(276c) Atomistic Simulation Studies On the Stability of Fenofibrate Nanocrystals in An Aqueous System by the Addition of Surfactants, Polymers, and Surfactant-Polymer Mixtures

In the pharmaceutical industry high-throughput screening and combinatorial chemistry are routinely used to select good drug candidates. A large number of poorly water soluble drugs are typically rejected due to poor bioavailability. Nanosizing the drug increases its bioavailability but typically nanocrystals agglomerate and lose their stability. It is therefore of crucial importance to develop methods that help maintain a stable nanocrystal suspension system without agglomeration. Over the past few decades, a number of different methods have been developed for this purpose. A widely used technique is to add surfactants or water-soluble polymers to the drug suspension system.

It is generally believed that surfactant-coated or polymer-coated drug nanocrystals are less likely to agglomerate due to the strong quenching effects of the additives. However, experiments found that not all kinds of surfactants or polymers work well to stabilize drug suspension systems, and the effectiveness of stabilizers is typically analyzed by trial and error. In this work atomistic simulations are employed to study the stability of a Fenofibrate nanocrystal suspension system by adding surfactant, polymers, and their mixtures. Fenofibrate is a poorly water soluble drug used to reduce cholesterol levels in patients at risk of cardiovascular disease. Various surfaces (100), (010) and (001) of the drug nanocrystal are cleaved for studies. The attachment energies between a specific drug crystal surface and the pure solvent as well as between the drug and additives are studied. Our systems consist of the Fenofibrate molecule, the surfactants Tween 80 and Sodium Dodecyl Sulfate (SDS), as well as the polymers Pullulan and Hydroxylpropyl Methyl Cellulose(HPMC) in an aqueous system. We perform a systematic study of the two selected drugs in presence of Tween 80, SDS, Pullulan or HPMC, and for different polymer-surfactant mixtures. Our results show that addition of Tween 80 or SDS, or the polymer (Pullulan or HPMC) substantially enhance the stability of Fenofibrate nanocrystal in an aqueous system. Each additive has different quenching capabilities on different crystal faces. HPMC is overall the most efficient sole stabilizer, while Tween 80 shows more efficiency to block the growth of Fenofibrate on the surface (010). For the mixtures of the polymer (Pullulan or HPMC) and the surfactant (Tween 80 or SDS), we observe a synergistic effect between polymers and surfactants. Only in a few cases such as side-by-side configuration of the mixtures of Pullulan-SDS, Pullulan-Tween 80, and HPMC-Tween 80 on Fenofibrate crystal surface (010), the stabilization capability is not improved. Our analysis also shows that both geometry and chemistry factors between the polymer, the surfactant, and the drug crystal surface play important roles on the stability enhancement of the suspension system. Our simulation results are consistent with recent experimental findings at NJIT.