Evaluating Critical Quality Attributes of Modified Release Systems using Advanced Imaging Techniques

Abstract

Combination of physical and chemical stability during storage, excellent content uniformity, simplicity of administration and economical manufacturing make solid dosage forms the pharmaceutical drug delivery systems of choice for oral drug delivery. However, since not all active pharmaceutical ingredients (APIs) possess the necessary physico-chemical properties to be converted e.g. into simple tablets, modification often required. With the development of more complex modified drug delivery systems and since product performance is often a function of production parameters, the demand for more advanced quality control techniques has increased.

In this thesis, the advanced imaging techniques Raman imaging and terahertz pulsed imaging (TPI) were investigated to characterise critical quality parameters of modified drug release systems (matrices, coated tablets and pellets). Raman imaging is highly chemically selective and offers an excellent spatial resolution in axial and lateral. Thus, it was employed to analyse two lipid based matrix formulations in terms of component distribution and structural changes during dissolution testing. The distribution of drug, soluble and insoluble matrix components were mapped during dissolution testing revealing a non-uniform receding drug boundary. It was demonstrated that the lipid structure remained intact, whereas the water-soluble polymer rapidly dissolved and diffused from the matrix leaving a more extensive network of channels through which the dissolution medium could penetrate and the drug could diffuse.

TPI has the advantage of providing physico-chemical information from below the sample surface owing the unique feature of terahertz radiation (2 – 120 cm-1) to propagate through most pharmaceutical solids. Therefore, TPI was used to non destructively analyse critical coating quality attributes of delayed-release coated tablets coated in two different coater types. Whilst weight gain measurements failed to detect differences, TPI determined a lower mean coating thickness (CT) for tablets coated in a drum coater (DC) compared to fluid bed coater (FB) (p < 0.05). A more pronounced CT variation between the sides and centre band (22.5% compared to 12.5%), and a denser coating structure was observed for DC tablets compared to FB tablets, which was confirmed by drug release testing. Moreover, an intracoating interface, generated by a coating polymer spray application interruption, was readily determined by analysing the terahertz waveform for tablets coated by the DC and FB coater, respectively, while scanning electron microscopy (SEM) failed to verify the interface in DC tablets.

In addition, CT and drug layer uniformity of sustained-release coated pellets were evaluated by TPI. Difference in the CT between standard size pellets coated for different times (giving three groups with different CTs according to the weight-gain) but no difference in drug layer thickness (DLT) was determined. Further, no statistically significant differences in the average CT and DLT within batches (between pellets) but high thickness variability across individual standard size pellets was observed.

Overall, Raman mapping proved highly suitable for directly analysing multiple matrix components during drug release, offering deeper understanding of factors affecting drug release during the development of sustained-release matrices. Furthermore, TPI demonstrated potential as a non-destructive analytical technique to assess critical coating quality attributes related to coating process parameters of coated tablets and standard size pellets.