Laminar Dispersive and Distributive Mixing with Dissolution and Applications to Hot-melt Extrusion

Hot Melt Extrusion (HME), a novel and potentially disruptive process for manufacturing oral dosage pharmaceutical products, has been explored and studied in recent times, by both industrial and academic investigators, because of its potential of rendering poorly water-soluble active pharmaceutical ingredients (APIs) readily bioavailable to patients through oral dosages. This article presents a brief review of HME from the "elementary steps of polymer processing" perspective: handling of particulate solids, melting, mixing, devolatilization and stripping, pressurization, pumping, as well as dissolution of the API in molten polymeric excipient processed stream. In contrast to traditional polymer processing, the dissolution of the API in the molten excipient during HME is the most important, key, elementary step. The main focus of this article is to discuss the physico-chemical and transport phenomena involved in dissolution and the material, equipment design, and HME process variables which affect it. The main task of the dissolution is to completely dissolve APIs in polymeric melt within the shortest possible residence time, without raising the processed stream melt temperature, and eliminating the possibility of degradation of heat sensitive APIs. We concluded from our work that the dissolution process is a laminar forced convective diffusion process. We will also present results on how to promote the dissolution rate through three categories of variables: process variables (screw speed, feeding rate, barrel temperature,), equipment variables (screw elements and configurations) and material variables (viscosity ratio, solubility parameters and particle sizes of API and excipient particulates). A novel viscometric method for the determination of the solubility of APIs in polymeric melts will also be discussed.