log PN

Figure 6.6 Empirical relationship between intrinsic solubility of ionizable molecules and their octanol-water log P [pION]. [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]

The procedure takes as input parameters the measured (or calculated) pKa and the measured (or calculated) octanol-water partition coefficient, log P. The latter parameter is used to estimate the intrinsic solubility S0, using the Hansch-type expression [38], log S0 = 1.17 — 1.38 log P, or an improved version for ionizable molecules of moderate lipophilicity (Fig. 6.6):

Using the pKa and the estimated S0, the DTT procedure simulates the entire titration curve before the assay commences. Figure 6.7 shows such a titration curve of pro-poxyphene. The simulated curve serves as a template for the instrument to collect individual pH measurements in the course of the titration. The pH domain containing precipitation is apparent from the simulation (filled points in Fig. 6.7). Titration of the sample suspension is done in the direction of dissolution (high to low pH in Fig. 6.7), eventually well past the point of complete dissolution (pH < 7.3 in Fig. 6.7). The rate of dissolution of the solid, described by the classical Noyes-Whitney expression [37], depends on a number of factors, which the instrument takes into account. For example, the instrument slows down the rate of pH data taking as the point of complete dissolution approaches, where the time needed to dissolve additional solid substantially increases (between pH 9 and 7.3 in Fig. 6.7). Only after the precipitate completely dissolves, does the instrument collect the remainder of the data rapidly (unfilled circles in Fig. 6.7). Typically, 3-10 h is required for the entire equilibrium solubility data taking. The more insoluble the log S0 = —2.17 — 0.0082 log P — 0.134(log P)

0 0

Post a comment