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

Ramanaiah Chennuru

doi:10.1021/acs.cgd.6b01462

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

2016-12-30

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Srividya Ramakrishnan

Sudarshan Mahapatra *

DOI：10.1021/acs.cgd.6b01462

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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 (thermo-dynamically 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.

Keyword:

CRYSTAL-STRUCTURE PREDICTION

HIRSHFELD SURFACE-ANALYSIS

CENTER-DOT-O

PHARMACEUTICAL COCRYSTALS

INFRARED-SPECTROSCOPY

SOLVENT INCLUSION

DIOL HOST

FORM-II

ISOSTRUCTURALITY

POLYMORPHISM

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

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