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Buffer in biological &

pharmaceutical
systems
Buffer in biological &
pharmaceutical systems
• I. In vivo biological buffer systems
Øa) Blood
Ø b) Lacrimal fluid
• II. Pharmaceutical Buffers
• III. Pharmaceutical significance of
buffers
I. In vivo biological buffer
systems

Øa) Blood
Ø b) Lacrimal fluid
a) Blood

Blood is maintained at a pH of about 7.4 by:


v 1° buffers in the plasma &
v 2° buffers in the erythrocytes.

vThe buffer capacity of blood = 0.039 gram equiv. per liter/pH


unit for whole blood of which: 0.031 by the cells
0.008 by the plasma
a) Blood
• When the pH of the blood
goes below 7.0 or
• above 7.8, life is in serious
danger.
• The pH of the blood in
diabetic coma is dropped to
about 6.8
b) Lacrimal fluid

• Tears have a great degree of buffer


capacity, allowing a dilution of 1:15 with
neutral distilled water before an alteration
of pH is noticed.
• The pH of tears is about 7.4 with a range of
7 to 8
II. Pharmaceutical Buffers
• Examples
• Steps of formulation
• Factors considered in formulation
II. Pharmaceutical Buffers
• Buffer solutions are used in
pharmaceutical formulation
particularly in ophthalmic
preparations
• Examples
ØGifford
ØSorensen
ØThe Clark-
Clark-Lubs
Gifford buffer
• suggested two stock
solutions of:
Øboric acid and
monohydrated sodium
carbonate
ØpH values from about 5 - 9.
Sorensen buffer
• proposed a mixture of salts
of:
Ø sodium phosphate
Ø pH 6 to 8.
The Clark-
Clark-Lubs buffer
• mixtures and their pH ranges
Øa. pH 1.2 to 2.2: HCl and KCl
Øb. pH 2.2 to 4.0: HCl and potassium
hydrogen phthalate
Øc. pH 4.0 to 6.2: NaOH and potassium
hydrogen phthalate
Ød. pH 5.8 to 8.0: NaOH and KH2
KH2PO
PO4
4
Øe. pH 7.8 to 10 : H
H3
3B03
03,, NaOH and KCl

Sodium chloride is added to buffer mixture


to make it isotonic with body.
The following steps should be used
in preparing buffer systems
• a. Select a weak acid having
a pKa approximately equal to
• the pH wanted to insure
maximum buffer capacity.
vPka= pH
Steps of preparing buffer solution
• b. From the buffer equation,
calculate the ratio of salt and
weak acid required to obtain the
desired pH.
• The buffer equation is suitable
for calculations within the pH
range of 4 to 10.
• log Cu/Ci = pKa - pH
Steps of preparing buffer solution
• c. Consider the individual concentrations
of the buffer salt and acid needed to
obtain a suitable buffer capacity.

• β = 2.3 C Ka[H3O+]
(Ka + [H3O+])2

• A concentration of 0.05 to 0.5 molar is


sufficient and buffer capacity of 0.01 to
0.1 is sufficient.
Steps of preparing buffer solution

• d. Finally, determine the pH


and buffer capacity of the
completed buffered
solution using a pH meter.
Factors of some importance in the choice
of pharmaceutical buffer
• Availability of chemicals
• Sterility of the final solution.
• Stability of the drug and buffer on
aging.
• Cost of materials.
• Freedom from toxicity.
Ø For example, a borate buffer,
because of its toxic effects, cannot
be used for a solution to be
administrated orally or parenterally
III-Significance of pharmaceutical
buffers
• Minimize Tissue irritation
• Optimum Therapeutic
Response
• Drug Stability
• Drug solubility
• Drug Activity
1-Tissue irritation
• due to large pH differences
between:
Øthe solution administered
Øthe physiological fluid
Tissue irritation is minimized:

• (a) The lower the buffer


capacity of the solution
• (b) The smaller the volume
used for a given concentration.
• (c) The larger the volume and
buffer capacity of the
physiological fluid
Parenteral solutions for injection into the
blood stream are usually not buffered or they
are buffered to a very low capacity so that the
buffers of the blood may bring them
within the physiological pH range.
2-Influence of Buffer Capacity and pH
on Optimum Therapeutic Response

• The undissociated form of a


weakly acidic or basic drug
has a higher therapeutic
activity than the dissociated
salt form WHY?
2-Influence of Buffer Capacity and pH
on Optimum Therapeutic Response

• Because: the undissociated form


is lipid soluble and can penetrate
body membranes, whereas the
ionic form is not lipid-soluble and
can only penetrate membranes
with great difficulty.
2-Influence of Buffer Capacity and pH
on Optimum Therapeutic Response
• Thus, the therapeutic response of weakly
basic alkaloids (used as ophthalmic drugs)
increases as the pH of the solution
increases, and hence-concentration of the
undissociated base, was increased.
• At a pH of about 4 these drugs are in the
ionic form and penetration is slow.
• When the tears bring the pH to about 7.4,
the drugs may exist in the form of the free
base depending on the dissociation
constant of the drug.
3-Influence of Buffer Capacity and pH on
Drug Stability
• Buffer is used to prevent changes in pH due to the
Ø alkalinity of the glass
Ø acidity of CO2 from dissolved air

• Solutions as Thiamine hydrochloride may be


sterilized by autoclaving without decomposition
if the pH is below 5 ; above this pH thiamine
hydrochloride is unstable.

• The stability of emulsions is pH dependent.


¬ The pH for maximum stability of a drug for ophthalmic use may
be far below that of the optimum physiological effect s
⇒1- solution of the drug can be buffered at a low buffer capacity
2- adjust pH to be a compromise between that of optimum
stability and the pH for maximum therapeutic action.

¬ Yet, when the solution is instilled in the eye, the tears


participate in the gradual neutralization of the solution and the
conversion of the drug from the physiologically inactive form to
the undissociated base the base can then readily penetrate the
lipoidal membrane.

¬ As the base is absorbed at the pH of the eye , more of the salt is


converted into base to preserve the equilibrium, hence the
alkaloidal drug is gradually absorbed.
4-PH and solubility.

• The influence of buffering on the solubility


of the alkaloidal base:

• at a low pH a base is predominantly in the


ionic form which is usually very soluble in
aqueous media
• as the pH is raised more undissociated
base is formed.

• Therefore, the solution should be buffered


at sufficiently low pH
5-Influence of Buffer Capacity and pH
on Drug Activity

• Drugs that are weak acids or


weak bases, may exist in
ionized or non ionized form.
They may be active in one
form but inactive in the other.
Such drugs have an optimum
pH range for maximum
activity.