Preparation And Property Study Of New Ibrutinib Solvates And Coamorphous State

Ibrutinib?IBT?is a highly selective and irreversible Bruton's tyrosine kinase inhibitor which effectively prevents the spread of tumors from B-cells to lymph by inhibiting Bruton's tyrosine kinases.IBT is used for the treatment of mantle cell lymphoma?MCL?,small lymphocyte lymphoma?SLL?and chronic lymphoblastic leukemia?CLL?.IBT belongs to the Biopharmaceutical Classification System?BCS?Class II.The medicinal crystalline form for IBT is Form A.Its solubility in water and bioavailability are both extremely low,thus it is very necessary to find new solid states of IBT with enhanced solubility and improved bioavailability.In this paper,IBT was studied and its crystalline Form A and Form C were used as starting materials.Through the using of different crystallization methods,temperatures,solvents and co-formers,the polymorphs of IBT were extensively screened.At last,three new IBT polymorphs including isopropyl acetate?IPA?solvate,tetrahydrofuran?THF?solvate and coamorphous ibrutinib?IBT?-saccharin?SAC?were found.Different techniques for solid state detection such as powder X-ray diffraction?PXRD?,differential scanning calorimetry?DSC?,thermogravimetric analysis?TGA?,hot-stage microscope?HSM?and Fourier transform infrared spectroscopy?FT-IR?,etc.were used for comprehensive characterizations of those IBT polymorphs.Meanwhile,new methods for preparation of four known polymorphs of IBT such as IBT Form C,dioxane?DIO?solvate,toluene?TOL?solvate and amorphous state have been developed.Solubility determination,dissolution study under supersaturated condition and physical stability study have been carried out for IBT solvates i.e.DIO solvate,TOL solvate,THF solvate and IPA solvate.In comparison to Form A,solubility determination showed the solubility of DIO,TOL,THF and IPA solvates were increased up to 3.3-5.1 times,3.8-6.3 times,3.1-4.9 times and 3.8-6.3 times respectively.Dissolution study under supersaturated condition showed that the four solvates were able to reach their maximum supersaturated concentrations within 4hours.Concentrations of TOL solvate and IPA solvate began to decrease dramatically after 10 hours,however the enhanced supersaturated concentrations of DIO solvate and THF solvate could be maintained for almost 48 hours.Physical stability study showed that the stability of TOL solvate and IPA solvate was quite good,however the stability of DIO solvate and THF solvate was relatively poor.The new IPA solvate with less toxic solvent toxicity,increased solubility and good stability was a better solid form and had the potential to develop into a pharmaceutical formulation.Solubility determination,dissolution study under supersaturated condition,in vitro dissolution study,stability study and in vivo pharmacokinetic study were carried out for coamorphous IBT-SAC.Solubility determination showed that the solubility of coamorphous IBT-SAC was increased up to 4.0-7.7 times compared to Form A.Dissolution study under supersaturated condition showed that coamorphous IBT-SAC could maintain its significantly increased supersaturated concentration for at least 48hours.In vitro dissolution study showed that the cumulative drug release of coamorphous IBT-SAC was increased up to 2.3-3.0 times compared to Form A.Stability study showed the obvious improvement in stability of coamorphous IBT-SAC compared to single-component amorphous IBT.Preliminary study of pharmacokinetic in rats showed that the C_maxax and AUC_0-t-t of coamorphous IBT-SAC were increased up to 2.9 and 1.3 times compared to Form A.The solubility,dissolution properties,stability and bioavailability of the new coamorphous IBT-SAC have been significantly improved which made it possible to develop into a final pharmaceutical formulation.The preparation of solvate and coamorphous state of poorly water-soluble crystalline drugs both are potentially useful methods for improving the solubility of drugs.Compared to Form A,IPA solvate and coamorphous IBT-SAC found by polymorphic screening had significantly improved solubility and good stability which were the two better solid forms of IBT found in this paper.