Breakage Study of the Urchinlike Crystal Clusters of Ibrutinib

Abstract

In this work, we investigate the impact of stirring and tableting on the breakup and deformation of the urchinlike crystal clusters of ibrutinib prepared by cooling crystallization. The breakup of clusters was induced directly in the dispersion unit of the light scattering device, typically used for the characterization of particulate materials in the pharmaceutical industry. This allows us to perform the experiment only with several milligrams of the sample. Computational fluid dynamics simulation was used to estimate the stresses to which the clusters were exposed to during the breakup experiment in the dispersion unit. The obtained results confirm the strong impact of the morphology of initial clusters on their breakup kinetics and steady-state sizes, with the strength of tested clusters covering the range from 180 to 1300 Pa. These values are significantly below the ibrutinib crystal hardness as determined by the nano- and microindentation experiment, revealing values above 253 MPa and leading to the breakup of the urchinlike crystal clusters of ibrutinib into individual crystals. Subsequently, the same ibrutinib crystal clusters were exposed to compaction pressures in the range of 38–565 MPa, using lactose monohydrate as a water-soluble model excipient having a hardness of 535 ± 59 MPa. It was found that below the ibrutinib crystal hardness, clusters break into smaller crystals, but when exceeding the ibrutinib crystal hardness, they deform plastically. A dissolution study demonstrates a significant impact of the abovementioned transformations on the dissolution profile of ibrutinib crystals. The developed methodology can provide information about the impact of various conditions used in drug product formulation, utilizing only a few milligrams of the sample, thus being suitable for the early stage of process development.