Formation of the First Non-Isostructural Cocrystal of Apremilast Explained

Abstract

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.

Structure–property relations of a unique and systematic dataset of 19 isostructural multicomponent apremilast forms

“…Sufficient single crystals were 18 out of the 22 tested molecules resulted in the formation of multicomponent form. Size of the guest molecule appears to be crucial parameter 8 .…”

Characterization and Insights into the Formation of New Multicomponent Solid Forms of Sofosbuvir

“…To improve the solubility and bioavailability of these drug molecules, it is necessary to find a new alternative solid form with enhanced physicochemical properties without changing the molecular structure of the drug . In this direction, pharmaceutical companies and academic researchers have now focused their interest on alternative crystalline forms such as different polymorphs − of the drug or multicomponent solid forms such as solvates, , salts, , and cocrystals. − These forms, while preserving the molecular structure of the active pharmaceutical ingredient (API), improve its properties such as solubility, physical and chemical stability, and so forth. − …”

Two anhydrous forms and one monohydrate of a cocrystal of axitinib and glutaric acid: characterization, property evaluation and phase transition study

“…16–19 Thus, it is necessary to carry out more research on cocrystal polymorphism including synthesis strategies, solid-state characterization, performance evaluation and phase transition processes, which is of great significance for better application of cocrystallization technology in the pharmaceutical field. 20–25…”