Unprecedented Packing Polymorphism of Oxindole: An Exploration Inspired by Crystal Structure Prediction

Crystal polymorphism, characterized by different packing arrangements of the same compound, strongly ties to the physical properties of a molecule. Determining the polymorphic landscape is complex and time‐consuming, with the number of experimentally observed polymorphs varying widely from molecule to molecule. Furthermore, disappearing polymorphs, the phenomenon whereby experimentally observed forms cannot be reproduced, pose a significant challenge for the pharmaceutical industry. Herein, we focused on oxindole (OX), a small rigid molecule with four known polymorphs, including a reported disappearing form. Using crystal structure prediction (CSP), we assessed OX solid‐state landscape and thermodynamic stability by comparing predicted structures with experimentally known forms. We then performed melt and solution crystallization in bulk and nanoconfinement to validate our predictions. These experiments successfully reproduced the known forms and led to the discovery of four novel polymorphs. Our approach provided insights into reconstructing disappearing polymorphs and building more comprehensive polymorph landscapes. These results also establish a new record of packing polymorphism for rigid molecules. The use of computational predictions, along with innovative crystallization techniques for oxindole, has led to the discovery of four new forms and the reconstruction of a previously presumed “disappearing polymorph”. The findings have established a new record for the largest number of packing polymorphs for rigid organic systems, where variations are indeed due to distinct crystalline packing arrangements with the same molecular conformation.