Please login first
1  Chemical and Biomolecular Engineering National University of Singapore


The design, formulation and manufacturing of engineered composites containing solid active pharmaceutical ingredient (API) and polymeric excipient(s), with precisely tailored composition and structure, have been of tremendous academic and industrial interest in recent years for two primary reasons. Firstly, from the perspective of pharmaceutical materials science and product design, engineered solid composites allow new and exciting possibilities in the creation of drug products with tailored dosage and release profiles. [1] Secondly, and equally importantly, such granular materials can have enhanced processability in terms of flow properties, and enable paradigm-shifting intensification (and simplification) of the traditional pharmaceutical manufacturing workflow, while also facilitating agile and decentralized supply chain models that can rapidly respond to evolving market forces. In particular, the latter is made possible by the use of engineered composites as intermediate drug products, which can be converted to the final dose form on-demand with minimal further processing, in customized and decentralized fashion.


This paper focuses on a recently developed technique, which combines microfluidic generation of droplets carrying dissolved API (with or without dissolved excipient material), and evaporative crystallization/solidification in thin films, to produce monodisperse spherical microparticles of crystalline API co-formulated with solid excipient in ‘bottom up’ fashion.[2-4] The formulation of both hydrophilic and hydrophobic drug molecules has been demonstrated using this technique. Interestingly, it has also been shown that the simultaneous solidification of hydrophobic drugs, such as 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY) or carbamazepine (CBZ), with a polymeric excipient, such as ethyl cellulose (EC), not only enables shorter crystallisation times, but also allows a remarkable degree of process-based selectivity over the polymorphic form of the crystalline drug. This method has the potential to be widely adopted as a simple method for single-step crystallisation and direct compaction of drugs and excipients, which circumvents several energy intensive downstream steps in the pharmaceutical manufacturing workflow, while also allowing the creation of ‘designer’ drug products with a hitherto unprecedented level of control over solid particle attributes. In this paper, we focus on a phenomenological study of the dynamics of simultaneous API/excipient solidification and structure formation within evaporating microfluidic emulsion droplets, in an attempt to delineate the basic and general elements of these processes [5]. In a model system comprising 5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (‘ROY’) as the drug and ethyl cellulose (‘EC’) as the excipient, we are able to demonstrate a diversity of particle structures, with exquisite control over the structural outcome at the single-particle level. Specifically, we demonstrate a coarse ‘macro’ particle structure and a finer ‘micro’ structure with our chosen model system. Further, we elucidate the key mechanistic elements responsible for the observed structural diversity using a combination of systematic experiments, thermodynamic arguments, and dissipative particle dynamics (DPD) simulations. We validate our method by applying it to fabricate microparticles containing ROY and a different matrix material, poly(lactic-co-glycolic acid) (‘PLGA’), and those comprising EC and a different drug, carbamazepine (‘CBZ’). Finally, we present preliminary investigations of in vitro drug release from two different types of CBZ-EC particles, highlighting how structural control allows the design of drug release profiles.