(631a) Relationship Between Solution Metastable Limit and Solubility

In pharmaceutical crystallization, and especially in the creation of nanoparticles, the degree of supersaturation and the mechanism of producing supersaturation can have a significant impact on the resultant solid particle properties.  For the creation of small particles it is beneficial to suppress the growth phase of crystallization in favor of the nucleation phase.  One way to do this is to operate very close to the metastable limit.  A difficulty that arises is that the metastable limit of a drug in a particular solvent is not an easy quantity to obtain.  Therefore, we seek a method to determine the metastable limit such that we can operate in the metastable zone at a high level of supersaturation but not exceed the metastable limit.  It has been empirically observed that the metastable limit curve (the metastable limit as a function of temperature) often mirrors the functionality of the solubility curve.  If this were generally true, evaluation of the metastable limit curve would be a straightforward shift of the solubility curve.  With the aim of exploring the functional relationship between the metastable limit curve and the solubility curve, we used gauge-cell Monte Carlo (MC) to simulate nucleation and determine the metastable limit and solubility of model drug compounds. 

We performed simulations on four different model drug compounds with increasing solubility to determine the solubility curve and metastable limit curve for each compound.  We determined that the mestastable limit curve and solubility curves show similar traits, both exhibiting a logarithmic functionality.  We also computed the metastable zone width (MSZW) for each compound, the difference between the metastable limit curve and the solubility curve.  When normalized to the drug solubility, the MSZW shows a decrease with increasing solubility indicating that as a more soluble drug will have more molecules in solution, it will therefore undergo more molecular collisions and nucleate at lower supersaturations.  We also relate the computed collision frequency to the MSZW to allow for prediction of the metastable limit curve from the solubility curve.  The results show similar trends to experimental results of drug nucleation.