DP0214: PHARMACEUTICAL

CALCULATIONS III
BY
PHARMACIST JAMES
Pharmacist James 01/30/2024
ISOTONIC SOLUTIONS
 Differentiate between the terms isosmotic, isotonic,
hypertonic, and hypotonic.
 Apply physical chemical principles in the calculation
of isotonic solutions.
 Perform the calculations required to prepare isotonic
compounded prescriptions.

Pharmacist James 01/30/2024

ISOTONIC SOLUTIONS
 When a solvent passes through a semipermeable membrane from a
dilute solution into a more concentrated one, the concentrations
become equalized and the phenomenon is known as osmosis.

 The pressure responsible for this phenomenon is termed osmotic

pressure and varies with the nature of the solute. If the solute is a non
electrolyte, its solution contains only molecules and the osmotic
pressure varies with the concentration of the solute.

 If the solute is an electrolyte, its solution contains ions and the

osmotic pressure varies with both the concentration of the solute and
its degree of dissociation. Thus, solutes that dissociate present a
greater number of particles in solution and exert a greater osmotic
pressure than undissociated molecules.
Pharmacist James 01/30/2024
ISOTONIC SOLUTIONS
 Like osmotic pressure, the other colligative properties of
solutions, vapor pressure, boiling point, and freezing point,
depend on the number of particles in solution.
 Therefore, these properties are interrelated and a change in
any one of them will result in a corresponding change in the
others. Two solutions that have the same osmotic pressure
are termed isosmotic. Many solutions intended to be mixed
with body fluids are designed to have the same osmotic
pressure for greater patient comfort, efficacy, and safety.
 A solution having the same osmotic pressure as a specific
body fluid is termed isotonic (meaning of equal tone) with
that specific body fluid.
Pharmacist James 01/30/2024
ISOTONIC SOLUTIONS
 Solutions of lower osmotic pressure than that of a
body fluid are termed hypotonic, whereas those having
a higher osmotic pressure are termed hypertonic.
 Pharmaceutical dosage forms intended to be added
directly to the blood or mixed with biological fluids of
the eye, nose, and bowel are of principal concern to the
pharmacist in their preparation and clinical application

Pharmacist James 01/30/2024

ISOTONIC SOLUTIONS
 Body fluids, including blood and tears, have the same
osmotic pressure as that of a 0.9% w/v sodium
chloride solution.
 Solutions having the same osmotic pressure as that of
0.9% w/v NaCl solution are said to be ISOTONIC
with blood.
 Solutions with a higher osmotic pressure than body
fluids are called hypertonic and those with a
lower osmotic pressure are called hypotonic.

Pharmacist James 01/30/2024

Special clinical considerations of tonicity
 It is generally accepted that for ophthalmic and
parenteral administration, isotonic solutions are better
tolerated by the patient than those at the extremes of
hypo- and hyper tonicity.
 With the administration of an isotonic solution, there is
a homeostasis with the body’s intracellular fluids.
Thus, in most instances, preparations that are isotonic,
or nearly so, are preferred.
 However, there are exceptions, as in instances in which
hypertonic solutions are used to ‘‘draw’’ fluids out of
edematous tissues and into the administered solution.
Pharmacist James 01/30/2024
Special clinical considerations of tonicity
 Most ophthalmic preparations are formulated to be isotonic, or
approximately isotonic, to duplicate ophthalmic tears for the comfort
of the patient.
 These solutions are also prepared and buffered at an appropriate pH,
both to reduce the likelihood of irritation to the eye’s tissues and to
maintain the stability of the preparations.
 Injections that are not isotonic should be administered slowly and in
small quantities to minimize tissue irritation, pain, and cell fluid
imbalance.
 The tonicity of small-volume injections is generally inconsequential
when added to large-volume parenteral infusions because of the
presence of tonic substances, such as sodium chloride or dextrose in
the large-volume infusion, which serve to adjust the tonicity of the
smaller added volume.
Pharmacist James 01/30/2024
Special clinical considerations of tonicity
 Intravenous infusions, which are hypotonic or hypertonic,
can have profound adverse effects because they generally are
administered in large volumes.
 Large volumes of hypertonic infusions containing dextrose,
for example, can result in hyperglycemia, osmotic diuresis,
and excessive loss of electrolytes.
 Excess infusions of hypotonic fluids can result in the osmotic
hemolysis of red blood cells and surpass the upper limits of
the body’s capacity to safely absorb excessive fluids.
 Even isotonic fluids, when infused intravenously in excessive
volumes or at excessive rates, can be deleterious due to an
overload of fluids placed into the body’s circulatory system.
Pharmacist James 01/30/2024
Physical/chemical considerations in the
preparation of isotonic solutions
 The calculations involved in preparing isotonic
solutions may be made in terms of data relating to the
colligative properties of solutions.
 Theoretically, any one of these properties may be used
as a basis for determining tonicity. Practically and
most conveniently, a comparison of freezing points is
used for this purpose. It is generally accepted that -
0.52C is the freezing point of both blood serum and
lacrimal fluid.

Pharmacist James 01/30/2024

Physical/chemical considerations in the
preparation of isotonic solutions
 When one gram molecular weight of any nonelectrolyte,
that is, a substance with negligible dissociation, such as
boric acid, is dissolved in 1000 g of water, the freezing
point of the solution is about 1.8C below the freezing point
of pure water.
 By simple proportion, therefore, we can calculate the
weight of any nonelectrolyte that should be dissolved in
each 1000 g of water if the solution is to be isotonic with
body fluids.
 Boric acid, for example, has a molecular weight of 61.8g;
thus (in theory), 61.8 g in 1000 g of water should produce
a freezing point of 1.86C. Therefore
Pharmacist James 01/30/2024
 Physical/chemical considerations in the
preparation of isotonic solutions

 Therefore
1.86 C = 61.8 g
0.52 x(g)
x=17.3 g
In short ,17.3 g of boric acid in 1000g of water ,having
a weight a weight –in-volume strength of approximately
1.73%(w/v), should make a solution isotonic with
lacrimal fluid.

Pharmacist James 01/30/2024

Physical/chemical considerations in the
preparation of isotonic solutions
 With electrolytes, the problem is not so simple. Because
osmotic pressure depends more on the number than on the kind
of particles, substances that dissociate have a tonic effect that
increases with the degree of dissociation; the greater the
dissociation, the smaller the quantity required to produce any
given osmotic pressure.
 If we assume that sodium chloride in weak solutions is about
80% dissociated, then each 100 molecules yields 180 particles,
or 1.8 times as many particles as are yielded by 100 molecules
of a nonelectrolyte. This dissociation factor, commonly
symbolized by the letter i, must be included in the proportion
when we seek to determine the strength of an isotonic solution
of sodium chloride (m.w. 58.5g):
Pharmacist James 01/30/2024
CALCULATION OF DISSOCIATION
FACTOR (i)
 The dissociation factor, symbolized by the letter i, can
be calculated by dividing the total number of particles
(which include undissociated molecules and ions) in a
solution by the number of particles before dissociation,
i.e.,

Pharmacist James 01/30/2024

CALCULATION OF DISSOCIATION
FACTOR (i)

Total number of particles of solute in a soln after dissociation

i = Number of particles before dissociation

 For example; What is the dissociation factor of NaCl,

having 80% dissociation in water? Assume that we
have 100 particles of NaCl prior to dissociation. Upon
80% dissociation, 100 molecules of sodium chloride
yield:

Pharmacist James 01/30/2024

CALCULATION OF DISSOCIATION
FACTOR (i)
Nacl →Na+ and Cl –
100 0 0 at t=0
20 80 80 after a certain time
Total =180
i=180/100= 1.8

Pharmacist James 01/30/2024

 Physical/chemical considerations in the
preparation of isotonic solutions

 Therefore
1.86 C x i = 58.5 g
0.52 x(g)

1.86 C x 1.8 = 58.5 g

0.52 x(g)
x=9.09 g
Hence, 9.09 g of sodium chloride in 1000 g of water should
make a solution isotonic with blood or lacrimal fluid. In
practice, a 0.90% w/v sodium chloride solution is considered
isotonic with body fluids.
Pharmacist James 01/30/2024
Brainstorming
1. What is the dissociation factor of potassium chloride,
having 80% dissociation in water?
2. What is the dissociation factor of zinc chloride,
having 80% dissociation in water?

Pharmacist James 01/30/2024

CALCULATION OF DISSOCIATION
FACTOR (i)
 Important note; if the number of ions is known ,we
may use the following values,
 Nonelectrolytes = 1
 Substances that dissociate into 2 ions =1.8
 Substances that dissociate into 3 ions =2.6
 Substances that dissociate into 4 ions =3.4
 Substances that dissociate into 5 ions =4.2

Pharmacist James 01/30/2024

SODIUM CHLORIDE EQUIVALENTS
OF DRUG SUBSTANCES
 A special problem arises when a prescription directs us to make
a solution isotonic by adding the proper amount of some
substance other than the active ingredient or ingredients.
 Given a 0.5% w/v solution of sodium chloride, we may easily
calculate that 0.9 g - 0.5 g = 0.4 g of additional sodium chloride
that should be contained in each 100 mL if the solution is to be
made isotonic with a body fluid.
 But how much sodium chloride should be used in preparing
100 mL of a 1% w/v solution of atropine sulfate, which is to be
made isotonic with lacrimal fluid? The answer depends on how
much sodium chloride is in effect represented by the atropine
sulfate.

Pharmacist James 01/30/2024

SODIUM CHLORIDE EQUIVALENTS OF
DRUG SUBSTANCES
 The sodium chloride equivalent of a chemical is defined as the
amount of sodium chloride (in grams ), which creates conditions
identical osmotic pressure equal to1 g of the drug.
 The sodium chloride equivalents are symbolized by the letter E.
 The quantities of two substances that are isotonic equivalents
are proportional to the molecular weight of each multiplied by
the i value of the other.
 Thus, if the molecular weight and i value of a given chemical are
known, one can calculate the sodium chloride equivalent, E, of
that chemical as follows:

Pharmacist James 01/30/2024

SODIUM CHLORIDE EQUIVALENTS
OF DRUG SUBSTANCES

E = MW of NaCl x i value of the chemical

i value of NaCl MW of the chemical

Pharmacist James 01/30/2024

SODIUM CHLORIDE EQUIVALENTS
OF DRUG SUBSTANCES
 To return to the problem involving 1 g of atropine sulfate in
100 mL of solution:
Molecular weight of sodium chloride = 58.5; i = 1.8
Molecular weight of atropine sulfate = 695; i = 2.6

695 x1.8 = 1 (g)

58.5 x 2.6 x (g) = 0.12 g of sodium chloride represented
by 1 g of atropine sulfate
 Because a solution isotonic with lacrimal fluid should
contain the equivalent of 0.90 g of sodium chloride in each
100 mL of solution, the difference to be added must be 0.90
g - 0.12 g = 0.78 g of sodium chloride.
Pharmacist James 01/30/2024
SODIUM CHLORIDE EQUIVALENTS
OF DRUG SUBSTANCES
 If the number of grams of a substance included in a
prescription is multiplied by its sodium chloride
equivalent, the amount of sodium chloride represented
by that substance is determined.
 The procedure for the calculation of isotonic solutions
with sodium chloride equivalents may be outlined as
follows:
 Step 1. Calculate the amount (in grams) of sodium
chloride represented by the ingredients in the
prescription. Multiply the amount (in grams) of each
substance by its sodium chloride equivalent.
Pharmacist James 01/30/2024
SODIUM CHLORIDE EQUIVALENTS
OF DRUG SUBSTANCES
 Step 2. Calculate the amount (in grams) of sodium
chloride, alone, that would be contained in an isotonic
solution of the volume specified in the prescription,
namely, the amount of sodium chloride in a 0.9% solution
of the specified volume. (Such a solution would contain
0.009 g/mL)
 Step3.Subtract the amount of sodium chloride represented
by the ingredients in the prescription (Step 1) from the
amount of sodium chloride, alone, that would be
represented in the specific volume of an isotonic solution
(Step 2). The answer represents the amount (in grams) of
sodium chloride to be added to make the solution isotonic.
Pharmacist James 01/30/2024
SODIUM CHLORIDE EQUIVALENTS
OF DRUG SUBSTANCES
 Step 4. If an agent other than sodium chloride, such as
boric acid, dextrose, or potassium nitrate, is to be used
to make a solution isotonic, divide the amount of
sodium chloride (Step 3) by the sodium chloride
equivalent of the other substance.

Pharmacist James 01/30/2024

Example
1. How many grams of sodium chloride should be used in compounding
the following prescription?
Rx
Pilocarpine Nitrate …………………..0.3 g
Sodium Chloride ………………….….q.s.
Purified Water ad………………….….30 mL
Make isoton. sol.
Sig. For the eye.
 Step 1. 0.23 x 0.3 g = 0.069 g of sodium chloride represented by the
Pilocarpine nitrate
 Step 2. 30 X 0.009 = 0.270 g of sodium chloride in 30 mL of an isotonic
sodium chloride solution
 Step 3. 0.270 g (from Step 2) - 0.069 g (from Step 1) = 0.201 g of sodium
chloride to be used, answer.
Pharmacist James 01/30/2024
Example
1. How many grams of boric acid should be used in
compounding the following prescription?
Rx
Phenacaine Hydrochloride 1%
Chlorobutanol 1/2%
Boric Acid q.s.
Purified Water ad 60
Make isoton. sol.
Sig. One drop in each eye.

Pharmacist James 01/30/2024

Example
 Step 1. 0.20 x 0.6 g = 0.120 g of sodium chloride represented by
Phenacaine hydrochloride
0.24 X 0.3 g = 0.072 g of sodium chloride represented by
Chlorobutanol
Total: 0.192 g of sodium chloride represented by both ingredients
 Step 2. 60 X 0.009 = 0.540 g of sodium chloride in 60 mL of an
isotonic sodium chloride solution
 Step 3. 0.540 g (from Step 2) - 0.192 g (from Step 1) = 0.348 g of
sodium chloride required to make the solution isotonic
But because the prescription calls for boric acid:
 Step 4. 0.348 g ÷ 0.52 (sodium chloride equivalent of boric acid)
= 0.669 g of boric acid to be used, answer.

Pharmacist James 01/30/2024

Brainstorming
1. How many grams of potassium nitrate could be used
to make the following prescription isotonic?
Rx
Sol. Silver Nitrate 60mL
1:500 w/v
Make isoton. sol.
Sig. For eye use.

Pharmacist James 01/30/2024

Brainstorming
1. How many grams of sodium chloride should be used in
compounding the following prescription?
Rx
Ingredient X 0.5
Sodium Chloride q.s.
Purified Water ad 50mL
Make isoton. sol.
Sig. Eye drops.
 Let us assume that ingredient X is a new substance for
which no sodium chloride equivalent is to be found in Table
11.1, and that its molecular weight is 295 and its i factor is
2.4.
Pharmacist James 01/30/2024
Using an Isotonic Sodium Chloride
Solution to Prepare Other Isotonic
Solutions
 A 0.9% w/v sodium chloride solution may be used to
compound isotonic solutions of other drug substances as
follows:
 Step 1. Calculate the quantity of the drug substance needed
to fill the prescription or medication order.
 Step 2. Use the following equation to calculate the volume of
water needed to render a solution of the drug substance
isotonic:
g of drug x drug’s E value =
0.009
mL of water needed to make an isotonic solution of the drug
(the volume of the drug substance is considered negligible)
Pharmacist James 01/30/2024
Using an Isotonic Sodium Chloride Solution to
Prepare Other Isotonic Solutions
 Step 3. Add 0.9% w/v sodium chloride solution to
complete the required volume of the prescription or
medication order.
Example: Using this method, determine the volume of
purified water and 0.9% w/v sodium chloride solution
needed to prepare 20 mL of a 1% w/v solution of
hydromorphone hydrochloride (E = 0.22).

Pharmacist James 01/30/2024

Using an Isotonic Sodium Chloride Solution to
Prepare Other Isotonic Solutions
 Step 1. 20 mL x 1% w/v = 0.2 g hydromorphone
needed
 Step 2. 0.2 g x 0.22
0.009
= 4.89 mL purified water required to make an isotonic
solution of hydromorphone hydrochloride, answer.
 Step 3. 20 mL - 4.89 mL = 15.11 mL 0.9% w/v
sodium chloride solution required, answer.

Pharmacist James 01/30/2024

Use of Freezing Point Data in Isotonicity
Calculations
 ∆Tf- the depression of freezing temperature of solution
shows how many degrees Celsius reduces the freezing
temperature of 1% solution compared to the freezing
point of pure solvent.
 Freezing point depression of serum -0.52

Pharmacist James 01/30/2024

Use of Freezing Point Data in Isotonicity
Calculations
 Freezing point data (∆Tf) can be used in isotonicity calculations
when the agent has a tonicic effect and does not penetrate the
biologic membranes in question (e.g., red blood cells). As
stated previously, the freezing point of both blood and lacrimal
fluid is -0.52C. Thus, a pharmaceutical solution that has a
freezing point of - 0.52C is considered isotonic.
 Representative data on freezing point depression by medicinal
and pharmaceutical substances are presented in Table 11.2.
Although these data are for solution strengths of 1% ( ∆Tf1%),
data for other solution strengths and for many additional agents
may be found in physical pharmacy textbooks and in the
literature. Freezing point depression data may be used in
isotonicity calculations as shown by the following:
Pharmacist James 01/30/2024
Use of Freezing Point Data in Isotonicity
Calculations
 The freezing point depression (or lowering) of a solvent
is dependent only on the number of particles in the
solution. Blood plasma has a freezing point of −0.52
{or freezing point depression of 0.52, i.e., (− [−0.52])}.
 Hypotonic solution will have a higher freezing point
and consequently need the addition of adjusting
substance to reach a freezing point of -0.52 C.
 If freezing point depression value of a chemical in
certain concentration is known, one can calculate the
concentration of that chemical required for isotonicity
by setting a proportion as follows;
Use of Freezing Point Data in Isotonicity
Calculations

Known percentage conc.

of a given chemical = X
Freezing point depression Freezing point
depression
of the chemical at that of blood plasma
concentration
Use of Freezing Point Data in Isotonicity
Calculations
X = Percentage conc. Of the chemical required to be
isotonic with blood plasma.
Since the freezing point depression of a series of
compound at 1% conc is readily available from standard
references, the above expression can be represented as;

1% chemical = X
Tf of the chemical Tf of the plasma or
tears
Examples
 1% NaCl solution has a freezing of 0.576 C. what is
the percentage concentration of NaCl required to make
isotonic solution.
Use of Freezing Point Data in Isotonicity
Calculations
 0.9% sodium chloride has the same osmotic pressure
and the same freezing point depression of 0.52 as that
of blood plasma, red blood cells, and tears.
 Drug solutions which have a freezing point depression
of 0.52 are, therefore, isotonic with blood .
 A list of freezing point depression values of selected
compounds at 1% concentration in table 11.2. These
_Tf values may be used to calculate the concentration
of tonicity agents, such as sodium chloride or boric
acid, needed to render a hypotonic drug solution
isotonic with blood plasma.
Use of Freezing Point Data in Isotonicity
Calculations
 The following steps may be used to find the
percentage concentration of NaCl required to render
hypotonic drug solutions isotonic with blood plasma;
 Step 1:Find the value of freezing point depression of
the drug at 1% concentration, _T1% f from Table 11.2
 Step 2:Subtract _T1% f of the drug from the value of
freezing point. depression of 0.9% sodium chloride
solution, i.e., 0.52. This difference may be symbolized
as _T′f, which is the freezing point lowering needed
for isotonicity
Use of Freezing Point Data in Isotonicity
Calculations
 Step 3:Since 0.9% sodium chloride has a freezing
point depression of 0.52, one can calculate the
percentage concentration of sodium chloride required
to lower the difference in freezing points, i.e., the
value obtained in Step 2, _T′f, by the method of
proportion.
Example of Calculations Using Freezing
Point Data
1. How many milligrams each of sodium chloride and
dibucaine hydrochloride are required to prepare 30 mL of
a 1% solution of dibucaine hydrochloride isotonic with
tears?
To make this solution isotonic, the freezing point must be
lowered to - 0.52. From table 11.2 it is determined that a
1% solution of dibucaine hydrochloride has a freezing
point lowering of 0.08. Thus, sufficient sodium chloride
must be added to lower the freezing point an additional
0.44 (0.52 - 0.08). Also from Table 11.2, it is determined
that a 1% solution of sodium chloride lowers the freezing
point by 0.58. By proportion:
Pharmacist James 01/30/2024
Example of Calculations Using Freezing
Point Data

1% (NaCl) = 0.58C
% (NaCl) 0.44C
x = 0.76% (the concentration of sodium chloride needed to lower the
freezing point by 0.44C, required to make the solution isotonic)
 Thus, to make 30 mL of solution,
30mL x1% = 0.3 g = 300 mg dibucaine hydrochloride, and
30 mL x 0.76% = 0.228 g = 228 mg sodium chloride, answers.
Note: Should a prescription call for more than one medicinal and/or
pharmaceutical ingredient, the sum of the freezing points is
subtracted from the required value in determining the additional
lowering required by the agent used to provide isotonicity.

Pharmacist James 01/30/2024

Example of Calculations Using Freezing
Point Data
You can also use the proportion as follows:

0.9% = 0.52C
x% 0.44C
X = 0.76%

Pharmacist James 01/30/2024

Example of Calculations Using Freezing
Point Data
Compound the following prescription.
Rx
Atropine sulfate 1%( the freezing point is
0.07)
Sodium chloride qs
Purified water ad 100
Make isoton. Soln
Sig. one drop in each eye
Example of Calculations Using Freezing
Point Data
Adjust 1000 ml of a 2% w/v solution of anhydrous
dextrose isotonic with body fluids; adjusting substance
is sodium chloride. The freezing point of 1% w/v
anhydrous dextrose solution is – 0.101 C.
Example of Calculations Using Freezing
Point Data
Render the following solution isosmotic with blood
and tears;
Ephedrine hydrochloride 0.1 g
Chlorbutol 0.1g
Water for preparations to 20ml
Adjusting substance is sodium chloride.
The freezing point of Ephedrine hydrochloride is 0.165
and Chlorbutol is 0.138.
Group work.
1. A local ophthalmologist is treating one of his patients for a post LASIK eye
infection that is not responding to topical ciprofloxacin. These infections,
although rare, can occur after laser in situ keratomileusis (LASIK) surgery for
vision correction. Topical amikacin sulfate has been shown to be effective for
the treatment of eye infections due to ciprofloxacin-resistant Pseudomonas,
Burkholderia ambifaria, Mycobacterium chelonae, and Mycobacterium
fortuitum. The ophthalmologist prescribes 60 mL of a 2.5% amikacin sulfate
isotonic solution, 2 drops in the affected eye every 2 hours. Amikacin sulfate
USP (C22H43N5O13•2H2SO2), m.w., 781.76, is an aminoglycoside-type
antibiotic containing 3 ions.
(a) Determine the weight in grams of amikacin sulfate needed to prepare the solution.
(b) Calculate the sodium chloride equivalent (E value) for amikacin sulfate.
(c) Calculate the amount of sodium chloride needed to make the prepared solution
isotonic.
(d) How many milliliters of 23.5 % sodium chloride injection should be used to
obtain the needed sodium chloride?

Pharmacist James 01/30/2024

Group work.
The agent brimonidine tartrate has a molecular weight
of 442 and dissociate into two ions when in solution. It is
used as a 0.1% ophthalmic solution in the treatment of
glaucoma.
Calculate:
(a) the sodium chloride equivalent of brimonidine
tartrate ,
(b) whether, without additional formulation agents ,a
0.1% solution would isotonic, hypotonic, or hypertonic
with tears.
The commercial product is available in 10mL container.
 Be the energy you want to attract
52 Pharmacist James 01/30/2024