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Understanding how molecular arrangements within crystals influence their thermal behavior is a fundamental question in solid-state chemistry. This topic is especially relevant in pharmaceuticals existing as enantiomers, molecules in two forms that are mirror images of one another but cannot be superimposed, which can exhibit distinct physical and chemical properties depending on their crystalline form.

Thalidomide is a notable example. Initially introduced as a sedative, it was withdrawn due to its devastating effects on embryos. However, in recent years, thalidomide has regained clinical importance as a treatment for conditions such as multiple myeloma and leprosy. Despite this renewed relevance, the physicochemical behavior of thalidomide in the solid state remains insufficiently explored.

To address this gap, a research team from Waseda University, led by Professor Toru Asahi and including graduate student Ayaka Matsumoto, Researcher Kenta Nakagawa, and Senior Researcher Takuya Nakanishi, conducted a comprehensive study investigating how temperature influences the crystal structures and molecular conformations of thalidomide's enantiomeric and racemic (mixture of left- and right-handed enantiomers) forms.

The team also included Assistant Professor Akiko Sekine, Institute of Science Tokyo; Professor Sota Sato, The University of Tokyo; and Professor Norio Shibata, Nagoya Institute of Technology. Their are published in the Journal of the American Chemical Society.

Lead researcher Prof. Asahi explains, "Although thalidomide is widely studied, significant gaps remain in our understanding of its physicochemical properties. Our goal was to clarify its thermal behavior and solid-state transformations, crucial factors for drug formulation and long-term stability that are not yet fully understood."

The team performed single-crystal X-ray diffraction analysis on both the enantiomeric and racemic forms of thalidomide crystals across a temperature range from 100 K to 423.15 K. These crystals were grown using the solvent evaporation method.

The study examined how the lattice parameters, linear and volumetric thermal expansivities, and intramolecular dihedral angles changed with temperature. The focus was on understanding how the crystal packing and dimer structures influenced these thermal responses.

Their analysis revealed distinct differences between the two crystal types. In the enantiomeric crystals, thalidomide molecules formed asymmetric homochiral dimers. Within these dimers, only one monomer, specifically the one with a larger reaction cavity, showed significant changes in dihedral angles as temperature increased. This created an asymmetric thermal response, leading to non-uniform expansion, as structural differences between the monomers grew with rising temperature.

In contrast, the racemic crystals featured symmetric heterochiral dimers. Both monomers had similar cavity sizes and underwent coordinated conformational changes, resulting in a more uniform thermal behavior across the crystal. These findings highlight that dimer symmetry plays a crucial role in governing temperature-dependent molecular motions within a crystal.

This study provides a valuable model for understanding how molecular arrangement and dimer symmetry affect the thermal and physicochemical behavior of chiral compounds. Insights into the differing thermal responses of enantiomeric and racemic forms can be extended to related drugs such as pomalidomide and lenalidomide, helping to predict crystal stability and solid-state properties more accurately.

Such knowledge supports key drug development processes, including formulation stability, crystallization optimization, and quality control, ultimately enhancing drug performance and safety.

"Looking ahead, this study lays a solid foundation for investigating the thermal behavior and structural stability of other chiral pharmaceuticals," says Prof. Asahi. "When combined with computational modeling and simulations, our approach can support the rational design of molecular crystals with optimized solid-state properties, ultimately advancing drug manufacturing and development."

By bridging a critical knowledge gap in thalidomide's solid-state behavior, this research not only deepens our understanding of a historically significant drug but also establishes a framework for studying and optimizing the thermal and structural properties of other chiral solid-state materials. These insights could pave the way for better-informed pharmaceutical applications and innovative crystal engineering strategies in the future.