High-Throughout Synthesis of Liquid Salts for Enhanced Transdermal Drug Delivery
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Perez Cuevas, Monica B.
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Abstract
Ionic liquids (ILs) have been shown to have interesting solvent properties and could potentially replace the need for solvents in drug formulations by incorporating the active pharmaceutical ingredient (API) as a counter ion. Currently, the development of novel ILs is limited by significant trial and error in the screening of suitable counterions. In this thesis, we developed an automated high-throughput method for the discovery of API-ILs by adapting a conventional multichannel pipetting station . We subsequently screened for and characterized a variety of NSAID-based ionic liquids in terms of their thermal stability, thermal transitions, aqueous solubility and permeative ability on ex-vivo porcine skin. In the 2nd part of our work, we screen over 1000 ion pair combinations that incorporate pharmaceutically relevant species and evaluate counterion influence over their synthetic outcome. Using this dataset, we found that higher incidence of liquid formation could be observed when cations had Bertz complexity indices >176 and either a rotatable bond count >4 or Aromatic Heavy Atom count > 5 (or both). In the last part of this work, we incorporate a machine learning model to capture insights relevant to API-IL design. Among the molecular descriptors evaluated, cationic NHOH counts and anionic rotatable bond counts as the top 2 features in the model. This work aims to generate insights into API-IL synthesis that facilitate the selection of ion pairs for formulators interested in this novel dosage form. We hope this will enable a more rational approach to the synthesis and design of API-ILs.
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2021-08-03
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Dissertation