Beta Blockers: their self-assembly and interaction with model membranes

  • Yixuan Yan

Student thesis: Phd


Many drug molecules contain hydrophobic and hydrophilic moieties in their structure, and are therefore amphiphilic. They can self-associate to form small, micelle-like aggregates when their concentrations in aqueous solution exceed their respective critical micelle concentrations. As a result, an amphiphilic drug may exhibit different therapeutic effects, depending upon whether the drug is in the aggregated form or not. In addition, the interaction of an amphiphilic drug with lipid membrane plays an important role in its therapeutic behaviour, due to the different interactions with phospholipids. The current work focuses on the amphiphilic drug, propranolol hydrochloride, its self-assembly in aqueous solutions and its interaction with model biomembranes, composed of 16:0-18:1 phosphocholine, in the absence and presence of 16:0-18:1 phosphoglycerol and cholesterol, respectively. Single/multi-contrast small angle neutron scattering (SANS), 1H NMR spectroscopy (NMR) and UV/vis absorption spectroscopy, with complementary all atom molecular dynamics (MD) simulations have been used to resolve the self-association of propranolol hydrochloride. While Langmuir trough measurements in combination with optical reflection techniques, namely ellipsometry, Brewster angle microscopy (BAM) and neutron reflectometry have been applied to shed light on the drug-membrane interaction. The results from SANS, NMR and MD simulations suggest that the self-assembly of (racemic) propranolol hydrochloride is concentration-dependent, with premicellar aggregation being observed at concentrations well below the CMC. The S-(-) enantiomer, studied using SANS, was found to form slightly larger aggregates than the racemic mixture. Within the temperature range studied using single-contrast SANS (293 - 415 K), an increase of temperature was observed to oppose to self-association of the drug. The aggregates of propranolol hydrochloride were found to contain a dry core of aromatic rings and a solvated shell comprising of side chains with the CH-pi interaction between the naphthalene rings playing an important role in the self-association of the drug in water. In contrast, the addition of electrolyte promotes the self-association of the propranolol hydrochloride and alters the nature of the interaction occurring between the aromatic rings from CH-pi to pi-pi interaction. A biomembrane interaction study demonstrated that the interaction of propranolol hydrochloride with model biomembranes is a complex process, causing immediate lipid loss and lipid phase separation, with the results indicating that, at equilibrium, more drug molecules than lipids molecules are present at the interface. The precise number and conformation of molecules at the interface was found to largely depend on the physical state of the membrane, i.e. starting surface pressure and lipid composition, as well as the drug concentration in the subphase. Ellipsometry and BAM experiments showed that the addition of POPG (30 mol%) or cholesterol (30 mol% or 46 mol%) to POPC membranes, affected the drug penetration at the interface by altering the heterogeneity of the membrane. Low Q neutron reflection measurements were important in revealing an immediate loss of lipid from the interface upon exposure to drug. The presence of a physiological concentration of sodium chloride strengthened the interaction between the drug and the membrane, with propranolol hydrochloride penetrating the lipid chain layer over time. Taken together, these findings unravel the molecular processes propranolol hydrochloride undergoes when delivered in vivo, and the insights will help improve the delivery of the drug for its clinical use.
Date of Award31 Dec 2022
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorRichard Campbell (Supervisor) & Jayne Lawrence (Supervisor)


  • multi-contrast neutron scattering/reflectometry techniques
  • air-water interface
  • core-shell structure
  • drug-membrane interaction
  • propranolol hydrochloride
  • self-association
  • amphiphile

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