the present invention provides a new crystalline form of ibrutinib , which has a higher solubility under physiological conditions than crystalline form a of wo2013184572 , and thus provides various advantages , such as enhanced bioavailability and reduced drug loading . the new crystalline form is physically and chemically stable , is not hygroscopic and does not become deliquescent at a high humidity , and is therefore convenient for long - term storage . moreover , the new crystalline form can be prepared using a simple process in a low cost , which is also highly valuable for further optimization and development of the drug in the future . in one aspect , the present invention provides a crystalline form of ibrutinib , designated as form i . in one embodiment , the crystalline form i is characterized by an x - ray powder diffraction pattern comprising the following 2θ values measured using cukα radiation : 5 . 2 °± 0 . 2 °, 17 . 6 °± 0 . 2 °, and 22 . 1 °± 0 . 2 °. in another embodiment , the crystalline form i is characterized by an x - ray powder diffraction pattern further comprising the following 2θ values measured using cukα radiation : 19 . 3 °± 0 . 2 °, 20 . 8 °± 0 . 2 °, and 22 . 4 °± 0 . 2 °. in another embodiment , the crystalline form i is characterized by an x - ray powder diffraction pattern further comprising the following 2θ values measured using cukα radiation : 16 . 2 °± 0 . 2 °, 18 . 1 °± 0 . 2 °, 18 . 9 °± 0 . 2 °, and 23 . 0 °± 0 . 2 °. the crystalline form i has an x - ray powder diffraction pattern substantially as shown in fig1 . the crystalline form i has a differential scanning calorimetric thermogram substantially as shown in fig2 , which exhibits an endothermic peak at about 135 . 1 ° c . the crystalline form i has a thermal gravimetric analysis thermogram substantially as shown in fig3 , which exhibits about 0 . 5 % weight loss up to 120 ° c ., suggesting that the crystalline form is substantially unsolvated and anhydrous . in another aspect , the present invention provides a process for preparation of ibrutinib form i , comprising : dissolving ibrutinib in alcohol , ether , or ketone , or a mixture or alcohol , ether , or ketone with an alkane ; and crystallizing said form i from the solution , either by equilibration under ambient conditions or by controlled cooling . in some embodiments , said dissolving is conducted in a mixed solvent system comprising an alcohol and an alkane . in some embodiments , said mixed solvent system comprises 2 - propanol and n - heptane . in another aspect , the present invention provides solid pharmaceutical compositions comprising ibrutinib form i . form i of ibrutinib together with one or more pharmaceutically acceptable excipients of the present invention may be further formulated as : solid oral dosage forms such as , but not limited to , powders , granules , pellets , tablets , and capsules ; liquid oral dosage forms such as , but not limited to , syrups , suspensions , dispersions , and emulsions ; and injectable preparations such as , but not limited to , solutions , dispersions , and freeze dried compositions . in another aspect , the present invention provides a method for treating cancer in a mammal , comprising administering a therapeutically effective amount of ibrutinib form i . in some embodiments , the cancer is a b cell malignancy . in some embodiments , the cancer is a b cell malignancy selected from chronic lymphocytic leukemia ( cll )/ small lymphocytic lymphoma ( sll ), mantle cell lymphoma ( mcl ), diffuse large b cell lymphoma ( dlbcl ), and multiple myeloma . in another aspect , the present invention provides use of ibrutinib form i in the manufacture of a medicament for the treatment of a disease or disorder related to btk activities . in an embodiment , the disease or disorder is a b cell malignancy selected from the group consisting of chronic lymphocytic leukemia ( cll )/ small lymphocytic lymphoma ( sll ), mantle cell lymphoma ( mcl ), diffuse large b cell lymphoma ( dlbcl ), and multiple myeloma . the following non - limiting examples further illustrate certain aspects of the present invention . analytical instrument : panalytical empyrean . the x - ray powder diffraction was conducted by mounting a sample of the crystalline material on a si single crystal low - background holder and spreading out the sample into a thin layer with the aid of a microscope slide . the 2θ position was calibrated against panalytical 640 si powder standard . the sample irradiated with x - rays generated by a copper long - fine focus tube operated at 45 kv and 40 ma with a wavelength of kα1 = 1 . 540589 angstroms and kα2 = 1 . 544426 angstroms ( kα1 / kα2 intensity ratio is 0 . 50 ). the collimated x - ray source was passed through a programmed divergence slit set at 10 mm and the reflected radiation directed through a 5 . 5 mm anti - scatter slit . the sample was exposed for 16 . 3 seconds per 0 . 013 ° 2 - theta increment ( continuous scan mode ) over the range 3 degrees to 40 degrees 2 - theta in theta - theta mode . the running time was 3 minutes and 57 seconds . the instrument was equipped with a rtms detector ( x &# 39 ; celerator ). control and data capture was by means of a dell optiplex 780 xp operating with data collector software . persons skilled in the art of x - ray powder diffraction will realize that the relative intensity of peaks can be affected by , for example , grains above 30 microns in size and non - unitary aspect ratios that may affect analysis of samples . the skilled person will also realize that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer . the surface planarity of the sample may also have a small effect . hence the diffraction pattern data presented are not to be taken as absolute values . dynamic vapor sorption ( dvs ) was measured via a sms ( surface measurement systems ) dvs intrinsic . the relative humidity at 25 ° c . were calibrated against deliquescence point of licl , mg ( no 3 ) 2 and kcl . typical parameters for dvs test are listed below . in 15 ml of 2 - propanol / n - heptane ( 2 : 3 , v / v ) was dissolved 513 mg of ibrutinib . the solution was equilibrated under ambient conditions for 24 h , and form i was obtained , which was analyzed by xrpd , dsc , and tga . the xrpd pattern of form i is displayed in fig1 . the xrpd data of form i produced in this example are listed in table 1 . the xrpd pattern of form i obtained from this example is displayed in fig1 , the dsc thermogram of form i obtained from this example is displayed in fig2 ; and the tga thermogram of form i obtained from this example is displayed in fig3 . in 1 . 6 ml of 2 - propanol / n - heptane ( 1 : 5 , v / v ) was dissolved 48 . 2 mg of ibrutinib to get a saturated solution of ibrutinib under 50 ° c . the solution was cooled from 50 ° c . to 5 ° c . at a cooling rate of 0 . 1 ° c ./ min , and form i was produced . the xrpd data of form i produced in this example are listed in table 2 . in 0 . 5 ml of acetone was dissolved 12 . 7 mg of ibrutinib , followed by the slow addition of 2 . 0 ml of n - heptane . the suspension was stirred at a rate of 1000 rpm for one day , and form i was produced . the xrpd data of form i produced in this example are listed in table 3 . kinetic solubility of ibrutinib in crystalline form i and in crystalline form a ( wo2013184572a1 ) in fed state simulated intestinal fluid ( fessif ) and simulated gastric fluid ( sgf ) were measured using the following procedures : 1 . weigh approximately 30 mg of ibrutinib crystalline form a or form i into a tared 4 - ml plastic vial and record the actual weight of the compound . 3 . cap the vials and keep all the suspension samples stirring at rt ( room temperature ) using a rolling incubator at a rate of 25 r / min . 4 . sample at 1 h , 4 h and 24 h respectively . about 0 . 6 ml aliquot of the suspension is transferred per time from solubility vial into a centrifuge filtration tube ( pore size of 0 . 45 μm ). 5 . centrifuge filtration tubes at a rate of 8500 rpm for 3 minutes at rt , collect 0 . 2 ml of supernatant for hplc quantification determination and collect the rest of solution for ph measurement , and separate the solid for xrpd characterization . the results displayed in table 4 suggest crystalline form i has higher solubility in comparison to crystalline form a ( wo2013184572a1 ). hygroscopicity of ibrutinib form i was investigated using dynamic vapor sorption ( dvs ). the dvs isotherm plot of form i displayed in fig4 and the detailed data listed in table 5 show that the sample has 0 . 19 % water uptake under 80 % rh , 25 ° c ., suggesting form i is non - hygroscopic . deliquescent : sufficient water is absorbed to form a liquid ; very hygroscopic : increase in mass is equal to or greater than 15 percent ; hygroscopic : increase in mass is less than 15 percent and equal to or greater than 2 percent ; slightly hygroscopic : increase in mass is less than 2 percent and equal to or greater than 0 . 2 percent . two samples of ibrutinib form i were stored under 25 ° c ./ 60 % rh and 40 ° c ./ 75 % rh , respectively , with dish open for 180 days . the chemical and physical stabilities of the samples were evaluated by high performance liquid chromatography ( hplc ) and xrpd . the xrpd patterns of form i under stress conditions are displayed in fig5 . the result of stability assessment tabulated in table 6 indicates that form i is physically and chemically stable under the stress conditions . the foregoing examples and description of the preferred embodiments should be taken as illustrating , rather than as limiting , the present invention as defined by the claims . as will be readily appreciated by a person skilled in the art , numerous variations and combinations of the features set forth above can be utilized without departing from the present invention as set forth in the claims . all such variations are intended to be included within the scope of the following claims . all references cited herein are incorporated by reference in their entireties .
crystalline form i of ibrutinib , processes for its preparation , pharmaceutical compositions comprising the new form , and use of form i of ibrutinib for treating or delaying diseases or disorders related to activity of bruton &# 39 ; s tyrosine kinase proteins are disclosed . the novel form was characterized by x - ray powder diffraction , differential scanning calorimetry , and other techniques . it can be readily prepared and is suitable for use in the preparation of solid dosage forms .