Development of new approaches for understanding and optimizing antisolvent crystallization processes

  • Corin Mack

Student thesis: Doctoral Thesis


As more and more complex molecules find their way to the market, alongside the increasing demand for pharmaceuticals, the need for development and improvement of key process steps is crucial. By reducing the time and amount of drug substance used up during each phase in the crystallisation development process, pharmaceuticals can be delivered to patients faster. To achieve our aim, three contributions have been made, looking at both single and multicomponent systems for solvent selection protocols alongside the development and application of a model equation to accurately describe antisolvent phase diagrams. Initially solubility and activity coefficient models were applied to different solute-solvent systems. In doing so, both the Margules and Wilson models showed accurate modelling capability with the experimental activity coefficients. Due to the parameters of the Wilson model, interactions between the solute-solvent molecules can be quantified. This information about molecular interaction from specific functional groups, allow solvent selection protocols to be engineered towards specific solvent systems. From the investigation of single solvent systems, antisolvent systems were investigated. By using compounds like those observed in industry such as salts and highly hydrophobic compounds, coupled with a temperature variation method, a generic model equation was developed encompassing the general trend observed by antisolvent phase diagrams systems for both synergistic and non-synergistic systems. This model allowed the prediction and optimization of key process characteristics such as yield and productivity at different temperature and antisolvent fractions, so identifying specific antisolvent fractions and temperatures where processes provide the most optimal results. The final contribution integrates the previous observations and techniques, revealing how well the Wilson model can describe antisolvent phase diagrams, while providing insight into the molecular interactions that dictate synergistic antisolvent phase diagrams. Although the multicomponent Wilson model was not able to describe synergistic relationships, the binary model was able to describe the systems at individual antisolvent fractions. From the binary equation, the interaction parameters at individual antisolvent fractions showed variation in non-ideality as the antisolvent fraction increases, identifying that the interaction parameters between the solute-solvent-antisolvent required are not static and change as the component content changes. From these variations, interpretations of how antisolvent phase diagrams behave is established with regards to molecular interactions occurring with the systems. From each of these contributions, an aspect of crystallization processes was encompassed, identifying either different strategies or developing methodologies which can help reduce the need for time-consuming studies. In doing so allowing a greater pace for getting drugs to patients.
Date of Award9 Feb 2023
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsUniversity of Strathclyde
SupervisorJoop Ter Horst (Supervisor) & Jan Sefcik (Supervisor)

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