Crystallisation and formulation of suspensions as long-acting injectables

The objective of the project is to produce a long-acting injectable (LAI) based on an aqueous suspension of crystalline particles of an active pharmaceutical ingredient (API). To achieve this objective, different techniques were studied to produce particles of the desired properties (e.g. particle size, solid-state, morphology) as well as the right excipient combinations to constitute a stable and successful formulation.

The first chapter provides an overview of key concepts such as solid-state, crystallisation, polymorphism, morphology, solubility, and particle size that are key to understanding the project focused on crystalline LAIs. It also contains a general classification and overview of the techniques used to produce particles, that in later chapters will be explored in detail. Finally, it contains a description of the properties of the APIs and the main excipients used throughout the project.

Chapter 2 focuses on the gas antisolvent (GAS) method to produce API particles of the desired solid-state form using additives. The challenge of controlling the stochastic crystallisation behaviour observed in small-scale experiments was successfully addressed. Moreover, one of the first steps in the production of a LAI formulation was achieved: the control of the polymorphic form of the selected API. The indomethacin metastable form (α polymorph) was systematically produced when poloxamer 407 was used as an additive in the GAS process. The selectivity of the polymorphic form was explored in depth with molecular modelling.

Chapter 3 focuses on the supercritical CO2-assisted spray drying (SASD) method to produce indomethacin and naproxen particles in a sorbitol matrix for their reconstitution in aqueous excipient solutions. This chapter went one step further and achieved a particle suspension of the desired particle size (~1-10 µm) and solid-state (stable form) of naproxen. The approach was not successful for indomethacin. The API-excipient interactions were studied by thermal analysis and modelling.

The previous Chapters 2 and 3 explored bottom-up technologies (GAS and SASD) whilst Chapter 4 studied top-down technologies to overcome limitations faced by the former methods, achieve the same objectives, and ultimately generate stable crystalline particle suspension.

In Chapter 4, particle suspensions of the desired particle size (~1-10 µm) and solid-state (stable form) of indomethacin and naproxen were successfully produced using jet milling (JM) and microfluidisation (MZ). The key parameters to mill particles to the target particle size, and a protocol to produce crystalline particle suspensions from dry powder were established in this work. The suspensions were compared and studied in a stability study that revealed differences between the techniques.

Chapter 5 compared the bottom-up methods (Chapters 2 and 3) and the well-validated top?down methods explored in the pharmaceutical industry (Chapter 4) to produce LAIs. The differences in the use of excipients and solvents, as well as the particle size, morphology and solid-state form of the final product, were compared across technologies. A scale-up scenario was assessed for each technique and a case study was evaluated following the learnings and conclusions reached in this project.

Chapter 6 includes the concluding remarks of the thesis and the future directions of where the research conducted herein is heading.