Purpose: Increasing numbers of poorly water-soluble drugs emerging from discovery pipelines have led to formulation delivery challenges. Poorly water-soluble drugs that exhibit limited in vivo bioavailability generate a need for bio-enabling formulation approaches, such as lipid-based formulations (LBF), to ensure maximal in vivo exposure. While traditionally, highly lipophilic drugs (i.e. ‘grease ball’ drugs) were considered to be suitable candidates for a LBF approach, to date few studies have attempted to explore the biopharmaceutical benefits of LBFs for ‘brick dust’ drug candidates due to excessive hydrophobicity which tends to lead to insufficient solubility in lipid excipients and dose loading limitations in LBF solutions. Therefore, the increasing pool of hydrophobic and lipophilic drug candidates emerging from discovery are traditionally not considered for a LBF approach. This creates a need for advanced LBF types to address the dose loading limitations and potentially unleash the additional lipid mediated effects for enhancing oral absorption such as increased post-digestive intestinal solubilisation, increased permeability and promotion of lymphatic transport. While there are a range of advanced LBFs available, studies to date have mostly been demonstrated with model drugs that no longer truly reflect the emerging drug discovery space and hence the applicability of these alternative LBF approaches to the current ‘brick dust’ pipeline drugs is unknown. The aim of this thesis was to explore the utility of advanced LBFs to overcome solubility limited oral absorption of poorly water-soluble ‘brick dust’ drugs, as well as the establishment of an industrial developability guide for LBF development for hydrophobic, lipophilic and high molecular weight drugs. Methods: The suitability of LBF suspensions, supersaturated LBF solutions (sLBF), LBF solutions using lipophilic salts and the chase dosing approach for current pipeline drugs was evaluated using the model ‘brick dust’ drugs nilotinib and venetoclax. In addition, the incorporation of precipitation inhibitors (PIs) into sLBFs was investigated. The formulations were assessed in vitro using the standard pH stat lipolysis setup as well as quick screening tools such as simulated post-digestive media or a solvent shift based supersaturation/precipitation assay. All tested formulations were subsequently evaluated in vivo either in rats or landrace pigs. Subsequently, based on the findings in these studies and current literature a LBF development guide was proposed. Results: This thesis has firstly demonstrated that while surfactant suspensions increased the bioavailability, poorly dispersible oil-only suspensions should be avoided, as it may lead to particle entrapment in the lipid vehicle. It was further shown that the concomitant administration (chase dosing) of the ‘brick dust’ drug, nilotinib, with LBF excipients increased the bioavailability in rats and was able to overcome the limitations of the poorly dispersible oily suspension approach. Thirdly it was demonstrated that highly digestible surfactants resulted in a higher bioavailability of nilotinib relative to low or non-digested surfactants using surfactant-only suspensions. Furthermore, it was shown that a thermally induced supersaturation approach achieved a higher drug loading in oily lipid excipients, which facilitated the use of sLBFs in pre-clinical in vivo studies. Subsequently, it was demonstrated that sLBFs increased the bioavailability of venetoclax in vivo. In addition, it was demonstrated that the use of PIs in such supersaturated lipid systems did not increase the bioavailability but rather showed a decreased bioavailability. Moreover, the thesis showed that a thermodynamically stable LBF solution, which was obtained via synthesis of lipophilic salts of venetoclax, increased the bioavailability significantly relative to the commercialised solid dispersion. The combined lipophilic salt-LBF solution achieved a bioavailability similar to the commercial solid dispersion in the fed state. Ultimately, the thesis also demonstrated that standard in vitro testing was useful in identifying LBF potential and in explaining observed formulation performance in vivo. However, the employed in vitro tools were not in all cases predictive of the in vivo situation, generating the need for more, fast and high throughput tools for these advanced LBF formulation approaches. Conclusion: This thesis demonstrated the utility of LBFs for drugs displaying both poor water and lipid solubility and therefore exhibit dose loading limitations in conventional lipid vehicles. A bioavailability increase was achieved with all LBF approaches, showing that dose limitations in a lipid vehicle due to excessive hydrophobicity do not preclude a LBF approach. However, it was also demonstrated that care should be taken in terms of the excipient choice and existing biopharmaceutical knowledge should be integrated to achieve the most effective LBF. A Lipid Formulation Developability Guide (LFDG) was proposed to provide industrial guidance on the development of LBFs for such drug candidates. Overall, the impact of this thesis is that the range of application for LBFs can be extended to include difficult to formulate ‘brick dust’ molecule throughout the development process.