First Crystal Structures of Pharmaceutical Ibrutinib: Systematic Solvate Screening and Characterization

Abstract

A search for new solid forms of an active pharmaceutical ingredient (API) is an integral part of the drug product development process. The studied compound, Ibrutinib, is a recently approved anticancer drug. The main aim of this study was to search for new solvates of Ibrutinib and to perform their structural characterization. To do so, we performed a tailor-made systematic solvate screening and tested several solution and slurry based methods in the solvate screening for their suitability and success rate. The phase composition of the screening samples was analyzed by Raman spectroscopy and powder X-ray diffraction. From the 11 tested solvents, eight solvates were prepared (with 4-hydroxy-4-methylpentan-2-on, dioxolane, α,α,α-trifluorotoluene, ortho-xylene, meta-xylene, para-xylene, anisole, and chlorobenzene). The crystal structures of all eight solvates were successfully solved from single-crystal X-ray diffraction data, and, to our best knowledge, this work is the first ever crystal structure study of Ibrutinib. The desolvation behavior of the prepared Ibrutinib solvates was studied by thermal methods (differential scanning calorimetry, thermogravimetric analysis, and hot-stage microscopy), and stability tests were performed to determine the strength of the API–solvent interaction. Dissolution experiments showed that the solvate formation can improve the dissolution rate by as much as 8.5 times, compared to the most stable nonsolvated form.

COMF: Comprehensive Model-Fitting Method for Simulating Isothermal and Single-Step Solid-State Reactions

“…Solid-state reactions (SSRs) induced by heating occur in a broad range of processes such as the desolvation and dehydration of pharmaceutical crystals [1][2][3][4][5][6][7][8] or thermal decomposition of solids, e.g., pyrolysis [9][10][11][12][13]. To elucidate the mechanisms of chemical changes occurring when heating the solid reactants and to characterize the factors that control this process, various solid-state kinetic models have been developed [14][15][16][17][18].…”

Solvate Formation of Bis(demethoxy)curcumin: Crystal Structure Analyses and Stability Investigations

“…These different phases have different properties, such as solubility, dissolution rate and bioavailability 1 . The chemical and physical properties of APIs could be significantly improved by developing new solid forms [2][3][4] . Since solvents are unavoidably used during processing, manufacturing or storage of APIs, the investigation of solvate formation deserves particular attention 5,6 .…”

Testing the flow-through capillary for the study of re-solvation processes in pharmaceutical compounds

“…Compared with other techniques, the main advantage of such X-ray powder diffraction measurement is the complete monitoring of the phase composition of the sample during the re-solvation and its relatively high data collection rate (for laboratory instruments, it starts from seconds). We decided to test the system with the flow-through capillary on the re-solvation of solvates of a pharmaceutical substance called ibrutinib (Zvonicek et al, 2017(Zvonicek et al, , 2018Figure 1). We have chosen its crystal forms of anisole solvate (IBR ANI) and fluorobenzene solvate (IBR FBZ) as suitable compounds for testing because of two main reasons.…”