RESUMO
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.
RESUMO
The nucleation behavior of the theophylline-salicylic acid 1:1 (THP:SA) cocrystal in chloroform has been investigated and compared with the corresponding behavior of the pure compounds. Induction times have been determined at different supersaturations at 10 °C under each condition in approximately 40-80 repetition experiments in 20 mL vials. Nucleation times, extracted from the median induction times by accounting for a nucleus growth time, have been used to determine the interfacial energy and the pre-exponential factor within the classical nucleation theory. Results show that the cocrystal at equal driving force has a longer nucleation time, or to reach equal nucleation time, the cocrystal requires a higher driving force. Pure theophylline is easier to nucleate than pure salicylic acid, despite the latter having a smaller molecular size, higher solubility, and is expected to form dimers already in the solution. The cocrystal is found to have an interfacial energy in between the respective values for the pure compounds. However, the higher molecular volume of the cocrystal, taken as the volume of the 1:1 theophylline-salicylic acid assembly, leads to the highest nucleation work, which, together with a low pre-exponential factor, explains why the cocrystal is the most difficult to nucleate. The experimentally extracted pre-exponential factor of the cocrystal is very similar to that of THP, and similar trends are observed from theoretical expressions of volume-diffusion- and surface-integration-controlled nucleation, respectively.