Physical pharmacy Dr/ Nagia Amr FaYed

Solution and Solubility

Mixture of two or more components that form a homogenous
True solution: molecular dispersion.
Solute: The dissolved agent (less part of the solution)
Solvent: The component in which the solute is dissolved (More part)
One in which equilibrium is established between dissolved
Saturated solution: and un- dissolved solute at a definite temperature.
Dissolved solute precipitate
Sub-saturated One that contains the dissolved solute in a concentration below
solution or that necessary for complete saturation at a definite temperature.
unsaturated solution:
A supersaturated Contains more of the dissolved solute than it contains in a
solution: saturated state at a definite temperature.
Solubility in a It is the concentration of the solute in a saturated solution at a
quantitative way: certain temperature.
Solubility in a It is the spontaneous interaction of (solute & solvent) to
qualitative way form a homogeneous molecular dispersion.
Supersaturated solution:
 Some salts (e.g. Sodium thiosulfate) dissolved in large amounts at an elevated
temperature and upon cooling fail to crystallize from the solution.
 Crystallization form supersaturated solution stimulated by adding a "seed
crystal" or scratching the side of the flask.
Solubility expressions
a) The solubility of a drug can be expressed in terms of:
1. Molarity Number moles of solute/volume of solution in liters
2. Normality Gram equivalent weight of solute/liter of solution

1|Page
Physical pharmacy Dr/ Nagia Amr FaYed
3. Molality Moles of solute/mass of solvent in Kilogram
4. Mole fraction Moles of solute/moles solute + moles of solvent
5. Percentage % W/W, %W/V, %V/V
b) The USP lists the solubility of drugs as: the number of ml of solvent in which 1 g of
solute dissolve.
 Example: l g of boric acid dissolves in 18 ml of water, and in 4 ml of glycerin.
c) Substances whose solubility values are not known are described by the
following:
Terms Parts of solvents require for 1 part of solute
Very soluble Less than 1 part
Freely soluble 1 to 10 parts
Soluble 10 to 30 parts
Sparingly soluble 30 to 100 parts
Slightly soluble 100 to 1000 parts
Very slightly soluble 1000 to 10,000 parts
Practically insoluble More than 10,000 parts
Determination of solubility
Points should be observed in solubility determination: ‫مهم‬
 The solute and solvent must be pure
 Saturated solution must be obtained
 The method of separation must be satisfied
 The method of analysis must be reliable ‫فعاله‬
 Temperature must be adequately controlled
Solute-Solvent interactions
N.B when the adhesive are more than the cohesive forces, the solubility or the miscibility
is enhanced. ‫تتحسن‬
 Adhesive force > Cohesion force

2|Page
 Physical pharmacy Dr/ Nagia Amr FaYed
 Selection of the most suitable solvent is based on "like dissolves like".
Examples:
 Polar solutes dissolve in polar solvents (salts & sugar dissolve in water).
 Non polar solutes dissolve in non-polar solvents (naphthalene dissolves in benzene).
 Semi polar solvents such as acetone and alcohol act as intermediate solvent.
1- If A-A > A-B  The solute will be excluded.
Example: Benzene & water
2- If B-B > A-A  the solvent will not be able to break the binding forces between
solute molecules.
Example: NaCl in benzene
3- If A-B > A-A or B-B, or the three forces are equal  the solute will disperse ‫ & تنتشر‬form
a solution
Example: NaCl in water
Classification of solvents
1. Polar solvents:
Polar solvents such as (water, glycols, methyl & ethyl alcohol), dissolve ionic solutes &
other polar substances.
Solubility of substances in polar solvents depends on:
a) Structural features.
b) Hydrogen bond formation.
c) Solvation through dipole interaction.
a) Structural features:
The ratio of polar to non-polar group in the molecule ( polarity  Solubility)
Ex: Straight chain ( C  polrity  solubility)
 Monohydroxy alcohols, aldehydes & ketones with > 5 Carbon atoms are
slightly soluble in water.

3|Page
 Physical pharmacy Dr/ Nagia Amr FaYed
Branching of the carbon chain in aliphatic alcohols  increases water solubility.
 Tertiary butyl alcohol more soluble than n-butyl alcohol.
When additional polar groups such in propylene glycol, glycerol and tartaric acid, water
solubility increase.
b) Hydrogen bond formation:
 Water dissolves phenols, alcohols and other oxygen & nitrogen containing
compounds that can form hydrogen bonds with water.
c) Solvation through dipole interaction:
 Polar solvents solvate molecules & ions through dipole interaction forces & H.B
2. Non polar solvents
 Non polar solvents are unable to reduce the attraction between the ions due to their low
dielectric constants.
 Non polar solvents can dissolve non polar solutes through weak Van der Waals forces
(London).
 Example: solutions of oils & fats in carbon tetrachloride or benzene.
3. Semi-polar solvents
 They can act as intermediate solvents to bring about miscibility of polar & non
polar liquids.
Example:
1. Acetone increases solubility of ether in water.
2. Propylene glycol increases the solubility of water and peppermint oil and of water and
benzyl benzoate.
The relation between polarity and solubility may be used in practice to alter the
solubility of a drug in a pharmaceutical solution.
 Solvent blending or co-solvency: is to mix solvents of different polarities to form a
solvent system of optimum polarity to dissolve the solute. solvents must be
miscible ‫مهمة‬

4|Page
 Physical pharmacy Dr/ Nagia Amr FaYed
Ex: Water, ethanol, glycerin, propylene glycol, polyethylene glycol 400 or sorbitol solution.
Solvents may be classified according to their dielectric constants as
Polar (δ > 50)
Semi polar (δ = 20 – 50) or
Non polar (δ = 1 – 20)
1) Solubility of gases in liquids
Examples of pharmaceutical solutions of gases dissolved in liquid include:
 Effervescent preparations
 Ammonia water& hydrochloric acid
 Aerosols
Solubility of gases in liquids
 It is the concentration of dissolved gas when it is in equilibrium with some of the
pure gas above the solution.
Factors affecting solubility of gas in liquid
1. Effect of Pressure
 Henry's law gives the relationship between gas pressure and gas solubility.
Henry's law states that in a dilute solution, the mass of a gas dissolved in a given
volume of liquid at a constant temperature is directly proportional to the partial
pressure of the gas.
C=σP
Caution: When the pressure above the solution is released (decreases), solubility of gas
decrease  the gas may escape from the container with violence.
 Occurs in effervescent solutions when the stopper container is removed.
2. Effect of temperature
As the temperature increases the solubility of gases decreases
 Owing to the great tendency‫ ميل‬of the gas to expand compared to the solvent.
Pharmaceutical application: The pharmacist should be cautious in opening containers of

5|Page
 Physical pharmacy Dr/ Nagia Amr FaYed
gaseous solutions in warm climates.
 A container filled with a gaseous with high vapor pressure, such as ethyl nitrite,
should be immersed in ice or cold water before opening the container, to reduce the
temperature and pressure of the gas.
3. Effect of electrolytes (Salting out)
 Adding electrolytes (NaCl) & non electrolytes (sucrose) to gaseous solutions 
induces liberation of gases from the solutions. This is referred to as salting out. Why?
This is due to the more affinity of the salt ions or the highly polar electrolyte for the water
and reduction of the aqueous environment adjacent to the gas molecules.
4. Effect of chemical reaction
 Gases such as hydrogen chloride, ammonia and carbon dioxide show deviation from
Henry's law, with a resultant increase in solubility.
Example: hydrogen chloride gas is about 10,000 times more soluble in water than oxygen.
2) Solubility of liquids in liquids
Examples of pharmaceutical solutions containing a liquid in anther liquid:
1. Hydro alcoholic solutions,
2. Aromatic waters, such as chloroform water and peppermint water,
3. Spirits and elixir
4. Medicated oils
Liquid-liquid systems may be divided into 2 categories:
1- Systems showing complete miscibility 2-Systems showing Partial miscibility
Complete miscibility occurs when: The Partial miscibility results when: Cohesive
adhesive forces (A-B) >> cohesive forces (A-A forces >> adhesive forces
or B-B). Such as phenol and water and water (A)
Such as alcohol & water - glycerin & alcohol and hexane (B).
- benzene & carbon tetrachloride. A-A > B-B.
3) Solubility of Solids in Solids

6|Page
Physical pharmacy Dr/ Nagia Amr FaYed
Substitution The molecular size of the solute is the same as that of the solvent
Interstitial effect The solute molecules are much smaller than the solvent molecules
4) Solubility of solid in liquid
Solution of solids in liquids are the most common type
Factors affecting the solubility of solids in liquids
1. Temperature
 Solubility of such solid increase as the temperature is increased. ‫طردي‬
 ∆H is positive and dissolution is endothermic ‫التفاعل ماص للحرارة‬
 Exothermic an increase in temperature, a decrease in solubility.
Plots of solubility versus temperature to
describe the effect of temperature on a given
system.
 Most of the curves are continuous.

 Sodium sulphate exists as the decahydrate Na2SO4, 10H2O up to dissolution in

water is an endothermic process.
 Its solubility therefore increases with rise in temperature until 32.5° is reached.
 Above this temperature the solid is converted into the anhydrous form Na2SO4, and
the dissolution of this compound is an exothermic process.
 The solubility change from a positive to a negative slope
2. Molecular Structure of solute
Example
1. The introduction of hydroxyl group increase the solubility as enhanced by the more
than 100 fold difference in the solubility of phenol and benzene
2. The conversion of a weak acid to its sodium salt  greater degree of ionic

7|Page
Physical pharmacy Dr/ Nagia Amr FaYed
dissociation
Ex: Aqueous solubility of Salicylic acid and its sodium salt, which are 1:550 and 1:1,
respectively.
3. Aqueous solubility decreased by modification of a parent drug such as esterification.
A reduction in solubility is beneficial in practice to provide a suitable method for:
b) Protecting the parent drug from
a) Masking the taste of a parent drug
excessive degradation in the GIT
Ex: Chloramphenicol palmitate is used in Ex: Erythromycin propionate is less soluble
rather than the more soluble and very bitter and less readily degraded than erythromycin.
chloramphenicol base
3. Nature of solvent and co-solvency
 A mixture of solvents is used to increase the solubility of weak electrolytes as
well as non-electrolytes.
Cosolvancy: increasing solubility of poorly soluble substance by the use of more than one
solvent or co-solvents such as
 Ethanol Glycerol Propylene glycol Sorbitol
Mechanism of co-solvents: decreasing the interfacial tension or altering the dielectric
constant of the medium
4. Crystal characteristics: polymorphism and solvation
 Conversion to the less soluble and most stable polymorph to the growth of crystals
in suspension formulations
 Many drugs exhibit polymorphism ex: steroids, barbiturates and sulphonamides.
 Amorphous powder lead to an increase in the solubility of a drug compared to that of
its crystalline form.
The effect of polymorphism on solubility
 Increasing the solubility of a crystalline material and its rate of dissolution by using a
metastable polymorph.

8|Page
Physical pharmacy Dr/ Nagia Amr FaYed
 Hydrated crystals has lower aqueous solubility than their un- hydrated forms
 The aqueous solubility of other (non-aqueous, solvates) is greater than those of the
un-solvated forms.
Example:
 Anhydrous penicillin is more soluble than trihydrated penicillin
 Theophylline anhydrous is more soluble than its monohydrate form.
This decrease in solubility can lead to precipitation of drugs from solutions.
5. Particle size of the solid
 The solubility of a substance increases with decreasing particle size
Indicated by the following Equation:
Log S/S0 = 2γ M / 2.303 RT p r
 When the particles have a very small radius, and any further decrease in size causes a
decrease in solubility.
6. PH effect
 Most of the drugs are either weak acid or weak base and are poorly soluble in water.
The solubility of such drugs affected by the change in pH:
 The solubility depends on the degree of ionization (K a), and K a depend on pH
  pH of weakly acidic drug,  unionized acid molecules in the solution increased 
 The solubility
 Solubility of weakly basic drug or their salt decrease with the increase in the pH
Precipitation: when the solubility of the unionized species is less than that of the ionized
form.
The relationship between pH and the solubility and pKa value of an acidic drug is given by
modified form of the Henderson-Hasselbalch equation:

For weak acid:

𝑺−𝑺𝟎
PH = pKa + log
𝑺𝟎

9|Page
Physical pharmacy Dr/ Nagia Amr FaYed
or basic drug the relationship is
𝑺𝟎
PH = pKa + log
𝑺−𝑺𝟎
7. Common ion effect
Thus, the addition of a compound bearing a common ion reduces the solubility of
sparingly soluble salt.
8. Effect of indifferent electrolytes on the solubility product
 If salts carrying no common ion added to a solution of slightly soluble electrolyte, it
increases the solubility as they tend to lower activity coefficient.
9. Effect of non-electrolytes on the solubility of electrolytes
The solubility of electrolytes depends on
 The dissociation of dissolved molecules into ions.
 Dielectric constant of the solvent
 Polar nature of the solvent.(Ex: Water)
If a water-soluble non-electrolyte such as alcohol added to an aqueous solution of a
sparingly soluble electrolyte, the solubility of the latter is decreased
 Because the alcohol lowers the dielectric constant
10. Effect of electrolytes on the solubility of non-electrolytes
 The presence of a very soluble electrolyte (e.g. ammonium sulphate), the ions of which
have affinity for water, will reduce the solubility of a non-electrolyte
 This effect is important in the precipitation of proteins.
11. Effect of complex formation
 The solubility of some solute in a liquid increased or decreased by the addition of
a third substance which forms a complex
 Complex formation aid to solubility in the preparation of solution of mercuric
iodide (HgI 2).
 The mercuric iodide is not soluble in water but is soluble in aqueous solutions of
potassium iodide because of the formation of a water-soluble complex ( K2 (HgI4))
10 | P a g e
Physical pharmacy Dr/ Nagia Amr FaYed
A number of compounds, such as nicotinamide and betacylodextrin used to increase the
solubility of poorly water-soluble drugs.

For example )‫(هااااام‬

1. Gentistic acid forms complex with caffeine that is less soluble than caffeine alone.
2. Tetracycline forms an insoluble complex with calcium ions present in milk or any other
preparation containing calcium salts.
12. Effect of Solubilizing Agents (SAA)
 Agents forming large aggregates or micelles in solution when their concentrations
exceed critical micelle concentration (CMC)
 In aqueous solution the center of these aggregates is a separate organic phase and
organic solutes taken up by the aggregates, producing an increase in their solubility
in water known as solubilization.
Colligative properties of solutions
Colligative properties of solutions are properties that depend upon the concentration of
solute molecules or ions, but not upon the identity of the solute.
1. Vapor Pressure Lowering
 Dissolving a nonvolatile substance in volatile liquid results in a lowering of the
liquid's vapor pressure.
 The presence of solute decreases the surface area to solvent molecules so reduces the
rate of solvent vaporization.
 The relationship between the vapor pressures and the concentration of components
is described by Raoult's law.
 The partial pressure exerted by any component of an ideal solution is equal to the
vapor pressure of the pure component multiplied by its mole fraction in the solution.
PA = XA Po A

11 | P a g e
Physical pharmacy Dr/ Nagia Amr FaYed
 The total pressure of a gaseous mixture is equal to the sum of partial pressures for all
its components (Dalton's law of partial pressure), the total vapor pressure exerted
by a solution containing components is:
P Solution = ∑ PA = ∑ XA Po A
A nonvolatile substance is one whose vapor pressure is negligible (Po = 0), and so the
vapor pressure above a solution containing only nonvolatile solutes is due only to the
solvent:
P Solution = X Solvent Po Solvent
Example:
Compute the vapor pressure of an ideal solution containing 92.1g of glycerin, C3H5(OH)3,
and 184.4g of ethanol is 0.178 atm at 40 0C. Glycerin is essentially nonvolatile at this
temperature.
P Solution = X Solvent Po Solvent
No. Mol. Of ethanol = 184.4 / 46.0 = 4 Mole
No. Mol. Of glycerin = 92.1 / 75.067 = 1Mole
4 𝑚𝑜𝑙𝑒
XC2H5OH = (1 𝑚𝑜𝑙𝑒+4 𝑚𝑜𝑙𝑒) = 0.8
P solution =X solvent P∘ solvent =0.8×0.178 atm=0.142atm
The vapor pressure of:
 Pure Ethanol is 0.178 atm at 40 oC
 Ethanol / glycerin solution is 0.142 atm at 40 oC
 Vapor pressure lowering 0.142 atm at 40 oC
2. Elevation of the Boiling Point of a Solvent
 The boiling point of a liquid is the temperature at which its vapor pressure is equal
to ambient atmospheric pressure
 The vapor pressure of a solution is lowered due to the presence of nonvolatile
solutes, the solution’s boiling point will be increased

12 | P a g e
Physical pharmacy Dr/ Nagia Amr FaYed
 The boiling point elevation and is directly proportional to the molal concentration of
solute species:
ΔTb = Kbm
 Boiling point elevation constants depend on the identity of the solvent
 The lowered vapor pressure and elevated boiling point depends on the total
number of solute particles, not on the mass or size or chemical identities of the
particles.
A 1 m aqueous solution of sucrose (342 g/mol) and a 1 m aqueous solution of ethylene
glycol (62 g/mol) will exhibit the same boiling point

3. Depression of the Freezing Point of a Solvent

 Solutions freeze at lower temperatures than pure liquids. “de-icing” schemes that
use salt
 Calcium chloride, or urea to melt ice on roads and sidewalks,
 Ethylene glycol as an “antifreeze” in automobile radiators.
 Rock salt (NaCl), (CaCl2), or a mixture of the two are used to melt ice.
 Seawater freezes at a lower temperature than fresh water and so the Arctic and
Antarctic oceans remain unfrozen even at temperatures below 0 °C (as do the body
fluids of fish and other cold-blooded sea animals that live in these oceans).
 The freezing point depression and is directly proportional to the molal concentration
of the solute

ΔTf = Kf m
 Boiling point elevation constants depend on the chemical identity of the solvent
Phase Diagram for an Aqueous Solution of a Nonelectrolyte
Phase diagrams for water and an aqueous solution are shown in Figure

13 | P a g e
Physical pharmacy Dr/ Nagia Amr FaYed

0 100

These phase diagrams show water (solid curves) and an aqueous solution of
nonelectrolyte (dashed curves)
For the solution is located beneath the corresponding curve for
The liquid-vapor curve
the solvent, depicting the vapor pressure lowering, ΔP
Consequently, at any given pressure, the solution’s boiling point is observed at a higher
temperature than that for the pure solvent
 For the solution is displaced left of that for the pure
The solid-liquid curve
solvent, representing the freezing point depression
The solid-gas curves  For the solvent and its solution are identical.
4. Osmosis and Osmotic Pressure of Solutions
 Osmosis results in the transfer of solvent molecules from a sample of low (or zero)
solute concentration to a sample of higher solute concentration.
 This causes the level of the solution to rise, increasing its hydrostatic pressure and
resulting in a faster transfer of solvent molecules back to the pure solvent side.
 When the pressure reaches a value that yields a reverse solvent transfer rate equal to
the osmosis rate, bulk transfer of solvent cease. This pressure is called the osmotic

14 | P a g e
Physical pharmacy Dr/ Nagia Amr FaYed
pressure (Π) of the solution.
The osmotic pressure of a dilute solution is related to its solute molarity, M, and absolute
temperature, T, according to the equation
II = MRT
Reverse Osmosis Water Purification
 If greater pressure is applied the water will go from the more concentrated solution to
a less concentrated (more pure) solution this is called reverse osmosis
 Reversed osmosis (RO) is used to purify water in many applications from
desalination plants in coastal cities to water – purifying machines in grocery stores,
and smaller reverse – osmosis household units
Examples of osmosis are evident in many biological systems
 Because cells are surrounded by semipermeable membranes.
 Solute concentrations are important when solutions are injected into the body
 Solutes in body cell fluids and blood serum  osmotic pressure of 7.7 atm.
 Solutions injected into the body must have the same osmotic pressure as blood
serum; that is, they should be isotonic with blood serum
Less concentrated solution More concentrated solution
 Hypotonic solution, is injected in  Hypertonic solution, is
sufficient quantity to dilute the blood injected, the cells lose water to
serum, water from the diluted serum the more concentrated
passes into the blood cells by osmosis, solution, shrivel, and possibly
causing the cells to expand and rupture. die in a process called
This process is called hemolys crenation
Practical applications of colligative properties:
 The preparation of isotonic intravenous & isotonic lacrimal solutions.
 The colligative properties of solutions may also be used in determining the molecular
weight of the solutes, or in case of electrolytes, the extent of ionization.

15 | P a g e
Physical pharmacy Dr/ Nagia Amr FaYed
Osmosis
It is a phenomenon in which a solvent pass through a semi-permeable membrane from a
dilute solution into a more concentrated one with the result that the concentrations tend to
become equalized.
 Osmosis refers to the flow of solvent only.
 If there is a movement of solute in the opposite direction the behavior is called
Diffusion.
Osmotic pressure
 It is the excess pressure which applied to a solution to prevent the passage of solvent
into it when both are separated by semi-permeable membrane.
1-Non-electrolyte: 2-An electrolyte:
 Solution contains only molecules  Solution contains ions and the osmotic
and the osmotic pressure of pressure of the solution varies with the
solution will vary only with the concentration and the degree of
concentration of solute. dissociation of solute.
Substances which dissociated to give large
number of ions in solution will have greater
osmotic pressure than that of un-dissociated
particles.
Iso-osmotic solution: No net movement of solute occurs across the membrane, then the
solutions
 Iso-osmotic and will have equal osmotic pressures.
Isotonic: If two iso osmotic solutions remain in osmotic equilibrium when separated
by a biological membrane
 Examples: 0.9% sodium chloride solution has an osmotic pressure identical to
that of body fluids and it is isotonic

16 | P a g e
Physical pharmacy Dr/ Nagia Amr FaYed
 Some solutions are iso-osmotic but not isotonic. This is because the physiology of
cell membrane must be considered.
Examples:
1) Boric acid solution 2) 1.8% solution of urea
That is iso-osmotic with blood is not  Has the same osmotic pressure as
isotonic!! Why?? 0.9% sodium chloride solution but
 Because it produces hemolysis‫ تحلل‬of red the urea solution produces
blood cells due to ability of boric acid to hemolysis.
cross the red blood cell membranes
 2% boric acid solution serves as an
isotonic ophthalmic preparation.
Effect of solution tonicity on blood cells
 If small quantity of blood is mixed with solution
1) Isotonic solution containing 0.9% of NaCl per 100 ml  The cells retain
their normal size
 Water will pass out of the cells through the cell
membrane until the salt concentration on both sides are
2) Hypertonic solution
identical.
(2% NaCl)
 The cell to shrink and become wrinkled
 Called "Plasmolysis" which is reversible process.
 Water enters the blood cells,
 Cell swell and finally burst with liberation of
3) Hypotonic solution
hemoglobin.
(0.2% NaCl)
 Called hemolysis which is an irreversible process
(dangerous).
 The eye can tolerate a range of tonicities as low as 0.6% and as high as 1.8% sodium
chloride solution.

17 | P a g e
Physical pharmacy Dr/ Nagia Amr FaYed
Isotonicity and different routes of administration
1) Subcutaneous  Is not necessarily to be isotonic because small dose but
injection: Isotonicity reduces pain.
2) Intramuscular  Should be isotonic or slightly hypertonic to increase
injection (I. M) penetration.
 Should be isotonic "Large volume"
3) Intravenous  Hypotonic cause hemolysis
injection (I.V)  Hypertonic solution may be administered slowly into a vein
 Hypertonic large volume administered through a cannula
into large vessels.

4) Intrathecal  Should be isotonic

injection
 Rapidly diluted by tear, but most of it is isotonic to decrease
5) Eye drops
irritation
6) Eye lotion  Preferably isotonic
7) Nasal drops  Isotonic, but not essentially

Methods of Adjusting Solutions Tonicity

These methods are classified to:
Class I Class II
 Adding substance to lower freezing  Adding H2o, then isotonic buffer
point of solution to -0.52°C solution to brought to the final volume
1. Freezing point depression (FPD) 1. White -Vincent method
"cryoscopic method". 2. Sprowis method
2. NaCl equivalent method.

1. Freezing point Method

Due to osmotic pressure is not a readily measurable quantity, it is usual to make use of the

18 | P a g e
Physical pharmacy Dr/ Nagia Amr FaYed
relationship between the colligative properties and to calculate the osmotic pressure from a
more easily measured property such as the freezing point depression.
 A solution which is isotonic with blood and lachrymal secretion has a freezing point
depression, ∆TF, of 0.52°C
 Freezing point depressions (∆TF) of 1 % solution for a series of drugs compounds
are given in reference texts (e.g. Remington and Merk index)
For example:

 1% NaCl solution has a freezing point depression of 0.576°C. Isotonic saline solution of
NaCl can be obtained by calculating the percentage concentration of sodium chloride
required to produce freezing point depression of 0.52 °C (fpd of blood and tears) by simple
proportion as:
1%  0.576 o C
X %  0.52 o C
1 𝑥 0.52
X= = 0.9 % (normal saline)  Isotonic solution
0.576
A- For non-electrolyte
𝑀.𝑤𝑡 𝑥 0.52
X (gm dissolved in 1000gm water) =
(1.86)

Example:
 Boric acid, has a M.wt 61.8, in theory 61.8g dissolved in 1000 gm water produce
freezing point - 1.86
𝑀.𝑤𝑡 𝑥 0.52 61.8 𝑥 0.52
=
(1.86) (1.86)

X = 17.3 gm in 1000 gm in water or 1.73 % W/V

 1.73 % W/V boric acid should make isotonic solution with lachrymal fluid.
B-For electrolyte

With electrolyte, the problem is different. Since osmotic pressure depends on the number
rather than the kind of particles.

19 | P a g e
Physical pharmacy Dr/ Nagia Amr FaYed
Dissociation factor (i) must be included in the proportion to determine the strength of
isotonic solution.
0.52 (C) x molecular weight
= g of solute per 1000g of water
1.86 (C)x dissociation factor (i)

Calculation of Dissociation factor:

Total number of particles of solute after dissociation
Dissociation factor (i) =
Number of particles before dissociatoin

In a weak solution of sodium chloride 80% is dissociation then each 100 molecules
yield 180 particles, or 1.8 times as many particles as are yielded by a non-electrolyte.

NaCl → Na + Cl

100%  80% + 80%

80 Na+ 80 Cl + (20 Undissociated NaCl) =180
𝟏𝟖𝟎
 Dissociation factor = = 1.8
𝟏𝟎𝟎

 The amount of sodium chloride (M.wt= 58.5) needed to prepare isotonic solution
is determined as following:
0.52 (C) x molecular weight 0.52 x 58.5
X= =
1.86 (C)x dissociation factor (i) 1.86 x 1.8

X = 9.09 g in 1000 g water or 0.9% w/v sodium chloride produce isotonic solution
with body fluids.

Substance Dissociation factor

A Non electrolyte 1
B Substance that dissociate into 2 ions 1.8
C Substance that dissociate into 3 ions 2.6
D Substance that dissociate into 4 ions 3.4
E Substance that dissociate into 5 ions 4.2
 The most widely used isotonicity modifiers are dextrose and sodium chloride.
20 | P a g e
Physical pharmacy Dr/ Nagia Amr FaYed
 Isotonicity adjustment made after the addition of all other ingredients because each
ingredient will contribute to the overall osmotic pressure of a solution.
Important notes
 F.P of blood & tears = - 0.52º
 Any solution has F.P = -0.52º is isotonic
 Any solution has F.P ˃ -0.52º is hypotonic (-0.4º hypotonic)
 Any solution has F.P < -0.52º is hypotonic (-0.6º hypertonic)
Add solute to hypotonic solution to reach f.p.d of blood (-0.52º).
Example:
Rx
Atropine sulfate 2%
Fpd (ΔTf) of atropine sulfate = 0.07 °C
Make isotonic with boric acid Q.S
(ΔTf) of boric acid = 0.39 °C
Purified water ad 15ml
𝟏% 𝟐%
=
𝟎.𝟎𝟕°𝐂 𝐗 º𝐂
X= 0.14°C

Freezing point depression required = 0.52 °C - 0.14 °C = 0.38 °C

1%  0.29

X  0.38
𝟎.𝟑𝟖
X=
𝟎.𝟐𝟗
= 1.3%

1.3 gm  100 ml

X gm  15 ml
X = 0.195 g of boric acid
2. Sodium Chloride Equivalent Method:
 Sodium chloride equivalent method is the most widely used method to adjust
isotonicity of pharmaceutical solutions.

21 | P a g e
Physical pharmacy Dr/ Nagia Amr FaYed
 NaCl equivalent (E): is the amount of NaCl that will give an equivalent osmotic
effect to that of 1 gm of the designate drug. (Based on number of particles)
 Sodium chloride equivalent (E or E Nac1 1%) for large number of drugs have
been published and can be obtained from some text books.
 Sodium chloride equivalent method is based on the fact that 0.9% concentration
of Sodium chloride in water gives an isotonic solution.
Example:
Calculate the amount of NaCl required to make the following ophthalmic solution isotonic.
Rx
Atropine sulfate 2%
NaCl Q.S
Aqua.dist.qs.ad. 15ml
M. ft. isotonic solution
Amount of drug in the solution. (2% x 15 = 0.3 g)
1gm Atropine  0.13gm NaCl
0.3 gm Atropine  X gm NaCl
X= 0.039 gm NaCl
Amount of sodium chloride for all solution = 0.9 x15 = 0.135 g
Amount of sodium chloride needed to make the desired volume of drug solution isotonic.
= 0.135 g - 0.039g = 0.096 g NaCl needed.
Note: If another substance to adjust tonicity, such as boric acid which 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
X= 0.192g boric acid
 The answer 0.192 g boric acid is very close to the 0.195 g boric acid that was
calculated using freezing point depression method.

22 | P a g e
Physical pharmacy Dr/ Nagia Amr FaYed
1. Freezing-point depression method

Step 1: Reference solution  1%  Freezing-point depression Tf  ‫بتكون معطى في المسألة‬

1%  Tf
Step 2: Contribution of drug  ‫بشوف كمية الدواء هتمثلي كام من درجة التجمد‬
= Amount of drug (%) X Tf for 1%
Step 3: 0.52 C – Step 2
𝟎.𝟗 %
Step 4: Sodium chloride needed =
𝟎.𝟓𝟐
x Step 3  ‫ مل‬011 ‫الكمية اللي هنطلعها هتكون لكل‬

𝑺𝒕𝒆𝒑 𝟒
Amount of NaCl equivalent =
𝟏𝟎𝟎
x volume ‫بتكون معطى‬
‫في المسألة‬
‫غالبا بعد‬
‫ ؟؟‬NaCl ‫ بأي مادة تانية غير ال‬Isotonicity ‫طيب لو عايز اظبط ال‬ ‫ او‬ad ‫كلمة‬
𝟏% q.s ‫ او‬To
=
𝑻𝒇
x Step 3
2. Sodium chloride equivalent method
Step 1: Reference solution: 0.9%, sodium chloride.
𝟎.𝟗 𝐱 𝐕𝐨𝐥𝐮𝐦𝐞
=
𝟏𝟎𝟎

Step 2: Contribution of drug = Amount of drug (gm) X E value

Amount of drug (%) x Volume
Or = X E value
100
Step 3: Step 1 – Step 2 = Amount of NaCl needed
Amount of NaCl needed
Step 4:
𝐸 𝑣𝑎𝑙𝑢𝑒

23 | P a g e
Physical pharmacy Dr/ Nagia Amr FaYed

Buffers and buffer Capacity

Buffer Solution
Definition They are solutions of a compound or mixture can resist‫ يقاوم‬changes in pH upon
addition of small quantities an acid or alkali.
Types of Buffer Solutions
(1) Acidic buffer solutions (pH < 7) (2) An alkaline buffer solution (pH > 7)
 Made from a weak acid and one of its  Made from a weak base and one of its
salts  often sodium salt. salts.
Example Example
 Solution of acetic acid (pKa=4.75) and  Solution of ammonia (pKa =9.25) and
sodium acetate. ammonium chloride.

Example for non-buffer system: A solution of NaCl in water (its pH=7

Buffer action
 Is the ability of a buffer solution to resist changes in pH upon addition of an acid or base
Example:
1- A mixture of weak acid (acetic acid) and its salts (sod. Acetate). This mixture consists of
CH3COOH molecules + CH3COO- & Na+
On addition of strong acid On addition of strong base

H+ (from the strong acid) + CH3COO- OH- (from the strong base) + CH3COOH

CH3COOH CH3COO- + H2O

 H+ ions are neutralized by acetate ions  OH- ions are neutralized by acetic acid
present in the mixture and there is very present in the mixture and there is very
little change in pH value of the mixture. little change in pH value of the mixture.
2-A mixture of a weak base (NH4OH) and its salt (NH4Cl) also behaves in a similar manner.
On addition of strong acid On addition of strong base
H+ (from the strong acid) + NH4OH → H2O + OH (from the strong base) + NH4 → NH4OH
- +

NH4+

Buffer equation
The pH of the buffer depends on
24 | P a g e
Physical pharmacy Dr/ Nagia Amr FaYed

1) The pKa of the buffering substance

2) The relative concentrations of conjugate acid and base
Can be calculated using the Hendreson-Hasselbalch equation. ‫مهمة‬
A. Buffer equation for weak acid and its salts (Acidic buffer)
(𝐬𝐚𝐥𝐭)
PH = Pka + log
(𝑨𝒄𝒊𝒅)
 This equation is satisfactory for calculation within pH range of 4 to 10.
B. Buffer solution for weak base and its salts: (Basic buffer)
Buffer solutions are not prepared from weak bases and their salts because of:
 The volatility
 Poor stability of the bases
 The dependence of their pH on pKw, which is often affected by temperature changes.

Example: a solution of ephedrine base and ephedrine hydrochloride(salt)

The buffer equation for weak base and its salts;
(𝐵𝑎𝑠𝑒)
PH= pKw - pKb + log
(𝑆𝑎𝑙𝑡)
Example: Estimate the pH of a solution Example: Calculate the pH of the buffer
containing 0.10 mole of ephedrine and 0.01 solution consisting of 0.1 M each of acetic acid
mole of ephedrine hydrochloride per liter of and sodium acetate (Pka of acetic acid= 4.76).
solutions. PKb of ephedrine is 4.64. Solution
(salt)
Solution: PH = Pka + log
(𝐴𝑐𝑖𝑑)
(𝐵𝑎𝑠𝑒)
PH= pKw - pKb + log PH = 4.76 + log (0.1/0.1)
(𝑆𝑎𝑙𝑡)

(0.1) PH = 4.76 + log 1

PH= 14 - 4.64 + log
(0.01)
PH 4.76
PH= 14 - 4.64 + 1 = 10.36
Buffer Capacity, buffer index, buffer efficiency, buffer coefficient, buffer value
 The magnitude of a buffer solution to resist changes in pH upon addition of an acid or base
 Or the ratio of increment ‫اضافه‬of strong base or acid (ΔB) to the small change in pH (Δ pH)
brought about by this addition.
 Or the amount of strong acid or base (in gm equivalent per liter) required to change the pH
of 1 liter of a buffer system by one unit.

β = ∆B/∆pH

25 | P a g e
Physical pharmacy Dr/ Nagia Amr FaYed

 The lager β is, the greater the buffer capacity of the system, that is greater its ability to
resist a pH change.
Van Slyke developed a more exact equation for calculation of buffer capacity β
𝟐.𝟑𝟎𝟑 𝐂 𝐊𝐚 [𝐇+]
β=
(𝑲𝒂+ [𝐇+]) 𝟐

Maximum buffer capacity

The greatest capacity (βmax) occurs where [salt]/[acid] = 1 and pH= pKa
 βmax = 0.576 C
Example: A buffer solution contained 0.1 M each of Example: What is the maximum
acetic acid and sodium acetate and its pH was 4.76. To buffer capacity of an acetate buffer
this, 0.01 moles of sodium hydroxide was added and the with a total concentration of 0.20
pH of resultant was 4.85. Calculate the buffer capacity. mol/l?

Solution: β= ∆B / ∆pH = 0.01/ 0.09 = 0.11 mol/L.pH β= 0.576 C = 0.576 x 0.2 = 0.1152

Factors affecting pH of the buffer solutions

I-Temperature effects
The pH of 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.
II-Dilution effects
 Dilution of an acidic buffer shows an increase in the pH
 Dilution of a basic buffer shows a decrease in the PH.
Dilution value is the change in pH of a buffer upon dilution with an equal volume of water.
 Dilution value less than 0.1 pH unit.
III- Salts effect
 Salt added to acidic buffer lowers its pH
 While salt 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 buffers in plasma and the
secondary buffer in erythrocytes.

26 | P a g e
Physical pharmacy Dr/ Nagia Amr FaYed

Primary buffers in erythrocyte include Secondary buffers include

 Carbonic acid/bicarbonate  Hemoglobin/oxyhemoglobin
 Acid/alkali sodium salt of phosphoric acid.  Acid/alkali potassium salt of
(NaH2PO4/Na2HPO4) phosphoric acid.
 Plasma proteins, which behave as acid in (KH2PO4/K2HPO4)
blood, can combine with bases and so act as
buffer
The physiological pH range of blood is 7.36 - 7.4.
2) Lacrimal 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
 The pH of urine is about 6 with a range of 4.5 to 7.8.
 When the pH of the urine is below normal values, hydrogen ions are excreted by the
kidneys.
 When the urine is above pH 7.4, hydrogen ions are retained by action of the kidneys in
order to return the pH to its normal range of values.
Pharmaceutical buffers
Buffers are used in pharmacy to:
a. Adjust pH of the product that required for maximum stability, maximum activity and
minimize the tissue irritation.
b. Maintain pH of product within optimal physiological pH range.
c. Maintain or adjust a specific pH for analytical purpose in pharmaceutical tests and assays.
I-Buffer in tablet formulation
Buffer added to tablets to:
a. Control the pH in the microenvironment surrounding the drug particles to enhance drug
dissolution and absorption,
b. Reduce gastric irritation in formulations of acidic drugs.
II-Buffer in ophthalmic preparation
Buffers are used in ophthalmic preparations to maintain the pH within the physiological pH

27 | P a g e
Physical pharmacy Dr/ Nagia Amr FaYed

range of the lacrimal fluid.

The lacrimal 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.
 Commonly used buffer systems involved in the ophthalmic preparation include;
Borate, phosphate and carbonate buffers.
III-Buffer in parenteral preparation
 The ideal pH of a parenteral preparation is 7.4.
 Parenteral preparation of highly alkaline pH (above 9) can cause tissue necrosis
 Acidic pH (below 3) can result in extreme pain at the site of injection.
 Buffers with low capacity are used to adjust pH to a suitable value for solubility and
stability.
 The pH of small volume parenteral is not necessary required to be at physiological pH
because blood has a good buffering capacity.
 The most commonly used buffers in parenterals are acetate, phosphate, citrate and
glutamate buffers.
IV-Buffers in creams and ointments
 The most commonly used buffers in creams and ointments include citric acid and its
salts or phosphoric acid and its salts.
Steps of Preparation of pharmaceutical buffers
 Select a weak acid having pKa= pH
 Determine the pH and buffer capacity experimentally using a pH meter.

28 | P a g e