(291h) Control of Crystallization Using Polymeric Additives

The control of crystallization from solution is important in a variety of fields, particularly in the pharmaceutical industry.  Dependent on the particular application at hand, it may be desirous to either induce or inhibit drug precipitation.  For example, many drugs currently in development are poorly water soluble, resulting in reduced bioavailability in the aqueous environment of the GI tract following oral administration.  One method for increasing drug uptake, and thus bioavailability, is to create a transient supersaturated solution in the GI tract so as to increase the driving force for drug uptake.  However, the natural tendency of a supersaturated solution of poorly soluble drug is to form a crystalline precipitate.  It is possible to delay this onset of precipitation through the use of bioactive polymers in the drug formulation which influence drug crystallization and keep the supersaturated solution in a metastable state.  Conversely, polymeric additives could also aid in promoting crystallization of a desired drug polymorph.  The addition of polymeric additives to drug solutions is a topic that has been studied in the literature, but most studies are concerned with the control of crystal growth rather than nucleation.  In this work, we aim to use molecular simulation techniques to further understand what general interactions influence crystal nucleation in a ternary drug-polymer-solvent system.

Our work initially focuses on a qualitative understanding of the system followed by extension to real systems.  We perform atomistic molecular dynamics (MD) simulations to obtain relative interaction ratios between the components of our desired drug-polymer-solvent system.  We then use this data to parameterize a coarse-grained Monte Carlo (MC) system which we utilize to study nucleation.  The MC simulations are done using the gauge-cell MC technique selected because it 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 calculate the energetic barrier to crystal nucleation and how this barrier is influences by the presence of polymer.

In simulating a model drug-polymer-solvent system we have found that the nucleation behavior is dependent on the interaction affinities of the polymer with the drug and with the solvent in addition to the relative molecular volumes of the polymer and drug.  When the polymeric additive interacts moderately with both the drug and solvent, and has a molecular volume equivalent to that of the drug, the result is for the polymer to promote nucleation.  For inhibition of drug nucleation, we have found that the polymer should have a strong interaction with the drug and have a molecular volume incommensurate with that of the drug.  This results in the polymer interrupting the emerging lattice structure of a newly forming drug crystal.

To validate our simulation results, we have extended our general system to a few specific systems.  We performed simulations on the systems of the drug felodipine with either the polymers hydroxypropyl methylcellulose (HPMC) – a case in which nucleation is inhibited or Polyvinylpyrrolidone (PVP) – in which the polymer does not seem to influence nucleation.  In addition, we have performed simulations on naringenin with either PVP or HPMC, an example of a system in which polymer promotes nucleation.