Study On Polymorphism Of Ibrutinib

Ibrutinib(formerly PCI-32765)is a first-in-class,oral Bruton’s tyrosine kinase(BTK)inhibitor and blocks signals that tell malignant B cells to multiply and spread uncontrollably,it has been recommended for the treatment of several blood and solid tumor cancers,including chronic lymphocytic leukemia(CLL),mantle cell lymphoma(MCL),Waldenstrom’s macroglobulinemia(WM)and so on.Ibrutinib has several polymorphs,three anhydrous forms(form A,form B and form C)have been reported in patent WO2013184572,and only form A is suitable for medicinal preparations.The stability relationship and mutual transformation conditions of ibrutinib form A and other crystalline forms have not been described.In this dissertation,ibrutinib was chosen as the research system,and the polymorphisms of ibrutinib were researched and discussed systematically.The details were as followed.First and foremost,form A was prepared by solution cooling crytallization and form B was prepared by anti-solvent crystallization.A new form(anisole solvate)of ibrutinib was discovered by recrystallizing from the anisole solvent,and form C was obtained by desolvation of anisole solvate.Then the four crystalline forms were characterized by powder X-ray diffraction(PXRD),infrared spectroscopy(IR),thermal gravimetric analysis(TGA),and differential scanning calorimetry(DSC).The single crystal of ibrutinib anisole solvate was cultivated,and the crystal structure data were obtained by single crystal X-ray diffraction(SCXRD).Anisole solvate belongs to triclinic with space group of P 1,cell parameters:a=10.1866(7)?,b=10.3612(9)?,c=14.0594(9)?,α=93.961(3)°,β=101.001(4)°,γ=116.217(4)°;V=1286.81(17)?~3,and Z=1.The solubility of ibrutinib form A in several organic solvents was measured by a gvimctric method,and the data were corrclated by experiential equations.The influences on solubility had also been discussed.Suspended crystal transformation method was used to explore mutual transformation conditions of ibrutinib polymorphisms(form A,form B,form C and anisole solvate),and verify the relative stability relationship of three anhydrous forms.Results indicate that,the relative stability of three anhydrous forms was clarified in an order as:form A>form C>form B.Form A acted as the stable polymorph and form B,form C acted as the metastable polymorphs over the entire temperature range.Besides,form A and form B,as well as form A and form C,were monotropically related.