| Lab Guide: Equations
Glossary
Physical
Chemical Properties
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Objective(s): Upon completion of this laboratory,
the student should be able to predict degree of
solubility of a drug in an acidic or basic
solution. Background:
The effect of hydrogen ion concentration is most
evident to the chemistry student in solubility
behavior. Most drugs are salts of weak
acids or bases. These salts are usually water
soluble while most of the unionized acid or base
forms of the drugs are practically insoluble.
Consequently, if a solution of a salt of a weakly
basic drug is made alkaline, free base may
precipitate. Precipitation of free acid may occur
if a solution of a weak acid is acidified.
Whether precipitation occurs or not depends on
the solubility of the unionized acid or base,
then pH of the solution in which the drug is
dissolved, and the dissociation constant of the
acid or base.
Procedure:
Three
titrations will be performed: sodium salicylate,
diphenhydramine HCl, and an unknown.
- 1. A stock solution of
sodium salicylate 5% in water
will be provided. Titrate
30 ml of the stock solution with
0.1N HCl until precipitation
occurs. Prepare titration in an
Erlenmeyer flask. Continuous
swirling must be performed in
order for the solutions to be
mixed sufficiently. Record the pH
of the solution at the point of
permanent precipitate formation.
From the information
provided and using the
information on the volume of HCl
needed for precipitate formation,
calculate the pH at which
precipitate formation would be
expected. Compare this value with
the actual pH at which a
precipitate was
observed.(Solubility of salicylic
acid at 25 C is 1 gm in 460 ml
water; M.W. of Salicylic acid is
138.1; M.W. of sodium salicylate
is 160.1; pKa =2.97)
2. In a similar
manner, 30 mL of 5%
Diphenhydramine HCl will be
titrated with a 0.1N solution of
NaOH. At the point of
precipitation, the pH will be
determined, and calculations as
described above will be
performed, with the obvious
difference being that
diphenhydramine HCl is the
conjugate acid of the basic drug,
diphenhydramine. The
solubility of diphenhydramine
free base is "Practically
insoluble in water", which,
by USP (United States
Pharmacopoeia)standards, means
one gram in >10,000mL of
water.
3. Lastly, using the
procedure described above,
titrate 30 ml of a 5% solution of
an unknown drug with 0.1N HCl
until precipitation occurs.
Calculate
the dissociation constant for the
unknown drug using the
information provided and the data
obtained for precipitation
procedure. In the
Henderson-Hasselbach equation,
the pH is the measured pH at the
point at which precipitation
occurs. The concentration
of the base and acid are
calculated, using the volume of
added HCl when indicated.
Now solve for pKa.
The solubility of the
undissociated form of the
compound is 3.4g/L; the molecular
weight of the undissociated form
is 122.12; and the molecular
weight of the salt form is
144.11.
Calculations:
- To calculate the pH of
precipitation for a solution of sodium
salicylate, literature values are
provided above for the pKa and
solubility of the free or undissociated
acid. The value for the concentration of
salt will be determined. In developing an
equation to describe the pH at the exact
point of precipitation the
Henderson-Hasselbach provides a starting
point.
Henderson-Hasselbach
Equation
- This equation is true
for acids or bases. The numerator (base) in
the log function is either the free base
or the conjugate base, while the denominator (acid) is
either the free acid or the conjugate
acid. If one
considers the situation of an acid drug
(salicylic acid), the numerator is the
conjugate base and the denominator is the
free acid.
Since at
the point of precipitation it is the
UNIONIZED (or undissociated or free) drug
molecule that precipitates out of
solution, the denominator (A) is equal to
the solubility of the unionized form of
the drug (So). So, expressed in
mass/volume is actually a concentration
term.
Now recall that the
numerator represents the conjugate base.
At the point of precipitation, the amount
of conjugate base is equal to the initial
amount of the conjugate base MINUS the
amount of base with has been converted to
the free acid by the addition of hydrogen
ions. The initial amount of conjugate
base is equal to the initial amount of
salt added (Cs). The amount
converted to the free acid is equal to
the solubility of the free acid (So).
Therefore, the amount (or concentration)
of conjugate base at the point of
precipitation is represented by the
equation
B = Cs
- So
For the
purposes of calculation, two important points
need to be made:
First,
all concentrations should be
expressed in MOLAR terms. This is because gram for
gram, the amount of active drug given by
the free drug is different from the
amount of active drug available from the
salt form because of the differences in
molecular weight.
Second,
the value for the
concentration of the salt, Cs, is NOT
found simply by converting 5% sodium
salicylate to a molar concentration. Since the total volume of
the solution is changed with the addition
of HCl, the total volume must be
considered. The easiest way to correct
for this volume change is to determine
the number of moles of salt added and
then divide by the total volume of the
solution at the point of precipitation.
The following equation is useful:
Cs =
gs/(vs
+ vHCl)
This
equation yields the MOLAR concentration of the
salt at the point of precipitation, which can
then be substituted into the above modified
Henderson-Hasselbach equation.
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