No abstract

Lenalidomide (LDM) is a thalidomide analogue known for its immunomodulation, antiangiogenic, and antineoplastic properties. However, to date, only two forms of lenalidomide [Form-1 (anhydrous) and Form-2 (hemihydrate)] are reported in the literature. Through a comprehensive polymorph screening herein, we report five forms of lenalidomide [Form-3 (DMF-solvate), Form-4 (anhydrous), Form-5 (DMSO solvate), Form-6 (acetone solvate), and Form-7 (dihydrate)]. Single crystal structures (for all forms) are established to provide potential knowledge about the intermolecular interactions, three-dimensional structures, and the nature of solvent/water within the lattice. Thermodynamic stability investigations revealed unusual solid state phase transformations which are relatively unexplored to date. It is noteworthy that all solvates upon desolvation convert to Form-1 (thermodynamically stable anhydrous form), whereas all hydrates upon dehydration convert to a metastable Form-4 (novel anhydrous form) which, upon further heating, converts to more stable Form-1. Correlation of results from modeling, single crystal analysis, and nonambient studies established “isostructurality” as one of the major factors leading to such bifurcated phase transformations. Mechanisms of desolvation and dehydration in different forms of LDM are explained by utilizing various analytical techniques such as variable temperature Fourier transform infrared spectroscopy, variable temperature powder X-ray diffraction, differential scanning calorimetry, and hot stage microscopy. A thorough understanding of the relationships between structure and thermodynamic properties is deemed a prerequisite which is considered vital in selecting the most suitable form for drug product development.

In the asymmetric unit of the crystal structure of nicotinamide-succinic acid (2/1), 2C(6)H(6)N(2)O x C(4)H(6)O(4), there are two independent nicotinamide molecules in general positions and two half succinic acid molecules which lie about inversion centres. The structure contains acid-pyridine and amide-amide synthons with nicotinamide molecules forming ladders of alternating R(2)(2)(8) and R(4)(2)(8) rings linked through succinic acid to generate a corrugated hydrogen-bonded sheet. This sheet is a common supramolecular unit found in other 2:1 nicotinamide-dicarboxylic acid cocrystals, but the presence of two crystallographically distinct nicotinamides with anti and syn conformations, forming two distinct sheets within the same structure, is a novel packing feature in this type of material.

The solid-state phase transition of a multicomponent active pharmaceutical ingredient (M-APIs), composed of (1:1) agomelatine and phosphoric acid (AGL-P), is characterized using a set of complementary techniques: in situ variable temperature powder X-ray diffraction (VT-PXRD), thermal analysis, spectroscopic techniques, and hot stage microscopy (HSM). It is observed that these dimorphic forms (AGL-P RT-form and HT-form) are enantiotropic and reversible in nature. The salt–cocrystal continuum of this system is demonstrated using ab initio powder XRD structure determination (SDPD) and dispersion corrected density functional theory (DFT-D2) analysis. Furthermore, this solid-state phase transition can be inferred as a martensitic-like transformation, where simultaneous proton migration and small conformational switching trigger the concerted molecular displacements of entire layers, leading to microscopic crystal contraction.