(656a) Digital Design of a Small Molecule Oral Suspension Homogenization Process

Oral suspensions form an important delivery platform for drug substances having low solubility in the aqueous phase. While offering the advantage of flexible dosage for the patient, formulating the oral suspension with uniform concentration of the drug substance remains an important challenge for formulators and process engineers. The homogenization of the drug product is achieved in various mixing vessels, which help in dispersing and dissolving formulation components using different types of mixing elements. A particular class of mixing vessels consists of a low-shear mixing tank attached to a high-shear homogenizer. This mixing vessel operates in a closed loop, wherein, the liquid suspension flows from low-shear tank into high-shear homogenizer and get pumped back to the main tank through a recirculation pipe. This is represented in the schematic diagram in Figure 1. Process development using physical experiments on such mixers remain challenging and resource and time consuming due to difficulties in sampling and lack of appropriate Process Analytical tools. Computer simulation methods offer a suitable alternative as a process development tool.

In this work, we have developed a Computational Fluid Dynamics (CFD) model of the mixing and eventual homogenization of an oral suspension drug product in a two-compartment vessel. The challenge of widely varying timescales in the two mixing compartments is overcome by using a workaround that allows for modeling the complex machinery of the high-shear homogenizer using a momentum source. This CFD model simulates flow of both solids and liquids and allows the determination of a homogenization timescale for the complex suspension. We compare the timescale obtained from modeling with that obtained from an in-line Focused Beam Reflectance Measurement (FBRM)-based probe mounted on a 30 Liter vessel. The two timescales exhibit a relatively good agreement with each other, allowing the validation of the CFD model. Once the model is validated, it is subsequently used to scale-up and optimize the process for larger commercial manufacture. Thus, the CFD model can be used as a scale-up tool, which allows for running digital DOEs and identifying operating conditions at scale. Such digital DOEs help to design and develop processes in resource-constrained situations.

Figure 1: Schematic diagram of the mixing vessel