3′-(N-Phthalimido)glutarimide, commonly known as thalidomide (TD), is one of the most famous chiral drugs, because of its tragic history. Although the R-enantiomers of TD have positive medical effects, the S-enantiomers have dangerous side effects, and consequently, the enantiomeric purity of TD in a solid state and the chiral inversion of TD in physiological conditions have attracted considerable attention and prompted discussion on the “TD paradox”. Subsequently, the physicochemical properties of TD in the solid state have been indicated to be as essential as those in the solution state for understanding the pharmacodynamics and pharmacokinetics of TD. Herein, we demonstrate that the sublimation method is beneficial in the crystal growth of TD compared with solvent–evaporation methods. Structural and optical analyses demonstrated that sublimination produced very thin, transparent, and defect-free single crystals with high crystal-surface parallelism; chromatographic analysis suggested that a chiral inversion of TD molecules occurs during the sublimation even beneath the melting point under ambient humidity. The potential occurrence of chiral inversion of TD in the gas phase with atmospheric water vapor is a crucial finding in the use of sublimation in purifying chiral drugs to avoid adverse drug-induced outcomes. The crystal growth and potential chiral inversion of TD by sublimation should contribute to providing important information for pharmaceutical sciences and industry.

中文翻译：

---

升华晶体生长过程中沙利度胺的手性反转

3′-( N-邻苯二甲酰亚胺)戊二酰亚胺，俗称沙利度胺(TD)，因其悲惨的历史而成为最著名的手性药物之一。虽然TD的R-对映体具有积极的医疗作用，但S-对映体具有危险的副作用，因此，TD在固态下的对映体纯度和TD在生理条件下的手性反转引起了人们的广泛关注并引发了讨论“TD悖论”。随后，对于理解 TD 的药效学和药代动力学，固态 TD 的理化性质与溶液状态的理化性质一样重要。在此，我们证明与溶剂蒸发方法相比，升华方法有利于 TD 晶体生长。结构和光学分析表明，升华可以产生非常薄、透明、无缺陷、晶面平行度高的单晶；色谱分析表明，即使在环境湿度下的熔点以下，TD 分子在升华过程中也会发生手性反转。在利用升华纯化手性药物以避免药物引起的不良后果的过程中，TD 在气相中与大气水蒸气发生手性反转的可能性是一个重要发现。 TD 升华的晶体生长和潜在的手性反转应该有助于为制药科学和工业提供重要信息。