Chemical and statistical considerations in the determination of partition coefficients of weakly ionizable drugs and poisons.
Equations have been developed that relate the concentration (or a parameter directly proportional to concentration, such as optical absorbance) of a weakly ionizable solute in a water-immiscible phase, in equilibrium with an aqueous phase, to the pH of the aqueous phase, the partition coefficient of the unionized solute and the phase volume ratio. These relationships have been used in the design of experimental methods for determining partition coefficients, which require measurement of solute concentration in only one phase. Data obtained in this way permit ready recognition of deviations from assumptions made in the development of the model; these assumptions include insolubility of the ionized solute in the water-immiscible phase and lack of interaction between buffer components and solute. Conditions for optimal liquid-liquid extraction of weakly ionizable solutes are more easily recognized. With these techniques, the negative logarithm of the acid dissociation constant (pK'a) and the logarithm of the octanol-water partition coefficient (log P) have been measured for warfarin (pK'a = 5.15 +/- 0.04; log P = 2.82 +/- 0.06), strychnine (pK'a = 8.29 +/- 0.02; log P = 2.23 +/- 0.04), phenol (pK'a = 9.88 +/- 0.02; log P = 1.75 +/- 0.05), procaine (pK'a = 8.11 +/- 0.04; log P = 1.10 +/- 0.08), and ephedrine (pK'a = 9.92 +/- 0.01; log P = 1.65 +/- 0.04) at 21 degrees C.
Opong-Mensah
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K
School of Pharmacy, University of Wisconsin, Madison, WI 53706, USA.
Woller
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Obaseki
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Porter
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