Investigation into the nucleation of the p‑hydroxybenzoic acid:glutaric acid 1:1 cocrystal from stoichiometric and non-stoichiometric solutions

The nucleation in the p-hydroxybenzoic acid:glutaric acid 1:1 cocrystal (PHBA:GLU) system has been investigated in stoichiometric and non-stoichiometric acetonitrile solutions by induction time experiments. Utilizing the ternary phase diagram, the supersaturated non-stoichiometric solutions were created with compositions along the invariant point boundary lines. In all cases, the PHBA:GLU cocrystal was the nucleating phase, even though the non-stoichiometric solutions were also supersaturated with respect to the pure solid phases. The nucleation of the cocrystal from the mixed solutions is found to be more difficult than the nucleation of the pure compounds from the respective pure solutions, as captured by lower pre-exponential factors (A). However, if the driving force is defined per reactant molecule instead of per heterodimer, the cocrystal nucleation difficulty is close to that of the more difficult-to-nucleate pure compound. The difference in nucleation difficulty of the cocrystal from stoichiometric and non-stoichiometric solutions was captured by differences in the interfacial energy, while the pre-exponential factor remained unchanged. Apart from the pure GLU system, the relation between the experimentally determined pre-exponential factors for the different systems correlates with calculated values using theoretical expressions for volume-diffusion and surface-integration control.