Solution-Phase Co-Oligomer Analysis as a Predictive Tool for Co-Crystal and Co-Amorphous Forms

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. By analyzing 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.