Christina Efthymiou1, L Magnus Bergström2, Jannik Nedergaard Pedersen3, Jan Skov Pedersen4, Per Hansson5. 1. Department of Pharmacy, Uppsala University, Box 580, 751 23 Uppsala, Sweden. Electronic address: chrefthy@yahoo.com. 2. Department of Pharmacy, Uppsala University, Box 580, 751 23 Uppsala, Sweden; Department of Medicinal Chemistry, Uppsala University, Box 574, 751 23 Uppsala, Sweden. Electronic address: magnus.bergstrom@ilk.uu.se. 3. Department of Chemistry and Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, Building 1590-252, 8000 Aarhus C, Denmark. Electronic address: jannik@inano.au.dk. 4. Department of Chemistry and Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, Building 1590-252, 8000 Aarhus C, Denmark. Electronic address: jsp@chem.au.dk. 5. Department of Pharmacy, Uppsala University, Box 580, 751 23 Uppsala, Sweden; Department of Medicinal Chemistry, Uppsala University, Box 574, 751 23 Uppsala, Sweden. Electronic address: per.hansson@ilk.uu.se.
Abstract
HYPOTHESIS: 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. EXPERIMENTS: 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. FINDINGS: 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).
HYPOTHESIS: 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. EXPERIMENTS: 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. FINDINGS: 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).