Common amphiphilic drug molecules often have a more rigid nonpolar part than conventional surfactants. The rigidity is expected to influence the self-assembling properties and possibly give rise to aggregation patterns different from that of regular surfactants. We have investigated self-assembling properties of the hydrochloride salts of adiphenine (ADP), pavatrine (PVT), and amitriptyline (AMT) at concentrations up to 50 wt% using small-angle x-ray scattering, dynamic light scattering, cryo-transmission electron microscopy, and surface tension measurements. All drugs form small micelles of oblate spheroidal shape at concentrations above the critical micelle concentrations (CMC). The micelles grow weakly in size up to about 20 wt%, where the aggregation number reaches a maximum followed by a slight decrease in size at higher drug concentrations. We observe a correlation between the decrease in micelle size at high concentrations and an increasing charge of the micelles, as the degree of ionization increases with increasing drug concentration and decreasing pH. In contrast to what has previously been reported, the aggregation behavior of all studied drugs resembles the closed association behavior of conventional surfactants with a short aliphatic chain as hydrophobic tail group i.e. the micelles are always small in size and lack a second CMC. CMC values were determined with surface tension measurements, including also lidocaine hydrochloride (LDC) and chlorpromazine hydrochloride (CHL).

We investigated the loading of an amphiphilic drug, amitriptyline hydrochloride (AMT), onto sodium polyacrylate hydrogels at low ionic strength, and its release at high ionic strength. The purpose was to show how the self-assembling properties of the drug and the swelling of the gel network influenced the loading/release mechanisms and kinetics, important for the development of improved controlled-release systems for parenteral administration of amphiphilic drugs. Equilibrium studies showed that single microgels (~100 µm) in a large solution volume underwent a discrete transition between swollen and dense states at a critical drug concentration in the solution. For single macrogels in a small solution volume, the transition progressed gradually with increasing amount of added drug, with swollen and dense phases coexisting in the same gel; in a suspension of microgels, swollen and collapsed particles coexisted. Time-resolved micropipette-assisted microscopy studies showed that drug self-assemblies accumulated in a dense shell enclosing the swollen core during loading, and that a dense core was surrounded by a swollen shell during release. The time evolution of the radius of single microgels was determined as functions of liquid flow rate, network size and AMT concentration in the solution. Mass transport of AMT in the surrounding liquid, and in the dense shell, influenced the deswelling rate during loading. Mass transport in the swollen shell controlled the swelling rate during release. A steady-state kinetic model taking into account drug self-assembly, core-shell phase separation, and microgel volume changes was developed and found to be in semi-quantitative agreement with the experimental loading and release data.