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

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

Development of Pharmaceutically Acceptable Crystalline Forms of Drug Substances via Solid-State Solvent Exchange

In the pharmaceutical industry, solid form screening plays an important role to discover forms that exhibit desired physicochemical properties for drug product development. This work describes an approach to meet this objective by the transformation of undesirable solvates to hydrates or cosolvates with water via solid-state solvent exchange. Case studies of two drug substances, imatinib mesylate and linagliptin, are discussed, where linaglipitin methanol/ethanol solvate was converted to an iso-structural hydrate and, similarly, imatinib mesylate methanol–water cosolvate was converted to a predominantly water-containing cosolvate. Through quality by design based optimization, temperature and relative humidity were identified as critical process parameters that impacted the rate of solvent exchange during humidification. In addition, crystallization parameters that impacted the crystal size were found to play a key role in determining the extent of solvent exchange. This unexpected effect of crystal size was investigated through single crystal structure elucidation and molecular modeling, which showed the solvent to be residing in channels oriented along the length of the crystal. The dimensions of these channels determined the ease of solvent exchange by controlling the rate and extent of diffusion of solvent molecules. With these case studies, this paper provides insight on robust process development for solid-state solvent exchange with an in-depth understanding of molecular level phenomena and critical process parameters

Second Harmonic Generation Guided Raman Spectroscopy for Sensitive Detection of Polymorph Transitions

Second harmonic generation (SHG) was integrated with Raman spectroscopy for the analysis of pharmaceutical materials. Particulate formulations of clopidogrel bisulfate were prepared in two crystal forms (Form I and Form II). Image analysis approaches enable automated identification of particles by bright field imaging, followed by classification by SHG. Quantitative SHG microscopy enabled discrimination of crystal form on a per particle basis with 99.95% confidence in a total measurement time of ∼10 ms per particle. Complementary measurements by Raman and synchrotron XRD are in excellent agreement with the classifications made by SHG, with measurement times of ∼1 min and several seconds per particle, respectively. Coupling these capabilities with at-line monitoring may enable real-time feedback for reaction monitoring during pharmaceutical production to favor the more bioavailable but metastable Form I with limits of detection in the ppm regime

Triboluminescence from Pharmaceutical Formulations

Triboluminescence (TL) is shown to enable selective detection of trace crystallinity within nominally amorphous solid dispersions (ASDs). ASDs are increasingly used for the preparation of pharmaceutical formulations, the physical stability of which can be negatively impacted by trace crystallinity introduced during manufacturing or storage. In the present study, TL measurements of a model ASD consisting of griseofulvin in polyethylene glycol produced limits of detection of 140 ppm. Separate studies of the particle size dependence of sucrose crystals and the dependence on polymorphism in clopidogrel bisulfate particles are both consistent with a mechanism for TL closely linked to the piezoelectric response of the crystalline fraction. Whereas disordered polymeric materials cannot support piezoelectric activity, molecular crystals produced from homochiral molecules adopt crystal structures that are overwhelmingly symmetry-allowed for piezoelectricity. Consequently, TL may provide a broadly applicable and simple experimental route for sensitive detection of trace crystallinity within nominally amorphous materials