FORMULATION FACTORS

Solution pH
The physiologic pH of blood and tears is approximately 7.4. Thus, from a comfort and safety
standpoint, this would be the optimal pH of ophthalmic and parenteral solutions. This may not be
possible, however, from a perspective of solubility, chemical stability or therapeutic activity.
Thus, some compromise must be made and product stability must be considered paramount.
When a formulation is administered to the eye, it stimulates the flow of tears. Tear fluid is
capable of quickly diluting and buffering small volumes of added substances, thus the eye can
tolerate a fairly wide pH range. Ophthalmic solutions may range from pH 4.5 - 11.5. But the
useful range to prevent corneal damage is 6.5 to 8.5.
Once we have determined the optimal pH of a product, we need a mechanism for adjusting and
maintaining the pH of the solution.
Buffers and Buffer Capacity
Buffers are compounds that resist changes in pH upon the addition of limited amounts of acids
or bases. Buffer systems are usually composed of a weak acid or base and its conjugate salt. The
components act in such a way that addition of an acid or base results in the formulation of a salt
causing only a small change in pH.
The pH of a buffer system is given by the Henderson-Hasselbach equation:

(for a weak acid and its salt)

(for a weak base and its salt)

where [salt], [acid] and [base] are the molar concentrations of salt, acid and base.
Buffer capacity is a measure of the efficiency of a buffer in resisting changes in pH.
Conventionally, the buffer capacity ( ) is expressed as the amount of strong acid or base, in
gram-equivalents, that must be added to 1 liter of the solution to change its pH by one unit.
Calculate the buffer capacity as:

= gram equivalent of strong acid/base to change pH of 1 liter of buffer solution

= the pH change caused by the addition of strong acid/base
In practice, smaller pH changes are measured and the buffer capacity is quantitatively expressed
as the ratio of acid or base added to the change in pH produced (e.g., mEq./pH for x volume).
The buffer capacity depends essentially on 2 factors:
1. Ratio of the salt to the acid or base. The buffer capacity is optimal when the ratio is 1:1;
that is, when pH = pKa
2. Total buffer concentration. For example, it will take more acid or base to deplete a 0.5 M
buffer than a 0.05 M buffer.
The relationship between buffer capacity and buffer concentrations is given by the Van Slyke
equation:

where C = the total buffer concentration (i.e. the sum of the molar concentrations of acid and
salt).
Just as we must often compromise the optimal pH for a product, so must we compromise on the
optimal buffer capacity of our solution. On the one hand, buffer capacity must be large enough to
maintain the product pH for a reasonably long shelf-life. Changes in product pH may result from
interaction of solution components with one another or with the product package (glass, plastic,
rubber closures, etc.). On the other hand, the buffer capacity of ophthalmic and parenteral
products must be low enough to allow rapid readjustment of the product to physiologic pH upon
administration. The pH, chemical nature, and volume of the solution to be administered must all
be considered. Buffer capacities ranging from 0.01 - 0.1 are usually adequate for most
pharmaceutical solutions.

Preparing a Buffer

Determine the optimal pH for the product, based on physical and chemical stability, therapeutic activity and
patient comfort and safety (must consider chemical and physical nature of the active and other ingredients
and the route administration).

Select a weak acid with a pKa near the desired pH (must be nontoxic and physically/chemically compatible
with other solution additives).

Calculate the ratio of salt to acid required to produce the desired pH (Henderson-Hasselbach equation).

Determine the desired buffer capacity of the product (consider stability of product, route of administration,
volume of dose, chemical nature of product).

Calculate the total buffer concentration required to produce this buffer capacity (Van Slyke equation).

Determine the pH and the buffer capacity of the completed buffer solution by using a reliable pH meter or pH
paper. (This may not always be practical, especially when small volume, sterile products are prepared.)

sample calculation:
Using Acetic Acid and Sodium Acetate prepare 500 ml of a buffer solution at pH 4.5 with a buffer capacity of 0.05.

Salt to Acid Ratio:

Total Buffer Concentration:

Final Calculations:

ISO-OSMOTICITY and ISOTONICITY

If a semi-permeable membrane (one that is permeable only to solvent molecules) is used to
separate solutions of different solute concentrations, a phenomenon known asosmosis occurs in
which solvent molecules cross the membrane from lower to higher concentration to establish a
concentration equilibrium. The pressure driving this movement is called osmotic pressure and
is governed by the number of "particles" of solute in solution. If the solute is a nonelectrolyte, the
number of particles is determined solely by the solute concentration. If the solute is an
electrolyte, the number of particles will be governed by both the concentration and degree of
dissociation of the substance.

Solutions containing the same concentration of particles and thus exerting equal osmotic
pressures are called iso-osmotic. A 0.9% solution of NaCl (Normal Saline) is iso-osmotic with
blood and tears. The term isotonic, meaning equal tone, is sometimes used interchangeably
with the term iso-osmotic. The distinction between these terms comes with the realization that
red blood cell membranes are not perfect semipermeable membranes, but allow passage of
some solutes, such as alcohol, boric acid, ammonium chloride, glycerin, ascorbic acid, and lactic
acid. Hence, a 2% solution of boric acid while physically measured to be iso-osmotic (containing
same number of particles) with blood, will not be isotonic (exerting equal pressure or tone) with
blood but is isotonic with tears. Practically speaking, this differentiation is rarely of significance
and isotonicity values calculated on the basis of the number of particles in solution is usually
sufficient.
The clinical significance of all this is to insure that isotonic or iso-osmotic solutions do not
damage tissue or produce pain when administered. Solutions which contain fewer particles and
exert a lower osmotic pressure than 0.9% saline are called hypotonicand those exerting higher
osmotic pressures are referred to as hypertonic. Administration of a hypotonic solution
produces painful swelling of tissues as water passes from the administration site into the tissues
or blood cells. Hypertonic solutions produce shrinking of tissues as water is pulled from the
biological cells in an attempt to dilute the hypertonic solution. The effects of administering a
hypotonic solution are generally more severe than with hypertonic solutions, since ruptured cells
can never be repaired. The eye can tolerate a range of tonicities as low as 0.6% and as high as
1.8% sodium chloride solution.
Several methods are used to adjust isotonicity of pharmaceutical solutions. One of the most
widely used method is the sodium chloride equivalent method. The NaCl equivalent (E) is the
amount of NaCl which has the same osmotic effect (based on number of particles) as 1 gm of the
drug.
sample calculation: Calculate the amount of NaCl required to make the following ophthalmic
solution isotonic.

Rx
Atropine Sulfate 2%
NaCl qs
Aqua. dist. q.s. ad. 30 ml
M.ft. isotonic solution

1. Determine the amount of NaCl to make 30 ml of an isotonic solution

2. Calculate the contribution of atropine sulfate to the NaCl equivalent

3. Determine the amount of NaCl to add to make the solution isotonic by subtracting (2)
from (1)

Other substances may be used, in addition to or in place of NaCl, to render solutions

isotonic. This is done by taking the process one step further and calculating the amount of
the substance that is equivalent to the amount of NaCl calculated in step 3.

For example, boric acid is often used to adjust isotonicity in ophthalmic solutions because
of its buffering and anti-infective properties. If E for boric acid is 0.50, then the amount of
boric acid needed to replace the NaCl in step 3 can be calculated:

or
or, more simply:
Thus, 0.38 g or 380 mg of boric acid would be required to render the previous ophthalmic
solution isotonic.
Isotonic Buffers
The addition of any compound to a solution will affect the isotonicity since isotonicity is a property of the number of
particles in solution. So the osmotic pressure of a solution will be affected not only by the drug but also by any buffer
compounds that are included in the formulation. But after these compounds have been added, it is still possible that
the solution will not be isotonic. It may be necessary to add additional sodium chloride to bring the solution to
isotonicity, but that would require doing the calculations as shown above.
An alternative to this approach is to use an isotonic buffer. There are two approaches to using isotonic buffers.
Approach 1
In the first approach, the drug is dissolved in an appropriate volume of water (V-value) to make the solution isotonic.
Then the remaining volume needed in the formulation is supplied by an isotonic buffer
An example:

Rx
Procaine HCl 2%
Aqua. dest. q.s. ad 15 ml
M.Ft. Isotonic, buffered injection

The formulation requires 0.3 g of Procaine HCl. V-value tables can been found in standard references and are
tabulated to tell how many ml of water, when added to 0.3 g of drug, will result in an isotonic solution. For Procaine
HCl, 7 ml of water added to 0.3 g of drug will make an isotonic solution. Therefore 0.3 g Procaine HCl is dissolved in 7
ml water, and then sufficient buffered, isotonic vehicle of appropriate pH is added to make 15 ml.
The pH of an isotonic Procaine HCl solution is 5.6. Therefore, an isotonic buffer of approximately that pH would be
used. One commonly used isotonic buffer is the Sorenson's Modified Phosphate Buffer.
The closest Sorenson's buffer to pH 5.6 would be pH 5.9. So to complete the formulation, 8 ml of pH 5.9 Sorensen's
buffer would be added to the 7 ml of Procaine HCl solution. The individual amounts of the Sorenson's buffer to add
can be determined:

Therefore, the compounding procedure would be to weigh 0.3 g Procaine HCl and 0.04 g NaCl, add 7 ml of H2O, 7.2
ml of 0.0667 M NaH2PO4, and 0.8 ml of 0.0667 M Na2HPO4. Filtration sterilize the solution and package in a sterile
final container.
The limitation to this approach is that the final formulation pH may be different than the desired pH. The final pH will
depend on the two pHs and buffer capacities of the Sorensen's buffer and the aqueous drug solution.
Approach 2

The second method is to use the Sorensen's buffer as the entire solvent of the formulation. In this situation, the
sodium chloride equivalent of the active drug is subtracted from the "NaCl required for isotonicity" listed in the table.
This method has the advantage that the pH of the final solution will be the pH of the selected Sorensen's buffer.
An example:

Ampicillin Sodium
30 mg/ml
Sodium Chloride
q.s.
Make 15 ml of sterile, buffered, isotonic solution at pH 6.6

1. A ratio calculation will show that 0.45 g of Ampicillin Sodium is needed for this formulation.

2. The sodium chloride equivalent for Ampicillin Sodium is 0.16. Therefore, the drug will contribute osmotic pressure
as if it was 0.072 g of sodium chloride.

3. To have a pH of 6.6, 9.0 ml of monobasic sodium phosphate solution and 6.0 ml of dibasic sodium phosphate
solution are needed. Then to adjust the isotonicity, 0.0735 g of sodium chloride is needed, but the Ampicillin Sodium
equivalent will account for 0.072 g. So an additional 0.0015 g of sodium chloride must be added.

Therefore, the compounding procedure would be to weigh 0.45 g of Ampicillin Sodium and 0.0015 g of sodium
chloride. Add 9.0 ml of monobasic sodium phosphate solution and 6.0 ml of dibasic sodium phosphate solution.
Filtration sterilize the solution and package in a sterile final container.