Microdissociation constants

The experimentally determined dissociation constants for the various stages of dissociation of polyprotic and zwitterionic drugs are referred to as macroscopic values. However, it is not always easy to assign macroscopic dissociation constants to the ionisation of specific groups of the molecule, particularly when the pKa values are close together, as discussed in section 3.5.4. The diprotic drug morphine has macroscopic pKa values of 8.3 and 9.5, arising from ionisation of amino and phenolic groups. Experience suggests that the first pKa value is probably associated with the ionisation of the amino group and the second with that of the phenolic group; but it is not possible to assign the values of these groups unequivocally and for a more complete picture of the dissociation it is necessary to take into account all possible ways in which the molecule may be ionised and all the possible species present in solution. We may represent the most highly protonated form of morphine, +HMOH, as +O, where the ' +' refers to the protonated amino group and the

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