O

pH 6

(phosphate)

Figure 4.8 Effect of buffer concentration on the hydrolytic rate constant for ciclosidomine at 60°C as a function of pH.

Reproduced from C. F. Carney, J. Pharm. Sci., 76, 393 (1987) with permission.

To remove the influence of the buffer, the reaction rate should be measured at a series of buffer concentrations at each pH and the data extrapolated back to zero concentration as shown in Fig. 4.8. If these extrapolated rate constants are plotted as a function of pH, the required buffer-independent pH-rate profile will be obtained. Figure 4.9 illustrates the simple type of pH-rate profile which is obtained with codeine sulfate.

As we can see from Fig. 4.9, this drug is very stable in unbuffered solution over a wide pH range but degrades relatively rapidly in the presence of strong acids or bases. Since the influence of buffer components has been removed, this plot allows us to calculate the rate constants for specific acid and base catalysis. Removing the terms for the effect of buffer from equation (4.44), we have

and consequently a plot of measured rate constant kobs against the hydrogen ion concentration [H+] at low pH will have a gradient equal to the rate constant for acid catalysis. Similarly, of course, if we plot kobs against (Note: pKw = 12.63 at 80°C.)

[OH0] at high pH, the gradient will be the rate constant for base-catalysed hydrolysis. Example 4.4 illustrates the calculation of these catalytic coefficients.

EXAMPLE 4.4 Calculation of rate constants for base-catalysed hydrolysis

The following data were obtained for the hydrolytic rate constant, kobs of codeine sulfate in aqueous buffer-free solution at 80°C

107kobs(s01) 5.50 4.40 2.30 1.25 0.70 pH 11.63 11.53 11.23 10.93 10.63

Determine graphically (a) the catalytic coefficient for base-catalysis, kOH-, and also (b) the coefficient for solvent catalysis, k0.