Mod 3.

2 - Colligative
Properties and Isotonic
Solutions
Mod 4 – Solubility and
Distribution Phenomena
ANA MARIE L. RUBENICIA, PHD
 Homogeneous Systems
Concentration Expressions of
Solutions
Electrolytes, Ionic Equilibria/ Buffers
Solutions
Colligative Properties of Solutions
Isotonic Solutions
Solubility and Distribution Phenomena
Colligative Properties of
Solutions
 Dissolution of the
dispersed phase
Solutions Does not scatter
light

Can’t be seen using

microscopy
PROPERTIES OF DRUG MOLECULES IN
A SOLUTION
ADDITIVE PROPERTIES
Depend on the total contribution of atoms in
the molecules or on the sum of the
properties of the constituents in a solution
Mass, Molar Refraction
CONSTITUTIVE PROPERTIES
Depend on the arrangement and to a lesser
extent on the kind of atoms within a molecule
Optical Rotation, Refractive index
COLLIGATIVE PROPERTIES
Depend mainly on the number of particles in
a solution
Colligative Properties of a
Solution 
Colligative Properties Four Colligative Properties:
This is defined as a physical 1. Vapor pressure
property of a solution that
depends mainly on the lowering
particles that are present in a 2. Boiling point
solution.
elevation
It is a physical property that
varies according to the 3. Freezing point
concentration of the dissolved depression
solute. 
4. Osmotic pressure
exists
Things to remember when it comes to the
application of colligative properties to
pharmaceutical systems:
 For non-electrolytes ⟶values of colligative
properties are the same for different solutes at the
same molar concentration.
 For strong electrolytes ⟶values of colligative
properties depend on the number of ions.
 For weak electrolytes ⟶values of colligative
properties depend on ionization.
 The solute is nonvolatile, and the solvent is water.
 Solutions are dilute.
Colligative Properties of a
Solution
When water is pure and does not contain solute,
 vapor pressure is 23.77 mmHg
 boiling point is 100 oC
 melting and freezing point is 0 oC
 osmotic pressure does not exist
When a non-volatile solute is added or is
dissolved in water and creates a solution,
the above properties of water are changed
when a solution is formed.
Colligative Properties of a
Solution 
Four Colligative Properties:

1. Vapor pressure lowering

2. Boiling point elevation
3. Freezing point depression
4. Osmotic pressure exists
Colligative Properties of a
Solution
Vapor Pressure of
Solutions
What is the effect in the vapor
pressure of water which is
23.77 mmHg when a non-
volatile solute is added?
Answer:
vapor pressure lowering 
the vapor pressure of a
solution is less than the pure
solvent
Colligative Properties of a
Solution
Vapor Pressure of
Solutions
vapor pressure lowering 
the vapor pressure of a
solution is less than the pure
solvent.
This is expressed by Raoult's
Law, which states
that the vapor pressure of a
solvent over a dilute solution is
equal to the vapor pressure of
the pure solvent, times the
mole fraction of the solvent in
the solution.
Colligative Properties of a
Solution
Boiling Point of
Solutions
What is the effect in the boiling
point of water (100 oC) when a
non-volatile solute is added?
Answer:
boiling point elevation 
there will be an increase in
100 oC of pure water when a
nonvolatile solute is added
forming a solution. 
Colligative Properties of a
Solution
Boiling Point of
Solutions
boiling point elevation  there
will be an increase in 100 oC of
pure water when a nonvolatile
solute is added forming a
solution. 
Tb )
Change in boiling point (
Tb = Kbm

Tb = boiling point elevation

Kb = molal elevation constant
or ebullioscopic constant,
for water it is 0.513 deg
Kg/mole
Colligative Properties of a
Solution
Boiling Point of
Solutions boiling point elevation
If you add 5 g of sucrose in 50
mL water, what will be the
boiling point when the change
Tb=
in boiling point is 1.05 (
1.05 )?
Answer:
Tb= 1.05

Tb = 101.05
Colligative Properties of a
Solution
Osmotic Pressure of
Solution Osmotic Pressure
Osmotic pressure is the
pressure that results from form
osmosis.
Osmosis is the diffusion of
the solvent through a semi-
permeable membrane that
allows only the solvent to pass
through it.
 Colligative Properties of a
Solution
Osmotic Pressure of
Solution Osmotic Pressure
Osmotic pressure is the pressure that results from form osmosis.
Osmosis is the diffusion of the solvent through a semi-permeable membrane
that allows only the solvent to pass through it.

A B

diffusion
Colligative Properties of a
Solution
Osmotic Pressure of
Solution Osmotic Pressure
 Osmosis always takes
place in the direction that
will equalize the
concentration of all
components on both sides
of the membrane. 
 When osmotic pressure is
equal on both sides of the
membrane, the system is
isoosmotic. In biological
fluids, the equilibration is
termed is isotonic.  
Colligative Properties of a
Solution
Osmotic Pressure of
Solution Osmotic Pressure
Colligative Properties of a
Solution
Freezing Point of
Solutions freezing point depression
What is the effect in the freezing point of
water which is 0 oC when a non-volatile
solute is added?
Answer:
freezing point depression,   there is
always a decrease in the temperature for
the freezing point of the solution
compared to that for pure water.
adding salt to pure water causes it to
freeze at a temperature below 0 oC.
Colligative Properties of a
Solution
Freezing Point of
Solutions
freezing point depression,   there
is always a decrease in the
temperature for the freezing point of
the solution compared to that for
pure water.
Tf )
Change in boiling point (
For nonelectrolytes ( value is always
equal to 1):
Tf = Kfm; 

Tf = freezing point depression

Kf = molal depression constant
or cryoscopic constant; for
water it is 1.86 deg Kg/mole
Colligative Properties of a
Solution
freezing point Tf )
Change in boiling point (
depression Kf = molal depression constant or
cryoscopic constant; for water it is
1.86 deg Kg/mole
Colligative Properties of a
Solution
 freezing point
depression
Calculate the freezing point depression of a 5 molal glucose solution,
Liso of glucose is 1.86.

Formula:

Substitution What is the freezing point of the 5 m

glucose solution?
= 1.86 x 5
=C-
= 9.3 C
=- C
Compute the freezing point depression of a solution containing 0.9%
by wt/volNaCl (molwt 58.5). L iso of NaCl is 3.4

Formula:

Substitution What is the freezing point of the 3 m

glucose solution?
= 3.4 x 0.154
=C-
= 0.52 C =C-
=- C
Isotonic Solutions
Isotonic Solutions

Isotonic Solutions
 Cause no swelling or contraction of the tissues with
which they come in contact, and produce no
discomfort when instilled into the eye, nasal tract,
blood or other tissues
Buffered Isotonic Solution
  Pharmaceutical solutions that are meant for
application to delicate membranes should be adjusted
to approximately the same osmotic pressure as that of
the body fluids.
 Nasal, ophthalmic and parenteral solutions
Isotonic Solutions
Pharmaceutical Solutions intended for
Delivery of Drug through Parenteral Route
Pharmaceutical Solutions intended for
Delivery of Drug through Ocular Route
Pharmaceutical Dosage
Form
Formulation of a Sterile Eye Drop
 Tetrahydrozoline HCl
(0.05%)
 Purified water
 Sodium chloride
 Boric acid
 Sodium borate
 Benzalkonium
chloride(0.01%)
 Edetate disodium (0.1%
Tonicity Adjustments
Methods
A. Freezing Point Depression Method
Solutions prepared to be isotonic have colligative
properties similar to those of body fluids
A typical standard isotonic solution employed in pharmacy
is sodium chloride solution 0.9% w/v or 0.009g/mL, which
has a freezing point depression of 0.52 oC.
What is the freezing point of normal saline solution or
0.9% NaCl in water? -->
− 0.52 o C.
Tonicity Adjustments
Methods
A. Freezing Point Depression Method
Solutions prepared to be isotonic have colligative
properties similar to those of body fluids
A typical standard isotonic solution employed in pharmacy
is sodium chloride solution 0.9% w/v or 0.009g/mL, which
has a freezing point depression of 0.52 oC.
What is the freezing point of normal saline solution or
0.9% NaCl in water?
0.52 deg C.
Tonicity Adjustments
Methods
A. Freezing Point Depression Method
Solutions prepared to be isotonic have colligative
properties similar to those of body fluids
Thus, to make a hypotonic solution isotonic, the freezing
point of hypotonic solution must be lowered to − 0.52 deg
C.
To lower the freezing point, tonicity agents may be added
such as NaCl, boric acid, dextrose, etc.
To calculate the amount of NaCl needed to make an
isotonic solution,
Tonicity Adjustments
Methods
B. Sodium Chloride Equivalent Method
As we have mentioned normal saline solution is 0.9% or
0.009 g/mL NaCl solution. 
The E value of any drug can be used to estimate the
amount of NaCl or other tonicity agents needed to make a
drug solution isotonic. Follow the steps below:
Tonicity Adjustments
Methods
B. Sodium Chloride Equivalent Method
Step 1: Convert the amount of drug in the solution to
its equivalent in sodium chloride.

Step 2: Comapre this amount with that present in

0.9% sodium chloride solution
)
Step3: Difference between the latter amount and the
equivalent amount to compute for the amount needed
for tonicity adjustment:
Calculate the amount of NaCl needed to make a 0.65 % w/v KCl solution
isotonic (E=0.76).

Step 1 – Identify the sodium Step 2 -Determine the amount of

chloride equivalent of KCl NaCl in normal saline in a volume
equal to that of the prescription
order (drug solution)

Step 3 - Calculate the amount of How to compound:

NaCl needed to make the drug
solution isotonic Dissolve 0.65 g of potassium
=- chloride  and add  0.406
= 0.9 g – 0.494 g g of sodium chloride in distilled
= 0.406 g water, to make 100 
mL drug solution.
Calculate the amount of NaCl needed to fill this prescription:
Rx
Zinc sulfate 120mg (E= 0.16)
Antipyrine 650 mg(E= 0.17)
NaClqs
Distilled water qs ad 60ml
Step 1 – Step 2 –

= 0.009
Calculate the amount of NaCl needed to fill this prescription:
Rx
Zinc sulfate 120mg (E= 0.16)
Antipyrine 650 mg(E= 0.17)
NaClqs
Distilled water qs ad 60ml
Step 1 – Step 2 –

Step 3 - Calculate the amount of How to compound:

NaCl needed to make the drug Dissolve 120 mg of zinc sulfate ,
solution isotonic 650 mg of Antipyrine and 410 mg of
=- NaCl in distilled water, and qs to 60
= ml.
0.54 g – 0.0192 g – 0.1105 g
= 0.410 g
Solubility and
Distribution
Phenomena
PREPARED BY ANA MARIE L. RUBENICIA, RPH, MS
PHARM
Overview
Exploring the phenomenon or facts of solubility and
distribution that governs pharmaceutical solutions. The
understanding of this phenomenon helps the pharmacist
to:

(1) select the best solvent for a new drug or a

mixture of drugs
(2) overcome problems arising during the
preparation of pharmaceutical solutions and
(3) have information about the structure and
intermolecular forces of the drug.
Objectives

 Describe solute, solvent, and solutions.

 Understand qualitatively and quantitatively
the theory and applications of solubility and
distribution phenomena.
 Define and understand the terms and concept
of solubility and miscibility
 Recognize factors that affect solubility
SOLUBILITY

Solubility – the concentration of solute in a

saturated solution at a certain temperature.
- the amount of solute wherein the solvent
can dissolve all the solute it can in a given
temperature.
- the spontaneous interaction of two or
more substances to form homogenous
molecular dispersion.
Solubility
SOLUTION
 A homogenous system in which the solute is molecularly dispersed, or
dissolved in a solvent.
Components of solution
Solvent – present in the greatest quantity. Types:
 Polar
 Nonpolar
 Semipolar
Solute – can be gases, liquids, or solids. Types:
 Non-electrolytes – do not form ions when dissolved in water; do not
conduct electric current.  Examples: Estradiol, glycerin, urea, and
sucrose
 Electrolytes -  form ions in solution, thus conduct electric current.
Examples
 Strong electrolytes – completely ionized in water (Ex.: Sodium chloride,
 Weak electrolytes – partially ionized in water (Ex.: Aspirin, Atropine)
Solutions and Solubility

Saturated solution – solution containing the

maximum concentration of a solute dissolved
in the solvent. The additional solute will not
dissolve in a saturated solution.  
Unsaturated or subsaturated solution –
solution containing the dissolve solute in a
concentration below that necessary for
complete saturation at a definite temperature.
 
Supersaturated solution – solution contains
more of the dissolved solute that it would
normally contain at a definite temperature,
were the undissolved solute is present .
Solubility Expression found
in USP/NF and Remington’s
Pharmaceutical Sciences
Descriptive Term
 
VERY SOLUBLE
FREELY SOLUBLE
SOLUBLE
SPARINGLY SOLUBLE
SLIGHTLY SOLUBLE
VERY SLIGHTLY SOLUBLE
PRACTICALLY INSOLUBLE OR More than 10,000 parts
INSOLUBLE
Parts of solvent (mL) required to dissolve
1 part of solute (g)
Less than 1 part
1 – 10 parts
10 – 30 parts
30 – 100 parts
100 – 1,000 parts
1,000 – 10,000 parts
 
Solubility

Types of Solvent
 Polar solvents
 Nonpolar solvents
 Semipolar solvents
Solubility

POLAR SOLVENTS
 Dissolve ionic solutes and
other polar substances.
Solubility

Polar Solvents
The solubility of various solutes in water may
be due to;
 Dipole moment
 Hydrogen bonds (dissolves phenols, alcohols,
aldehydes, ketones, amines and other O and N
containing compounds
 The difference in the acidic and basic character
of the constituents
 Structural features such as the ratio of the polar
to the nonpolar groups of the molecule
 Solubility
Polar Solvents
The solubility of substances is affected by structural
features:
 As the number of nonpolar chain of an aliphatic alcohol
increases, solubility in water decreases. 
 Straight-chain monohydroxy alcohols, aldehydes,
ketones, and acids with more than 4 or 5 carbons
cannot enter into the hydrogen-bonded structure of
water and hence are only slightly soluble
 Water solubility increases when additional polar groups
are present in the molecule as found in propylene
glycol, glycerin, and tartaric acid
 The branching of the carbon -chain reduces the nonpolar
effect and leads to an increase in water solubility.
Solubility

NON-POLAR SOLVENTS
Can dissolve nonpolar solutes through induced dipole
interactions. Such as oil dissolves carbon tetrachloride,
benzene, mineral oil.
Solubility

NON-POLAR SOLVENTS
 Unable to reduce attraction between ions of strong and
weak electrolytes due to low dielectric constant
 Aprotic solvents (neither accept nor donate protons), so
cannot break covalent bonds and ionize weak electrolytes
 Cannot form hydrogen bridges with nonelectrolytes.
 Can dissolve nonpolar solutes with similar internal
pressures through induced-dipole interactions (weak van
der Waals forces)
 Ionic and polar solutes are not soluble or are only slightly
soluble
Solubility

SEMIPOLAR SOLVENTS
induce certain degree of polarity in non polar solvent
molecules.
Solubility

SEMIPOLAR SOLVENTS
induce certain degree of polarity in non polar solvent
molecules.
 May act as intermediate solvents to bring out the
miscibility of polar and nonpolar liquids
 Examples;
 Acetone – increases the solubility of ether in water
 Alcohol – increases miscibility of the water-castor oil
mixture
 Propylene glycol – increases miscibility of water and
peppermint oil; water and benzyl benzoate
Solubility

SOLUBILITY OF LIQUIDS IN LIQUIDS

Liquid-liquid pharmaceutical solutions include;
 Spirits and elixirs – volatile oil + alcohol
 Collodions – ether + alcohol
 Aromatic waters – volatile oil + water
 Hydroalcoholic solutions – alcohol + water
 Lotions, sprays and medicated oils – blended fixed oils
Solubility

The Solubility of Liquids in Liquids  (Liquid -

Liquid System) 
Categories  of Liquid-Liquid System
 Complete miscibility
 Liquids that mix in all proportions
 Examples: Water-alcohol; glycerin-alcohol; alcohol-
acetone; benzene-CCl4
 Partial miscibility
 When liquids are mixed, two layers are formed, each
containing some of the other liquid in a dissolved
state.
 Examples: water-ether; water-phenol
Solubility
Partial Miscibility
The mutual solubilities of partially miscible liquids are
influenced by temperature (Critical Solution Temperature).
 Upper Consolute Temperature – the mutual solubilities
of the two conjugate phases increase with temperature
until the composition becomes identical.  A homogenous
or a single phase is formed Ex: phenol and water(66.8
deg C).
 Lower Consolute Temperature – the solubilities of two
liquid phase increase as the temperature is lowered Ex: 
 Triethylamine and water
 No Critical Solution Temperature – has neither an
upper nor a lower consulate temperature, shows partial
miscibility over the entire temperature range at which the
mixture exists. Ex : ethyl ether and water.
 Both Upper and Lower Consolute – nicotine and water
(208 and 60.8 deg C).
Solubility
SOLUBILITY OF LIQUIDS IN LIQUIDS
Solubility of Solids in Liquids (Solid-Liquid System)
 weak acids and bases  +  strong acids and bases = salt
form  (increases water solubility of the drugs)
 Carboxylic acids with more than 5 carbons are relatively
insoluble in water but form soluble salts with NaOH,
carbonates, and bicarbonates.
 Fatty acids with more than 10 carbon atoms form soluble
soaps with the alkali metals. Such as oleic acid is insoluble
in water but is soluble in alcohol and ether.
 Hydroxy acids (tartaric and citric acids) are quite soluble in
water because of their hydroxyl groups but not potassium
and ammonium bitartrates
 Sodium citrate + ASA = soluble acetylsalicylate ion
Factors Affecting Solubility

 Temperature
 Polarity and Hydrogen Bonding
 Particle Size
 pH
 Solvents
Solubility

Rephrasing “like dissolves like”---

Solubility of a substance can be predicted only qualitatively and
depends on SOLVENT – SOLUTE INTERACTION, such as with
the concept of “like dissolves like” and other considerations as
polarity, dielectric constant, association, solvation, internal
pressures, acid-base reaction, end other factors. 
 Temperature
 Polarity and Hydrogen Bonding
 Particle Size
 pH
 Solvents
The end…