k (h−1) | Reaction Medium 1 H2O pH 7.40 | Reaction Medium 2 D2O pD 7.40 | Reaction Medium 3 D2O pD 7.40/MeCN (80:20) |
---|---|---|---|
β1-D | 0.026 | 0.0083 | 0.0049 |
β1-2 | 0.18 | 0.13 | 0.072 |
2-α1 | 0.23 | 0.072 | 0.072 |
α1-2 | 2.6 | 1.1 | 1.3 |
2-3 | 0.12 | 0.040 | 0.023 |
3-2 | 0.048 | 0.026 | 0.014 |
3-4 | 0.059 | 0.034 | 0.019 |
4-3 | 0.085 | 0.059 | 0.058 |
X-D | 0.0058 | 0.0033 | 0.0023 |
Ratio am/h | 6.9 | 15.7 | 14.7 |
Ratio 2/1α | 11.3 | 15.3 | 18.1 |
Ratio 2/3 | 0.4 | 0.7 | 0.6 |
Ratio 3/4 | 1.4 | 1.7 | 3.0 |
Σs2 | 20.2 | 2.3 | 0.81 |
Rate constants are shown in the reaction scheme depicted in Fig. 1. X-D is the hydrolysis of the acyl-migrated isomers to S-naproxen aglycone (D = drug), which is fitted as one parameter (kX-D = kα1-D= k2-D = k3-D =k4-D). The pseudoequilibrium concentration ratios between the α-1-, α/β-2-, α/β-3-, and α/β-4-O-acyl isomers are calculated by the ratio of the reversible acyl-migration first order rate constants in the equilibrium. Ratio am/h is the ratio between acyl migration (kβ1-2) and hydrolysis (kβ1-D) for S-nap-g. Σs2 is the sum of squares from the kinetic fitting to the analytical data for each reaction medium.