(30b) Solvate Devolatilization Via Hot Melt Extrusion

Hot melt extrusion (HME) has grown in importance in the pharmaceutical industry as a means to enhance bioavailability of active pharmaceutical ingredients (APIs) with poor aqueous solubility. The many additional advantages of HME operations have yet to be fully explored in pharmaceutical applications. Work presented here seeks to leverage HME's broad industrial use to remove solvent from process melts, and apply this to pharmaceutical operations.

Solvates of active pharmaceutical ingredients (APIs) with organic solvents are often encountered during research and process development. Despite the fact that solvates often reject impurities more efficiently, have crystallizations that tend to be robust, and yield API with higher bulk densities and enhanced flow properties, solvates are generally avoided in final API deliveries for drug formulation due to ICH Q3C residual solvent specifications.

An investigation was done to see whether HME could be used to devolatilize solvates of crystalline APIs. Three solvates, with a range of solvent concentrations and boiling points were evaluated. These were each blended with a representative polymer excipient in concentrations typically found in final drug products and then each blend was run through a 16mm lab extruder under a variety of processing conditions (blend feed rate, screw speed, vacuum level, etc). The extruded material was then analyzed for residual solvent content and the results compared to the ICH Q3C residual solvent specifications. These results showed that HME can easily remove low boiling solvents to levels well below the ICH Q3C guidelines. Requiring somewhat more careful adjustment to operating conditions, higher boiling solvents necessitated more energy input and residence time within the extruder to meet the desired residual solvent specifications.

Beyond the ability to deliver API with more desirable physical properties, as outlined above, the process of devolatilization during extrusion processing offers significant operational advantages. Isolating a solvate or slightly solvent wet API and utilizing HME's inherent devolatilization capabilities yields a global optimum between drug product and drug substance processes. This approach significantly reduces cycle times and capital expenditures associated with drug substance operations without adding cost to drug substance operations.