Solution Phase Co Oligomer Analysis As A Predictive Tool For Co Crystal

Zhiyu Liao, Immacolata Abate, Rebecca Beveridge, and Klaas Wynne

1. School of Chemistry, University of Glasgow, G12 8QQ, UK

2. Dept. of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1XL, UK

klaas.wynne@glasgow.ac.uk

Abstract

Multicomponent molecular solids underpin technologies ranging from pharmaceuticals to functional materials, including co-amorphous drug delivery systems (CAMS). However, there is no general method to predict whether a mixture of small molecules will form a cocrystal, a homogeneous glass, or separate crystalline phases. Here we show that solution-phase noncovalent oligomers, detected by nanoelectrospray ionization mass spectrometry (nESI-MS), enable direct prediction of the solid-state forms obtained from multicomponent mixtures.1 By analysing the distribution and stoichiometry of mixed oligomers formed in dilute solution, we find that well-defined complexes with a fixed molar ratio reliably precede the formation of stoichiometric cocrystals, whereas disordered ensembles of mixed aggregates with variable composition lead instead to single-phase amorphous solids. In contrast, the absence of detectable mixed oligomers correlates with macroscopic phase separation into the individual crystalline components. This solution-phase oligomer analysis operates on microliter sample volumes, requires no prior structural information and is compatible with a wide range of molecular systems. Our results establish a mechanistic link between pre-nucleation aggregation in solution and the emergent structure of multicomponent molecular solids, enabling rapid, physically grounded screening of co-formers and co-assemblies across fields from pharmaceutical formulation to materials science.

Figure from Wynne_2.docx

Figure 1 – Schematic representation of a predictive workflow for co-structure formation in drug formulations using solution-phase oligomer analysis. nESI-MS reveals the detailed distribution and stoichiometry of oligomers and co-oligomers formed in solution. These molecular signatures serve as precursors that indicate the propensity of forming either co-crystals or co-amorphous solids.

References

(1) Liao, Z.; Abate, I.; Beveridge, R.; Wynne, K. Solution-Phase Co-Oligomer Analysis as a Predictive Tool for Co-Crystal and Co-Amorphous Forms. ChemRxiv 2026. https://doi.org/10.26434/chemrxiv.10001669/v1.