Calorimetric determination of the partition coefficient for chlorpromazine hydrochloride in aqueous suspensions of dimyristoylphosphatidylcholine vesicles.

Lipid suspensions containing from 0.1 to 0.2% by weight dimyristoylphosphatidylcholine were mixed in a flow calorimeter with equal volumes of chlorpromazine hydrochloride at concentrations ranging from 6 X 10(-5) to 1.2 X 10(-4) M. The vesicle bilayer volume fraction of the suspension was determined by density measurements. Linear relationships were obtained between heat production per ml suspension and chlorpromazine concentration at each level of lipid volume. Using phase partitioning as a model, the values of the partition coefficient and the enthalpy change were found to be K'c = 1300 and delta H = -30 kJ X mol-1 at 25 degrees C. Heat outputs at slightly higher concentrations of chlorpromazine increased less than linearly because of repulsive forces between neighboring chlorpromazine cations absorbed in the bilayer phase. At still higher concentrations the slope increased again but partition coefficients became variable, which indicated a change in the nature of the interaction. In batch calorimeter titrations at higher concentrations a sharp increase in heat output was observed at the critical micelle concentration of chlorpromazine (4 mM) and a final leveling off at 6 mM. Enthalpies of dilution of chlorpromazine obtained in separate experiments were large and endothermic, but no break in the curve could be detected at the critical micelle concentration.