Abstract by Anne Linnet Skelbæk-Pedersen
Tablets are by far the most commonly used administration form for delivery of active pharmaceutical ingredients (APIs). Pharmaceutical materials are known to deform upon applied pressure, and deformation is a key material characteristic to obtain a successful tablet product. Pharmaceutical materials are typically defined by their predominant deformation behaviour, which can be divided into elastic and plastic deformation and fragmentation. Several methods have previously been proposed for assessing deformation behaviour, however, all of these lack the ability to quantify fragmentation on a particle level upon tableting.
The overall aim of this thesis was to determine the influence of fragmentation on tablet properties and performance. This was done by firstly introducing new methods to quantify particle fragmentation upon tableting both destructively and non-destructively. Particle size distributions (PSDs) before and after tableting were obtained and a new parameter, termed the particle size from inflection point (PSIP) was introduced deriving a single data point from each PSD. The PSIP as a function of compression pressure characterized the fragmentation profiles, which described fragmentation well based on the PSDs. The fragmentation profiles followed an exponential decay function, from where the fragmentation degrees were derived, which allowed for quantification of fragmentation.
The PSIP approach described the fragmentation behaviour of four model tableting excipients well and it was found that larger particles fractured more extensively than smaller particles. Brittle materials furthermore fractured to the same particle size regardless of the initial particles size, whereas larger initial particles of ductile materials remained larger upon tableting compared to smaller initial particles.
Near-infrared (NIR) and terahertz time-domain spectroscopy (THz-TDS) were useful for non-destructive evaluation of fragmentation upon tableting based on scattering analysis. However, THz-TDS was superior as it enabled differentiation between different initial particle sizes as well as allowed for quantification of fragmentation. The absorbance spectra from the THz-TDS measurements were well described by a power law and a parameter from the power law was fitted as a function of compression pressure, which followed an exponential decay function. The fragmentation degrees were again derived and compared to those obtained from the PSD measurements, which verified that fragmentation could be quantified non-destructively based on scattering analysis of THz-TDS measurements.
Fragmentation had a direct impact on tablet properties and performance, hereunder tablet formation, water ingress into tablets, and dissolution rate. No increase in the tablet mechanical strength was observed before almost all fragmentation had occurred, which was explained by fragmentation resulting in further particle rearrangement, which limited formation of inter-particle bonds. Extensive fragmentation of a brittle material was furthermore identified to result in the same water ingress time for tablets of two different initial size fractions. Oppositely, tablets containing larger initial particles of a plastically deforming material resulted in longer water ingress time compared to tablets of smaller initial particles. This was explained by limited particle fragmentation of the plastically deforming material upon tableting, and thereby differences in the microstructure of the tablets containing different initial particle sizes. Finally, compression-induced fragmentation increased dissolution rate of compressed particles of a brittle API. The deformation behaviour of materials can thus be concluded to have paramount importance for tablet performance.