Please remember these concepts:
processes can be at equilibrium.
But with changes in condition -
concentration, temperature - the
system will no longer be at equilibrium
and will adjust to try to get there
equilibrium concentrations of H3O+
and OH- are vanishingly
small in pure water.
weak acid or a weak base drug, in water,
will disassociate to some extent.
The pH of the drug solution will
depend upon the pKa.
stabilize pH. This stabilized
acidity determines the form of drug
disassociation in systems. The
conveniently handles drug ionization
questions for buffered systems like the
It is almost ALWAYS
desirable to have a drug compound that can exist
in a solution. Even if ultimately the drug will
not be administered as a solution (either oral or
intravenous), researchers involved in the initial
phases of drug development need the compound to
be soluble. During pre-clinical trials, any
animal studies that are done will initially use
intravenous administration of the drug. Initial
stability studies of the drug may be carried out
with the drug in solution.
Of course, water solubility
is preferred, but that is not always possible.
Water is the ideal solvent: it is inexpensive, it
has no pharmacological activity of its own, it is
widely available, and its characteristics are
As stated previously, it is
desirable to be able to make a solution,
preferably aqueous, during the drug discovery
process. Medicinal chemists employ several
techniques to accomplish this, among them
preparing a prodrug, a complex, changing the
crystalline state, and, most importantly for our
discussion, preparation of salt forms.
Drug molecules may be
active in only the undissociated state.
Unfortunately, they are also LEAST soluble in the
unionized or undissociated form. So the dilemma
for the chemist is to synthesize a salt form of
the compound that is water soluble, but that will
not negatively impact the other characteristics
of the compound.
Another consideration is
the absorption of the drug from the
gastrointestinal tract, assuming oral
administration. The drug must get from the lumen
or cavity of the gastrointestinal tract to the
circulation on the other side. Membranes of the
GI tract are lipoidal or fatty in nature, as is
the membrane surrounding the brain. Unionized
molecules cross these lipoidal membranes much
more rapidly than the ionized species. In fact,
without another transport mechanism such as a
pump or enzyme transport system, ionized
substances dont cross these membranes at
all! (Go here
to see why the phrase "Never say never"
this is the problem we face:
in Gastrointestinal Lumen
of Ionization is dependent on pH, which
varies with location
(more lipophilic) drug crosses membrane
of GI into bloodstream
of Ionization is dependent on pH which is
7.4 in normal, healthy humans
(more lipophilic) drug crosses the blood
in Central Nervous System, the site of
action for phenobarbital