Melt extrusion and continuous manufacturing of pharmaceutical materials

Abstract

Melt extrusion is an alternative processing technique that operates continuously, reduces the total number of unit operations, allows for incorporation of difficult-to-process drug substances, and has the potential to achieve tablets of better quality and consistency compared to traditional methods. Thus, our goal was to evaluate melt extrusion as a viable processing alternative and expand our scientific knowledge such that we gain predictive capabilities of tablet characteristics, i.e., quality by design. This new knowledge will aid future process design thereby helping to reduce time and costs associated with pharmaceutical solid dosage form production. The residence time distribution for melt extrusion has been characterized using a single parameter model. When combined with assumed first-order reaction rate kinetics and an Arrhenius reaction rate constant, the model can accurately predict the amount of drug product lost to temperature driven degradation. The model prediction agreed well with experimentally determined fractional conversion. The physical stability of amorphous Molecule A was characterized using enthalpy of relaxation measurements. Molecular level rearrangements are the source of physical instability for the fragile glass forming Molecule A. The instability can be modified by introducing a second component, which contributes to the overall enthalpy change. Coating amorphous Molecule A tablets with a polyvinyl alcohol based coating material reduces moisture uptake during storage. The coating material preferentially uptakes water from the atmosphere, restricting moisture from entering the tablet core and causing premature dissolution or degradation. The dissolution behavior of Molecule A tablets can be tailored with the addition of water soluble materials. Dissolution rate constants for Molecule A tablets have been calculated for different formulations and can be used as a resource when designing new solid dosage forms with desired dissolution characteristics. A novel 100% Molecule A melt extrusion process has been created, reducing the number of overall unit operations and eliminating troublesome blending inconsistencies. An additional formulation that maintains the crystallinity of Molecule A by processing with polyethylene glycol below Molecule A's melting temperature is physically and chemically stable and ready for implementation in a continuous production line. The mixing achieved within the extruder for this formulation is sufficient to eliminate a pre-mixing unit operation.