Nucleation in the Theophylline/Glutaric Acid Cocrystal System

The nucleation kinetics in the theophylline/glutaric acid (THP/GLU) cocrystal system in chloroform was investigated by performing small-scale induction time experiments. By larger-scale crystallization experiments, isolation and characterization of the nucleating phase reveal that β-glutaric acid (β-GLU) is the solid phase initially nucleating from the stoichiometric solution, in spite of the supersaturation with respect to the cocrystal being much higher. The 1:1 THP/GLU cocrystal then appears to nucleate on the surface of the β-glutaric acid crystals, and transformation from the β-GLU crystals, which are metastable in the mixed solution, into the thermodynamically stable cocrystal takes place. The kinetics of nucleation of β-GLU in pure chloroform solution and in a mixed stoichiometric solution of GLU and theophylline (THP) is determined and compared with previous data for nucleation of THP II from chloroform at the same temperature. The results reveal that the THP in the mixed solution increases the β-GLU solubility and greatly facilitates the nucleation of β-GLU. Evaluated within the classical nucleation theory, it is found that compared to the pure system, there is a significant increase in the preexponential factor of β-GLU nucleating from the mixed solution, which relates to a higher concentration of GLU in the mixed solution. β-GLU nucleation from a pure solution requires a clearly higher driving force to nucleate at the same time as THP II from a pure solution due to a higher interfacial energy.