7678 As protein aggregation is driven primarily by hydrophobic interactions with contributions from polar interactions, 13 this could indicate that the increase in polar interaction is contributing to the overall stability of the protein by tipping the scales in the direction of polar interaction, and making the hydrophobic destabilising interactions less signicant overall. This notion is further supported by the near total lack of interaction between HSA and the naturally-ocurring phospholipids under study; compounds with the largest hydrophobic tails and comparatively small head groups have little interaction. Similarly, Spans (in essence polysorbates lacking PEG) and polysorbates with more than one fatty acid ester, such as PS85 and PS25, perform worse in terms of APR SASA shielding than PSBN, a branched compound with little nonpolar content and a high proportion of PEG content. This also implies that an increase in molecular weight is not sucient to increase anti-aggregation activity, further supported by the absence of impact of molecular weight as a descriptor or as a factor within a descriptor within PLS. Together with the observation that larger molecules have a tendency to wrap around HSA, this could imply that the head group initiates the interaction before recruiting the tail in wrapping around more hydrophobic areas of the protein. It can also be seen that longer interacting compounds are making end-to-end contact with each other within a shallow channel on the protein surface (Figure ). This is reminiscent of binding behaviour observed in crystallographic binding studies with short-and medium-chain fatty acids. 84,85 However, the concentrations of lipid used in the membrane studies are typically signicantly greater than those of excipients in the present study; typically, these are millimolar as opposed to 0.1 % w/w, which results in concentrations in the range of 0.10 to 0.18 mM. For all phospholipids with at least 12 carbons in their fat chains, this concentration range is above the critical micellar concentration (CMC);