Model-based formulation of amorphous solid dispersions made by hot-melt extrusion

Abstract

Regarding hot-melt extrusion in early pharmaceutical formulation and process development, techniques and procedures are needed to simplify the application of hot-melt extrusion (HME) and to decrease the effort in terms of material and time. Such simplified techniques and procedures would encourage researchers to confirm the suitability of HME as a valid processing option for their final formulation without the drawbacks of extensive formulation evaluation in early-stage development and expensive and time-consuming process evaluation for every formulation. As a first step to identify the optimal and stable formulation for forming amorphous solid dispersions (ASDs), a reliable theoretical identification of a soluble API/polymer system would lead to a thermodynamically stable ASD with a prolonged shelf life. Secondly, a theoretical consideration of process conditions would further reduce the number of trials needed to optimize and scale-up the HME process to manufacture the required ASD. Concerning these two major challenges in early formulation development of amorphous solid dispersions by means of hot-melt extrusion, e.g. polymer selection and process optimization, the following aims in this thesis have been investigated and realized. First, a robust and fast procedure was defined to determine the API solubility in polymeric matrices by means of differential scanning calorimetry, along with the a connection of physicochemical API properties to their solubility in polymeric matrices. Secondly, the correlation between glass transition temperature (<em>T_g</em>) and melt viscosity of an amorphous solid dispersion was evaluated and validated. This technique allows the estimation of melt viscosity, thus short-cutting rheological measurements, and direct implementation in HME simulation, enabling especially the formulation screening for ASDs. Together, realization of these aims reduces the extensive formulation screening and process experimentation for HME and enables the use of HME as an approach for formulating ASDs.