Co-processing pharmaceutical ingredients to engineer novel multifunctional excipients

The simplicity and cost-effectiveness of direct compression makes it a preferred method of commercial tablet manufacturing. Excipients play a central role in determining the success of direct compression. Currently available directly compressible excipients are typically effective at relatively high proportion of >50% (w/w). For high-dose APIs, incorporation of such high excipient load is inappropriate, as this may necessitate the formation of large tablets, which may be difficult to ingest. Thus, high-dose APIs (especially for poorly flowable and difficult to compact) are often considered unsuitable for tablet manufacturing by direct compression. In interactive mixtures, small guest particles (typically <10 µm) adhere to larger host particles. We hypothesized that small binder particles could express a binder action as well as a flow additive action, if they could form a suitable interactive mixture with large APIs. However, many such small particles are highly cohesive, which limits their de-agglomeration, dispersion and consequently the ability to form a homogeneous interactive mixture. Thus, the aim of this thesis was to understand the impact of the cohesion of small binder particles on their interactive mixing behaviour and consequently extension of their potential excipient performance i.e., binder and flow additive actions. A model pharmaceutical binder, polyvinylpyrrolidone (PVP) was co-sprayed with L-leucine to engineer small low-cohesion binder particles. In these composite particles, L-leucine enriched at the surfaces and manipulated the surface physico-chemical properties (such as morphology, surface energy and its crystalline character), which allowed control over cohesion. Low cohesion small binder particles de-agglomerated efficiently and formed a more homogeneous interactive mixture with paracetamol (active pharmaceutical ingredient, API) compared with high cohesion binder particles. The homogeneous interactive mixing allowed small binder particles to express enhanced binder and flow additive actions. The flow additive action improved while inherent binder activity reduced with reducing cohesion. This decline in binder activity was attributed to the reduction in the compactability (or bonding ability) of binder particles. However, manipulation of mechanical properties (increasing plastic deformability) allowed improvement of the binder activity of such low cohesion binder particles. High performance excipients are necessary to facilitate direct compression of high-dose APIs. Our study showed that binder and flow additive action are mutually exclusive excipient properties and the knowledge of interactive mixing allowed creation of composite excipients with elements of both flow additive and binder action. Manipulation of the surface physico-chemical and mechanical properties via smart particle engineering enabled small binder particles to express an optimum flow additive and binder performances. Thus, this knowledge could enable rational engineering and development of high-performance direct compression excipients, which would enable direct compression of poorly compactable and poorly flowable high-dose APIs.