Drugs and polymers in dissolving solid dispersions : NMR imaging and spectroscopy

Abstract: The number of poorly water-soluble drug substances in the pharmaceutical pipeline is increasing, and thereby also the need to design effective drug delivery systems providing high bioavailability. One favourable formulation approach is preparation of solid dispersions, where dispersing a poorly water-soluble drug in a water-soluble polymer matrix improves the dissolution behaviour and the bioavailability of the drug. However, in order to take full advantage of such formulations the impact of material properties on their performance needs to be investigated.   An experimental toolbox has been designed, and applied, for analysing the processes which govern the behaviour of solid pharmaceutical formulations in general, and that of solid dispersions in particular. For the purpose of monitoring multifaceted phenomena in situ during tablet dissolution, nuclear magnetic resonance (NMR) spectroscopy and NMR imaging are superior to many other techniques, both on macroscopic and molecular levels. The versatility of NMR with its isotope and chemical selectivity allows one to follow the influence of the original tablet properties on polymer mobilisation, drug migration and water penetration selectively. Mapping these processes on relevant time scales in dissolving tablets highlighted the gel layer inhomogeneity below the originally dry tablet surface as a key factor for drug release kinetics.   Furthermore, NMR relaxometry has been shown to provide novel information about the particle size of the drug and its recrystallisation behaviour within swelling solid dispersions. The NMR experiments have been complemented and supported by investigation of the crystalline state, the powder morphology and the surface composition of the dry solid dispersions. These experiments have been performed by X-ray photoelectron spectroscopy (XPS),  scanning electron microscopy (SEM), powder X-ray diffraction (pXRD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and dynamic contact angle (DAT) measurements.   The methods presented in this thesis provide a new avenue towards better understanding of the behaviour of solid dispersions, which in turn may result in more effective distribution of promising drug candidates despite their low water-solubility.