In recent years, major pharmaceutical companies have started using high-throughput screening and combinatorial chemistry to select good drug candidates. However, many poorly water soluble drugs (hydrophobic) are screened out far too early. Recent pharmaceutical advances have shown that preparing this type of drugs as nanocrystals can greatly increase their solubility and bioavailability. In order to maintain nanoparticle size, and reduce agglomeration, surfactants and polymers are used in the drug formulation. While experiments have shown that surfactants aid in nanocrystal stabilization, not all are created equally and different surface functionalities determine completely different behaviors. Therefore, surfactant/drug-surface interactions emerges as a relevant topic to apply molecular dynamic simulations. These simulations can validate experiments and even screen potential surfactant candidates prior to conducting experiments. In addition, molecular simulations can also examine the overall stability of the drug-surfactant system. In this work, atomistic simulations via Materials Studio® are employed to study the stability of nanocrystal-surfactant systems. Griseofulvin has been chosen as our poorly water soluble drug candidate. Griseofulvin is an antifugal drug with poor solubility which is used to treat skin or nails infections of both animals and humans. Several polymers and surfactants are tested including Tween 80, Pullulan, and Hydroxylpropylmethylcellulose (HPMC).

In our simulations, the drug is cleaved along the (100), (010), and (001) planes in order to study the interaction between the drug surface and the surfactant. The attachment energies between a specific drug crystal surface, the pure solvent, and the surfactant/polymer are calculated during the simulations. Hartman–Perdok theory suggests that the relative growth rate of crystal faces is proportional to the attachment energy of the faces. A comparison between attachment energies can conclude the overall effect of the stabilizer, or combination of stabilizers. In turn, the results reflect the stability of the nanocrystal aqueous system. Simulation results are obtained for non-ionic surfactant Tween 80, water-soluble polymer Pullulan and polymer HPMC. At this point, all three stabilizers have shown significant effects in stabilizing the nanocrystals in the aqueous system. Overall, HPMC is the most efficient stabilizer. Pullulan and Tween 80, while significant, are not as efficient in terms of stabilization if used alone. However, using a mixture of the two has shown a remarkable synergetic effect specifically on a side-by-side adsorption configuration of the surfactant and the polymer on the drug crystal surface. Other adsorption configurations, such as surfactant on top of the polymer or vice versa, do not show nearly as much improvement. This can imply that experimentally mixing Tween 80 with Pullulan with the nanocrystal suspension will achieve better stabilization than either stabilizer alone. Other comparisons between the three stabilizers have also been conducted, although they have not shown results as effective as the Tween 80/Pullulan system.