Titrations

The pH-metric technique consists of two linked titrations. Typically, a pre-acidified solution of a weak acid is alkalimetrically titrated to some appropriately high pH; octanol (or any other useful organic partition solvent that is immiscible with water) is then added, and the dual-solvent mixture is acidimetrically titrated back to the starting pH. After each titrant addition, pH is measured. If the weak acid partitions into the octanol phase, the two assays show non overlapping titration curves, as shown in Fig. la for flumequine and Fig. lb for diacetylmorphine. (The horizontal axes in Fig. 1 are in units of base equivalents, defined as the number of moles of base titrant added per mole of drug substance titrated.) The greatest divergence between the two curves occurs in the buffer region. Since the pKa is approximately equal to the pH at the mid-buffer inflection point (equivalent to 0.5 in Fig. 1), the two-part assay yields two constants: pKa and p0Ka, where p0ATa is the apparent constant derived from the octanol-containing segment of data. A large difference between pKa and p0K¿ indicates a large value of log P.

Flumequine (Z5°C, 0.15M NoCI)

Flumequine (Z5°C, 0.15M NoCI)

Equivalents

Equivalents

Figure 1. Water (squares) and 1:1 octanol/water (triangles) titration curves (0.15 m KCI) of (a) weak acid, flumequine (pK„ 6.27), and (b) weak base diacetyl-morphine (p/Ca 7.96). Octanol causes the curve to shift to higher pH with the weak acid and to lower pH with the weak base.

Equivalen ts

Equivalen ts

Figure 1. Water (squares) and 1:1 octanol/water (triangles) titration curves (0.15 m KCI) of (a) weak acid, flumequine (pK„ 6.27), and (b) weak base diacetyl-morphine (p/Ca 7.96). Octanol causes the curve to shift to higher pH with the weak acid and to lower pH with the weak base.

For a monoprotic weak acid which dissolves both in water and a water-immiscible partition solvent (e. g., octanol), the partition coefficient (which is a true equilibrium constant) is defined as

where [HA] is the weak acid aqueous concentration, moles/liter aqueous solution, and [HA]0RG is the concentration in the oil phase, moles/liter of organic solvent. For this simple system the relation between log P and pKR is simply

r where

^ _ vol. organic phase vol. aqueous phase

If the two phases are equal in volume and the substance is considerably lipophilic, then Eq. (2) reduces to log PHA ~ (paK3 - pKa). In Fig. la, the octanol volume equals the aqueous volume, so by inspection, log P = 1.7 for flumequine. For a monoprotic weak base, B, partitioning the corresponding equation is

Similarly, for equivolume titrations of lipophilic bases, log PB ~ -(p0£a-p/Q. In Fig. lb, the octanol volume equals the aqueous volume, so by inspection, log P = 1.6 for diacetylmorphine.

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