The location of amantadine hydrochloride and free base within phospholipid multilayers: a neutron and X-ray diffraction study.

Concomitant neutron and X-ray studies were undertaken in order to locate accurately the anti-influenza and Parkinson's disease drug amantadine in multilayers of 1,2-dioleoyl-sn-glycero-3-phosphocholine. The X-ray data were phased using the swelling series method and the neutron data were phased using D2O/H2O exchange and a variation of the isomorphous replacement technique. The sets of data complement each other and reveal two populations of amantadine within the bilayer. One site is close to the bilayer surface, the other is much deeper. The majority of the amantadine occupies the surface site. The relative occupancy, but not the position, of the two locations appears to be dependent upon the initial protonation state of the drug. No evidence of bilayer perturbation was observed with either the protonated or the deprotonated forms of amantadine.