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Single‐crystal X‐ray diffraction (SCXRD) is the preferred and most accurate technique for determining molecular structures. However, it can present challenges when dealing with specific small molecules and active pharmaceutical ingredients (APIs), as many do not form quality crystals without coformers or can be unstable. In this study, we introduce tetrakis(guanidinium) pyrenetetrasulfonate (G4PYR), a robust guanidinium‐organosulfonate (GS) framework that efficiently encapsulates small molecules and APIs rich in functional groups. The hydrogen bonding frameworks formed by G4PYR display well‐ordered structures with predictable pyrene‐pyrene distances, making them ideally suited for targeting arene‐based APIs with pendant groups. Successful encapsulation of various guests, including benzaldehyde, benzamide, and arenes containing multiple hydrogen bond donors and acceptors like uracil and thymine, was achieved. Furthermore, we successfully encapsulated important pharmaceutical and biologically relevant compounds, such as lidocaine, ropinirole, adenosine, thymidine, and others. Notably, we present a workflow for investigating host‐guest complex formation using powder X‐ray diffraction and high throughput experimentation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Herein we report the use of tetrakis (guanidinium) pyrenetetrasulfonate (G4PYR) and bis (guanidinium) 1,5‐napthalene disulfonate (G2NDS) to catalyze the cyclization of 2‐cyanobenzamide (1) to isoindolone (2). Moreover, we demonstrate the remarkable selectivity of these guanidinium organosulfonate hosts in encapsulating 2 over 1. By thoroughly investigating the intramolecular cyclization reaction, we determined that guanidinium and the organosulfonate moiety acts as the catalyst in this process. Additionally, 2 is selectively encapsulated, even in mixtures of other structurally similar heterocycles like indole. Furthermore, the tautomeric state of 2 (amino isoindolone (2–A) and imino isoindolinone forms (2–I)) can be controlled by utilizing different guanidinium organosulfonate frameworks. [ABSTRACT FROM AUTHOR]