Abstract
Improving dissolution of poorly-water soluble drugs: from
dosage form design to manufacture
Wedad Kamal Ali MSc Pharmacy
Solid dispersions have been employed as a method to improve the dissolution rate and hence
the bioavailability of Class II poorly-water soluble drugs. The objective of the thesis was to
investigate, the mechanisms of dissolution enhancement of poorly-water soluble drugs by solid
dispersion in hydrophilic carriers that have surface activity. Ibuprofen was used as a primary
model drug; the study was then expanded to test these systems with other poorly-water soluble
drugs chosen for a range of functional groups and physicochemical properties. Possible
intermolecular interactions between drugs and poloxamer were investigated. Differential
scanning calorimetry, Fourier transform infrared spectroscopy, and X-ray diffractometry
confirmed intermolecular interaction at 2:1 ratio; this correlated with the greatest dissolution
enhancement. Scanning electron microscopy showed changes in the size and habit of ibuprofen
crystals in solid dispersions at various mole ratios (drug: poloxamer 407). Raman microscopy and
mapping was used to investigate the distribution of drug in solid dispersions of various drug
loads showing largely homogenous dispersions at 2:1 ratios and heterogeneous systems above
2:1 ratio. Several manufacturing and formulation modifications were applied to improve the
dissolution and the mechanical properties of solid dispersions. These were based on the
formation of nanoporous structure prior or during the dissolution process. Amongst these
modified solid dispersions, those prepared by incorporation of fast dissolving sugars showed a
remarkable enhancement in the dissolution rate of ibuprofen. Both modified and unmodified
solid dispersions were processed into tablets and release of drug from tableted solid dispersion
was investigated. Poloxamer polymeric micelles were investigated over a range of
concentrations. The size and size distribution of poloxamer micelles were greatly affected by
temperature, concentration and drug load. Dissolution testing revealed that the release of drug
from poloxamer micelle was not significantly different to that from solid dispersion of similar
drug load suggesting micelle formation from both formulations during dissolution.