The design and manufacture of immediate-release optimal solid dosage forms

Abstract

Pharmaceutical manufacturing has traditionally been considered largely a matter of regulatory compliance. Consequently, it has been inefficient, but it is now increasingly being recognized as an opportunity for cost reduction. Recent initiatives by regulatory authorities, and by the industry, aim at easing regulations and encouraging process innovation. Even though significant improvements, especially in process control and minimization of process interruptions, have been achieved, the underlying process technology has not changed for decades. For example, typical process steps to produce the most common pharmaceutical products, immediate-release solid dosage forms, from drug substance and excipient are: blending, wet granulating, drying, milling and screening, blending, tableting, coating, and so on. A new process, such as blending combined with solvent-less, multi-component injection-molding could greatly simplify manufacturing. Injection-molding, however, yields a non-porous material, intrinsically different from the state-of-the-art powder-compacted, porous dosage forms. This may appear problematic, because current products rely on a large surface area-to-volume ratio to achieve immediate drug release. In addition, process rates previously achieved by injection-molding solid dosage forms have been comparably low -- offsetting some of the benefits offered by that process. In this thesis, an analytical approach is first developed to model drug release from non-porous dosage forms, comprising a fast eroding excipient and randomly distributed drug particles in it. The model considers the central role of microstructure in drug release. Particular importance is given to the role of clusters of connected, slowly eroding drug particles, and to the effect of drug particle protrusion, due to their slow erosion rate, from the eroding excipient surface. The model is validated by dissolution experiments. Good agreement is observed between the model and the experimental data. The drug release model is then used in product design for manufacturing as an optimization problem -- with manufacturing performance as objective function and design specifications as constraints. It is found that the drug volume fraction needs to be about 0.5 to efficiently produce non-porous dosage forms in specification, which implies that an excessive amount of excipient material is required. Therefore, new product designs are proposed: a cellular excipient micro-structure with up to ten-fold reduction in excipient content. The new designs are further shown to allow injection-molding of immediate-release dosage forms that meet specifications with a three-fold increase in injection-molding process rate compared with conventional designs.