(306e) The Influence of Polymer Properties On the Inhibition of Crystallization | AIChE

(306e) The Influence of Polymer Properties On the Inhibition of Crystallization


Tomassone, M. S. - Presenter, Rutgers University
Tomasini, M. - Presenter, Rutgers University

A number of strategies have been developed for dissolving drugs with poor intrinsic solubility. Often, this involves the use of composite substances comprised of both drug and amphiphilic surfactants. One method to enhance hydrophobic drug solubility is to decrease the size of the drug particles to nanoscale, but this increases their surface energy leading to aggregation and possibly re-crystallization of the particles. Re-crystallization of drug molecules after dissolution in the gastrointestinal (GI) tract results in drug precipitation prior to absorption, reducing bioavailability and overall effect. Polymer adsorption to the surface of a drug crystal nucleus can effectively block the addition of drug particles and slow the growth of a crystal. In this work, we aim use Monte Carlo (MC) and Molecular Dynamics (MD) simulation to further understand how polymers inhibit drug crystallization from solution and use our results to predict the best inhibitors of crystallization for a given drug substance. We develop a qualitative model of the system followed by extension to real systems. We perform atomistic MD simulations to obtain the adsorption properties of polymer on a drug crystal surface. Using this data, we perform coarse-grained MD simulations to match the atomistic MD simulations and provide parameters for subsequent MC simulations. The MC simulations are done using the gauge-cell MC technique. This method mimics the equilibrium between the system of interest and implicit reservoirs, one for each component. The implicit reservoirs or ?gauges' act to both restrict density fluctuations in the system and to measure the chemical potential of a particular component. This allows for the simulation of metastable and unstable states such as crystal nuclei below their critical size. Given the resulting isotherms produced from the gauge-cell MC technique, we can calculate the nucleation barriers and the influence that polymer has on the drug nucleation barrier. In studying a drug-solvent-polymer system, we have determined that with addition of polymer to the system, for the same chemical potential, increasing the amount of polymer in the system results in increased drug solubility and a reduction in the nucleation barrier. We have also shown that increasing the polymer concentration acts to decrease the thermodynamic limit of solubility (spinodal), aiding in the formation of a nucleus. In addition to polymer concentration, we also examine the polymer properties such as length, affinity for the drug, and block structure and their influence on the nucleation barrier. This work has also been extended to a real system involving felodipine as the model hydrophobic drug and Polyvinylpyrrolidone (PVP) as the polymer.