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.

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Ceritinib is an anaplastic lymphoma kinase (ALK) inhibitor used for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). This BCS class IV drug is developed by Novartis and traded under the name Zykadia. To date two forms [Form A (marketed form) and B] of ceritinib are disclosed in international patent application US 2013/0274279 A1. However, the crystal structure and insight into any solid form of this compound are not available in the literature. In order to achieve better physicochemical properties compared to known solid forms of this compound, novel polymorph identification is chosen as one of the challenging paths to address the issue. In our comprehensive polymorph screening, including in silico and experimental investigations, we discovered three novel solid forms of ceritinib. Out of these three solid forms, two are neat (Form 1 and Form 3) and the remaining one is a hydrate (Form 2). All synthesized forms are further characterized by powder X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy. It is interesting to note that the discovery of this hydrate is in sync with the prediction done using COSMO-RS theory (COSMOthermX software). The current article includes the first single crystal structure of ceritinib Form 1. All forms (Form 1, 2, and 3) of ceritinib are subjected to physicochemical property evaluation like solubility in buffers with a pH range of 1–7, dissolution, and stability. In aqueous solutions and pH 4.5 (acetate buffer), the solubility of Form 2 and 3 is high compared to Form 1, whereas in 0.1 N HCl and 0.01 N HCl Form 1 has a higher solubility compared to Forms 2 and 3. A six-month stability study indicates that all forms (Forms 1, 2, and 3) are stable in ICH stability conditions like accelerated (40 °C ± 2 °C, 75% RH ± 5% RH), long-term (25 °C ± 2 °C, 60% RH ± 5% RH), and low temperature (2–8 °C) conditions. A thorough polymorph screening protocol, including in silico prediction, single crystal structure, and physicochemical properties of different forms and structure property correlations for ceritinib are enlightened in the current paper.

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