TY - JOUR
T1 - Thermodynamics and crystallization of the theophylline-glutaric acid cocrystal
AU - Zhang, Shuo
AU - Rasmuson, Åke C.
PY - 2013/3/6
Y1 - 2013/3/6
N2 - This work investigates the thermodynamics and crystallization of the theophylline-glutaric acid 1:1 cocrystal. It is found that the cocrystal physically decomposes at 120 °C (i.e., in the range between the melting points of the two pure compounds). The solubility of the cocrystal and pure compounds has been determined in chloroform and acetonitrile. In chloroform, the theophylline concentration of the saturated solution over the cocrystal is clearly higher than that in the saturated solution over pure theophylline I/II, while for glutaric acid the situation is the opposite. With the solubility data, the Gibbs free energy of the formation of the cocrystal from solid theophylline II and solid ß-glutaric acid at 30 °C can be estimated to -0.39 kJ mol-1. The work reveals that polymorphism in the pure components of a cocrystal can dramatically influence the phase diagram and shift an incongruently dissolving case into a kinetically stabilized congruent case. In chloroform, the cocrystal dissolves incongruently with respect to the stable form I of theophylline but congruently with respect to the metastable theophylline II. However, the cocrystal is stable in a stoichiometric solution for more than 2 weeks. Given sufficient time, the system should transform into a solid phase being a mixture of cocrystal and stable theophylline I, in equilibrium with a solution that has the composition of the corresponding invariant point. In acetonitrile, where the glutaric acid solubility is much higher than that of theophylline II, the cocrystal dissolves, clearly incongruently. The region where the cocrystal is the only solid stable phase is clearly shifted toward the glutaric acid side and is fairly narrow. In both solvents the cocrystal can readily be produced by isothermal slurry conversion crystallization to a reasonable level of productivity, as long as the process is operated in a region of the phase diagram where the cocrystal is the only stable (or reasonably metastable) solid phase.
AB - This work investigates the thermodynamics and crystallization of the theophylline-glutaric acid 1:1 cocrystal. It is found that the cocrystal physically decomposes at 120 °C (i.e., in the range between the melting points of the two pure compounds). The solubility of the cocrystal and pure compounds has been determined in chloroform and acetonitrile. In chloroform, the theophylline concentration of the saturated solution over the cocrystal is clearly higher than that in the saturated solution over pure theophylline I/II, while for glutaric acid the situation is the opposite. With the solubility data, the Gibbs free energy of the formation of the cocrystal from solid theophylline II and solid ß-glutaric acid at 30 °C can be estimated to -0.39 kJ mol-1. The work reveals that polymorphism in the pure components of a cocrystal can dramatically influence the phase diagram and shift an incongruently dissolving case into a kinetically stabilized congruent case. In chloroform, the cocrystal dissolves incongruently with respect to the stable form I of theophylline but congruently with respect to the metastable theophylline II. However, the cocrystal is stable in a stoichiometric solution for more than 2 weeks. Given sufficient time, the system should transform into a solid phase being a mixture of cocrystal and stable theophylline I, in equilibrium with a solution that has the composition of the corresponding invariant point. In acetonitrile, where the glutaric acid solubility is much higher than that of theophylline II, the cocrystal dissolves, clearly incongruently. The region where the cocrystal is the only solid stable phase is clearly shifted toward the glutaric acid side and is fairly narrow. In both solvents the cocrystal can readily be produced by isothermal slurry conversion crystallization to a reasonable level of productivity, as long as the process is operated in a region of the phase diagram where the cocrystal is the only stable (or reasonably metastable) solid phase.
UR - http://www.scopus.com/inward/record.url?scp=84876945865&partnerID=8YFLogxK
U2 - 10.1021/cg3014859
DO - 10.1021/cg3014859
M3 - Article
AN - SCOPUS:84876945865
SN - 1528-7483
VL - 13
SP - 1153
EP - 1161
JO - Crystal Growth and Design
JF - Crystal Growth and Design
IS - 3
ER -