METHODS OF PREPARING CO-CRYSTALS OF IBRUTINIB WITH CARBOXYLIC ACIDS

Abstract

The present invention relates to co-crystals of ibrutinib and a pharmaceutical composition comprising the same as well as a method of preparing the same.

Claims

1. A method of preparing a co-crystal of ibrutinib comprising the steps of: a. suspending ibrutinib with a carboxylic acid in a suitable solvent, b. heating the obtained suspension until a clear solution is obtained, c. optionally keeping the obtained solution for some time and/or under stirring, and d. subsequently cooling the solution to room temperature.

2. The method according to claim 1, wherein the solvent is a polar organic solvent.

3. The method according to claim 2, wherein the polar organic solvent is a C1 -C6 aliphatic alcohol.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0054] FIG. 1 shows the .sup.1H-NMR spectrum of ibrutinib:benzoic acid co-crystal (1:1) (.sup.1H-NMR in DMSO-d.sub.6, 400 MHz).

[0055] FIG. 2 shows the XRPD diffractogram of ibrutinib:benzoic acid co-crystal (1:1).

[0056] FIG. 3 shows an XRPD diffractogram of ibrutinib:benzoic acid co-crystal (1:1) (at the top) compared with a simulated powder diffractogram produced from the atomic positions resulting from the three-dimensional x-ray structure of ibrutinib:benzoic acid co-crystal (1:1).

[0057] FIG. 4 shows an UHPLC/UV analysis of ibrutinib:benzoic acid (1:1) co-crystal. Signal at Rt=2.49 min corresponds to benzoic acid.

[0058] FIG. 5 shows the position of benzoic acid bound through hydrogen bonds to ibrutinib base as observed in the three-dimension crystal structure analysis of a single crystal on ibrutinib:benzoic acid co-crystal (1:1).

[0059] FIG. 6 shows the .sup.1H-NMR spectrum of ibrutinib:fumaric acid co-crystal (2:1) (.sup.1H-NMR in DMSO-d.sub.6, 400 MHz).

[0060] FIG. 7 shows the XRPD diffractogram of ibrutinib:fumaric acid co-crystal (2:1).

[0061] FIG. 8 shows an UHPLC/UV analysis of ibrutinib:fumaric acid (2:1) co-crystal. Signal at Rt=1.67 min corresponds to fumaric acid.

[0062] FIG. 9 shows the position of fumaric acid bound through hydrogen bonds to ibrutinib base as observed in the three-dimension crystal structure analysis of a single crystal on ibrutinib:fumaric acid co-crystal (2:1).

[0063] FIG. 10 shows the .sup.1H-NMR spectrum of ibrutinib:succinic co-crystal (.sup.1H-NMR in DMSO-d.sub.6, 400 MHz).

[0064] FIG. 11 shows the XRPD diffractogram of ibrutinib:succinic acid co-crystal.

[0065] FIG. 12 shows an UHPLC/UV analysis of ibrutinib:succinic acid co-crystal.

[0066] FIG. 13 shows the position of succinic acid bound through hydrogen bonds to ibrutinib base as observed in the three-dimensional crystal structure analysis of a single crystal on ibrutinib:succinic acid co-crystal (2:1).

[0067] FIG. 14 shows the XRPD diffractogram of ibrutinib:fumaric co-crystal after stress testing.

[0068] FIG. 15 shows the XRPD diffractograms of ibrutinib co-crystals compared to ibrutinib form E, each before and after storage for 12 weeks.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0069] Analytical Methods

[0070] .sup.1H-NMR Spectroscopy

[0071] Instrument: Varian Mercury 400 Plus NMR Spectrometer, Oxford AS, 400 MHz.

[0072] UHPLC/UV

[0073] Instrument: Agilent 1290 Infinity

[0074] Wavelength 258 nm

[0075] Column: Kinetex C18 1504.6 mm, 6 m

[0076] Column temp.: 40 C.

[0077] Injection volume: 1 l

[0078] Solvent A: acetonitrile

[0079] Solvent B: 0.2% formic acid+0.1% heptafluorobutyric acid

[0080] Flow: 0.8 ml/min

TABLE-US-00001 time [min] solvent B [%] 0.00 55 10.00 10 12.00 10 12.50 55

[0081] X-Ray Powder Diffraction (XRPD)

[0082] First Method:

[0083] The samples were measured on a D8 Advance powder X-ray diffractometer (Bruker AXS, Karlsruhe, Germany) in a rotating PMMA sample holder (diameter: 25 mm; depth: 1 mm) in reflection mode (Bragg-Brentano geometry). Conditions of the measurements are summarized in the table below. Raw data were analyzed with the program EVA (Bruker AXS, Karlsruhe, Germany).

TABLE-US-00002 radiation Cu K.sub.1/.sub.2 source 34 kV/40 mA detector Vantec-1 (electronic window: 3) K filter Ni (diffracted beam) measuring circle diameter 435 mm detector window slit 12 mm anti-scatter slit (diffracted beam) 8 mm divergence slit v6.00 (variable) Soller slit (incident/diffracted beam) 2.5 2 range 2 2 55 step size 0.016 step time 0.2 s

[0084] Second Method (for Stress Testing):

[0085] The analysis of was performed on ARL (SCINTAG) powder X-Ray diffractometer model XTRA equipped with a solid stage detector. Copper radiation of 1.5418 was used.

[0086] Scanning parameters: range: 2-40 degrees two-theta; scan mode: continuous scan; step size: 0.05, and a rate of 3 deg/min.

[0087] X-Ray Singe Crystal Diffraction (XRD)

[0088] The crystal was measured on an Oxford Diffraction XCALIBUR diffractometer with area detector at 180 K with a wavelength of 1.54180 .

[0089] For the following experiments and examples, the starting compound ibrutinib form A was obtained as described in WO 2013/184572.

Example 1: Preparation of Ibrutinib:Benzoic Acid Co-Crystal (1:1)

Experiment 1

[0090] 204 mg (0.46 mmol) ibrutinib form A was suspended together with 56 mg (0.46 mmol) benzoic acid in 1 mL MeOH at room temperature (RT). The suspension was heated to 75 C. A clear solution was obtained. The solution was let slowly cooled down to RT while a white solid started to precipitate. The precipitate was isolated by filtration and dried at 50 C. /10 mbar for 24 hours (Yield: 65%).

[0091] The sample was analysed by means of XRPD and .sup.1H-NMR spectroscopy.

Experiment 2

[0092] 204 mg (0.46 mmol) ibrutinib form A was suspended together with 56 mg (0.46 mmol) benzoic acid in 1 mL MeOH at 30 C. After stirring, a clear solution was obtained. The solution was let stirring for 60 minutes while a white solid started to precipitate. The precipitate was isolated by filtration and dried at 50 C./10 mbar for 24 hours (Yield: 45%). The sample was analysed by means of XRPD and .sup.1H-NMR spectroscopy.

Experiment 3

[0093] 2,4 g (5.5 mmol) ibrutinib form A was suspended together with Benzoic acid 0.67 g (5.5 mmol) in MeOH (50 mL) at 30 C. After stirring of the suspension a clear solution was obtained. The solution was let evaporate in rotavap until an approximately volume of 10 mL. A white solid started to precipitate. The solution was let overnight with stirring at 30 C. for the complete precipitation. It was isolated by filtration and dried at 40 C./10 mbar for 72 hours. (Yield: 68%).

[0094] The sample was analysed by means of XRPD and .sup.1H-NMR spectroscopy.

[0095] The results of Experiments 1 to 3:

[0096] .sup.1H-NMR Spectroscopy

[0097] The sample was analyzed in a 400 MHz-NMR spectrometer. As solvent, DMSO-d.sub.6 was used. The .sup.1H-NMR spectrum is shown in FIG. 1. The signals are summarized below (*=signals of benzoic acid):

[0098] 1.57 (br. s., 1H); 1.84-1.97 (m, 1H); 2.12 (br. s., 1H); 2.25 (qd, J=11.93, 4.11 Hz, 1H); 2.86-3.09 (m, 1H); 3.11-3.26 (m, 1H); 3.30 (br. s., 1H); 3.53-3.77 (m, 1H); 4.06 (d, J=13.29 Hz, 1H); 4.19 (br. s., 1H); 4.54 (d, J=11.34 Hz, 1H); 4.70 (br. s., 1H); 5.57 (d, J=9.78 Hz, 1H); 5.69 (d, J=10.17 Hz, 1H); 6.00-6.21 (m, 1H); 6.51-6.77 (m, 1H); 6.77-7.02 (m, 1H); 7.09-7.19 (m, 5H); 7.39-7.51 (m, 4H(2H*)); 7.54-7.73 (m, 3H(1H*)); 7.91 -7.96 (m, 2H)*; 8.24 (s, 1H); 12.93 (br. s., 1H*).

[0099] The integration values of the 1.93 ppm signal (1H) of ibrutinib and the 2 orto-hydrogens from benzoic acid (7.93 ppm) were 1 and 2 resp. It corresponds with a ibrutinib:benzoic acid=1:1 molar ratio.

[0100] X-Ray Powder Diffraction (XRPD)

[0101] The product was characterized by means of x-ray powder diffraction. It is shown in the FIG. 2.

TABLE-US-00003 most characteristic peaks [ 2] 0.2 2 sample Primary characterising peaks Secondary characterising peaks ibrutinib:benzoic acid (1:1) 9.1 12.1 13.7 13.9 23.0 16.1 16.2 19.1 20.1 21.2

[0102] The complete list of XRPD diffraction peaks of ibrutinib benzoic acid co-crystal (1:1):

TABLE-US-00004 Angle Relative Intensity (2) % 9.1 12.5% 12.1 17.9% 13.7 3.9% 13.9 5.3% 15.1 23.9% 16.1 5.9% 16.2 3.6% 17.3 7.1% 18.2 19.8% 19.1 7.7% 19.5 4.5% 20.1 4.7% 21.2 24.0% 22.1 7.9% 23.0 100.0% 23.9 17.7% 24.4 6.5% 25.8 2.3% 27.9 27.6% 28.6 5.2% 29.1 1.3% 30.3 8.9% 31.3 2.5% 32.5 2.3% 33.6 2.4% 34.9 2.0% 35.3 1.8% 35.8 2.6% 36.7 3.1% 38.0 2.1% 39.2 1.7% 40.2 1.7% 42.8 3.5% 43.8 2.2% 45.3 1.2% 45.9 1.1% 46.9 1.2% 47.9 2.7% 49.9 2.8%

[0103] Also a comparative of this diffractogram with the simulated powder pattern from the single-crystal study results is shown in FIG. 3.

[0104] UHPLC/UV

[0105] The chromatogram from UHPLC/UV analysis is shown in FIG. 4. No impurities were detected (Rt=2.486 min: benzoic acid; Rt=3.763 min: ibrutinib).

[0106] Storage Stability of Ibrutinib:Benzoic Acid

[0107] One batch of the ibrutinib:benzoic acid cocrystal (stability batch) was stored in open and closed containers in a climate chamber at 40 C./75% relative humidity (accelerated conditions). After storage for 4, 8 and 12 weeks, samples were analyzed by UHPLC/UV (chemical purity) as well as by XRPD (solid state stability). The results of UHPLC/UV analysis, summarized in the following table demonstrate that the chemical purity of the ibrutinib:benzoic acid cocrystal remained unchanged.

TABLE-US-00005 Conditions (40 C./75% RH) Open Close 4 Weeks 99.74% 99.90% 8 Weeks 99.77% 99.90% 12 Weeks 99.80% 99.91%

[0108] The results of XRPD analysis confirmed that the solid state of the ibrutinib:benzoic acid cocrystal remained unchanged during storage under accelerated conditions.

[0109] X-Ray Single Crystal Study of Ibrutinib:Benzoic Acid Co-Crystal (1:1)

[0110] The absolute configuration of the determined molecular structure matched the expected configuration, the Flack parameter was refined to a value of 0.04(13), thus it corroborates the assignment. Hydrogen atoms were refined according to a riding model with exception of heteroatom-bonded hydrogen atoms whose positions were refined without restraints.

TABLE-US-00006 Empirical formula C.sub.32H.sub.30N.sub.6O.sub.4 Formula weight 562.63 Temperature 180 K Wavelength 1.54180 Crystal system triclinic Space group P1 Unit cell dimensions a [] 7.3974(2) b [] 9.7644(2) c [] 9.9369(2) [] 82.965(2) [] 81.427(2) [] 88.055(2) Volume [.sup.3] 704.30(1) Z 1 Density (calculated) [g .Math. cm.sup.3] 1.326 Absorption coefficient [mm.sup.1] 0.731 F(000) 296 Crystal size [mm] 0.72 0.47 0.38 Theta range for data collection 4.53 to 77.22 Index ranges 9 h 9, 12 k 12, 12 l 12 Reflections collected 22735 Independent reflections [R(int)] 5472 (0.047) Completeness to Theta = 77.22 97.8% Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.76 and 0.20 Refinement method Full-matrix least-squares on F.sup.2 Data/parameters/restraints 5467/390/8 Goodness-of-fit on F.sup.2 0.9338 Final R indices [I > 2(I)] R.sub.1 = 0.0343, wR.sub.2 = 0.0922 Flack parameter 0.04(13) Final R indices [all data] R.sub.1 = 0.0351, wR.sub.2 = 0.0944 Largest diff. peak and hole 0.18 and 0.15 [e .Math. .sup.3]

[0111] As is shown in FIG. 5, the packing of ibrutinib:benzoic acid co-crystal, consist in 1 molecule of ibrutinib and 1 molecule of Benzoic acid, i.e. a molar ratio of 1:1 with a triclinic symmetry.

[0112] There are three hydrogen bonds in the structure.

[0113] Firstly, the H-bond between ibrutinib and benzoic acid (O4-H45 . . . N5) what confirms that the new solid state is a co-crystal, instead of a benzoate salt of ibrutinib. If the carboxyl group were deprotonated, the electrons would delocalize, causing almost same length of both CO bonds (C26-O3 and C26-O4 in FIG. 5b). In this case, it is clear that the carboxyl group is protonized, as there is a distance CO of 1.219(2) (C26-O3) and COH, with CO 1.313(2) (C26-O4). The carboxyl proton was located in difference Fourier map and its position was refined without restraints.

[0114] Secondly, H-bond between ibrutinib and benzoic acid (N4-H . . . O3) is a soft-moderate H-bond which makes stronger the union between ibrutinib and the co-former.

[0115] And finally, there is a H-bond between the amine group of ibrutinib and the carbonyl group of the next ibrutinib molecule.

[0116] The calculated atom distances and the angle of the H-bonds:

TABLE-US-00007 DH . . . A DH () H . . . A () D . . . A () DH . . . A() H-bond 1 O4H45 . . . N5 0.97(3) 1.64 2.582(2) 163(3) H-bond 2 N4H44 . . . O3 0.94 2.26 3.164(2) 161(2) H-bond 3 N4H43 . . . O1 0.92(2) 2.19 2.846(2) 127(2)

Example 2: Preparation of Ibrutinib:Fumaric Acid Co-Crystal (2:1)

Experiment 1

[0117] 3 g (6.8 mmol) ibrutinib form A was suspended together with 0.8 g (6.8 mmol) fumaric acid in 27 mL MeOH at room temperature (RT). The suspension was heated to 70 C. A clear solution was obtained. The solution was let slowly cooled down to RT while a white solid started to precipitate. The precipitate was isolated by filtration and dried at 40 C./10 mbar for 72 hours (Yield: 70%).

[0118] The sample was analysed by means of XRPD and .sup.1H-NMR spectroscopy.

Experiment 2

[0119] Analogous to the Experiment 1, the procedure was performed with 800 mg (1.8 mmol) ibrutinib form A and 210 mg (1.8 mmol) fumaric acid with a 43% yield.

[0120] The sample was analysed by means of XRPD and .sup.1H-NMR spectroscopy.

Experiment 3

[0121] 1 L reactor was charged with ibrutinib (50 g), fumaric acid (26.35 g) and methanol (350 mL), the mixture was heated to 68 C. until dissolution. The solution was cooled to 45 C. during 1 hour and seeded with ibrutinib:fumaric acid co-crystals. The mixture was cooled to 35 C. during 1 hour and stirred at 35 C. for 2 hours until precipitate was obtained. The slurry was cooled to 0 C. during 6 hours and stirred at 0 C. overnight.

[0122] The slurry was filtered under vacuum, washed with cooled methanol (100 mL) and dried at 50 C. over 72 hours in vacuum to give 49.46 g of white solid (Yield: 87.5%).

[0123] The results of Experiments 1 to 3:

[0124] .sup.1H-NMR Spectroscopy

[0125] The sample was analyzed in a 400 MHz-NMR spectrometer. As solvent, DMSO-d.sub.6 was used. The .sup.1H-NMR spectrum is shown in FIG. 5. The signals are summarized below (*=signals of fumaric acid):

[0126] 1.57 (br. s., 1H); 1.75-2.01 (m, 1H); 2.11 (br. s., 1H); 2.18-2.46 (m, 1H); 2.65 (s, 1H); 3.01 (d, J=9.78 Hz, 1H); 3.20 (br. s., 1H); 3.68 (br. s., 1H); 4.06 (d, J=12.12 Hz, 1H); 4.19 (br. s., 1H); 4.52 (br. s., 1H); 4.69 (br. s., 1H); 5.57 (d, J=10.17 Hz, 1H); 5.69 (d, J=11.34 Hz, 1H); 5.99-6.19 (m, 1H); 6.52-6.63 (m, 1H*); 6.64-6.77 (m, 1H); 6.78-6.98 (m, 1H); 7.09-7.19 (m, 4H); 7.31-7.53 (m, 2H); 7.64 (d, J=7.82 Hz, 2H); 8.24 (s, 1H); 13.10 (br. s., 1H*).

[0127] The integration values of the 1.93 ppm signal (1H) of ibrutinib and the 6.60 ppm signal (2H) from fumaric acid were 1 and 1 resp. It corresponds with a ibrutinib:fumaric acid=2:1 molar ratio.

[0128] X-Ray Powder Diffraction (XRPD)

[0129] The product was characterized by means of x-ray powder diffraction. It is shown in the FIG. 6.

[0130] The x-ray powder diffractogram of ibrutinib:fumaric acid co-crystal is characterized by the following signals:

TABLE-US-00008 most characteristic peaks [ 2] 0.2 2 sample Primary characterising peaks Secondary characterising peaks ibrutinib:Fumaric acid 9.9 17.4 18.7 20.5 21.7 6.5 13.0 18.2 22.4 23.9

[0131] The complete list of XRPD diffraction peaks of ibrutinib fumaric acid co-crystal (2:1):

TABLE-US-00009 Angle (2) Relative Intensity % 6.5 3.8% 9.9 14.0% 10.1 4.3% 10.5 3.1% 10.8 6.8% 11.9 5.4% 12.6 4.6% 12.8 4.4% 13.0 6.9% 14.7 2.7% 15.2 2.2% 17.4 32.8% 18.2 100.0% 18.7 14.6% 19.8 15.0% 20.5 72.4% 21.0 8.5% 21.7 95.9% 22.4 17.6% 23.6 20.2% 23.9 29.5% 24.4 18.4% 25.2 4.4% 25.7 13.7% 26.8 12.4% 28.1 17.7% 29.3 15.4% 30.6 8.3% 31.5 5.4% 32.0 2.9% 33.1 3.7% 33.4 4.7% 34.4 2.3% 35.8 8.8% 36.5 4.6% 38.8 3.7% 40.4 3.9% 41.6 5.4% 43.4 4.1% 45.6 4.4% 46.8 4.6% 49.1 2.5% 50.2 3.6% 52.6 1.7% 53.5 3.3%

[0132] UHPLC/UV

[0133] The chromatogram from UHPLC/UV analysis is shown in FIG. 8. No impurities were detected (Rt=1.671 min: fumaric acid, Rt=3.728 min: ibrutinib).

[0134] Storage Stability of Ibrutinib:Fumaric Acid

[0135] One batch of the ibrutinib:fumaric acid cocrystal (stability batch) was stored in open and closed containers under accelerated conditions. After storage for 4, 8 and 12 weeks, samples were analyzed by UHPLC/UV (chemical purity) as well as by XRPD (solid state stability). The results of UHPLC/UV analysis, summarized in the following table demonstrate that the chemical purity of the ibrutinib:fumaric acid cocrystal remained unchanged.

TABLE-US-00010 Conditions (40 C./75% RH) Open Close 4 Weeks 99.85% 99.93% 8 Weeks 99.91% 99.93% 12 Weeks 99.83% 99.90%

[0136] The results of XRPD analysis confirmed that the solid state of the ibrutinib:fumaric acid cocrystal remained unchanged during storage under accelerated conditions.

[0137] X-Ray Single Crystal Study of Ibrutinib:Fumaric Acid Co-Crystal (2:1)

TABLE-US-00011 Temperature 180 K Wavelength 1.54178 Crystal system triclinic Space group P1 Unit cell dimensions a [] 9.8994 (5) b [] 9.9979 (5) c [] 13.9063 (7) [] 93.268 (2) [] 99.856 (2) [] 115.655 (2) Volume [.sup.3] 1208.96 (6)

[0138] As is shown in FIG. 9, the packing of ibrutinib:fumaric acid cocrystal consists of two molecules of ibrutinib in dimeric formation and one molecule of fumaric acid, i.e. a molar ratio of 2:1 with a triclinic symmetry. The dimer is formed through hydrogen bonds between N4-H2 and N35 and N34-H4 and N5 of the respective ibrutinib molecules. The amide group of ibrutinib establishes H-bonds with the acid group of fumaric acid (both carboxylic groups of fumaric acid are connected with H-bonds to ibrutinib: O61-H5 to O31 and O63-H6 to O6 of the respective molecules. Moreover, the ibrutinib dimer is bonded to the next dimer in the crystal lattice with two H-bonds per molecule: N4-H1 to O31 and N34-H3 to O1. The geometry of fumaric acid clearly shows distances typical for CO and COH, which are C61-O61 1.329(3) , C61-O62 1.197(3) , C64-O63 1.312(3) and C64-O64 1.207(3) .

[0139] If the fumaric acid is deprotonated, the distances of CO would be approximately the same distance, reflecting the electron resonance of the possible anion.

[0140] The calculated atom distances and angles of the H-bonds are the following:

TABLE-US-00012 DH . . . A DH () H . . . A () D . . . A () DH . . . A() H-bond 1 N4H2 . . . N35 0.899 2.159 3.056(5) 175.28(7) H-bond 2 N34H4 . . . N5 0.887 2.000 2.885(5) 175.89(8) H-bond 3 O61H5 . . . O31 0.897 1.818 2.714(5) 178.22(9) H-bond 4 O63H6 . . . O1 0.907 2.043 2.737(5) 132.32(8) H-bond 5 N4H1 . . . O31 0.878 2.359 3.052(5) 135.92(7) H-bond 6 N34H3 . . . O1 0.873 2.524 3.193(5) 133.98(7)

[0141] Stress-Testing of Ibrutinib Co-Crystal with Fumaric Acid

[0142] A sample of the Ibrutinib-fumaric acid co-crystal was tested for its polymorphic stability to extreme conditions. The following conditions were applied to small samples (about 0.1 g each) of the powdery co-crystal: [0143] 1. 1 minute of 3 tons pressure, using T25 ATLAS power press (by Specac). [0144] 2. About 1 minute of strong grinding using pestle and mortar. [0145] 3. About 1 minute of strong grinding using pestle and mortar after adding one drop of water to the powder. [0146] 4. About 1 minute of strong grinding using pestle and mortar after adding one drop of ethanol to the powder. [0147] 5. About 1 minute of strong grinding using pestle and mortar after adding one drop of isopropanol to the powder. [0148] 6. Heating to 100 C. for 30 minutes. [0149] 7. 1 week storage under 100% relative humidity at room temperature.

[0150] All the samples were tested in XRPD after the stress-tests. No change was observed in the XRPD pattern, as shown in FIG. 14.

Example 3: Preparation of Ibrutinib:Succinic Acid Co-Crystal

Experiment 1

[0151] 143 mg (0.32 mmol) ibrutinib was suspended together with 156 mg (1.32 mmol) succinic acid in 1 mL MeOH at room temperature (RT). A clear solution was obtained after 5 minutes of stirring. After 60 minutes a white solid started to precipitate. The solution was let overnight with stirring at RT for the complete precipitation. The precipitate was isolated by filtration (Yield: 21%).

[0152] The sample was analysed by means of XRPD and .sup.1H-NMR spectroscopy.

Experiment 2

[0153] 1 g (2.3 mmol) ibrutinib was suspended together with 1 g (8.5 mmol) succinic acid in 7 mL MeOH at room temperature (RT). A clear solution was obtained after 15 minutes of stirring. After 60 minutes, a white solid started to precipitate. The solution was let over the weekend with stirring at RT for the complete precipitation. The precipitate was isolated by filtration (Yield: 67%).

[0154] The sample was analysed by means of XRPD and .sup.1H-NMR spectroscopy.

[0155] The results of Experiments 1 to 2:

[0156] .sup.1H-NMR Spectroscopy

[0157] The sample was analyzed in a 400 MHz-NMR spectrometer. As solvent, DMSO-d.sub.6 was used. The .sup.1H-NMR spectrum is shown in FIG. 10. The signals are summarized below (*=signals of succinic acid):

[0158] 1.57 (br. s., 1H); 1.92 (d, J=13.69 Hz, 1H); 2.12 (br. s., 1H); 2.18-2.32 (m, 1H); 2.38 -2.42 (m, 3H*); 2.88-3.07 (m, 1H); 3.10-3.27 (m, 1H); 3.70 (d, J=10.56 Hz, 1H); 4.06 (d, J=13.29 Hz, 1H); 4.19 (br. s., 1H); 4.54 (d, J=12.12 Hz, 1H); 4.69 (br. s., 1H); 5.57 (d, J=9.78 Hz, 1H); 5.69 (d, J=10.56 Hz, 1H); 6.00-6.18 (m, 1H); 6.54-6.77 (m, 1H); 6.77-6.98 (m, 1H); 7.09-7.20 (m, 5H); 7.33-7.51 (m, 2H); 7.65 (d, J=7.82 Hz, 2H); 8.24 (s, 1H); 12.10 (br. s., 1H*).

[0159] The integration values of the 1.92 ppm signal (1H) of ibrutinib and the 2.40 ppm signal (4H) from succinic acid were 1 and 2.5 resp.

[0160] X-Ray Powder Diffraction (XRPD)

[0161] The product was characterized by means of x-ray powder diffraction. It is shown in the FIG. 11.

[0162] The x-ray powder diffractogram of ibrutinib:succinic acid cocrystal is characterized by the following signals:

TABLE-US-00013 most characteristic peaks [ 2] 0.2 2 sample Primary characterising peaks Secondary characterising peaks IBT:Succinic acid 17.3 17.9 20.2 21.5 21.8 9.8 11.5 13.0 18.3 23.2

[0163] The complete list of XRPD diffraction peaks of ibrutinib:succinic acid co-crystal

TABLE-US-00014 Angle (2) Relative Intensity % 6.5 3.3% 9.8 10.2% 10.2 4.0% 10.8 7.3% 11.5 2.7% 12.5 6.3% 13.0 8.5% 14.7 3.3% 15.2 1.7% 15.7 1.2% 17.3 31.3% 17.9 49.4% 18.3 97.5% 19.7 16.2% 20.2 100.0% 21.5 67.1% 21.8 76.9% 23.2 33.1% 23.8 15.9% 24.2 25.2% 25.1 4.3% 26.1 21.3% 26.7 5.4% 27.2 15.1% 28.6 11.6% 29.0 13.3% 29.7 7.2% 30.2 10.0% 31.0 7.6% 31.2 8.4% 32.3 5.0% 33.4 4.1% 38.1 7.4% 40.7 4.7% 43.0 4.7% 49.5 4.7%

[0164] UHPLC/UV

[0165] The chromatogram from UHPLC/UV analysis is shown in FIG. 12 (Rt=3.693 min: ibrutinib;

[0166] succinic acid not detected at this wavelength).

[0167] Storage Stability of Ibrutinib: Succinic Acid

[0168] One batch of the ibrutinib:succinic acid cocrystal (stability batch) was stored in open and closed containers under accelerated conditions. After storage for 4, 8 and 12 weeks, samples were analyzed by UHPLC/UV (chemical purity) as well as by XRPD (solid state stability). The results of UHPLC/UV analysis, summarized in the following table demonstrate that the chemical purity of the ibrutinib:succinic acid cocrystal remained unchanged.

TABLE-US-00015 Conditions (40 C./75% RH) Open Close 4 Weeks 99.91 99.91 8 Weeks 99.91 99.91 12 Weeks 99.92 99.92

[0169] The results of XRPD analysis confirmed that the solid state of the ibrutinib:succinic acid cocrystal remained unchanged during storage under accelerated conditions.

[0170] X-Ray Single Crystal Study of Ibrutinib:Succinic Acid Co-Crystal (2:1)

TABLE-US-00016 Temperature 180K Wavelength 1.54178 Crystal system triclinic Space group P1 Unit cell dimensions a [] 10.0016 (3) b [] 13.8869 (4) c [] 18.0873 (5) [] 81.479 (1) [] 88.755 (1) [] 79.974 (1) Volume [.sup.3] 2446.48 (7)

[0171] The packing of ibrutinib:succinic acid cocrystal in one unit cell in a triclinic symmetry P1 consists of four molecules of ibrutinib and two molecules of succinic acid, i.e. a molar ratio of 2:1. The packing is stabilised by complex H-bond network of chains formed by Ibrutinib:succinic acid:ibrutinib unities. One of the two unities is shown in FIG. 13. The hydrogen atoms were found in relevant positions close to the succinic acid. The geometry of succinic acid clearly shows distances typical for CO and COH, which are C124-O127 1.316(4) , C124-O128 1.205(4) , C121-O125 1.327(3) and C121-O126 1.197(4) .

[0172] If the succinic acid is deprotonated, the distances of CO would be approximately the same distance, reflecting the electron resonance of the possible anion.

[0173] The calculated atom distances and angles of the H-bonds from the succinic acid to ibrutinib of the two unities in the unit cell are the following:

TABLE-US-00017 DH . . . A DH () H . . . A () D . . . A () DH . . . A() H-bond 1 O127H1271 . . . O91 0.823 1.894 2.7104) 171.29(17) H-bond 2 O125H1251 . . . O1 0.892 1.838 2.714(4) 166.69(16) H-bond 1 O137H1371 . . . O61 0.938 1.802 2.708(4) 161.45(14) H-bond 2 O135H1351 . . . O31 1.050 1.700 2.706(4) 159.00(16)

Example 4: Pharmaceutical Formulations of Ibrutinib Co-Crystals

Experiment 1: Capsules

[0174]

TABLE-US-00018 Ibrutinib:benzoic acid co-crystal 179 mg (corresponds to 140 mg free base) Aerosil 200 (silicium dioxide) 5 mg Prosolv SMCC90 (silicified micro 197 mg crystalline cellulose) Ac-di-sol (croscramellose sodium) 40 mg Magnesium stearate 3 mg

[0175] Active ingredient and Aerosil were premixed, subsequently all other ingredients except magnesium stearate were blended in a free fall mixer for 15 min. Then, sieved magnesium stearate was added and the mixture was blended for further 5 min. The final blend was filled into capsules.

TABLE-US-00019 Ibrutinib:fumaric acid co-crystal 158.5 mg (corresponds to 140 mg free base) Aerosil 200 (silicium dioxide) 5 mg Prosolv SMCC90 (silicified micro 197 mg crystalline cellulose) Ac-di-sol (croscramellose sodium) 40 mg Magnesium stearate 3 mg

[0176] Active ingredient and Aerosil were premixed, subsequently all other ingredients except magnesium stearate were blended in a free fall mixer for 15 min. Then, sieved magnesium stearate was added and the mixture was blended for further 5 min. The final blend was filled into capsules.

Experiment 2: Tablets

[0177]

TABLE-US-00020 Ibrutinib:benzoic acid co-crystal 179 mg (corresponds to 140 mg free base) Aerosil 200 (silicium dioxide) 5 mg Prosolv SMCC90 (silicified micro 197 mg crystalline cellulose) Ac-di-sol (croscramellose sodium) 40 mg Magnesium stearate 5 mg

[0178] Active ingredient and Aerosil were premixed, subsequently all other ingredients except magnesium stearate were blended in a free fall mixer for 15 min. Then, sieved magnesium stearate is added and the mixture was blended for further 5 min. The final blend was compressed into tablets.

TABLE-US-00021 Ibrutinib:fumaric acid co-crystal 158.5 mg (corresponds to 140 mg free base) Aerosil 200 (silicium dioxide) 5 mg Prosolv SMCC90 (silicified micro 197 mg crystalline cellulose) Ac-di-sol (croscramellose sodium) 40 mg Magnesium stearate 5 mg

[0179] Active ingredient and Aerosil were premixed, subsequently all other ingredients except magnesium stearate were blended in a free fall mixer for 15 min. Then, sieved magnesium stearate was added and the mixture was blended for further 5 min. The final blend was compressed into tablets.

Comparative Example 1: Storage Stability of Ibrutinib Form E According to WO 2013/184572

[0180] Ibrutinib free base Form A (1 g) was suspended in toluene (12 mL) and the resulting slurry was stirred for 3.5 d at room temp. The product was filtered off and dried under reduced pressure for 22h to provide Ibrutinib free base Form E.

[0181] Ibrutinib Form E was stored for twelve weeks at a temperature of 40 C. and a relative humidity of 75%. Ibrutinib Form E transformed into ibrutinib Form A, as shown in FIG. 15 in comparison with the ibrutinib co-crystals according to the invention which remained stable during storage. This experiment demonstrates the surprisingly improved stability of the co-crystals of the invention over the prior art crystal form.

Comparative Example 2: Wettability

[0182] The wettability of the below compounds was determined by contact angle measurement. For this purpose, the substances were pressed (2 t*cm.sup.2) to a pellet. On each pellet were placed three water drops (2 L) on three individual measurement points and the contact angle was measured with the apparatus OCA40 (DataPhysics Instruments) on two sides of the drop. The determined values are given in table below.

TABLE-US-00022 API Form contact angle Ibrutinib free base form A 67.9 2.1 Ibrutinib fumaric acid 56.8 2.4 Irbutinib succinic acid incapable of measurement* *The contact angle of the co-crystal of ibrutinib and succinic acid was incapable of measurement because the wettability of this co-crystal is so high that the water drops immediately spread over the surface and the water sunk into the pellet.

[0183] A lower contact angle corresponds to an increase in wettability of the substance. An increased wettability facilitates granulation, in particular wet granulation of the substance. Therefore, as the co-crystals of the present invention have a lower contact angle and, thus, an increased wettability compared to ibrutinib free base, the co-crystals have advantageous properties with respect to further processing of the compound into pharmaceutical preparations.