Buffer solutions:

• Buffer is a system, usually an aqueous solution (or mixtures of compounds) that

can resist changes in pH upon addition of small quantities of an acid or alkali.
Buffer solutions are composed of:
1) A weak acid and its salt (conjugated base), or
2) A weak base and its salt (conjugated acid).

Buffer action:
• It is the ability of a buffer solution to resist changes in pH upon addition of an acid
or base.
Example for non-buffer system
• A solution of NaCl in water (its pH = 7)
➢ Addition of 1 ml of 0.1 N HCl solutions lowers its pH value to 3.
➢ Addition of 1 ml of 0.1 N NaOH solution raises its pH value to 11.
 NaCl is not a buffer.
Example for buffer system
1. A mixture of weak acid (acetic acid) and its salts (sodium acetate)
• The mixture consists of CH3COOH molecules + CH3COO- + Na+.
On addition of strong acid;
H+ (from the strong acid) + CH3COO- → CH3COOH
H+ ions are neutralized by acetate ions present in the mixture and there is
very little change in pH value of the mixture.
On addition of strong base;
OH- (from the strong base) + CH3COOH → CH3COO- + H2O
OH- ions are neutralized by acetic acid present in the mixture and there is
very little change in pH value of the mixture.
☺ So, the mixture weak acid and its salt act as a buffer system which resists the
change of the pH upon addition of a strong acid or strong base.

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 2. A mixture of a weak base (NH4OH) and its salt (NH4Cl) also behaves in
a similar manner.
A buffer is a solution containing a weak acid and its conjugate base in similar amounts.
This combination reduces the pH change upon addition of strong acid or base by
converting H1+ (or OH1-) to weaker acids (or bases).

Buffer equations (Henderson-Hasselbalch equations):

1. Buffer equation for weak acid and its salts
[𝑠𝑎𝑙𝑡]
𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔
[𝑎𝑐𝑖𝑑]
This equation is satisfactory for calculations within pH range of 4 to 10.
The pH of a buffer solution depends on:
1) The pKa of buffering substances.
2) The relative concentrations of acid & its conjugate base.
Example: Calculate the pH of the buffer solution consisting of 0.1 M each of acetic
acid and sodium acetate (pKa of acetic acid = 4.76).
Solution:
[𝑠𝑎𝑙𝑡] 0.1
𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔 → 𝑝𝐻 = 4.76 + 𝑙𝑜𝑔 = 4.76
[𝑎𝑐𝑖𝑑] 0.1
2. Buffer equation for weak base and its salt
[𝑏𝑎𝑠𝑒]
𝑝𝐻 = 𝑝𝐾𝑤 − 𝑝𝐾𝑏 + 𝑙𝑜𝑔
[𝑠𝑎𝑙𝑡]
E.g. ephedrine base and ephedrine hydrochloride.
 Buffers are not usually prepared using weak bases and their salts because of the
poor stability, volatility and the dependence of their pH on pKw which is affected
by temperature.
Example: Estimate the pH of a solution containing 0.10 mole of ephedrine and 0.01
mole of ephedrine HCl per liter of solutions. (pKb of ephedrine is 4.64).
Solution:
[𝑏𝑎𝑠𝑒] 0.1
𝑝𝐻 = 𝑝𝐾𝑤 − 𝑝𝐾𝑏 + 𝑙𝑜𝑔 → 𝑝𝐻 = 14 − 4.64 + 𝑙𝑜𝑔 = 10.36
[𝑠𝑎𝑙𝑡] 0.01

Buffer Capacity:
• The magnitude of resistance to change in pH on addition of an acid or a base is
called buffer capacity (β), buffer index, buffer efficiency, and buffer coefficient or
buffer value.

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Buffer capacity (β) is defined as:
• The ratio of increment of strong base or acid (expressed as moles of H+ or OH-)
to the small change in pH brought about by this addition.
𝛥𝐵
𝛽=
𝛥 𝑝𝐻
➢ Where: ΔB = the small increment of strong base or acid added to the buffer
solution to produce a pH change of Δ pH
• This equation gives only an approximation of the buffer capacity of a solution.
• Buffer capacity can be defined as the amount of strong acid or base (in gm
equivalent/liter) required to change the pH of 1 liter of a buffer system by one unit.

Example: A buffer solution contained 0.1 M each of acetic acid and sodium acetate and
its pH was 4.76. to this, 0.01 mole of sodium hydroxide was added, and the pH of the
resultant solution was 4.85. Calculate the buffer capacity.
Solution:
∆𝐵 0.01
𝛽= = = 0.11
∆𝑝𝐻 4.85 − 4.76

Van Slyke's Equation:

Van Slyke developed a more exact equation for calculation of buffer capacity.
𝐾𝑎 [𝐻 + ]
𝛽 = 2.303 𝐶
(𝐾𝑎 + [𝐻 + ])2
• C = the total buffer concentration (the sum of the molar concentrations of the acid
and the salt).
Maximum buffer capacity:
The maximum buffer capacity occurs when pH = pKa or when (H+) = Ka
𝛽𝑚𝑎𝑥 = 0.576 𝐶
Example: What is the maximum buffer capacity of an acetate buffer with a total
concentration of 0.20 mole/L?
Solution:
𝛽𝑚𝑎𝑥 = 0.576 𝐶
𝛽𝑚𝑎𝑥 = 0.576 × 0.2 = 0.1152

Factors affecting pH of the buffer solutions:

1. Temperature effects
• The activity coefficient and PKa value of a buffer are dependent on the temperature.
So, temperature change will cause changes in pH of the buffer.

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 • Buffer of weak base and its salts show greater changes with temperature.
• An increase in temperature lowers the pH of boric acid/sodium borate buffer and
raises the pH of acetic acid/acetate buffer.
2. Dilution effects
• Dilution of an acidic buffer shows an increase in the pH, while dilution of a basic
buffer shows a decrease in the pH.
Dilution value:
• The change in pH of a buffer upon dilution with an equal volume of water.
• Dilution value for most pharmaceutical buffer systems are usually less than 0.1 pH
unit.
3. Salts effects
Addition of neutral salt lowers the activity coefficient of the ions so;
• Salt added to acidic buffer lowers its pH, while that added to a basic buffer increases
its pH.
• The change in pH is not greater than 0.1 pH units.

Biological buffers
1. Blood:
Blood is maintained at a pH of about 7.4 by the primary buffer in the plasma and the
secondary buffer in the erythrocytes:
A. Buffers in the plasma: The plasma contains:
• Carbonic acid/bicarbonate
• Acid/alkali sodium salts of phosphoric acid.
• Plasma proteins, which behave as acids in blood, can combine with bases and so
act as buffers.
B. Buffers in the erythrocytes: The buffer systems consist of:
• Hemoglobin/ oxyhemoglobin
• Acid/alkali potassium salts of phosphoric acid.
N.B: When the pH of the blood goes below 7.0 or above 7.8, life is in serious danger. In
diabetic coma, the pH of blood drops to 6.8.
2. Lachrymal fluid:
• The pH of tears is about 7.4 with a range of 7 to 8.
• 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.
3. Urine:
• Average pH of urine is about 6 with a range of 4.5 to 7.8.

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 • When the pH of urine is altered beyond this range, remidal action is taken by the
kidneys in the form of retention or excretion of hydrogen ions in order to maintain
pH within range.

Pharmaceutical buffers
Buffers are used in pharmaceutical formulation to:
1) Adjust the pH of the product that required for maximum stability, maximum
activity and minimize the tissue irritation.
2) Maintain the pH of product within optimal physiological pH range.
1. Buffer in tablet & capsule formulation:
• To control the pH in the microenvironment surrounding the drug particles to
enhance drug dissolution and absorption.
• Buffers used in formulation of acidic drug to reduce the gastric irritation.
2. Buffers in ophthalmic preparations:
• Buffers are used in ophthalmic preparations to maintain the pH within the
physiological pH range of the lachrymal fluid.
• The lachrymal fluid has a good buffering capacity and solutions with pH 3.5 and
10.5 can be tolerated with little discomfort. Outside this pH range, irritation of the
eye with increase in the lacrimation can occur.
• Ideally ophthalmic preparations should be formulated at the physiological pH but
this pH is not the ideal pH for best solubility and or stability of the drug.
N.B: The un-dissociated (unionized) form of a weakly acidic or basic drug has a higher
therapeutic activity than the dissociated (ionized) salt form. WHY?
Because: the un-dissociated 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.
Most ophthalmic drugs are weakly basic;
• At low pH, these drugs are present in the dissociated (ionized) form which is
usually very soluble in aqueous media; at this pH, the drug has low therapeutic
value. Why?
• Buffers are added to adjust the pH of weakly basic drugs to a value that ensure
drug solubility or stability.
• When the solution is instilled into the eye the pH of the solution slowly rises by
effects of eye buffer system where the weak base (dissociated form) converted into
the undissociated form which provides the maximum therapeutic effect.

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 • Commonly used buffer systems [with low buffer capacity.Why?] involved in the
ophthalmic preparation include; Borate, phosphate and carbonate buffers.
3. Buffers in parenteral preparations:
• Parenteral preparation of highly alkaline pH (above 9) can cause tissue necrosis
while acidic pH (below 3) can result in extreme pain at the site of injection.
• The ideal pH of a parenteral preparation is 7.4
• The pH of small volume parenterals is not necessary required to be at physiological
pH why? Because the blood has a good buffering capacity.
• The pH selected for such product is a compromise between the stability and
solubility of the drug as well as the irritancy of the preparation.
• Buffer with low capacity are used for adjusting the required pH necessary for
solubility and stability.
• The most commonly used buffers in parenterals are acetate, phosphate, citrate
and glutamate.
4. Buffers in creams and ointments:
• Topical products have tendency to undergo pH change during storage which may
adversely affect the stability of the product.
• Buffers are used to maintain the suitable pH of such products.
• The most commonly used buffers in creams and ointments include citric acid and
its salts or phosphoric acid and its salts.

Preparation of pharmaceutical buffers:

Steps of preparing buffer solution;
1. Select a weak acid having a PKa approximately equal to the pH wanted to insure maximum
buffer capacity. PKa= pH
2. From the buffer equation, calculate the ratio of salt and weak acid required to obtain the
desired PH.
Log [Acid] / [Salt] = PKa - pH
3. Consider the individual concentrations of the buffer salt and acid needed to obtain a
suitable buffer capacity.
4. Finally, determine the pH and buffer capacity experimentally using a pH meter.
Factors of some importance in the choice of pharmaceutical buffer:
1. Availability of chemicals.
2. Sterility of the final solution.
3. Stability of the drug and buffer on aging.
4. Cost of materials.
5. Freedom from toxicity.

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