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Complex injectable formulations, such as protein therapeutics, controlled release systems and cell therapy products, are gaining a paramount position in the therapy of many life-threatening and chronic diseases. Most of these products have in common that sub-visible particles (SVP), i.e., particulate matter in the size range of about 1 – 100 µm, are critical quality attributes. Most protein therapeutics are liquid or freeze-dried formulations in which the presence of SVP is unwanted; many injectable controlled release systems are based on particulate drug delivery systems in the sub-visible size range; and cell concentration and viability are important characteristics of cell therapy products. With the continuous improvement of existing and emerging particle analysis techniques, the potentials of these tools in addressing current characterization challenges in the field of complex injectable formulations have to be investigated. Therefore, the aim of this thesis was to develop methods, based on a set of state-of-the-art particle analysis techniques, for characterization of pharmaceutically relevant sub-visible particles and to study the value of these methods in the characterization of complex injectable formulations.

Carbon dioxide was used as a drying medium for the preparation of micro-size powders from aqueous solutions in a high-pressure spray-drying process. This technology was shown to be an alternative to traditional drying processes that could be successfully used for the dry formulation of therapeutic proteins, the preparation of stable amorphous products, the selective production of polymorphs and pseudomorphs, and the design of particles.

There are many diseases of the central nervous system (CNS), like Parkinson's disease, Alzheimer's disease, depression, schizophrenia, epilepsy, migraine headache, and HIV infection in the brain. However, treatment is difficult since many drugs cannot reach the brain in sufficient quantities due to the existence of the blood-brain barrier (BBB). This barrier is situated at the interface of blood and brain and its primary function is to maintain the homeostasis of the brain. The research described in this thesis was initiated to meet the challenge of drug delivery across the BBB. The focus was to explore the possibilities for drug delivery to the brain via the transferrin receptor (TfR). Although drug delivery to the brain via the TfR is not selective, it is effective. A mechanistic approach was chosen in which the binding and association of Tf, Tf-drug conjugates and Tf-tagged liposomes by BCEC in vitro was determined. The efficiency of delivery depends mainly on the size of the cargo: a 40 kDa protein does not affect the association of Tf by the TfR, while a liposomal drug carrier (100 nm in diameter) affects both the association and the intracellular routing.