Iso-Structurality Induced Solid Phase Transformations: A Case Study with Lenalidomide

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.

Isomorphism: `molecular similarity to crystal structure similarity' in multicomponent forms of analgesic drugs tolfenamic and mefenamic acid

“…Analyses of crystal structures for MFA reveal the existence of identical or very similar crystal structures for each TFA type. Such a high degree of matching suggests that, by exploring the landscape for a model system, one can practically find possible crystal structures for other similar systems (Chennuru et al, 2017). Similarly, crystal structures of single-component TFA and MFA are analysed.…”

“…On the other hand, isostructurality has advantages such as reliable structure versus property knowledge transfer (Chennuru et al, 2017;Wood et al, 2012;Reddy et al, 2006;Krishna et al, 2016;Saha & Desiraju, 2017b), and formation of solid solutions for tuning physicochemical properties (Elgavi et al, 1973;Vangala et al, 2002;Pigge et al, 2006). In general, polymorphism and isostructurality are perceived as opposite phenomena.…”

The Solid-State Structures of Cyclic NH Carboximides

“…The remaining three structures exist with more complex forms of hydrogen bonding. Compound 195 [171] (Figure 58) is a second form of 191 whose structure is quite different. The primary interaction is between the imide NH and the lactam carbonyl, leading to a C(7) ribbon structure as shown.…”

Chemical Bonding in Crystals and Their Properties

“…All solvates but water belong to the same group as two trospium chloride polymorphs [113]. Dehydration and desolvation of lenalidomide follow "isostructurality" in crystal packing: All solvates at heating convert to its' thermodynamically stable anhydrous form, whereas all hydrates upon dehydration convert to a metastable anhydrous polymorph able to transform upon further heating to the stable polymorph [114]. Analysis of H-bonding and crystal packing similarity for the crystal structures of vitamin D analogs showed that various conformations of its A-ring are predetermined by H-bonding of hydroxyl group both in crystals and in the binding pocket of the vitamin D receptor and that the exocyclic methylene group also influences H-bonding pattern in solids [66].…”