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Expanding the design space for the development of lipid-based formulations
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Date
2025-12-19
Authors
Ryan, Callum D.
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Publisher
University College Cork
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Abstract
With an ever-increasing number of lead candidates emerging from drug discovery that display poor biopharmaceutical profiles there is a necessity for the development of bio-enabling formulations such as lipid-based formulations (LBF). However, the formulation design of LBFs is challenging as there are multiple solubilities to consider such as drug solubility in the lipid vehicle, drug solubility in the aqueous colloidal phase following dispersion and digestion of the LBF in gastrointestinal fluids. Strategies such as computational pharmaceutics and lipophilic salt synthesis are growing areas of research that can both support structured guidance in formulation strategy to determine drug suitability for formulation as an LBF, as well as enhancing drug solubility in lipid excipients to allow greater dose loading. Accordingly, the aim of this thesis was to examine the application of integrating several computational predictions relating to drug candidate suitability for LBF development via prediction of both quality target product profile characteristics and formulation performance indicators for LBF culminating in a industrially applicable developability framework. This thesis also sought to expand the current knowledge surrounding lipophilic salts through exploration of alternative counterions for synthesis, the biorelevance of in vitro protocols and stability upon longterm storage. The suitability of alkyl sulfates and sulfonates for use as counterions to form lipophilic salts of
The suitability of alkyl sulfates and sulfonates for use as counterions to form lipophilic salts of venetoclax was investigated. Long-term stability studies of LBFs containing lipophilic salts were conducted while methods to stabilise the formulation were also explored. The effect of an in vitro gastric dispersion step was also assessed for LBF containing lipophilic salts. A number of computational predictive tools relating to LBF development were integrated to form a developability framework, which was then applied to all drugs licenced by the FDA from 2010-2023 to determine if there were any ‘missed opportunities’. Further the framework was applied in the development of macozinone, a drug that displays challenges regarding formulation.
This thesis has introduced several approaches that have expanded the design space which can be used in the development of LBFs. The development of an innovative integrated computational approach to better inform drug candidate suitability for LBF development has been proposed with a number of different drug candidates used as examples. The proposed framework can allow for a rapid assessment of drugs for use as LBF’s and support decision making in early-stage preclinical development for poorly soluble drugs where targeted LBF specific in vitro studies can be recommended to experimentally validate predictions made for drug products within drug development pipelines based on readily available physicochemical properties. This thesis has also expanded on the current knowledge relating to the utility of lipophilic salts. The versatility of alkyl sulfates and sulfonates as alternative counterions to docusate has been shown, where comparable dose loadings and in vitro performances were observed for venetoclax lipophilic salts. While the longterm stability of lipophilic salts has been demonstrated with methods of formulation stabilisation demonstrated via the addition of excess counterions. Excess counterions did not negatively impact the in vitro performance of the drug. Current in vitro methods for assessment of lipophilic salts have also been expanded where the importance of the incorporation of a gastric dispersion step has been shown to improve the robustness of current methods. The absence of a gastric phase in vitro can lead to differing final aqueous concentrations of lipophilic salts due to a lack of and or presence of ionization of free drug species. Overall, the outputs of this thesis have demonstrated the significance of both computationally informed and experimentally confirmed aspects of drug developability being used in tandem to expand the design space of LBFs.
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Keywords
Lipid-based formulation
Citation
Ryan, C. D. 2025. Expanding the design space for the development of lipid-based formulations. PhD Thesis, University College Cork.