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.
The under-oil crystallization method was successfully adopted for the crystallization of organic salts. Compared with the previously reported vapour-diffusion-based nano-crystallization technique, the under-oil method generated single crystals of more different salts for all studied compounds.
In this paper, we present a comprehensive crystallographic study of Ibrutinib polymorphs and their behavior. Three neat polymorphs (A, B, and C) and a methanol solvate (F) were obtained and characterized. The structures of forms A, C, and F were solved from single-crystal diffraction data. Form B has only ever been prepared as a powder, and its structure solution has, so far, not been successful. Polymorph C is a desolvate of the methanol solvate F, and its structure was solved via the single-crystal to singlecrystal transformation. The analysis of the solved structures revealed significant differences in the crystal packing of form A in comparison with the previously described Ibrutinib structures, enabling it to crystallize in a higher symmetry space group (monoclinic vs triclinic). The structures also revealed a high similarity between forms C and F, explaining their mutual transformability. To further analyze the solids, we performed DSC, long-term slurry transformations, intrinsic dissolution experiments, and DVS. FT-Raman spectroscopy was used for the preliminary characterization and fast distinction between the forms. We have also performed basic energy calculations to estimate the strength of the various present H-bonds. All methods confirmed the polymorph A to be the thermodynamically most stable form.
Search for new multicomponent solid forms has become a key step in pharmaceutical drug development. Apremilast, a poorly soluble API used for the treatment of psoriatic arthritis, was used as a model compound in this work. There have been several isostructural cocrystals of this API already described in the literature. In this paper, a new isostructural cocrystal (with phthalic acid) and solvates (with oxylene and fluorobenzene) of the studied compound were successfully designed. Furthermore, to the best of our knowledge, this work is the first ever to prepare a non-isostructural cocrystal of apremilast with cinnamic acid. The crystal structures of all the new multicomponent forms were successfully solved using single crystal X-ray diffraction. The differences between the formation of the isostructural and nonisostructural forms are explained in detail using the structural characterization of the prepared forms and the density functional theory calculations (B3LYP/6-31G(d,p) level of theory). The physicochemical characterization complemented the structural one, including the thermal properties (differential scanning calorimetry, DSC) and the intrinsic dissolution rate (IDR). The samples were further characterized by X-ray powder diffraction (XRPD) and Raman spectroscopy. The dissolution experiments showed that the new multicomponent solids can improve the intrinsic dissolution rate by up to 500% compared to the polymorph of apremilast used in the marketed drug product.
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