 3: Preparation of crystalline ibrutinib Form D18
0.5 g of Ibrutinib and 3 mL of Octanoic acid were taken together and stirred at 25oC. The contents were heated to 50oC and then cooled to 25oC and 3 mL of ethyl acetate was added. The contents were 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 D18
Example 4: Preparation of crystalline ibrutinib Form D19
4.0 g of Ibrutinib and 20 mL of Hexanoic acid were taken together and stirred at 25oC. The contents were heated to 40oC and then cooled to 25oC. 30 mL of n-heptane and 30 mL of methyl tert-butyl ether were added and stirred for 18 hours at 5oC. The contents were filtered at 25oC and dried in vacuum tray drier at 40oC for about 6-7 hours to afford the title compound.
Result: Form D19
Example 5: Preparation of crystalline ibrutinib Form D19
20.0 g of Ibrutinib and 30 mL of Hexanoic acid were taken together and stirred at 25oC. The contents were heated to 50oC and then cooled to 25oC. 200 mL of n-hexane and 10 mL of methyl tert-butyl ether were added and stirred for 16 hours at 5oC. The contents were filtered at 25oC and dried in vacuum tray drier at 40oC for 24 hours to afford the title compound.
Result: Form D19
Example 6: Preparation of crystalline Ibrutinib Form D20a
2.0 g of Ibrutinib was taken in 5.0 mL of Butyric acid at 25°C. 3 mL of methyl tert-butyl ether and 25 mL of n-Heptane were added to the above contents and stirred for 2-3 hours. The contents were filtered at 25°C to obtain the title compound.
Result: Form D20a
Example 7: Preparation of crystalline Ibrutinib Form D20
Form-D20a was dried in Vacuum tray drier for about 12-72 hours at 25°C to obtain the title compound.
Result: Form D20
Example 8: Preparation of crystalline Ibrutinib Form D21
2.0 g of Ibrutinib and 5 mL of Pentanoic acid were taken together and stirred at 25oC. 25 mL of n-heptane and 3 mL of methyl tert-butyl ether were added and stirred for 3 hours at 25oC. The contents were filtered at 25oC and dried in vacuum tray drier at 25oC for 72 hours to afford the title compound.
Result: Form D21
Example 9: Preparation of crystalline Ibrutinib Form D22
20.0 g of Ibrutinib and 60 mL of Pentanoic acid were taken together and stirred at 25oC. The contents were cooled to 5oC and 540 mL of n-heptane and 100 mL of methyl tert-butyl ether were added and stirred for 4 hours at 5oC. The contents were filtered at 25oC and dried in vacuum tray drier at 25oC for 42 hours to afford the title compound.
Result: Form D22
Example 10: Preparation of crystalline Ibrutinib Form D18
750 g of Ibrutinib and 3000 mL of Octanoic acid were taken together in a round bottom flask and stirred for 1 h at 25oC. Methyl tert-butyl ether (1 L) added to the flask and stirred for 5 minutes at 25°C to get clear solution. The solution was filtered through micron filter to get particle free solution and additional Methyl tert-butyl ether (2 L) was added to the obtained particle free solution and n-Heptane (13.5 L) added to the flask over a period of 20-30 minutes at 25°C. The reaction mass was stirred for 12 h at 25°C. The precipitated material was filtered and washed with n-Heptane (1.5 L) and dried under vacuum suction under further dried in vacuum tray drier.
Yield: 840 g.
Example 11: Preparation of crystalline Ibrutinib Form D19
750 g of Ibrutinib and 3750 mL of Hexanoic acid were taken together in a round bottom flask and stirred for 1 h 30 minutes at 25oC. Methyl tert-butyl ether (3750 mL) added to the flask and stirred for 15 minutes at 25°C to get clear solution. The solution was filtered through micron filter to get particle free solution and stirred for 20 minutes and n-Heptane (22.5 L) added to the flask over a period of about 2 h at 25°C. The reaction mass was stirred for 22 hrs at 25°C. The precipitated material was filtered and washed with n-Hpetane (1.5 L) and dried under vacuum suction and further dried in vacuum tray drier.
Yield: 900 g.
,CLAIMS:We Claim:
1. Crystalline Form D18 (Octanoic acid solvate) of Ibrutinib characterized by an X-ray powder diffraction pattern comprising the peak at about 4.23, 8.43 and 12.65 ± 0.20 degrees 2-theta.
2. Crystalline Form D18 of Ibrutinib of claim 1, further characterized by PXRD pattern having additional peaks at about 16.89, 17.33, 18.70, 21.13 and 24.05 ± 0.20 degrees 2-theta.
3. A process for preparing crystalline Form D18 of Ibrutinib, comprising the steps of;
a) mixing Ibrutinib and Octanoic 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 D19 (Hexanoic acid solvate) of Ibrutinib characterized by an X-ray powder diffraction pattern comprising the peak at about 4.48, 8.97 and 12.25 ± 0.20 degrees 2-theta.
6. Crystalline Form D19 of Ibrutinib of claim 5, further characterized by PXRD pattern having additional peaks at about 18.05, 19.90, 21.49 and 23.26 ± 0.20 degrees 2-theta.
7. A process for preparing crystalline Form D19 of Ibrutinib, comprising the steps of;
d) mixing Ibrutinib and Hexanoic acid;
e) mixing an anti-solvent with content of step a); and
f) isolating the Hexanoic acid solvate of Ibrutinib.
8. The process of claim 7 wherein, the anti-solvent is mixture of methyl tert-butyl ether and n-heptane.
9. A pharmaceutical composition comprising crystalline Ibrutinib Form D18 and pharmaceutically acceptable excipients.
10. A pharmaceutical composition comprising crystalline Ibrutinib Form D19 and pharmaceutically acceptable excipients.