Preparation And Properties Study Of New Amorphous Form Of Ibrutinib

Ibrutinib?IBR?is an irreversible Bruton's tyrosine inhibitor indicated for the treatment of adult patients with mantle cell lymphoma,chronic lymphocytic leukemia,small lymphocytic lymphoma,waldenstr?m's macroglobulinemia and chronic graft versus-host disease.Since IBR was approved by FDA in 2013,it had showed good performance and huge market prospect.Being class II drug in the biopharmaceutical classification system?BCS?,low solubility of IBR limits its in-vivo absorption,which results in low bioavailability of 2.9%under fasting condition.Hence,seeking for new Ibrutinib solid forms with improved solubility,dissolution rate and stability,will enhance drug bioavailability and provide options for the development of new formulations.In this paper,amorphous IBR was prepared to improve the solubility of IBR for lacking of long-range order,which avoid overcoming lattice energy.However,amorphous state is prone to recrystallization.Hence,polymer carrier and small molecular excipient were used to stablize it.Drug is highly dispersed in polymer carrier at amorphous solid dispersion?ASD?.Through different kinds of polymer and weight ratios of drug/polymer screening,IBR-HPMCAS?1:3,w/w?solid dispersion exhibited significant advantages,including nine times higher solubility than IBR Form A in p H 6.8 buffer and higher dissolution rate?over 75%release at 15 min?.And IBR-HPMCAS?1:3,w/w?solid dispersion kept stable amorphous state at accelerated stability conditions for 180 days,which may attribute to higher Tg increased by HPMCAS then decrease molecular mobility and impede the process of recrystallization.From?Tg analysis,IBR-HPMCAS?1:3,w/w?solid dispersion had great positive deviations,which indicated there was strong interaction between IBR and HPMCAS.At the same time,FT-IR spectra showed the interaction between the drug and the carrier,which was also an important reason why the carrier can stabilize amorphous IBR.Coamorphous system?CAS?is a kind of single-phase amorphous system beween drug and small molecular excipient,which has the advantages in improving solubility and stability.Tartaric acid?TA?,citric acid?CA?,malic acid?MA?,and succinic acid?SA?were chosen to be coformers.IBR-Acid CASs were prepared,optimized,and the properties of IBR-Acid CASs were also characterized.IBR-TA CASs,IBR-CA CASs,IBR-MA CASs and IBR-SA CASs with 2:1 and 1:1 molar ratio were successfully prepared by solvent evaporation method.All coamorphou samples showed higher solubility than IBR Form A,and IBR-TA?2:1?CAS showed optimal properties,whose solubility was increased up to 4.5 times.IBR-TA?2:1?CAS kept stable amorphous state for 180 days at accelerated stability condition.The possible interaction between IBR and carboxylic acid was investigated through glass transition temperature?Tg?analysis and FT-IR spectra.It seemed that?and/or?hydroxyl played an important role in increasing Tg value,which indicated that hydroxyl participated in the formation of interaction.From FT-IR spectra,the main differences in IBR-Acid CASs were that the changes of NH₂ peak and shifts of amide carbonyl stretching vibrations peak in IBR and the changes of hydroxyl peak and shifts of carboxylic carbonyl stretching vibrations peak in carboxylic acid,which indicated these main groups participated in the formation of interaction.Compared with the FT-IR spetra of carboxylate and combined with the?p Ka analysis,there were no salt bonds but hydrogen bonds between IBR and carboxylic acids.In summary,optimal amorphous solid dispersion and coamorphous system both showed solubility advantage and kept good physical stability.IBR-HPMCAS?1:3,w/w?solid dispersion showed higher solubility than IBR-TA?2:1?CAS,but the weight of TA in IBR-TA?2:1?CAS was just one in sixth of IBR.In a conclusion,both of them provided more options for the further development of new formulation with the advantages of solubility,dissolution,stability and bioavailability.