Temperature-dependent changes in thalidomide crystal structure revealed by Waseda University led group

A research group led by Professor Toru Asahi of the Faculty of Science and Engineering at Waseda University, Researcher Kenta Nakagawa and Senior Researcher Takuya Nakanishi of the Comprehensive Research Organization at the same university, Graduate Student Ayaka Matsumoto of the Graduate School of Advanced Science and Engineering, Assistant Professor Akiko Sekine of the Department of Chemistry, School of Science at Institute of Science Tokyo, Professor Norio Shibata of the Department of Life Science and Applied Chemistry at Nagoya Institute of Technology, and Project Professor Sota Sato of the Graduate School of Engineering at the University of Tokyo has announced that they have measured the temperature dependence of thalidomide's crystal structure over a wide temperature range and revealed differences in the temperature dependence between enantiomeric and racemic crystals. This achievement is expected to contribute to the crystallization and quality assurance of chiral pharmaceuticals in general. Their findings were published in the Journal of the American Chemical Society, an international academic journal, on March 27.

Thalidomide is known as a chiral drug that exhibits mirror-image isomerism, existing as stereoisomers that have the same atomic arrangement but different three-dimensional configurations (R-form and S-form), similar to the relationship between right and left hands. It was once sold worldwide as a pain relief and sedative drug but became a major problem when it was reported to cause birth defects in fetuses when taken by pregnant women. Subsequent research reported that only the S-form has teratogenic properties. Currently, it is again receiving attention as its efficacy against multiple intractable diseases such as multiple myeloma and leprosy has been revealed.

Thalidomide crystals exist in two forms: "enantiomeric crystals" composed of only R-form or S-form, and "racemic crystals" composed of equal amounts of R-form and S-form. Racemic crystals have two polymorphs (α-form and β-form), both with dimers as their basic structure. The molecular arrangement and intermolecular distances in both crystals are strikingly similar, with few comparable examples. However, differences in physicochemical properties, particularly changes in molecular and crystal structures with temperature variation, remained unclear.

In this study, the researchers compared the changes in enantiomeric and racemic crystals associated with temperature variations and investigated how slight differences in the molecular environment affect thermal expansion.

Single crystal samples of each type capable of withstanding high temperatures were grown using the solvent evaporation method. X-ray structural analysis was performed on the R-form and S-form of enantiomeric crystals and the α-form and β-form of racemic crystals over a very wide temperature range from -173℃ to 150℃.

As a result, clear differences were confirmed between enantiomeric and racemic crystals in the temperature dependence of lattice parameters and thermal expansion coefficients. Furthermore, focusing on the structure, the group found that in enantiomeric crystals, the structural differences between the two types of monomers that form pairs become even greater with increasing temperature, whereas in racemic crystals, the R-form and S-form molecules have equal temperature dependence for structural changes, maintaining symmetry.

Nakagawa commented: "Although thalidomide is a socially well-known and important drug, there is still a lack of research on its basic physical properties. In particular, despite thalidomide being sold and administered in solid state, almost all research on thalidomide's chirality has been conducted in solution, with very few studies on the solid state except for a few examples, including our research. By further developing this research and evaluating the chirality of thalidomide 'in its solid state' without going through the liquid state, we aim to clarify the thermal properties and solid-state reactions of thalidomide in solid form from a physicochemical perspective, which have not been elucidated until now."

Journal Information
Publication: Journal of the American Chemical Society
Title: How Temperature Change Affects the Lattice Parameters, Molecular Conformation, and Reaction Cavity in Enantiomeric and Racemic Crystals of Thalidomide
DOI: 10.1021/jacs.4c18394