{"id":85090,"date":"2025-06-25T15:00:46","date_gmt":"2025-06-25T06:00:46","guid":{"rendered":"https:\/\/www.waseda.jp\/top\/en\/?p=85090"},"modified":"2025-06-25T11:17:08","modified_gmt":"2025-06-25T02:17:08","slug":"life-in-a-nutshell-new-species-found-in-the-carapace-of-late-cretaceous-marine-turtle-2-2-2-2-2-2-2-2-2-2-2-3-3-2-2-3-2-3-2-2-2-3-2-2-2-3-3-3-3-2-2-2-3-2-2-2-2","status":"publish","type":"post","link":"https:\/\/www.waseda.jp\/top\/en\/news\/85090","title":{"rendered":"Decoding Thermal Behavior in Crystals: Insights from Thalidomide"},"content":{"rendered":"

Decoding Thermal Behavior in Crystals: Insights from Thalidomide<\/strong><\/h1>\n

Unraveling the impact of dimer symmetry on temperature-dependent properties of chiral drug crystals<\/em><\/p>\n

The molecular arrangement of thalidomide in its crystalline form significantly influences its behavior at high temperatures. Comparative analysis of its different crystal forms revealed distinct differences in thermal expansion and molecular motion, driven by symmetry. These findings highlight the critical role of crystal packing in determining solid-state properties and provide a valuable framework for enhancing the stability and performance of pharmaceuticals through targeted crystal engineering strategies.<\/strong><\/p>\n

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Image title: Decoding Thalidomide Crystal Behavior at Different Temperatures
\nImage caption: Temperature and crystal structure drive structural shifts in thalidomide, revealing unique dimer behavior and thermal response patterns in the solid state
\nImage credit: Professor Toru Asahi from Waseda University, Japan
\nLicense type: Original content
\nUsage restrictions: Cannot be reused without permission<\/p><\/div>\n

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, 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 Initially introduced as a sedative, it was withdrawn due to its devastating effects on embryos.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.<\/p>\n

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\u2019s 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 findings were made available online in the Journal of the American Chemical Society<\/em> <\/a>on 27 March 2025 and published in Volume 147, Issue 14 on 9 April 2025. Lead researcher Prof. Asahi explains, \u201cAlthough 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<\/em>.\u201d<\/p>\n

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.<\/p>\n

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.<\/p>\n

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.<\/p>\n

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.<\/p>\n

\u201cLooking ahead, this study lays a solid foundation for investigating the thermal behavior and structural stability of other chiral pharmaceuticals<\/em>,\u201d shares Prof. Asahi. \u201cWhen 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.\u201d<\/em><\/p>\n

By bridging a critical knowledge gap in thalidomide\u2019s 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.<\/p>\n

Reference<\/strong><\/p>\n

Title of original paper<\/strong>: How Temperature Change Affects the Lattice Parameters, Molecular Conformation, and Reaction Cavity in Enantiomeric and Racemic Crystals of Thalidomide
\nDOI<\/strong>:10.1021\/jacs.4c18394<\/a>
\nJournal<\/strong>: Journal of the American Chemical Society<\/em>
\n<\/em>Article Publication Date<\/strong>: March 27, 2025
\nAuthors<\/strong><\/strong>: Ayaka Matsumoto1<\/sup>, Kenta Nakagawa<\/a>2<\/sup>, Takuya Nakanishi2<\/sup>, Akiko Sekine3<\/sup>, Sosuke Kojo3<\/sup>, Mizuki Kira1<\/sup>, Sota Sato2,4<\/sup>, Norio Shibata5<\/sup>, and Toru Asahi<\/a>1
\n<\/sup>Affiliation<\/strong>:
\n1<\/sup>Faculty of Science and Engineering, Waseda University
\n2<\/sup>Comprehensive Research Organization, Waseda University
\n3<\/sup>Department of Chemistry, School of Science, Institute of Science Tokyo
\n4<\/sup>Integrated Molecular Structure Analysis Laboratory, Department of Applied Chemistry, School of Engineering, The University of Tokyo
\n5<\/sup>Department of Engineering, Nagoya Institute of Technology<\/p>\n

About Professor Toru Asahi from Waseda University, Japan<\/strong><\/p>\n

Dr. Toru Asahi is a distinguished Professor at Waseda University, Japan, with over 30 years of research experience and more than 200 scientific publications. He holds a Ph.D. in Science and an MBA in Technology Management. Dr. Asahi is affiliated with the Faculty of Science and Engineering and serves as Director of the Global Consolidated Research Institute for Science Wisdom. His interdisciplinary research spans chiral science, materials science, bioinformatics, and sustainable food systems. He leads major national initiatives, including Japan\u2019s Moonshot R&D and ERATO programs, and is widely recognized for his leadership in scientific innovation and cross-disciplinary research.<\/p>\n","protected":false},"excerpt":{"rendered":"

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