Hierarchical Particle Approach for Co-Precipitated Amorphous Solid Dispersions for Use in Preclinical In Vivo Studies

Amorphous solid dispersions (ASD) have become a well-established strategy to improve exposure for compounds with insufficient aqueous solubility. Of methods to generate ASDs, spray drying is a leading route due to its relative simplicity, availability of equipment, and commercial scale capacity. However, the broader industry adoption of spray drying has revealed potential limitations, including the inability to process compounds with low solubility in volatile solvents, inconsistent molecular uniformity of spray dried amorphous dispersions, variable physical properties across batches and scales, and challenges containing potent compounds. In contrast, generating ASDs via co-precipitation to yield co-precipitated amorphous dispersions (cPAD) offers solutions to many of those challenges and has been shown to achieve ASDs comparable to those manufactured via spray drying. This manuscript applies co-precipitation for early safety studies, developing a streamlined process to achieve material suitable for dosing as a suspension in conventional toxicity studies. Development targets involved achieving a rapid, safely contained process for generating ASDs with high recovery yields. Furthermore, a hierarchical particle approach was used to generate composite particles where the cPAD material is incorporated in a matrix of water-soluble excipients to allow for rapid re-dispersibility in the safety study vehicle to achieve a uniform suspension for consistent dosing. Adopting such an approach yielded a co-precipitated amorphous dispersion with comparable stability, thermal properties, and in vivo pharmacokinetics to spray dried amorphous materials of the same composition.

A Hybrid Continuum-Particle Approach for Fluid-Structure Interaction Simulation of Red Blood Cells in Fluid Flows

Transport of cells in fluid flow plays a critical role in many physiological processes of the human body. Recent developments of in vitro techniques have enabled the understanding of cellular dynamics in laboratory conditions. However, it is challenging to obtain precise characteristics of cellular dynamics using experimental method alone, especially under in vivo conditions. This challenge motivates new developments of computational methods to provide complementary data that experimental techniques are not able to provide. Since there exists a large disparity in spatial and temporal scales in this problem, which requires a large number of cells to be simulated, it is highly desirable to develop an efficient numerical method for the interaction of cells and fluid flows. In this work, a new Fluid-Structure Interaction formulation is proposed based on the use of hybrid continuum-particle approach, which can resolve local dynamics of cells while providing large-scale flow patterns in the vascular vessel. Here, the Dissipative Particle Dynamics (DPD) model for the cellular membrane is used in conjunction with the Immersed Boundary Method (IBM) for the fluid plasma. Our results show that the new formulation is highly efficient in computing the deformation of cells within fluid flow while satisfying the incompressibility constraints of the fluid. We demonstrate that it is possible to couple the DPD with the IBM to simulate the complex dynamics of Red Blood Cells (RBC) such as parachuting. Our key observation is that the proposed coupling enables the simulation of RBC dynamics in realistic arterioles while ensuring the incompressibility constraint for fluid plasma. Therefore, the proposed method allows an accurate estimation of fluid shear stresses on the surface of simulated RBC. Our results suggest that this hybrid methodology can be extended for a variety of cells in physiological conditions.