We explore the effects of particle size and solvent environment on the thermodynamic stability of two pairs of polymorphs subjected to ball-mill neat grinding (NG) and liquid assisted grinding (LAG). Two systems were studied: (i) forms I and II of a 1 : 1 theophylline : benzamide cocrystal and (ii) forms A and B of an aromatic disulfide compound. For both systems, the most stable-bulk polymorph converted to the metastable-bulk polymorph upon NG. LAG experiments yielded different outcomes depending on the amount of solvent used. This was further investigated by performing carefully controlled LAG experiments with increasing μL amounts of solvents of different nature. With these experiments, we were able to monitor form A to B and form I to II conversions as a function of solvent concentration and derive polymorph equilibrium curves. The concentration required for a switch in polymorphic outcome was found to be dependent on solvent nature. We propose that these experiments demonstrate a switch in thermodynamic stability of the polymorphs in the milling jar. Form B, the stable-bulk polymorph, has less stable surfaces than form A, thus becoming metastable at the nanoscale when surface effects become important. Ex situ diffraction and electron microscopy data confirm crystal sizes in the order of tens of nanometers after the ball mill grinding experiments reach equilibrium. DFT-d computations of the polymorph particles stabilities support these findings and were used to calculate cross-over sizes of forms A and B as a function of solvent. Attachment energies and surface stabilities of the various crystalline faces exposed were found to be very sensitive to the solvent environment. Our findings suggest that surface effects are significant in polymorphism at the nanoscale and that the outcomes of equilibrium ball-mill NG and LAG experiments are in general controlled by thermodynamics.
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