IPS - Physical Pharmacy SC Presentation 202324

Integrated Pharmaceutical Sciences 1
PHYSICAL PHARMACY
Ana Marie L. Rubenicia, PhD, RPh

Lecturer
Physical Pharmacy
Application of physical, chemical, and

biological principles in the formulation of
a drug product.
To understand and develop dosage forms
and drug delivery systems
Dosage Form and Drug Delivery Design
Drug
 agent or substance intended for use in the diagnosis, cure,
mitigation, treatment and prevention of disease
Dosage form
 form suited for administration to the patient
Drug product
 a finished dosage form that contains an active drug ingredient
(palatable, convenient, safe, and effective)
Drug delivery systems
 Physical carriers used to deliver medications to specific areas
 Means of administering drugs to the body in a safe, efficient,
reproducible and convenient manner
DRUG + DOSAGE FORM  DRUG PRODUCT
General Considerations for
Dosage Forms Design
 Before a medicinal agent is formulated into one or more
dosage forms, among the factors considered are the physical
and chemical properties of the drug substance and various
therapeutic considerations.
Physical Chemical Biological

 Physical description
 Molecular structure
 Particle size
 Molecular form
 Melting point
 Reactivity  Drug reaching the site of action
 Crystalline structure
 Polymorphism  Elicit of biologic response
 Solubility
 Salt form of the drug Etc
Etc
 pKa and pH
etc
New drug development process
What part is the process Physical
Pharmacy utilized?
IPS Physical Pharmacy - AMRubenicia
Physical Pharmacy
Pharmaceutics:
The science that deals with the development of a drug product.
 Physical Pharmacy
 Biopharmaceutics
• Pharmacokinetics
• Pharmacodynamics
• Physical Pharmacy:
• deals with the physicochemical principles
underlying the development of a successful
dosage form
- Part A -
PHYSICAL PHARMACY
PRINCIPLES
A1. Binding Forces Between

Molecules
- Part A -
PHYSICAL PHARMACY PRINCIPLES
IPS Physical Pharmacy
Binding Forces Between Molecules

• Intramolecular forces VS intermolecular forces
Intramolecular Forces
• “within molecules”
• e.g. Ionic/electrovalent
and Covalent Bonds
Intermolecular Forces
• “between molecules”
• e.g. Van der Waals
Forces, H-bonds
Binding Forces Between Molecules

• Repulsive and Attractive Forces
When molecules interact with each other,

they do so by the actions repulsive and
attractive forces.
• Attractive Forces: “together”
1. Cohesive forces – like
molecules
2. Adhesive forces – unlike
molecules
• Repulsive Forces:
“apart”
At 3 − 4 × 10−8 cm distance, the
attractive and repulsive forces are
equal.
Intermolecular Binding Forces
There are four main types of intermolecular attractive forces:

Van der Waals attractive forces
 Keesom forces (dipole-dipole)
 Debye forces (dipole-induced dipole)
 London forces (induced dipole-induced dipole)
Ion Dipole forces
Ion- dipole forces
Ion- induced dipole forces
Additional and critical attractive force:
Hydrogen bonding
Keesom forces
• Occur when polar molecules

possessing permanent dipoles,
having partial positively charged and
a partial negatively charged end,
interact. → Polar molecule + Polar
molecule
• Dipole-dipole forces
• Orientation effect
Energy of attraction: 1 to 7 kcal/mol
Examples of molecules with permanent
dipoles: water, hydrochloric acid,
alcohol, acetone and phenol. Also
stabilizes protein secondary structure.
Module 1: Introduction to Physical Pharmacy

Debye forces
• Occur when polar molecules

produce a temporary electric
charge dipole in nonpolar
molecules→ polar molecule +
non polar molecule
• Dipole-induced dipole forces
• Induction effect
Examples of easily polarized
molecules are ethylacetate,
methylene chloride and ether.

London forces
• Occur in by internal vibrations in
nonpolar molecules to produce
attraction that arises because of
fluctuating dipoles in neighboring
atoms→non polar molecule + non
polar molecule
• Induced dipole-induced dipole forces
• Dispersion effect
Energy of attraction: 0.5 to 1kcal/mol
(forces are temporary)
Examples of nonpolar molecules
exhibiting London forces are organic
compounds such as carbon disulphide,
carbon tetrachloride and hexane. Also
are found in aliphatic regions of lipid
bilayers for stabilization. Responsible for
liquefaction of gases.

• Ion-dipole forces
• Molecules that are polar are
attracted to either positive or
negative charges→
ion + polar molecule
Examples is a quaternary
ammonium ion with a tertiary
amine.

• Ion-induced dipole forces
• The forces of attraction are
induced by the close proximity of
a charged ion to the nonpolar
molecule → ion + nonpolar
molecule
Examples is iodine and potassium
iodide.

• The Hydrogen Bond
Hydrogen bond can be

intramolecular and intermolecular.
• It is the bond that cause the
attraction of H atom for a strongly
electronegative atom such as O,
N, F, and S.
• It’s a strong type of dipole-dipole
interaction.
• It is partly covalent in nature
• Responsible for the unusual
properties of water such as high
boiling point.
A2. States of Matter
- Part A -
Matter
• Anything that has mass and occupies
space
19
Molecules are
Molecules close but Molecules are
packed close randomly far apart
together orderly arranged
Flows and Fills any

Rigid
assumes shape container
of container completely
20
21
How are the molecules of solid, liquid and
gas behaving? What is responsible for the
behavior?
deposition
Drug products may appear in liquid, solid,
polyphasic, and aerosolized dosage forms.
Thus, to develop a drug product it is

important that we understand the states of
matter; which are the
solid, liquid, and gas they may also be
referred to as phases of matter.
A3. The Gaseous State
- Part A -
The Gaseous State
• Gas exerts pressure.

• Force/Area
• Dynes/cm2 , atm, mm Hg
• Gas has volume.
• Occupies space
•L
• mL = cm3
• Gas equation
• absolute or Kelvin scaleL
• 0 o C = 273.15 Kelvin (K)
Gas Laws
• Assumptions:
• No intermolecular attraction
• Exhibit perfectly elastic
collision
• “rebound with the same
acceleration”
• Formulated by:
• Boyle
• Charles
• Gay-Lussac
Boyle’s Law
• Pressure-Volume relationship at constant T
• Robert Boyle in 1662, states that the pressure (p)
of a given quantity of gas varies inversely with its
volume (v) at constant temperature
𝑃1 𝑉1 = 𝑃2 𝑉2
Charles’ Law
• Volume-Temperature relationship at constant P
• States that the volume of an ideal gas is directly
proportional to the absolute temperature at
constant pressure.
𝑉1 𝑉2
=
𝑇1 𝑇2
Gay-Lussac’s Law
• Pressure-Temperature relationship at constant V
• states that the pressure of a given amount of gas held at
constant volume is directly proportional to the Kelvin
temperature.
𝑃1 𝑃2
=
𝑇1 𝑇2
Combined Gas Laws
General Ideal Gas Law
This equation is correct only for 1 mole

(i.e., 1 g molecular weight)
of gas; for n moles it becomes
Avogadro’s Principle
- states that equal volume of mass at the same
temperature and pressure contain the same
number of molecules.
𝑁 = 6.02 × 1023 molecules / mole

Ideal Gas Law

𝑷𝑽 = 𝒏𝑹𝑻
𝑷 → 𝒂𝒕𝒎
𝑽→𝑳
𝒏 → 𝒎𝒐𝒍
𝑻→𝑲
𝑹 → 𝒎𝒐𝒍𝒂𝒓 𝒈𝒂𝒔 𝒄𝒐𝒏𝒔𝒕𝒂𝒏𝒕

R = 0.08205 liter atm/mole K
R = 8.314 x 106 erg /mole K
R = 8.314 joules/mole K or 1.987 cal/mole K
Ideal Gas Law

𝒏𝑹𝑻 𝑷𝑽
𝑷= 𝒏=
𝑽 𝑹𝑻
𝒏𝑹𝑻 𝑷𝑽
𝑽= 𝑹=
𝑷 𝒏𝑻
𝑷𝑽
𝑻=
𝒏𝑹
Derivation of R:
Calculate the Molar Gas Constant, R.
• 1 mole of gas under STP (standard
temperature, 0oC and pressure, 760 mm Hg)
has a volume of 22.414 Liters.
• R = 0.08205 liter atm/mole K
𝟕𝟔𝟎 𝒎𝒎 𝑯𝒈
𝒂𝒕𝒎 = 𝟏 𝒂𝒕𝒎 𝒙
𝟏 𝒂𝒕𝒎
𝑲 = 𝒐𝑪 + 𝟐𝟕𝟑. 𝟏𝟔
Solution:
1 mole of gas under STP (standard temperature, 0oC and
pressure, 760 mm Hg) has a volume of 22.414 Liters.
𝑷𝑽
𝑹=
𝒏𝑻
(𝟏 𝒂𝒕𝒎)(𝟐𝟐. 𝟒𝟏𝟒 𝑳)
𝑹=
(𝟏 𝒎𝒐𝒍)(𝟐𝟕𝟑. 𝟏𝟔 𝑲)
𝒂𝒕𝒎 𝑳
𝑹 = 𝟎. 𝟎𝟖𝟐𝟎𝟓
𝒎𝒐𝒍 𝑲
Ideal Gas Equation
If 1500 mg of a drug in the vapor state occupies 150 mL at 320 K and 920
mmHg, what is its approximate molecular weight?
Formula: Derive formula for mol wt
𝑃𝑉 = 𝑛𝑅𝑇 𝑚𝑜𝑙 𝑤𝑡 𝑃𝑉 = 𝑔𝑅𝑇
𝑔𝑅𝑇
𝑃𝑉 = 𝑔𝑅𝑇
𝑚𝑜𝑙 𝑤𝑡
𝑚𝑜𝑙 𝑤𝑡 =
𝑃𝑉
Given: Substitution:
g =1.5 g 1.5𝑥0.082𝑥320
𝑚𝑜𝑙 𝑤𝑡 =
R = 0.08205 L atm/mole K 1.21𝑥0.15
T = 320 K
P = 920 mmHg x 1atm/760 mmHg = 1.21 atm
1𝐿
V = 150 mL× = 0.15𝐿
1000𝑚𝐿
Answer:
mol wt = 218.67 g/mole
Calculation of Molecular Weight using

the Ideal Gas Law.
𝒈𝑹𝑻
𝑴𝑾 =
𝑷𝑽
𝑴𝑾 𝒙 𝑷𝑽
𝒈=
𝑹𝑻
The general behavior of gasses with variations
of pressure, volume and temperature can be
given by the _____.
A. Boyle’s law equation

B. Charle’s law equation
C. Gat-Lucssac’s law equation
D. Ideal gas equation
E. Both A and B
REFERENCE:
Physical Pharmacy
Kinetic Molecular Theory (KMT)

• Explains the behaviour of gases
• Supports the validity of gas laws
Kinetic Molecular Theory
Negligible volume
(↑temp,↓pressure)
No interaction under
low pressure
kinetic energy
proportional with
temperature
Elastic bodies and

individual molecules
have different
velocities.
Kinetic Molecular Theory

Fundamental Kinetic Equation
where P – pressure; V - volume occupied by any number n of molecules of mass m

having an average velocity . Using this fundamental equation, we can obtain the root
mean square velocity (usually written μ) of the molecules by an ideal gas.
Root Mean Square Velocity
Graham’s Law , who showed that a lighter gas

difuses more rapidly through a porous membrane
than does a heavier one.
van der Waals Equation for Real Gases
Ideal gas vs Real gas

Real gases are NOT composed of infinitely
small and perfectly elastic non-attracting
spheres.
• Real gas molecules;

• Have finite volume
• Tend to attract one another
The van der Waals Equation for Real Gases
( P + a n2) (V – nb) = nRT

V2
Internal pressure
Excluded volume
van der Waals Equation for Real Gases
𝒂𝒏𝟐
(𝑷 + 𝟐 )(𝑽 − 𝒏𝒃) = 𝑹𝑻
𝑽
When the volume of gas is large

where pressure is low, the
molecules are well dispersed.
𝑷𝑽 = 𝑹𝑻
States that the concentration of dissolved gas is proportional to the

partial pressure of the gas above the solution at equilibrium
Root Mean Square Velocity

Liquefaction of Gases
cool
Gas velocity
loss of KE
decreases
A4. The Liquid State
- Part A -
Liquid state
• Possess less kinetic energy than gases

• Occupy a definite volume denser than gas
• Take the shape of the container
• Incompressible
Liquefaction of gases
Temperature and Pressure

Cooling of gas (low
temperature, cold)
gas molecules loses its
kinetic energy in the form of
heat,
and the velocity of the
molecules decreases +
application of pressure
(increase in pressure) applied
to gas -->
gas molecules are brought
within the sphere of van der
Waals forces and converted
into the liquid.
Gaseous state Liquid state
pressure
temperature
If the temperature is elevated suficiently, a value

is reached above which it is impossible to liquefy
a gas irrespective of the pressure applied.
• Critical Temperature
- Temperature above which liquid no longer exist
• Critical Pressure
- Pressure required to liquefy a gas at Tcrit
• Supercritical fluids
- Mesophase that is between liquid and gas that
exist above critical temperature
Liquefaction of gases
CRITICAL TEMPERATURE (CT),
The critical temperature of water is 374 °C or 647 K, its critical pressure r

is 218 atm. CT and CP of He = 5.2 K and 2.26 atm,
It is the temperature above which a gas cannot be liquefied
even if very high pressure is applied.
A. Critical temperature
B. Latent heat of vaporization
C. Latent heat fusion
D. Melting point
E. Either A or D
REFERENCE:
Physical Pharmacy
AEROSOL is a liquid mixture

of product concentrate and
propellant that are maintained
under high
pressure and below the
critical temperature. Its
preparation is based on the
principle of liquefaction of
gases.
Aerosols
• Gas can be liquefied at high pressure in a
closed chamber and low temperature.
• van der Waals Equation
• An aerosol is a suspension of fine solid

particles or liquid droplets in a gas.
• Gas  Propellant
• Liquid under pressure but Gas at atmosphere
• CFC (chlorofluorocarbons) – ozone depletion
• Nitrogen and CO2
Vapor Pressure of Liquids

• Liquid molecules with the highest KE and proximity to a
surface break away from the surface of the liquid and
pass into the gaseous state.
• Some molecules subsequently return to the liquid state.

Vapor Pressure of Liquids

• The pressure of the saturated vapour above the
liquid is called equilibrium VAPOR PRESSURE.
As T Increases  More Vapor (gas)  VP increases

The Liquid State
Boiling Point
Vapor pressure =
atmospheric pressure
--> All the absorbed heat is used

to change the liquid to vapor, and the temperature
does not rise until the liquid is completely vaporized.
The Liquid State
Boiling Point
760mmHg=BP 100deg C
700mmHg= 97.7deg C
17.5mmHg = 20deg C
Elevated places→
What eq?
lower vapor pressure =
lower boiling point
Clausius – Clapeyron Equation
• Describes the relation of vapour pressure and absolute temp of

liquid.
• Latent Heat of Vaporization - heat absorbed when liquid
vaporizes at normal BP
Boiling Point
• For HC, simple ROH and RCOOH
• ↑ MW (longer chain), ↑BP
• Branching, ↓BP
• Non-Polar molecules have low BP and ∆𝑯𝒗 .

• Due to London forces
• Polar molecules have high BP and ∆𝑯𝒗 .
• Due to H-bonds
A5. The Solid State
- Part A -
Solids
• Characterized of having fixed shapes, nearly incompressible

• Have strong intermolecular forces, very little kinetic energy
• Their atoms vibrate in fixed positions about an equilibrium
position, there is very little translational motion
Crystalline solids Amorphous solids

Have definite shape Do not occur in
characteristic geometrical
shapes.
Orderly arranged Possess great disorder
Have sharp melting point Show fracture in an
irregular manner when
hammered gently
Crystalline solids
• The molecules or atoms are arranged in repetitious three-

dimensional lattice units
• If the arrangement or geometry is highly ordered
Crystalline solids
Types based on geometric forms

• Cubic -NaCl
• Tetragonal –Urea
• Hexagonal –Iodoform
• Rhombic –Iodine
• Monoclinic –sucrose
• Triclinic -boric acid
urea
iodine
sucrose
It is an example of solids which exists in tetragonal form
A. Sodium chloride
B. Iodoform
C. Sucrose
D. Urea
E. All of the above
REFERENCE:
Physical Pharmacy
It is an example of solid which exists in monoclinic form.
A. Urea
B. Boric acid
C. Iodine
D. Sucrose
E. All of the above
REFERENCE:
Physical Pharmacy
The following are example o amorphous
solids except.
A. Glass
B. Woods
C. Plastics
D. Sodium chloride
E. All of the above
REFERENCE:
Physical Pharmacy
The following are examples of crystalline solids
except.
A. Sucrose
B. Glass
C. Boric acid
D. Iodine
E. All of the above
REFERENCE:
Physical Pharmacy
Solvates
•Complex formed when solvent is
incorporated within the crystal lattice
• Hydrate – if solvent is WATER
Polymorphism
• Ability of a compound to crystallize as more than one
distinct crystalline species with different internal
lattices
Polymorphic Changes & Properties
1. Enantiotropic - change is reversible, e.g. Sulfur
2. Monotropic - Unstable, change is unidirectional at all T & P, e.g.
glyceryl stearates
3. Isotropic - imilar (identical) properties in all directions
4. Anisotropic - different properties in various directions along the crystal
Polymorphism
Polymorphs –solids that have more than pne crystalline form. Have
- have different physical properties including different melting points and
solubilities
Polymorphic Changes & Properties

Example: theobroma, cocoa butter
Form Melting Point (in °C)

Gamma (most unstable) 18
Alpha 22
Beta prime 28
Beta (most stable) 34.5
It is the phenomenon where compounds
exists in more than one crystalline and/or
amorphous form.
A. Polymorph
B. Polymorphic form
C. Modification
D. Polymorphism
E. None of the above
REFERENCE:
Physical Pharmacy
A6. The Liquid Crystalline State

and Supercritical Fluids
- Part A -
Liquid Crystalline
• 4th Phase of matter ( Mesophase, Plasma)
• It is characterized by molecules being organic, elongated and
rectilinear (in shape), rigid and possesses strong dipoles and
that are easily polarizable groups.
2 Main Types of Liquid Crystalline

Supercritical Fluid
• A mesophase formed from the
gaseous state where the gas is
held under a combination of
temperatures and pressures
that exceed the critical point
of a substance
• Have properties intermediate to
those of liquids and gases, like
gas that having permeate solid
substances (gas-like property)
and like liquid that has high
densities that can be regulated
by pressure (liquid-like
property).
Molecules that are mobile in 2 directions and
can rotate in a single axis.
A. Smectic
B. Mesophase
C. Nematic
D. Neither B nor C
E. Supercritical fluid
REFERENCE:
Physical Pharmacy
A7. Phase Diagram
- Part A -
Phase Diagram
 Graphical representation of the
states of matter that exist as
temperature and pressure are
varied.
 It is a graphic way to summarize
the conditions under which
equilibria exist between the
different states of matter.
 Such a diagram also allows us to
predict which phase of a
substance is present at any given
temperature and pressure.
Latent Heat/ Molar Heat
• Heat necessary for 1 mole of a gas, solid or liquid to change to

another phase
• Either gaine (absorbed) or lost (released)
NOTE: without latent heat, no phase transition
Molar Heat of Fusion (ΔHf)
• Heat absorbed to convert 1

mole of solid to liquid
• Heat released to convert 1
mole of liquid to solid
Molar Heat of Sublimation (ΔHs)

mole of solid to gas
mole of gas to solid
Molar Heat of Vaporization (ΔHv)

mole of a liquid to gas
mole of a gas to liquid
It is the process of the transformation
of solids directly into the vapor phase
without passing into the
intermediate liquid phase.
A. Evaporation
B. Condensation
C. Distillation
D. Sublimation
E. All of the above
REFERENCE:
Physical Pharmacy
It is the quantity of heat absorbed when a
change of state from liquid to vapor that
occurs at its boiling point without
changing the temperature of the materials.
A. Latent heat of fusion

B. Latent heat of vaporization
C. Latent heat of sublimation
D. Latent heat of condensation
REFERENCE:
Physical Pharmacy
A8. Phase Rule
- Part A -
Phase Rule
 Used to determine the number of independent
variables (temperature, pressure, concentration) that
must be set in order to define a system (F).
 It relates
1. number of independent variables or degree of freedom
(F),
2. number of phases that can coexist (P) and
3. number of components making up the phases (C)
 in a system at equilibrium.
𝑭 = 𝑪– 𝑷 + 𝟐
One Component System
• F = C –P + 2
• Example – component is only
water
It can exist as
- solid only, liquid only, or gas
only
- Solid-liquid co-exist, liquid-
gas co-exist, solid-gas co-
exist
- Solid-liquid-gas are co-
existing
B
Number Deg of Comments

of Phases Freedom
F = C –P + 2
1 F = 1-1+2 Bivariant: two
F=2 variables (temp
and pressure)
must be fixed to
define the
system.
2 F= 1-2+2 Univariant: one

F=1 variable(temp or O
pressure) must
be fixed to
define the
system.
3 F=1-3+2 Invariant: temp

F=0 and pressure is
already fixed
and defined.
Phase Diagram for Systems Containing Liquid Phases
Phase
• a homogeneous, physically distinct, and

mechanically separable portion of a system.
• It is uniform throughout.
Two One One Two

Phases Phase Phase Phases
sand NaCl Alcohol Oil

+ completely in water in water
water dissolved
water
The Phase Rule: F = C – P + 2
Liquid water + Water vapour

Phase/s = L + G
P=2
Components = Water ONLY
C=1
F=1–2+2=1 One variable can be controlled
univariant
Liquid ethanol + Liquid water

Phase/s = L + L  Miscible
P=1
Components = Ethanol + Water
C=2
F=2–1+2=3
Three variables can be controlled
trivariant
Liquid Hexane + Liquid water

Phase/s = L + L  Not Miscible
P=2
Components = Hexane + Water
C=2
F=2–2+2=2
Two variables can be controlled
bivariant
Applying the Phase rule, determine F
in the following system:
Ice in liquid water
A. F = 0 𝑪=𝟏
𝑷=𝟐
B. F = 1
𝑭=𝑪−𝑷+𝟐
C. F = 2
𝑭=𝟏−𝟐+𝟐
D. F = 3 𝑭=𝟏
Two-Component System
• Aka Condensed system
• System in which vapour phase is ignored and
only the solid and/or liquid phases are
considered
• Containing Liquid-Liquid Phases
• Containing Solid-Liquid Phases: Eutectic Mixtures
Liquid-Liquid System
• Binodal curve
- area within the curve represents a two phase system; Any point beyond
it is a single phase
• Critical solution temperature (upper consolute
temperature)
- temperature beyond which every proportion of A & B will exist as 1-
phase; maximum temperature to obtain a one phase system
• Tie Line
-line from which a system separates into phases of constant
composition; used to approximate the proportions of components A & B
existing at a particular temperature
• Conjugate phases
- phases of constant composition that separate when a mixture is
prepared within the boundary of the 2-phase system
Solid-Liquid System
Eutectic Mixture
 The composition of two or more compounds that exhibits a
melting temperature lower than that of any other mixture of the
compounds.
MPA+B < MPA or MPA+B < MPB
 Eutectic point - the point at which the liquid and solid phases
have the same composition, co existing.
 Example: Salol-Camphor
• Eutexia - phenomenon of lowering the melting point due to

combinations of components (thymol-salol; camphor-menthol)
Three Component System
1. Ternary system – a system

consisting 3 components
existing in phase equilibrium.
2. Temperature are pressure
are both made constant
3. Consists of two liquids that
are partially miscible to each
other and the third component
acts as co-solvent which has
the affinity to both immiscible
layers
The least number of intensive variables
that must be fixed to describe the
system completely.
A. Number of phases
B. Number of components
C. Number of intermediates
D. Number of degrees of freedom
REFERENCE:
Physical Pharmacy and Pharmaceutical
Sciences 5th ed., Sinko, P. p.48
It is the temperature at which a solid passes into
liquid state under atmospheric pressure.
A. Latent heat
B. Freezing point
C. Melting point
D. Boiling point
E. Both A and B
REFERENCE:
Physical Pharmacy
The point at which the liquid and solid phases
have the same composition, co existing or
the is the lowest temperature that liquid
phase can exist in salol-thymol system.
A. Critical point
B. Triple point
C. Melting point
D. Eutectic point
E. Boiling point
REFERENCE:
Physical Pharmacy
- Part B -
ELECTROLYTES AND
NON-ELECTROLYTES
B1. Overview of Dispersed

Systems
- Part B -
ELECTROLYTES AND NON-ELECTROLYTES
Coarse Dispersion
Introduction
• System – a bounded space or an exact
quantity of a material
• Dispersion – consists of at least two phases
with one or more dispersed phase (internal)
contained in a single continuous (external)
phase
• Phase – a distinct homogenous part of a
system
DISPERSION
(DISPERSED SYSTEM)
DISPERSED
DISPERSION PHASE
MEDIUM (INTERNAL)
(EXTERNAL
or
CONTINUOUS)
Coarse Dispersion
Types of Dispersion
1. MOLECULAR DISPERSION
- diameter of particles < 1 nm
- A.k.a. True Solutions (one-phase)
2. COLLOIDAL DISPERSION
- diameter of particles 1 to 500 nm
- e.g. gelatin mixture, milk
3. COARSE DISPERSION
- diameter of particles > 500 nm
- Ex. Emulsions and suspensions
Module 3: Homogeneous Systems
TRUE SOLUTIONS
• Binary solutions – composed of only
two substances
• A mixture of two or more components
that form a homogenous molecular
dispersion or one-phase system
• (Particle size: <1 nm)
• Components/Constituents:
1. Solute – lesser amount (solid)
2. Solvent – greater amount
(liquid, water)
Types of Solution (States of Matter)

Types of Solute
NON-ELECTROLYTES ELECTROLYTES
Do not ionize in water Ionize in water (forms ions)
Do no conduct electric current Conduct electric current
Ex. Sucrose, glycerin, Sub-types:
naphthalene, urea a. Strong Electrolytes
- completely ionized
- Ex. HCl, NaCl
b. Weak Electrolytes
- partially ionized
- Ex. Most drugs,
organic acids/bases
𝐻𝐶𝑙 → 𝐻+ + 𝐶𝑙 −
Strong Electrolyte
Before: 100 0 0
After: 0 100 100
Equilibrium
𝐻𝑂𝐴𝑐 𝐻+ + 𝑂𝐴𝑐 −
Weak electrolyte
Before: 100 0 0
After: 30 70 70
B2. True Solutions

(Molecular Dispersion)
- Part B -
Solvent
The phase of the solution; usually constitutes the largest

proportion of the system
• Protophilic or basic solvent
• Proton-accepting (acetone, ether, and liquid ammonia)
• Protogenic solvent
• proton-donating (formic acid, acetic acid, sulfuric acid, liquid HCl, and
liquid HF)
• Amphiprotic solvents
• act as both (water and the alcohols)
• Aprotic solvents
• neither accept nor donate protons; neutral (hydrocarbon)
Concentration Expressions
• The concentration of a solution can be
expressed either in terms of:
𝑞𝑢𝑎𝑛𝑡𝑖𝑡𝑦 𝑜𝑓 𝑠𝑜𝑙𝑢𝑡𝑒
a)
𝑣𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝑠𝑜𝑙𝑢𝑡𝑖𝑜𝑛
𝑞𝑢𝑎𝑛𝑡𝑖𝑡𝑦 𝑜𝑓 𝑠𝑜𝑙𝑢𝑡𝑒
b)
𝑚𝑎𝑠𝑠 𝑜𝑓 𝑠𝑜𝑙𝑣𝑒𝑛𝑡 (𝑜𝑟 𝑠𝑜𝑙𝑢𝑡𝑖𝑜𝑛)
Concentration Expressions
𝒎𝒐𝒍𝒆𝒔 𝒐𝒇 𝒔𝒐𝒍𝒖𝒕𝒆 𝒈
Molarity 𝑴= 𝑴=
𝑳 𝒐𝒇 𝒔𝒐𝒍𝒖𝒕𝒊𝒐𝒏 𝑴𝑾 𝒙 𝑳𝒔𝒐𝒍𝒏
𝒆𝒒𝒖𝒊𝒗𝒂𝒍𝒆𝒏𝒕𝒔 𝒐𝒇 𝒔𝒐𝒍𝒖𝒕𝒆 𝒈 𝒙 𝒇𝒆𝒒

Normality 𝑵= 𝑵=
𝑳 𝒐𝒇 𝒔𝒐𝒍𝒖𝒕𝒊𝒐𝒏 𝑴𝑾 𝒙 𝑳𝒔𝒐𝒍𝒏
𝒎𝒐𝒍𝒆𝒔 𝒐𝒇 𝒔𝒐𝒍𝒖𝒕𝒆 𝒈
Molality 𝑴= 𝑴=
𝑳 𝒐𝒇 𝒔𝒐𝒍𝒗𝒆𝒏𝒕 𝑴𝑾 𝒙 𝑳𝒔𝒐𝒍𝒗𝒆𝒏𝒕
𝒑𝒂𝒓𝒕 𝑿
% Concentration %𝑿= 𝒙 𝟏𝟎𝟎
𝒕𝒐𝒕𝒂𝒍 𝑻
Molality (m) molal
What are the molality of glucose (mol wt =180) in a solution containing 6.70 g of glucose and 150 g of water?
Solve for # of moles:

m𝑜𝑙𝑎𝑙𝑖𝑡𝑦 𝑚 = 𝑔 𝑜𝑓 𝑠𝑜𝑙𝑢𝑡𝑒 6.7𝑔
𝑚𝑜𝑙𝑒𝑠 𝑚𝑚𝑜𝑙𝑒𝑠 𝑚𝑜𝑙𝑒 = =
= 𝑚𝑜𝑙 𝑤𝑡 180 𝑔 𝑝𝑒𝑟 𝑚𝑜𝑙𝑒
𝐾𝑔 𝑜𝑓𝑠𝑜𝑙𝑣𝑒𝑛𝑡 𝑔 𝑜𝑓𝑠𝑜𝑙𝑣𝑒𝑛𝑡
𝒎𝒐𝒍𝒆 = 𝟎. 𝟎𝟒 𝒎𝒐𝒍𝒆
Wt of solvent = 150 g Substitute:

0.04 𝑚𝑜𝑙𝑒 𝑥 1000
m=
150 𝑔
𝒎𝒐𝒍𝒆 𝒎𝒎𝒐𝒍𝒆𝒔
m= 𝟎. 𝟐𝟎 𝒐𝒓
𝑲𝒈 𝒐𝒇 𝒔𝒐𝒍𝒗𝒆𝒏𝒕 𝒈 𝒐𝒇 𝒔𝒐𝒍𝒗𝒆𝒏𝒕
B3. Solubility Phenomena
- Part B -
Definition of Solubility
• Quantitative:
• the concentration of solute in a saturated solution
at a certain temperature
• Qualitative:
• the spontaneous interaction of two or more
substances to form a homogeneous molecular
dispersion
Solutions and Solubility
Saturated solution – solution containing the

maximum concentration of a solute
dissolved in the solvent.
- Solute in solution is in equilibrium with the solid phase
Unsaturated or subsaturated solution –

solution containing the dissolve solute in a
concentration below that necessary for
complete saturation at a definite temperature.
- Solute concentration < saturation point
Supersaturated solution – solution contains
more of the dissolved solute that it would
normally contain at a definite temperature,
were the undissolved solute is present.
- Solute concentration > saturation point
Solutions and Solubility

• Saturated
- Solute in solution is in equilibrium with the solid
phase
• Unsaturated or Subsaturated
- Solute concentration < saturation point
• Supersaturated
- Solute concentration > saturation point
(undissolved solutes are present)
Solubility Expressions
Dissolution – transfer of molecules or ions from
a solid state into solution
Solubility – extent of dissolution
• Qualitatively based on:
United States Pharmacopeia (USP)
- Classified into seven (7) groups
• Quantitatively as:
- Molarity (M, mol/L)
- Molality (m, mol/kg)
- Percentage (% w/w, w/v or v/v)
USP Descriptive Terms for Solubility
Parts of Solvent
Solubility Range
Description Required for One
(mg/mL or g/L)
part of solute
VERY SOLUBLE (VS) <1 >1000

FREELY SOLUBLE (FS) 1-10 100-1000
SOLUBLE (S) 10-30 33-100
SPARINGLY SOLUBLE (SPS) 30-100 10-33
SLIGHTLY SOLUBLE (SS) 100-1,000 1-10
VERY SLIGHTLY SOLUBLE (VSS) 1,000-10,000 0.1-1
PRACTICALLY INSOLUBLE (PI) >1,0000 <0.1
What is the general term used to express the
solubility of 1 part of a given solute in 1000 to
10,000 parts of solvent?
A. Slightly soluble
B. Very slightly soluble
C. Sparingly soluble
D. Practically insoluble
E. all of the above
REFERENCE:
Physical Pharmacy
B3.1. Factors Affecting Solubility
- Part B -
SOLUBILITY PHENOMENA
SOLVENT-SOLUTE INTERACTIONS
• Like dissolves like.
• The greater the similarity between the solute and the
solvent (similar physical-chemical properties), the
greater the solubility.
Polar Solvents
• Solubility of drug is due in large measure to
polarity of solvent (dipole moment).
• Polar solvent + Ionic or Polar solutes
• Ability to form H-bonds is more significant.

• Water dissolves:
- Phenols
- Alcohols
- Aldehydes
- Ketones
- Amines
Polar Solvents
• Solubility depends on structural features.
• E.g.
• ROH: longer chain, less water-soluble
• Straight chain monohydroxy ROH, RCHO, RCO,
RCOOH: > 4C or 5C, slightly soluble in water
• Branching: Increases water solubility
Non-polar Solvents
• Non-polar Solutes + Non-polar Solvents
• Due to Induce Dipole Interactions
• E.g.
Oils and Fats are soluble in CCl4, benzene,
mineral oil.
Semipolar Solvents
• Can induce a certain polarity in nonpolar
solvents, e.g. ketones and alcohols
• Benzene + Alcohol  Miscible
• Can act as intermediate solvents
• Polar + Nonpolar liquids  Miscible
• Propylene glycol + Water + Peppermint oil

 Miscible
Solubility Based on Polarity

Dielectric Constants
• a quantity measuring the ability of a substance
to store electrical energy in an electric field.
• Lower dielectric constant

• Decreasing polarity (less polar)
• Decreasing water solubility (less water-soluble)
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
EFFECT OF TEMPERATURE
In general, upon dissolution, solid/liquids become
more soluble as the temperature increases.
↑ Temp ↑ KE Molecules break IMF ↑ Solubility
• For substances that exhibit endothermic reaction

↑ Temperature ↑ Solubility e.g. KNO3, KCl
• For substance that exhibit exothermic reaction

↑ Temperature ↓ Solubility e.g. Na2SO4,
Ca(OH)2
For gases, ↑ Temperature ↓ Solubility
Effect of Temperature
Solubility in Water Solubility in Water
Substance Remarks
(Before heating) (After heating)
Significant increase in
#1 KNO3
solubility of solid
EFFECT OF pH
• Most important drugs are weak acids or bases.
• Acidic Drugs + Acid (low pH)

 Precipitates (decreased solubility)
• Basic Drugs + Base (high pH)

 Precipitates (decreased solubility)
A + A  Unionized (lipophilic/ water-insoluble)

B + B  Unionized (lipophilic/ water-insoluble)
A + B  Ionized (hydrophilic/ water-soluble)
EFFECT OF pH
• Phenobarbital + high pH  Ionized

• (weak acidic) (basic) (soluble)
• Atropine + low pH  Ionized

• (weak basic) (acidic) (soluble)
Physical Pharmacy - AMRubenicia
EFFECT OF pH
Most important drugs are weak acids or bases.
A + A  Unionized (lipophilic/ water-insoluble)

Weak acidic drug in the stomach (↓pH) (A + A) – un ionized
form  faster absorption, poor dissolution
A + B  Ionized (hydrophilic/ water-soluble)

Weak acidic drug in the intestines (↑pH) (A + B) –ionized
form poor absorption, faster dissolution
Effect of pH
Substance Remarks
(+ Acid or Base)
(+ 6 M HCl)
#1 Diphenydramine No visible reaction

HCl (NVR)
salt
(+ 6 M NaOH)
#2 Diphenydramine Drug precipitates

HCl out of the solution
salt
Effect of pH
Substance Remarks
(+ Acid or Base)
(+ 6 M HCl)
Drug precipitates
#3 Pen G Sodium
out of the solution
salt
(+ 6 M NaOH)
No visible reaction
#4 Pen G Sodium
(NVR)
salt
EFFECT OF PARTICLE SIZE

• As a particle becomes smaller, the surface
area increases.
• The larger surface area allows greater
interaction with the solvent which causes an
increase in solubility.
General Solubility Rules
The following are some general solubility rules that can be useful in
many cases
to help predict water solubility of organic drug molecules:
1. Like dissolves like. The greater the similarity between the solute and
the solvent (similar physical-chemical properties), the greater the
solubility.
2. Solubility in water is increased by increasing the capacity of the

solute for H bonding with polar groups (e.g., OH, NH2, SO3H, COOH).
3. Solubility in water is decreased with an increase in the number of

carbon atoms in the solute (i.e., an increase in molecular weight without
increasing polarity). For example, polymers with a high molecular
weight are
insoluble.
General Solubility Rules
The following are some general solubility rules that can be useful in many
cases
to help predict water solubility of organic drug molecules:
4. For many organic molecules, a high melting point means low

water solubility.
5. cis (z) Isomer is more soluble than trans (e) isomer; cis has a
lower melting point.
6. Increasing unsaturation increases solubility in polar solvents.

7. Anhydrous solutes are more soluble than are those that are
crystalline (hydrates).
PRESENCE OF SALTS
Salting-in: added salt increases hydrophilicity
of the solution
Salting-out: added salt reduces the available
amount of water  solute precipitates
B4. Ionic Equilibria
- Part B -
Introduction
• Ionization – formation of ions
• Dissociation – separation of a species into to
two or more
• An acid must have a base present in order to
function as an acid, and vice versa.
Acids 𝐻𝐴 + 𝐻2𝑂 ↔ 𝐻3𝑂+ + 𝐴-

Bases 𝐵 + 𝐻2𝑂 ↔ 𝑂𝐻- + 𝐵𝐻+
Water Ionization 𝐻2𝑂 + 𝐻2𝑂 ↔ 𝐻3𝑂+ + 𝑂𝐻-
HCl
THEORY ACID BASE
Arrhenius Liberates H+ Liberates OH-
Proton (H+) Proton (H+)

Bronsted-Lowry donor acceptor
e- pair e- pair
Lewis acceptor donor
Note: An acid must have a base present in order to function as an acid,

and vice versa.
Classification of Solvents
1) PROTOPHILIC
– proton acceptor, basic
Ex. Acetone, ether, ammonia
2) PROTOGENIC
– proton donor, acidic
Ex. Formic acid, acetic acid, HCl
3) AMPHIPROTIC
– both proton acceptor and donor
Ex. WATER and alcohol
4) APROTIC
– neither proton acceptor and donor, neutral
Ex. HC
Ionization of Weak Acids
𝐻𝐴𝑐 + 𝐻2 𝑂 𝐻3 𝑂+ + 𝑂𝐴𝑐 −
𝑯𝟑 𝑶+ 𝑨𝒄−
𝑲𝒂 =
𝑯𝑨𝒄
→ molar concentration in
molarity (M) or mol/L
𝑲𝒂 → 𝒂𝒄𝒊𝒅𝒊𝒕𝒚 𝒄𝒐𝒏𝒔𝒕𝒂𝒏𝒕
Ionization of Weak Bases
𝐴𝑐 − + 𝐻2 𝑂 𝑂𝐻− + 𝐻𝐴𝑐
𝑶𝑯− 𝑯𝑨𝒄
𝑲𝒃 =
𝑨𝒄−
→ molar concentration in
𝑲𝒃 → 𝒃𝒂𝒔𝒊𝒄𝒊𝒕𝒚 𝒄𝒐𝒏𝒔𝒕𝒂𝒏𝒕
Ionization of Water
• Autoprotolysis (self-ionization) of water:
𝐻2 𝑂 + 𝐻2 𝑂 𝐻3 𝑂+ + 𝑂𝐻−
𝑲𝒘 = 𝟏. 𝟎 𝒙 𝟏𝟎−𝟏𝟒
𝑲𝒘 → 𝒘𝒂𝒕𝒆𝒓 𝒅𝒊𝒔𝒔𝒐𝒄𝒊𝒂𝒕𝒊𝒐𝒏 𝒄𝒐𝒏𝒔𝒕𝒂𝒏𝒕/

𝒂𝒖𝒕𝒓𝒐𝒑𝒓𝒐𝒕𝒐𝒍𝒚𝒔𝒊𝒔 𝒄𝒐𝒏𝒔𝒕𝒂𝒏𝒕/
𝒊𝒐𝒏 𝒑𝒓𝒐𝒅𝒖𝒄𝒕 𝒐𝒇 𝒘𝒂𝒕𝒆𝒓
Ionization of Polyprotic Electrolytes
• Monoprotic
- donates/accepts one proton (one 𝑲𝒂 )
• Polyprotic
- donates/accepts two or more protons
(a) Diprotic (dibasic) H2CO3 𝑲𝒂𝟏 , 𝑲𝒂𝟐
(b) Triprotic (tribasic) H3PO4 𝑲𝒂𝟏 , 𝑲𝒂𝟐 , 𝑲𝒂𝟑
Ampholytes
• Species that can function either as an acid or
as a base
• Amphoteric in nature
• Ex. Amino acids and proteins

 ZWITTERION – both positive and negative charges
B4.1. pH Calculations
- Part B -
pH value
• The degree of acidity and basicity depends on
𝑯+ , 𝑶𝑯− , 𝒑𝑯 or 𝒑𝑶𝑯.
𝒑𝑯 < 𝟕 Acidic
𝒑𝑯 = 𝟕 Neutral
𝒑𝑯 > 𝟕 Basic/ Alkaline

Module 3: Homogeneous Systems p. 152
Sorensen’s pH
• “p” function  negative logarithm of a value
𝒑𝑯 = − 𝐥𝐨𝐠 𝑯𝟑 𝑶+
or
𝒑𝑯 = − 𝒍𝒐𝒈 𝑯+
[ ]  molar concentration in
Problem:
• The hydronium ion concentration of a 0.1 M
phenobarbital solution was found to be
3.24 x 10-3 M. What is the pH of this solution?
𝒑𝑯 = −𝒍𝒐𝒈[𝑯+ ]
𝒑𝑯 = −𝒍𝒐𝒈(3.24 x 𝟏𝟎−𝟑 ) 𝒑𝒓𝒆𝒔𝒔 [𝑬𝒙𝒑] for x10
𝒑𝑯 = 𝟐. 𝟒𝟗
pH and [H+]
𝒑𝑯 = − 𝒍𝒐𝒈 𝑯+
𝑯+ = 𝒂𝒏𝒕𝒊𝒍𝒐𝒈 −𝒑𝑯
𝑯+ = 𝟏𝟎−𝒑𝑯
Problem:
• If the pH of a solution is 4.72, what is the
hydronium ion concentration?
[𝑯+ ] = 𝟏𝟎−𝒑𝑯
[𝑯+ ] = 𝟏𝟎−𝟒.𝟕𝟐 𝒔𝒉𝒊𝒇𝒕 𝒍𝒐𝒈 − "𝒑𝑯"
[𝑯+ ] = 1.91 x 10−𝟓 M

pH, pOH and [OH-]

𝒑𝑶𝑯 = − 𝒍𝒐𝒈 𝑶𝑯−
𝑶𝑯− = 𝟏𝟎−𝒑𝑶𝑯
𝒑𝑯 + 𝒑𝑶𝑯 = 𝟏𝟒
𝒑𝑯 = 𝟏𝟒 − 𝒑𝑶𝑯
𝒑𝑶𝑯 = 𝟏𝟒 − 𝒑𝑯
Notes:
•pH and pOH lie between 0-14.
•The exponential term in the scientific

notation gives you an idea of the pH, and
vice versa.
•Example: [H+]=1 x 10-8

pH = 8
Relationships:
↑ 𝑯+ ↓ 𝒑𝑯 ↑ 𝒑𝑶𝑯
 the more acidic the substance is
↑ 𝑶𝑯− ↓ 𝒑𝑶𝑯 ↑ 𝒑𝑯
 the more basic the substance is.
Homogeneous Systems
Problem:
• At 25oC, what are the molar hydronium and
hydroxide concentration of benzoic acid
solution with a pH of 2.87?
Homogeneous Systems
Problem:
• At 25oC, what are the molar hydronium and
hydroxide concentration of benzoic acid
solution with a pH of 2.87?
[𝑯+ ] = 𝟏𝟎−𝒑𝑯
[𝑯+ ] = 𝟏𝟎−𝟐.𝟖𝟕 𝒔𝒉𝒊𝒇𝒕 𝒍𝒐𝒈 − "𝒑𝑯"
[𝑯+ ] = 1.35 x 10−𝟑 M
𝒑𝑶𝑯 = 𝟏𝟒 − 𝒑𝑯
𝑶𝑯− = 𝟏𝟎−𝒑𝑶𝑯
𝒑𝑶𝑯 = 𝟏𝟒 − 𝟐. 𝟖𝟕 = 𝟏𝟏. 𝟏𝟑
𝑶𝑯− = 𝟏𝟎−𝟏𝟏.𝟏𝟑
[𝑶𝑯− ] = 7.41 x 10−𝟏𝟐 M
STRONG ACIDS STRONG BASES

HCl LiOH
HI NaOH
HBr KOH
HNO3 RbOH
HClO4 CsOH
*H2SO4 (diprotic) Ca(OH)2,
Ba(OH)2
Sr(OH)2
Strong Acid
𝒑𝑯 = − 𝒍𝒐𝒈 𝑪𝒂
Strong Base
𝒑𝑯 = 𝟏𝟒 + 𝒍𝒐𝒈 𝑪𝒃
Weak Acid
𝑪𝒂
*approximation, > 𝟏𝟎𝟎
𝑲𝒂
𝟏
𝒑𝑯 = − 𝒍𝒐𝒈 𝑪𝒂 𝒙 𝑲𝒂
𝟐
Weak Base
𝑪𝒃
*approximation, > 𝟏𝟎𝟎
𝑲𝒃
𝟏
𝒑𝑯 = 𝟏𝟒 + 𝒍𝒐𝒈(𝑪𝒃 𝒙 𝑲𝒃 )
𝟐
Problem:
1. Calculate the pH of 1.0 x 10-10 M HCl.
2. Calculate the pH of 0.002 M niacin solution

(Ka=1.4 x 10-5).
#1:Calculate the pH of 1.0 x 10-10 M

HCl.
𝒑𝑯 = − 𝒍𝒐𝒈 𝑪𝒂
𝒑𝑯 = − 𝒍𝒐𝒈(𝟏 𝒙 𝟏𝟎−𝟏𝟎 )
𝒑𝑯 = 𝟏𝟎. 𝟎𝟎
#2: Calculate the pH of 0.002 M niacin

solution (Ka=1.4 x 10-5).
𝟏
𝒑𝑯 = − 𝒍𝒐𝒈 𝑪𝒂 𝒙 𝑲𝒂
𝟐
𝟏
𝒑𝑯 = − 𝒍𝒐𝒈 𝟎. 𝟎𝟎𝟐 𝒙 𝟏. 𝟒 𝒙 𝟏𝟎−𝟓
𝟐
𝒑𝑯 = 𝟑. 𝟕𝟖
- Part D -
BUFFER SOLUTIONS
B5. Buffers
- Part B -
BUFFER AND ISOTONIC SOLUTIONS
Homogeneous Systems
Introduction
• Buffers are compounds or mixture of
compounds, that by the presence in solution,
resist pH changes upon addition of
small quantities of acid or alkali. (Sinko, 2006)
• The resistance to pH is known as buffer action.

Homogeneous Systems
Buffers
This property results from the

presence of a buffer pair which
consists of either:
• Weak acid and some salt of a weak acid or
its conjugate base
• Weak base and some salt of a weak base or
its conjugate acid
Homogeneous Systems
The Buffer Equation

“Henderson-Hasselbalch Equation”
For Weak acid and its salt:
[𝒔𝒂𝒍𝒕]
𝒑𝑯 = 𝒑𝑲𝒂 + 𝐥𝐨𝐠 (Eq. 10)
[𝒂𝒄𝒊𝒅]
↓
(molar ratio)
For Weak base and its salt:
[𝒃𝒂𝒔𝒆]
𝒑𝑯 = 𝒑𝑲𝒘 − 𝒑𝑲𝒃 + 𝐥𝐨𝐠 (Eq. 11)
[𝒔𝒂𝒍𝒕]
Homogeneous Systems
Problem:
What is the pH of a solution containing 0.10 moles of acetic
acid and 0.05 moles of sodium acetate per liter of solution?
The acid dissociation constant of acetic acid is 1.75 x 10-5 at
25oC.
A) 3.56
B) 4.46
C) 5.01
D) 5.06
Solution:
[𝒔𝒂𝒍𝒕]
𝒑𝑯 = 𝒑𝑲𝒂 + 𝐥𝐨𝐠
[𝒂𝒄𝒊𝒅]
𝒎𝒐𝒍𝒔 𝟎.𝟎𝟓
𝑳𝒔 𝟏
𝒑𝑯 = 𝒑𝑲𝒂 + 𝐥𝐨𝐠 𝒎𝒐𝒍𝒂 𝒑𝑯 = 𝟒. 𝟕𝟔 + 𝐥𝐨𝐠 𝟎.𝟏𝟎
𝑳𝒂 𝟏
𝟎. 𝟎𝟓
𝒑𝑯 = 𝟒. 𝟕𝟔 + 𝐥𝐨𝐠
𝟎. 𝟏𝟎
𝒑𝑯 = 𝟒. 𝟒𝟔
Buffer Capacity (β)

•The magnitude of resistance of buffer to
pH changes
•Also known as:
• Buffer index
• Buffer efficiency
• Buffer value
•Different from buffer action property

Exact Equation for Buffer Capacity

Exact formula/Koppel-Spiro Van Slyke’s Equation
𝑲𝒂 𝑯+
𝜷 = 𝟐. 𝟑𝑪
(𝑲𝒂 + 𝑯+ )𝟐
𝑪 → 𝒕𝒐𝒕𝒂𝒍 𝒄𝒐𝒏𝒄𝒆𝒏𝒕𝒓𝒂𝒕𝒊𝒐𝒏 𝒐𝒇 𝒃𝒖𝒇𝒇𝒆𝒓, 𝒕𝒉𝒂𝒕 𝒊𝒔, 𝒕𝒉𝒆 𝒔𝒖𝒎 𝒐𝒇 𝒕𝒉𝒆

𝒎𝒐𝒍𝒂𝒓 𝒄𝒐𝒏𝒄𝒆𝒏𝒕𝒓𝒂𝒕𝒊𝒐𝒏𝒔 𝒐𝒇 𝒕𝒉𝒆 𝒂𝒄𝒊𝒅 𝒂𝒏𝒅 𝒕𝒉𝒆 𝒔𝒂𝒍𝒕
Maximum Buffer Capacity
Maximum Buffer Capacity: occurs when pH =

pKa or 𝑯+ = ka
𝜷𝒎𝒂𝒙 = 𝟎. 𝟓𝟕𝟔𝑪
B5.1. In vivo Biologic Buffer

Systems
- Part B -
In vivo Biologic Buffer Systems

• BLOOD
 maintained at pH 7.4
 Primary Buffer in plasma
1) Carbonic acid/ Bicarbonate buffer
2) Na salts of phosphoric acid buffer
 Secondary Buffer in erythrocytes
1) Hemoglobin/Oxyhemoglobin
2) K salts of phosphoric acid buffer
 Life-threatening at pH < 6.9 or pH > 7.8
In vivo Biologic Buffer Systems

• LACRIMAL FLUID (TEARS)
 maintained at pH 7.4
 Discomfort and flow of tears at pH < 6.6 and
pH > 9
• URINE
 average pH 6 (about 4.5 to 7.8)
B5.2. Pharmaceutical Buffers
- Part B -
Pharmaceutical Buffers
• Frequently used in formulation of ophthalmic solutions
• Gifford
 Boric acid + sodium carbonate (pH 5-9)
• Sorensen
 Salts of sodium phosphate + NaCl (pH 6-8)
a.k.a. Phosphate Buffered Saline (PBS)
• Palitzsch
 Boric acid + sodium borate + NaCl (pH 7-9)
Pharmaceutical Buffers
• Clark-Lubs Mixtures
General Procedures for Preparing

Pharmaceutical Buffer Solutions:
1. Select a weak acid having pKa approximately
equal to the desired pH at which the buffer is
used.
2. Calculate the molar ratio of salt and weak acid.
3. Concentration of individual salt and acid of
0.05 to 0.5 M is sufficient.
4. Other factors: stability, compatibility, sterility,
availability, safety, cost
5. Determine the pH and 𝜷. Adjust if necessary.
Homogeneous Systems
Preparation of 300 mL Acetate Buffer
Measure the pH > pHreq (too basic), + more acid
pHinitial. pH < pHreq (too acidic) + more base
Record.
(400-mL beaker)
Continue adding until the
X mL of 0.1 M Acetic acid
(HOAc) pHrequired is reached.
+
Record.
Y mL of 0.1 M Sodium acetate
(NaOAc)
Homogeneous Systems
Strong Acid and Bases

(Buret)
Buffer Solution
(with Stirrer Bar)
pH meter Magnetic stirrer

Homogeneous Systems
Buffer Initial pH Reading Adjusted (Final) pH Reading
D
These are solutions of compounds or mixtures
of compounds which resist changes in their pH
upon addition of small quantiteis of acid or
alkali.
A. Ionizing solutions
B. Buffer solutions
C. Electrolytes
D. Either A or B
REFERENCE:
Physical Pharmacy
B6. Colligative Properties
- Part B -
Solutions When water is pure and does not contain solute,
boiling point is 100 oC
melting and freezing point is 0 oC
vapor pressure at 25 𝒐𝑪 is 23.77 mmHg
osmotic pressure does not exist
A non-volatile solute is
added, in the water solvent
and a solution is formed.
What will happen to the
mentioned properties of
water?
Colligative Properties
• The freezing point, boiling point, vapor

pressure and osmotic pressure of a solution
also depend on the relative proportion of the
molecules of the solute and the solvent.
• These are called colligative properties (Greek:
“collected together”) because they depend chiefly on
the number of particles in a solution rather than on
the nature of the constituents.
Things to remember when it comes to the
application of colligative properties to
pharmaceutical systems:
• Colligative properties are the same for equal

concentrations of solutions.
2 % Solution A 2% Solution B
 the colligative properties of the 2 solutions are
approximately the same and are directly proportional.
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
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
The addition of a non-
volatile solute lower the
VP of pure water.
Solutions
Vapor pressure lowering  the

vapor pressure of a solution is less
than the pure solvent.
What will be the vapor pressure at 25
𝑜
𝐶 (vapor pressure of pure water is
23.8 mmHg)𝑜𝑓 𝑎 𝑠𝑜𝑙𝑢𝑡𝑖𝑜𝑛 containing
10 of glucose and 1000 g of water
when its vapor pressure lowering
∆𝑃 = 0.12 𝑚𝑚𝐻𝑔?
𝑃𝑠𝑜𝑙𝑢𝑡𝑖𝑜𝑛 = 𝑃𝑜 - ∆𝑃
𝑃𝑠𝑜𝑙𝑢𝑡𝑖𝑜𝑛 = 23.8 mmHg – 0.12 mmHg
𝑃𝑠𝑜𝑙𝑢𝑡𝑖𝑜𝑛 = 23.68 mmHg
• 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.
• 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.
Change in boiling point (Tb )
Tb = Kbm
Tb = boiling point
elevation
Kb = molal elevation
constant or ebullioscopic
constant, for water it is
0.513 deg Kg/mole
Electrolytes: Tb = iKbm
• Boiling Point of • boiling point elevation

Solutions
If you add 5 g of sucrose

in 50 mL water, what will
be the boiling point when
the change in boiling point
is 1.05 𝑜𝐶 (Tb = 1.05
𝑜𝐶 )?
Answer:
Tb = 1.05 𝑜𝐶
Tb = 100 +1.05 𝑜𝐶
= 101.05 𝑜𝐶
• Osmotic Pressure of • Osmotic Pressure

Solution
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.
𝜋 = 𝑅𝑇𝑚
R = Molar gas constant
R = 0.0821
T = in Kelvin
π = osmotic pressure in atm

Solution
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

Solution

Solution
2 % NaCl 0.9 % NaCl or NSS 0.2 % NaCl

COLLIGATIVE PROPERTIES
• Properties of solutions that depend mainly on the
number rather than nature of the constituents
Four Colligative Properties of Solutions:

• Vapor pressure lowering
• Boiling point elevation
• Freezing point depression
• Osmotic pressure exists
• Freezing Point of freezing point depression

Solutions
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.
• 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.
Change in freezing point (Tf )
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
Electrolytes: Tf = iKfm
FOR NON-ELECTROLYTES
COLLIGATIVE EXPRESSION
CONSTANT IN AQUEOUS SOLUTION
PROPERTY
(For DILUTE SOLUTIONS)
∆𝑝 = 0.018𝑝1 𝑚
• The addition of a non-volatile solute
lowers the VP of a liquid
𝑝1 = vapor pressure water
𝑚 = molality of solution • A liquid in a closed container will
Vapor Pressure Raoult’s Law – lowering of a establish an equilibrium with its vapor
Lowering vapor pressure of a solvent is • When equilibrium is reached, vapor
equal to the product of the exerts a pressure (vapor pressure)
mole fraction of the solute and • VOLATILE – exhibits VP
vapor pressure of the solvent. • NONVOLATILE – no measurable VP
• BP – temp at which liquid pressure is
∆𝑇𝑏 = 𝐾𝑏 𝑚
equal to atmospheric pressure (1 atm =
𝐾𝑏 = Ebullioscopic constant or 760 mmHg)
molal elevation constant; 𝑲𝒃 =
Boiling Point • The boiling point of a solution containing
0.51
Elevation a nonvolatile solute would be higher than
the pure solvent because the solute
would lower the vapour pressure of the
solvent
FOR NON-ELECTROLYTES
COLLIGATIVE EXPRESSION
CONSTANT IN AQUEOUS SOLUTION
PROPERTY
(For DILUTE SOLUTIONS)
• FP – temp at which the solid and liquid phases

are in equilibrium under an external pressure
= Cryoscopic constant
Freezing Point or molal depression • In general, solutions have a lower freezing
Depression point than the pure solvent
constant • Applications:
𝑲𝒇 = 1.86 • Salt is spread on roads to melt ice
• Ethylene glycol as “anti-freeze”
• Osmosis – movement of water across a
𝜋 = 𝑅𝑇𝑚 semipermeable membrane from low to high
concentration
R = Molar gas constant
Osmotic
R = 0.0821 • This is the pressure required to offset the
Pressure movement of solvent thru a s. membrane
T = in Kelvin
π = osmotic pressure in • Also defined as the pressure required to
atm prevent osmosis in solutions.
Compute the freezing point depression of a solution containing 0.9%
by wt/vol NaCl (mol wt 58.5). i value of NaCl is 1.83.
Formula: 𝑔𝑥1000
𝑚=
𝑚𝑜𝑙𝑤𝑡𝑥𝑔 𝑠𝑜𝑙𝑣𝑒𝑛𝑡
∆ 𝑇𝑓 = 𝑖𝐾𝑓 𝑚 𝑜𝑟 𝐿𝑖𝑠𝑜 m 0.9𝑥1000

𝑚=
58.5𝑥100
𝑚 = 0.154
Substitution What is the freezing point of the

NSS?
∆ 𝑇𝑓 = 1.83 x 1.86 x 0.154
𝑜
𝑇𝑓 = 0 C - ∆ 𝑇𝑓
𝑜
∆ 𝑇𝑓 = 0.52 C =0
𝑜
C - 0.52 deg 𝐶
𝑇𝑓
𝑻𝒇 = - −𝟎. 𝟓𝟐𝒐 C
Colligative Properties
Cause the cell to shrink Cell remains normal Cause the cell to swell then burst
Homogeneous Systems
FOR ELECTROLYTES:
Multiply the calculated ∆𝒑, ∆𝑻𝒃 , ∆𝑻𝒇 or 𝝅 by its

dissociation factor (i).
𝒊 = 𝜶𝒏 + 𝟏 − 𝜶
Where; 𝒊 → 𝒗𝒂𝒏′ 𝒕 𝑯𝒐𝒇𝒇 𝒇𝒂𝒄𝒕𝒐𝒓
𝜶 → 𝒅𝒆𝒈𝒓𝒆𝒆 𝒐𝒇 𝒅𝒊𝒔𝒔𝒐𝒄𝒊𝒂𝒕𝒊𝒐𝒏
𝒏 → 𝒏𝒖𝒎𝒃𝒆𝒓 𝒐𝒇 𝒊𝒐𝒏𝒔 𝒇𝒐𝒓𝒎𝒆𝒅
Homogeneous Systems
Problem:
Zinc sulfate is a 2-ion electrolyte, dissociating
40% in a certain concentration.
Calculate its (i) dissociation factor.

𝒊 = 𝜶𝒏 + 𝟏 − 𝜶
A) 1.2
𝜶 = 𝟎. 𝟒𝟎 (𝒊𝒏 𝑫𝒆𝒄𝒊𝒎𝒂𝒍𝒔)
B) 1.4
𝒏=𝟐
C) 1.6
𝒊 = (𝟎. 𝟒 𝒙 𝟐) + 𝟏 − 𝟎. 𝟒
D) 1.8
𝒊 = 𝟏. 𝟒
B7. Isotonic Solutions
- Part B -
Homogeneous Systems
Introduction
• In addition to carrying pH adjustment, pharmaceutical
solutions that are meant for application to delicate
membranes of the body should also be adjusted to
approximately the same osmotic pressure with the
body fluids.
Introduction
• ISOTONIC SOLUTIONS
- Causes no swelling or contraction of tissues
 Produce no discomfort in the eye, nasal tract, blood or body
tissues
- Has the same salt concentration, hence same
osmotic pressure as the RBC
- 0.9% NaCl solution (Normal Saline Solution – NSS)
• Hypertonic Solutions: > 0.9% NaCl

- Causes outward passage (Shrinkage/Crenation)
• Hypotonic Solutions: < 0.9% NaCl
- Causes swelling, which leads to bursting (Hemolysis)
Isotonicity value
• Refers to the concentration of aqueous NaCl solution
having the same colligative properties as the solution
in question.
Homogeneous Systems
0.9%
Drug NaCl
solution =
% NaCl
Salt concentration (tonicity) in terms of

NaCl content
Measurement of Tonicity
• HEMOLYTIC METHOD
• Based on the appearance of RBC suspended in solutions
• Hypotonic  liberates oxyHgB
• COLLIGATIVE PROPERTIES
• Based on slight differences in vapor pressure, freezing
point or boiling point
Homogeneous Systems
0.9%
Drug NaCl
solution <
Less than
% NaCl
Add more NaCl or other tonic agent

Methods of Adjusting Tonicity

• Class I Methods
- NaCl or other substance is added
1) Cryoscopic Method
2) Sodium chloride Equivalent Method
• Class II Methods
- water is added to the drug, followed by sufficient
isotonic solution
1) White-Vincent Method
2) Sprowls Method
Sodium Chloride Equivalent Method
• Sodium Chloride Equivalent (E)

- a.k.a. “tonicic equivalent” of a drug
- the amount of NaCl that is equivalent to 1 gram of the
drug
- See Table 8-4
- Example:
E value for Ascorbic Acid = 0.18
0.18 𝑔 𝑁𝑎𝐶𝑙
1 𝑔 𝐴𝑠𝑐𝑜𝑟𝑏𝑖𝑐 𝑎𝑐𝑖𝑑
Approximation of E value from Liso
𝑳𝒊𝒔𝒐
𝑬 ≅ 𝟏𝟕
𝑴𝑾
*See Table 8-3 for Average Liso values

Problem:
Calculate the approximate E
value for a new amphetamine
HCl derivative (MW=187
g/mol).
This drug is a uni-univalent 𝑬 ≅ 𝟏𝟕
𝑳𝒊𝒔𝒐
salt. 𝑴𝑾
𝟑. 𝟒
𝑬 ≅ (𝟏𝟕)( )
𝟏𝟖𝟕
A) 0.30
B) 0.31 𝑬 ≅ 𝟎. 𝟑𝟎𝟗𝟎𝟗 = 𝟎. 𝟑𝟏
C) 0.32
D) 0.33
Solution:
𝑳𝒊𝒔𝒐
𝑬 ≅ 𝟏𝟕
𝑴𝑾
𝟑. 𝟒
𝑬 ≅ (𝟏𝟕)( )
𝟏𝟖𝟕
𝑬 ≅ 𝟎. 𝟑𝟎𝟗𝟎𝟗 = 𝟎. 𝟑𝟏
Homogeneous Systems
B7.1.Methods of Adjusting Tonicity
Sodium Chloride Equivalent

Method
Homogeneous Systems
Convert to NaCl
equivalent
Drug NaCldrug
Total Convert to NaCl

equivalent
NaCltotal
Solution
NaCl NaCltotal - NaCldrug
NaClneeded
needed
Note: In the following problems, the

amount of NaCl is expressed in grams.
If NaCl is the tonicity agent …
Step 1: 𝑵𝒂𝑪𝒍𝒅𝒓𝒖𝒈 = 𝑬𝒅𝒓𝒖𝒈 𝒙 𝒈𝒅𝒓𝒖𝒈
%𝒅𝒓𝒖𝒈
or use 𝑵𝒂𝑪𝒍𝒅𝒓𝒖𝒈 = 𝑬𝒅𝒓𝒖𝒈 𝒙 𝒙 𝒎𝑳𝒔𝒐𝒍𝒏
𝟏𝟎𝟎
Step 2: 𝑵𝒂𝑪𝒍𝒕𝒐𝒕𝒂𝒍 = 𝟎. 𝟎𝟎𝟗 𝒙 𝒎𝑳𝒔𝒐𝒍𝒏
Step 3: 𝑵𝒂𝑪𝒍𝒏𝒆𝒆𝒅𝒆𝒅 = 𝑵𝒂𝑪𝒍𝒕𝒐𝒕𝒂𝒍 −𝑵𝒂𝑪𝒍𝒅𝒓𝒖𝒈

(A) 0.33 g
(B) 0.34 g
(C) 0.35 g
(D) 0.36 g
Step 1: Step 1:
𝑵𝒂𝑪𝒍𝒅𝒓𝒖𝒈 = 𝑬𝒅𝒓𝒖𝒈 𝒙 𝒈𝒅𝒓𝒖𝒈 𝑵𝒂𝑪𝒍𝒅𝒓𝒖𝒈 = 𝟎. 𝟐𝟑 𝒙 𝟎. 𝟓 𝒈
= 𝟎. 𝟏𝟏𝟓 𝒈
%𝒅𝒓𝒖𝒈
𝑵𝒂𝑪𝒍𝒅𝒓𝒖𝒈 = 𝑬𝒅𝒓𝒖𝒈 𝒙 𝒙 𝒎𝑳𝒔𝒐𝒍𝒏
𝟏𝟎𝟎
Step 2: Step 2:
𝑵𝒂𝑪𝒍𝒕𝒐𝒕𝒂𝒍 = 𝟎. 𝟎𝟎𝟗 𝒙 𝟓𝟎
𝑵𝒂𝑪𝒍𝒕𝒐𝒕𝒂𝒍 = 𝟎. 𝟎𝟎𝟗 𝒙 𝒎𝑳𝒔𝒐𝒍𝒏
= 𝟎. 𝟒𝟓 𝒈
Step 3: Step 3:
𝑵𝒂𝑪𝒍𝒏𝒆𝒆𝒅𝒆𝒅 = 𝟎. 𝟒𝟓 𝒈 − 𝟎. 𝟏𝟏𝟓 𝒈
𝑵𝒂𝑪𝒍𝒏𝒆𝒆𝒅𝒆𝒅 = 𝑵𝒂𝑪𝒍𝒕𝒐𝒕𝒂𝒍 −𝑵𝒂𝑪𝒍𝒅𝒓𝒖𝒈 = 𝟎. 𝟑𝟑𝟓 𝒈
If NaCl is NOT the tonicity agent …
Step 1: 𝑵𝒂𝑪𝒍𝒅𝒓𝒖𝒈 = 𝑬𝒅𝒓𝒖𝒈 𝒙 𝒈𝒅𝒓𝒖𝒈
%𝒅𝒓𝒖𝒈
or use 𝑵𝒂𝑪𝒍𝒅𝒓𝒖𝒈 = 𝑬𝒅𝒓𝒖𝒈 𝒙 𝒙 𝒎𝑳𝒔𝒐𝒍𝒏
𝟏𝟎𝟎
Step 2: 𝑵𝒂𝑪𝒍𝒕𝒐𝒕𝒂𝒍 = 𝟎. 𝟎𝟎𝟗 𝒙 𝒎𝑳𝒔𝒐𝒍𝒏
Step 3: 𝑵𝒂𝑪𝒍𝒏𝒆𝒆𝒅𝒆𝒅 = 𝑵𝒂𝑪𝒍𝒕𝒐𝒕𝒂𝒍 −𝑵𝒂𝑪𝒍𝒅𝒓𝒖𝒈
𝑵𝒂𝑪𝒍𝒏𝒆𝒆𝒅𝒆𝒅
Step 4: 𝒈𝒂𝒈𝒆𝒏𝒕 =
𝑬𝒂𝒈𝒆𝒏𝒕
(A) 0.08 g
(B) 0.16 g
(C) 0.32 g
(D) 0.64 g
Step 1: Step 1:
𝟐
𝑵𝒂𝑪𝒍𝒅𝒓𝒖𝒈 = 𝑬𝒅𝒓𝒖𝒈 𝒙 𝒈𝒅𝒓𝒖𝒈 𝑵𝒂𝑪𝒍𝒅𝒓𝒖𝒈 = 𝟎. 𝟏𝟑 𝒙 𝒙 𝟓𝟎
𝟏𝟎𝟎
%𝒅𝒓𝒖𝒈 = 𝟎. 𝟏𝟑 𝒈
𝑵𝒂𝑪𝒍𝒅𝒓𝒖𝒈 = 𝑬𝒅𝒓𝒖𝒈 𝒙 𝒙 𝒎𝑳𝒔𝒐𝒍𝒏
𝟏𝟎𝟎
Step 2: Step 2:
𝑵𝒂𝑪𝒍𝒕𝒐𝒕𝒂𝒍 = 𝟎. 𝟎𝟎𝟗 𝒙 𝟓𝟎
𝑵𝒂𝑪𝒍𝒕𝒐𝒕𝒂𝒍 = 𝟎. 𝟎𝟎𝟗 𝒙 𝒎𝑳𝒔𝒐𝒍𝒏
= 𝟎. 𝟒𝟓 𝒈
Step 3: Step 3:
𝑵𝒂𝑪𝒍𝒏𝒆𝒆𝒅𝒆𝒅 = 𝟎. 𝟒𝟓 𝒈 − 𝟎. 𝟏𝟑 𝒈
𝑵𝒂𝑪𝒍𝒏𝒆𝒆𝒅𝒆𝒅 = 𝑵𝒂𝑪𝒍𝒕𝒐𝒕𝒂𝒍 −𝑵𝒂𝑪𝒍𝒅𝒓𝒖𝒈 = 𝟎. 𝟑𝟐 𝒈
Step 4: Step 4:
𝟎. 𝟑𝟐
𝑵𝒂𝑪𝒍𝒏𝒆𝒆𝒅𝒆𝒅 𝒈𝒂𝒈𝒆𝒏𝒕 = = 𝟎. 𝟔𝟒 𝒈
𝒈𝒂𝒈𝒆𝒏𝒕 = 𝟎. 𝟓
𝑬𝒂𝒈𝒆𝒏𝒕
Homogeneous Systems
Methods of Adjusting Tonicity
White-Vincent Method
Homogeneous Systems
B. White-Vincent Method
• If water and isotonic diluting agent are used, the
volume in mL of isotonic solution that may be
prepared by mixing drug with water, followed by
isotonic diluting agent to the required volume
𝑽 = 𝒘 𝒙 𝑬 𝒙 𝟏𝟏𝟏. 𝟏
Where; w = gram of drug

E = NaCl equivalent of drug
%𝒅𝒓𝒖𝒈
𝑽= 𝒙 𝒎𝑳𝒔𝒐𝒍𝒏 𝒙 𝑬 𝒙 𝟏𝟏𝟏. 𝟏
𝟏𝟎𝟎
Homogeneous Systems
Drug + Water mL isotonic solution
Isotonic Total mL
mL isotonic solution
+ diluting
agent
Solution
Homogeneous Systems
Calculate volume in mL of isotonic solution that
may be prepared by mixing drug with water, using
the White-Vincent method.
Rx Zinc sulfate (E=0.16) 0.3%

Sterile water, ad q.s.
Sodium chloride 0.9%, ad 50 mL
Make isotonic solution.

Homogeneous Systems
𝒈𝒅𝒓𝒖𝒈
𝑽= 𝒙 𝒎𝑳𝒔𝒐𝒍𝒏 𝒙 𝑬 𝒙 𝟏𝟏𝟏. 𝟏
𝟏𝟎𝟎
𝟎. 𝟑
𝑽= 𝒙 𝟓𝟎 𝒙 𝟎. 𝟏𝟔 𝒙 𝟏𝟏𝟏. 𝟏
𝟏𝟎𝟎
𝑽 = (𝟎. 𝟏𝟓) 𝒙 𝟎. 𝟏𝟔 𝒙 𝟏𝟏𝟏. 𝟏

𝑽 = 𝟐. 𝟔𝟔𝟔𝟒 𝒎𝑳
𝑽 = 𝟐. 𝟔𝟕 𝒎𝑳
Homogeneous Systems
Preparation:
Dissolve 0.15 g zinc sulfate in sterile H2O up to

2.67 mL and complete the volume to 50 mL with
an isotonic vehicle.
Water is added to the drug, followed by
sufficient isotonic solution
A. White Vincent method

B. Freezing point depression method
C. Sodium chloride equivalent method
D. Cryoscopic Method
REFERENCE:
Physical Pharmacy
- Part C -
COLLOIDAL DISPERSION
C1. Characteristics of Colloids
- Part C -
Colloidal Dispersion
Characteristics:
1. Particle size between 1 nm to 500 nm
2. Not resolved by ordinary microscope
3. Visible by electron microscope
4. Pass through filter paper
5. Do not pass through semipermeable
membrane
6. Diffuse very slowly
• Examples: Jelly, Polymers, Milk, Paint, Chees

:aerosols, emulsions, foams, hydrosols
C2. Properties of Colloids
- Part C -
Optical Properties of Colloids

1. Faraday-Tyndall Effect
- Scattering of light by colloidal particles
- widely used for determining MW of colloids
2. Electron microscope
- Used to observe the size, shape, and
structure of colloidal particles
- Has higher resolution power than
optical microscope
Photo taken by: Group 3 - BSP2A

Photo taken by: Group 3 - BSP2A

Kinetic Properties of Colloids

1. Brownian Movement
- random movement of colloidal particles
- velocity increases with decreasing particle size
2. Diffusion
- spontaneous movement from high to low
concentration until uniform system is achieved
- a direct results of Brownian movement
- can be expressed by Fick’s First Law

3. Osmotic Pressure
- can be described by van’t Hoff equation: 𝝅 = 𝒄𝑹𝑻
4. Sedimentation (Settling)
- velocity of sedimentation is given by Stoke’s law
5. Viscosity
- resistance to flow of a system under applied stress
- more viscous  greater force to make it flow
- affected by shape of particles
e.g. SPHERICAL  less viscous
LINEAR  more viscous

6. Electric
• Nerst Potential / Electrothermodynamic potential -
difference in potential between the actual surface of the
particle (particle surface) and the electroneutral region
of the dispersion (bulk of the liquid)
• Zeta Potential / Electrokinetic Potential - difference
in potential between the surface of the tightly-bound
layers (particle surface) and the electroneutral region of
the dispersion (bulk of the liquid) (⬇zeta potential
results to flocculation)
The key difference between Nernst potential and Zeta potential is that
Nernst potential is given for a biological cell or an electrochemical cell
whereas zeta potential is given for a colloidal dispersion.
Module 5: Heterogeneous Systems
Stability of Colloidal Systems

The presence and magnitude of a charge in a
colloidal particles in important.
• Stabilization is achieved by:

1) Providing particles with electric charge
- Adding small amount of electrolyte to lyophobic sols
2) Surrounding particles with protective solvent sheath

- adding hydrophilic sol (protective colloids) to
hydrophobic colloids
 Protective property is expressed in Gold Number
Gold Number
• Protective property is expressed in Gold Number
• The lower the gold number, the higher is the

protective ability.
• Gelatin (with G.N. 0.01) is more effective than

acacia (with G.N. 0.2)
C3. Methods of Separation and

Purification of Colloidal Particles
- Part C -
Methods of Separation and Purification

of Colloidal Particles
1. DIALYSIS
- uses a semipermeable membrane of collodion or
cellophane
2. ULTRAFILTRATION
- filtration conducted under negative pressure
(suction)
3. ELECTRODIALYSIS
- hasted by use of electric potential across the
membrane
Hemodialysis
C4. Types of Colloidal Systems
- Part C -
Types of Colloidal Systems

1. Lyophilic Colloids
- “solvent-loving”
- high affinity to dispersion medium  SOL
- e.g. Acacia/water, Gelatin/water,
Celluloid/amyl acetate

2. Lyophobic Colloids
- “solvent-hating”
- little attraction to DM
- composed of inorganic materials in water
(e.g. Au, Ag, As2S3, S, AgI)
- require dispersion methods
 particle size reduction
a. ULTRASONICATION
b. COLLOID MILL
- require condensation methods

3. Association (Amphiphilic) Colloids
- amphiphiles
 have two distinct regions
of opposing solution affinities
with the same molecule or ions
C5. Pharmaceutical Applications of

Colloids
- Part C -
Pharmaceutical Applications of
Colloids
1. Hydrogels
- a colloidal gel in which water is DM
- used for
a) wound healing
b) scaffolds in tissue engineering
c) sustained-release of drugs
Colloids
2. Microparticles
- small (0.2-5um), loaded microspheres of
polymers
- developed as carriers for vaccines and
anticancer drugs
- increase efficiency of drug delivery,
release and targetting
Colloids
2. Microparticles
Colloids
3. Liposomes
- consists of an outer membrane and an
inner liquid core
- formed with phospholipids
- loaded with pharmaceutical through:
1) lipophilic compounds  lipophilic membrane
2) hydrophilic compounds  hydrophilic core
Colloids
4. Micelles
- similar to liposomes but do not have inner
liquid compartment
- used for delivery of hydrophobic
pharmaceuticals
Colloids
5. Microemulsions and Nanonemulsions
- usually formed with homogeneous
particles
6. Nanoparticles
- submicroscopic colloidal drug carrier
- composed of oily or aqueous core
surrounded by thin polymer membrane
- Part D -
D. INTERFACIAL
PHENOMENA
DISPERSION
(DISPERSED SYSTEM)
DISPERSED
DISPERSION PHASE
MEDIUM (INTERNAL)
(EXTERNAL
or
CONTINUOUS)
Suspensions – solid in liquid Understanding

Emulsions – oil/water or water/oil interfacial
phenomena
D1. Definition
- Part F -
INTERFACIAL PHENOMENA
Surface and Interfacial Tension
SURFACE (sur-fis)
• Boundary of gas-solid or gas-liquid
air
oil
water
INTERFACE (inter-feys)
• The boundary between two phases
• Liquid Interfaces air

• e.g. L-G or L-L
• Solid Interfaces oil
• e.g. S-G or S-L
water
Interfacial Phenomena
Properties of molecules at surfaces
Cohesive forces – attraction

Adhesive
between like molecules attraction
Adhesive forces – attraction
between unlike molecules
Tension
Interfacial tension or
surface tension causes
immiscible phases to
resist
Cohesive
mixing and shrink their
attraction
surfaces.
Bulk
• Cohesive forces
• Adhesive forces
Due to cohesive
attraction, the molecules
at the surface experience
inward force towards
the bulk.
Surface tension
and Interfacial
tension
 counterbalance the net
inward pull.
Interfacial tension
• Surface Tension – S/G and L/G

• The force per unit length that must
be applied parallel to the surface
so as to counterbalance the inward
pull
• Units: dynes/cm or N/m
• Symbol: γ (gamma)
• Interfacial Tension – S/L and L/L
• Force per unit length existing at
the interface of two immiscible
liquids (liquid-liquid), solid-liquid
and solid-solid.
• Units: dynes/cm or N/m
• γLL γLS γSS
When one of the two phases of matter is a gas or
vapor, the boundary between them is referred to as
__.
A. Surface
B. Interface
C. Colloidal
D. Fluid
REFERENCE:
Physical Pharmacy
It is the force acting between two immiscible liquid
phases.
A. Surface tension
B. Interfacial tension
C. Cohesional tension
D. Either A or b
E. Either A or C
REFERENCE:
Physical Pharmacy
D4. Surface Active Agents

(Surfactants)
- Part D -
What to do to produce a stable emulsion?

Properties of molecules at interfaces

Surface Free Energy
• Molecules near the surface of liquids

possess excess potential energy as
compared to molecules located at the bulk
of the liquid.
• Thus, energy is proportional to the size of
the free surface. This called “surface free
energy
• The increase in liquid surface, the
energy of the liquid also increases.
Heterogeneous Systems - Interfacial Phenomena
Surface Free Energy

Increase in surface free energy (𝒘, 𝒆𝒓𝒈𝒔)
– work that must be done to increase
surface area.
𝑊 = 𝛾∆𝐴
𝑊 = 𝑠𝑢𝑟𝑓𝑎𝑐𝑒 𝑓𝑟𝑒𝑒 𝑒𝑛𝑒𝑟𝑔𝑦 𝑖𝑛𝑐𝑟𝑒𝑎𝑠𝑒 𝑖𝑛 𝑒𝑟𝑔𝑠
𝑑𝑦𝑛𝑒𝑠
𝛾 = 𝑠𝑢𝑟𝑓𝑎𝑐𝑒 𝑡𝑒𝑛𝑠𝑖𝑜𝑛 𝑖𝑛
𝑐𝑚 2
∆𝐴 = 𝑖𝑛𝑐𝑟𝑒𝑎𝑠𝑒 𝑖𝑛 𝑎𝑟𝑒𝑎 𝑖𝑛 𝑐𝑚
Liquid takes the form with minimal free

surface and minimal surface energy
What is to be done to increase surface
area/interfaces at the same time decrease
surface free energy/interfacial tension to
facilitate dispersion?
Answer: addition of amphiphiles
Surface Active Agents (Surfactants)
• Also called amphiphiles
• Molecules or ions that are

adsorbed at the interfaces
• Lowers the interfacial tension

 Increases miscibility
Amphiphiles
Are surface active agents
or surfctants (emulsifying
agents)
• The dual character of their
molecule (amphiphilic =
hydrophilic & lipophilic)
• Head or hydrophilic head
- hydrophilic part or the
polar part
• Tail or lipophilic tail -
lipophilic or the non-polar
part. See the
Stable Emulsion
• Application of
Surfactants
Surfactants are materials
that
Increase surface area of
dispersed phase with the
dispersion medium by
• lower the surface tension
or interfacial tension (or
increase the adhesive
attraction between
immiscible
phases) between two
liquids or between a liquid
and a solid.
• lower surface free energy
Hydrophile-Lipophile Balance
• HLB SYSTEM
• Used to classify surfactants
• Hydrophile-Lipophile Balance
• Classifies the polar-nonpolar nature of the
emulsifier
• the balance of the hydrophilic and lipophilic
properties of an emulsifying agent or emulsifier
determines whether an o/w or w/o emulsion will
result
The Hydrophilic-Lipophilic Balance

(HLB) System for Surfactants
According to Bancroft Rule:
• HYDROPHILIC (water-loving) amphiphiles
have higher HLB values (9 to 12) values
results in the formation of
O/W  Oil in water

(less) (more)
The Hydrophilic-Lipophilic Balance

(HLB) System for Surfactants
According to Bancroft Rule:
• LIPOPHILIC (oil-loving) amphiphiles are having
lower HLB values (2 to 6) values results in
the formation of
W/O  Water in Oil

(less) (more)
Classification of Surfactants
• Anionic surfactants
• Consist of the soaps of alkali, amines and metals,
sulphated alcohols and sulphonates
• Cationic surfactants
• More popular as antiseptics or disinfecting agents
due to their bactericidal action
• Widely used as preservatives and for sterilizing
contaminated surfaces
• Ampholytic surfactants
 Possess both cationic and anionic groups in the
same molecule and their ionic characteristics
depend on the pH of the system
• Non-ionic surfactants
 useful for oral and parenteral formulations because
of their low irritation and toxicity
A. Spans (Non-ionic surfactants)
 Products of the esterification of a sorbitan with a fatty acid 
sorbitan esters
 Low HLB number
 Insoluble in water
 Used as W/O emulsifiers
B. Tweens (Non-ionic surfactants)
 Ethoxylated derivatives of sorbitan esters  polysorbates
 High HLB number
 Soluble in water
 Used as O/W emulsifiers
• Polymeric surfactants
- for highly stable concentrated suspensions
D2. Measurement of Surface and

Interfacial Tensions
- Part D -
Capillary Rise Method

• Most accurate method (liquid is undisturbed)
• For surface tension ONLY
Capillary Rise Method

1
𝛾 = 𝑟ℎ𝜌𝑔
2
𝛾 → surface tension of liquid
(dynes/cm)
𝑟 → internal radius of tube (cm)
ℎ → height which liquid rises (cm)
𝜌 → density of liquid (g/cm3)
𝑔 → acceleration due to gravity
(981 cm/sec2)
A. Measurement of Surface Tension of

a Liquid using Capillary Rise Method
Problem:
•A sample of chloroform rose to a height of
3.67 cm at 20oC in a capillary tube having
an inside radius of 0.01 cm.
•What is the surface tension of
chloroform at this temperature?
•The density of chloroform is 1.476 g/cm3.
Solution:
𝟏
𝜸 = 𝒓𝒉𝝆𝒈
𝟐
1
𝛾 = (0.01)(3.67)(1.476)(981)
2
𝛾 = 𝟐𝟔. 𝟓𝟔𝟗𝟗𝟗 𝒅𝒚𝒏𝒆𝒔/𝒄𝒎
𝛾 = 𝟐𝟔. 𝟓𝟕 𝒅𝒚𝒏𝒆𝒔/𝒄𝒎
Du Noűy Ring Method

• DuNoűy Tensiometer
• Widely used for measuring
surface and interfacial tension
• Principle:
• The force necessary to
detach a Platinum-Iridium
ring immersed at the
surface or interface
D3. Spreading
- Part D -
SPREADING
Spreading
When oil is added on liquid
surface of water, the
following may occur;
substrate
(A) Oil cannot spread

 LENS
(B) Oil spread as thin film
OR monolayer of oil with
a lens
SPREADING COEFFICENT
The ability of one liquid to spread over another
𝑺 = 𝛾𝑆𝑢𝑏 − 𝛾𝑆𝑝𝐿 − 𝛾𝑆𝑢𝑏/𝑆𝑝𝐿
𝛾𝑆𝑢𝑏 → Surface tension of substrate (MAIN)

𝛾𝑆𝑝𝐿 → Surface tension of spreading liquid
𝛾𝑆𝑢𝑏/𝑆𝑝𝐿 → Interfacial tension between substrate
and spreading liquid
𝑺 ≥ 𝟎 → 𝒔𝒑𝒓𝒆𝒂𝒅𝒊𝒏𝒈 𝒐𝒄𝒄𝒖𝒓𝒔
Problem
• If oleic acid (𝛾 = 32.5 𝑑𝑦𝑛𝑒𝑠/𝑐𝑚) is placed on
top of water (𝛾 = 72.8 𝑑𝑦𝑛𝑒𝑠/𝑐𝑚), will it
spread over the water?
• The interfacial tension between oleic acid and

water is 𝛾 = 15.6 𝑑𝑦𝑛𝑒𝑠/𝑐𝑚.
Note: Water  Substrate (Main)

Oleic acid  Spreading liquid
Solution:
𝑺 = 𝜸𝑺𝒖𝒃 − 𝜸𝑺𝒑𝑳 − 𝜸𝑺𝒖𝒃/𝑺𝒑𝑳
𝑺 = 𝟕𝟐. 𝟖 − 𝟑𝟐. 𝟓 − 𝟏𝟓. 𝟔
𝑺 = 𝟐𝟒. 𝟕 > 𝟎
Answer: Yes. Spreading occurs.
Fatty alcohols and acids have high spreading

coefficients due to the presence of polar groups
D5. Adsorption at Solid Interfaces
- Part D -
Adsorption at Solid Interfaces

• Solid-Gas Interfaces
Adsorbent – material used to adsorb gas
Adsorbate – substance being adsorbed
PHYSICAL ADSORPTION CHEMISORPTION

• Held by weak forces • Held by strong forces
(van der Waal’s) (covalent)
• Reversible (desorption) • Irreversible
• Fast • Slow
Solid-Liquid Interfaces
• ACTIVATED CHARCOAL
- Residue from destructive fractional distillation of
various organic materials, treated to increases its
ADSORPTIVE POWER
- Highly porous, high surface area
- Used as antidote
Wetting Property
• The tendency of liquids to move from the
surface to the bulk solid
 decrease surface tension
Contact Angle
- angle between the liquid
droplet and the surface
over which it spreads
Contact Angle
• Complete wetting is exhibited if the contact

angle, ϴ is ______.
D6. Interfacial Phenomena in

Pharmacy
- Part D -
Interfacial Phenomena in Pharmacy

• These are significant factors that affect:
1. Adsorption of drugs in dosage forms

2. Penetration of molecules through biologic
membranes
3. Emulsion formation and stability
4. Dispersion of solids to form suspensions
This method is suitable for measuring the surface
tension and not for interfacial tension.
A. Wilhelmy plate method

B. Ring detachment method
C. Capillary rise method
D. Du Noűy Ring Method
REFERENCE:
Physical Pharmacy
Spans and tweens are examples of commonly used ___
surfactants.
A. Anionic
B. Cationic
C. Ampholytic
D. Nonionic
REFERENCE:
Physical Pharmacy
Which of the following statements is/are true about
surfactants with HBL values of between 3 and 6?
A. Hydrophilic
B. Form w/o emulsions
C. Form o/w emulsions
D. Both A and B
REFERENCE:
Physical Pharmacy
It is also known as Van der Waals adsorption .
A. Physical adsorption
B. Chemical adsorption
C. Desorption
D. Chemisorptions
E. All of the above
REFERENCE:
Physical Pharmacy
- Part E -
E. COARSE DISPERSION
E1. Characteristics of Coarse

Dispersion
- Part E -
Characteristics of Coarse Dispersion
• Particle size between greater than 500 nm

• Visible under ordinary microscope
• Do not pass through filter paper
• Do not pass through semipermeable membrane
• Do not diffuse
• Examples:
• Most pharmaceutical suspensions and emulsions
E2. Pharmaceutical Suspension
- Part E -
Pharmaceutical Suspension
Dispersed Phase: Insoluble Solid

Types:
A. Orally administered suspensions
1. antibiotic suspension - 125 to 500 mg per 5 mL of solid material.
2. antacid and radiopaque suspensions – has high concentration of dispersed
solid
B. Externally applied suspensions - concentration > 20%
C. Parenteral suspensions - that contains 0.5% to 30% of solid particles
and whose viscosity and particle size are important factors.
Advantages of Pharmaceutical
Suspension
1. Make insoluble drugs more palatable (pleasant to
taste)
2. Provide suitable dosage form for dermatologic
materials to skin and mucous membranes
3. Parenteral administration of water-insoluble drugs
Characteristics of an Acceptable
Suspension
1. Suspended material should NOT settle rapidly
2. Sediments do NOT for a hard cake
3. Readily dispersed when shaken
4. Not too viscous
For lotions:
5. Easily spread
6. Dry quickly
7. Have acceptable color and odor
Physical Stability of Suspensions
1. Particles do not aggregate.

2. They remain uniformly distributed throughout.
3. Easily resuspended by moderate agitation
Interfacial Properties of Suspended
Particles
Flocculation - formation of light, fluffy conglomerates or floccules that are
held together by weak Van der Waals forces. Flocs or floccules
Aggregation –the process where the particles adhere by stronger forces in
compacted cake. (worst than flocculation). Aggregates
Caking – growth and fusing together of crystals in the precipitate to produce
a solid aggregates
Interfacial Properties of Suspended
Particles
Coarse Dispersion
Flocculated Suspension Deflocculated Suspension

Volume of sediment = 50 mL Volume of sediment = 47 mL
Coarse Dispersion
Question:
Suppose that two 100-mL
suspensions were prepared
and allowed to settle for
60 minutes, identify the
which suspensions shows
(a) Flocculated system
(b) Deflocculated system
Suspension A Suspension B
Volume of Volume of
sediment = 89 mL sediment = 60 mL
Settling in Suspensions
 Velocity of sedimentation is expressed by Stoke’s

Law
 Dilute Suspension  Free Settling
 >5% Suspension  Hindered Settling
 Larger particles settle more rapidly.

Coarse Dispersion
Sedimentation Parameters
1.a) Sedimentation Volume of Flocculated Suspension (𝑭)
𝑽𝒖
𝑭=
𝑽𝒐
𝑽𝒖 → 𝒖𝒍𝒕𝒊𝒎𝒂𝒕𝒆 𝒐𝒓 𝒇𝒊𝒏𝒂𝒍 𝒗𝒐𝒍𝒖𝒎𝒆 𝒐𝒇 𝒔𝒆𝒅𝒊𝒎𝒆𝒏𝒕
𝑽𝒐 → 𝒐𝒓𝒊𝒈𝒊𝒏𝒂𝒍 𝒗𝒐𝒍𝒖𝒎𝒆 𝒐𝒇 𝒔𝒖𝒔𝒑𝒆𝒏𝒔𝒊𝒐𝒏
1.b)Sedimentation Volume of Deflocculated Suspension (𝑭∞ )
𝑽∞𝒖
𝑭∞ =
𝑽𝒐
𝑽∞𝒖 → 𝒖𝒍𝒕𝒊𝒎𝒂𝒕𝒆 𝒐𝒓 𝒇𝒊𝒏𝒂𝒍 𝒗𝒐𝒍𝒖𝒎𝒆 𝒐𝒇 𝒔𝒆𝒅𝒊𝒎𝒆𝒏𝒕 𝒐𝒇 𝒕𝒉𝒆 𝒅𝒆𝒇𝒍𝒐𝒄𝒄𝒖𝒍𝒕𝒆𝒅 𝒔𝒖𝒔𝒑𝒆𝒏𝒔𝒊𝒐𝒏
Coarse Dispersion
2) Degree of Flocculation (𝜷): more fundamental

parameter
𝑭
𝜷=
𝑭∞
𝑭 → 𝑺𝒆𝒅𝒊𝒎𝒆𝒏𝒕𝒂𝒕𝒊𝒐𝒏 𝑽𝒐𝒍𝒖𝒎𝒆 𝒐𝒇 𝑭𝒍𝒐𝒄𝒄𝒖𝒍𝒂𝒕𝒆𝒅 𝑺𝒖𝒔𝒑𝒆𝒏𝒔𝒊𝒐𝒏
𝑭∞ → 𝑺𝒆𝒅𝒊𝒎𝒆𝒏𝒕𝒂𝒕𝒊𝒐𝒏 𝑽𝒐𝒍𝒖𝒎𝒆 𝒐𝒇 𝑫𝒆𝒇𝒍𝒐𝒄𝒄𝒖𝒍𝒂𝒕𝒆𝒅 𝑺𝒖𝒔𝒑𝒆𝒏𝒔𝒊𝒐𝒏

Coarse Dispersion
𝑭≥𝟏  pharmaceutically acceptable
𝑭, 𝑭∞ 𝒂𝒏𝒅 𝜷 are unitless.
Coarse Dispersion
Practice Problem:
In the following pair of 100-mL suspensions,

calculate:
a) Sedimentation volume of flocculated suspension

b) Sedimentation volume of deflocculated suspension
c) Degree of Flocculation, 𝜷
Coarse Dispersion
Suspension W Suspension Z
Coarse Dispersion
Answer:
Sedimentation volume of flocculated suspension (Susp W)

𝟑𝟕 𝒎𝑳
𝑭= = 𝟎. 𝟑𝟕
𝟏𝟎𝟎 𝒎𝑳
Sedimentation volume of deflocculated suspension (Susp Z)

𝟑𝟑 𝒎𝑳
𝑭∞ = = 𝟎. 𝟑𝟑
𝟏𝟎𝟎 𝒎𝑳
Degree of Flocculation, 𝜷
𝟎.𝟑𝟕
𝜷= = 𝟏. 𝟏𝟐
𝟎.𝟑𝟑
Formulation of Suspensions
Two approaches commonly used in the preparation of physically

stable suspensions.
1)The use of a structured vehicle or solvent to maintain
deflocculated particles in suspension or keeping these
particles suspended.
2)The application of the principles of flocculation to
produce flocs that easily settle and resuspend with
minimum agitation.
Components of Suspension
1) Wetting Agents
 surfactants that decrease the solid–liquid interfacial tension and
contact angle between the solid particles and the liquid vehicle.
 This is generally the first step during the formulation of
suspension.
2) Flocculating agents
 Neutral electrolytes that are capable of reducing the zeta potential of
suspended charged particles to zero
Components of Suspension
3) Dispersing Agents (Deflocculants)

 do not appreciably lower the surface and interfacial tension but are used
to produce deflocculated suspensions.
4) Suspending agents
 retard settling and agglomeration of the particles by functioning as an
energy barrier, which minimizes interparticle attraction.
A. Protective colloids
 Do not reduce interfacial tension
 Used in low concentration (0.1%)
 Forms mechanical barrier around particles
B. Viscosity-builders
Preparation of Suspensions
1. Precipitation method
• pH precipitation - applicable to only those drugs where solubility
depends on the pH value.
• Organic solvent precipitation
2. Dispersion Method
 the vehicle must be formulated so that the solid phase is easily
wetted and dispersed.
3. Controlled Flocculation
 Wetting agent + Vehicle  + Drug  Slurry  Sieved  Agitated
 + Flocculating agent  Agitated  Allowed to settle  +
Adjuvants  Dilute to final volume
E3. Pharmaceutical Emulsions
- Part E -
Pharmaceutical Emulsions
A thermodynamically unstable system consisting of at

least two immiscible liquids
 Dispersed phased (liquid) as globules
 Dispersion medium as other liquid
 Stabilized by emulsifying agent
 Primary – Surfactants
 Auxilliary – Hydrophilic colloids, finely divided solids
Types of Emulsion
1. Oil-in-water (O/W) Emulsion

• Dispersed Phase  Oil
• Continuous Phase  Water
 usually for oral administration
 emulsifiers: SLS, triethanolamine
2. Water-in-oil (O/W) Emulsion

• Dispersed Phase  Water
• Continuous Phase  Oil
 usually for external application
 emulsifiers: sodium palmitate, sorbitan esters (Spans)
Physical Stability of Emulsions
• Upward Creaming • Downward Creaming
• observed in O/W type • observed in W/O type

where the dispersed phase where the internal phase is
is less dense than the heavier (denser) than the
continuous phase continuous phase,
• so the globules settle.
• where sedimentation
becomes negative.
Physical Stability of Emulsions
• Creaming • Breaking
• Globules or dispersed phase is • The film surrounding the globules

coated by a protective sheath of has been destroyed and tend to
emulsifying agent and forms coalesce.
cream floccules. • Simple mixing fails to resuspend
• Can be redispersed and a the globules in a stable
uniform mixture is reconstituted emulsified form.
by agitation. • IRREVERSIBLE process
• REVERSIBLE process
Phase Inversion
• involves the change of emulsion type from o/w to w/o or vice versa and
is considered an instance of instability.
Suspensions and emulsions are two types of
_____ dispersion.
A. Colloidal
B. Coarse
C. Either A or B
D. Neither A nor B
REFERENCE:
Physical Pharmacy
It is the ratio of the sedimentation volume of
the flocculation suspension to the
sedimentation volume of the suspension
when deflocculated.
A. Sedimentation volume
B. Degree of flocculation
C. Sedimentation parameter
D. Sedimentation tare
E. All of the above
REFERENCE:
Physical Pharmacy
This is generally the first step during the
formulation of suspension.
A. Wetting of particles
B. Controlled flocculation
C. Rheological alteration
D. Emulsification
REFERENCE:
Physical Pharmacy
Observed in W/O type where the internal phase
is heavier (denser) than the continuous
phase, so the globules settle.
A. Downward creaming
B. Phase inversion
C. Upward creaming
D. Breaking
E. All of the above
REFERENCE:
Physical Pharmacy
t is a system in which oil is the dispersed or
dispersed or discontinuous phase and water is
continuous phase.
A. Water-in-Oil emulsion
B. Oil-in-Water emulsion
C. Either A or B
D. Neither A nor B
REFERENCE:
Physical Pharmacy
- Part F -
F. MICROMERITICS
F1. Particle Size and Size

Distribution
- Part F -
MICROMERITICS
Micromeritics
MICROMERITICS
• The science and technology of small particles
•Particle size
• Related to;
(a) physical,
(b) chemical, and
(c) pharmacologic properties of a drug
• A size of a spherical particle is characterized
by its diameter.
• Can affect the drug release from dosage forms
Micromeritics
MICROMERITICS
• The successful formulation of;

1. suspensions,
2. emulsions, and
3. tablets
… from the viewpoints of both physical stability
and pharmacologic response, also depends on
the particle size achieved in the product.
Micromeritics
Particle Size and Size Distribution
• A size of a spherical particle is characterized

by its diameter.
Micromeritics
Particle Size Distribution
• Monodisperse
- Collection of particles of uniform size
• Polydisperse
- Collection of particles of more than one size
•Particle Size Distribution

- Represents the number of particles in each size
present in a given sample
Micromeritics
Methods of Determining Particle

Size Distribution
• Number of particles
- Optical microscopy, electron microscopy
• Weight of particles
- Sieving, sedimentation, centrifugation
• Light scattering by particles
- Photon correlation spectroscopy
• Volume of particles
- Coulter counter method
Set-up for Sieving Technique
The largest
aperture size
The smallest
sieve number
Micromeritics
Micromeritics
Particle Shape and Surface area
•Particle Shape affects

- Packing properties
- Flowability
- Surface area
•Specific Surface
- defined as the surface area per unit volume
or per unit weight
Micromeritics
As the particle size DECREASES,

INCREASES
surface area ___________.
SA (side) = 6 SA (side) = 12 SA (side) = 24

Methods for Determining Surface Area
1. Adsorption Method
amount of a gas or liquid solute that is
adsorbed onto the sample of powder to form
a monolayer is a direct function of the surface
area of the sample.
QUANTASORB
2. Air Permeability Method

 the rate at which a gas or liquid permeates
a bed of powder is related to the surface
area exposed to the permeant.
 FISHER SUBSIEVE SIZER
F2. Flow Properties of Powders
- Part F -
MICROMERITICS
PROPERTIES OF POWDERS
Fundamental Properties
1. Particle size distribution
2. Surface area
Derived Properties
1. Porosity
2. Packing arrangement
3. Density
4. Bulkiness
5. Flow Properties
6. Compaction
Flow Properties of Powder
• Powders may be (a) free-flowing or (b) cohesive/sticky.
• Factors that affect flow properties;

1. Particles size (larger  better flow)
2. Particle shape (spherical  better flow)
3. Porosity (lower  better flow)
4. Density (higher  better flow)
5. Surface texture (smoother  better flow)
Micromeritics
Angle of Repose (𝜭)

• The maximum angle possible
between the surface of a pile of
powder and the horizontal plane.
𝒉
𝜭= 𝒕𝒂𝒏−𝟏
𝒓
ℎ → ℎ𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑡ℎ𝑒 𝑝𝑖𝑙𝑒

𝑟 → 𝑟𝑎𝑑𝑖𝑢𝑠 𝑜𝑓 𝑡ℎ𝑒 𝑝𝑖𝑙𝑒
𝛳 → ”𝑡ℎ𝑒𝑡𝑎” 𝑖𝑛 𝑑𝑒𝑔𝑟𝑒𝑒( 𝑜 )
 can be determined using the Fixed Funnel Method
 Glidants - excipients used to improve the flow
properties of granular powders
Micromeritics
−1
ℎ
ϴ = tan ( )
𝑟
Where h = height of the pile
r = radius of the pile
lower 𝜭, (better/poorer) the flow

Micromeritics
B. Flow Property of Powders

(Angle of Repose) by Fixed
Funnel Method
Micromeritics
Starch Citric acid
Talc Activated carbon

Learning Micromeritics: From Laboratory-Based to Home-Based Approach
Table 1. Flow Properties and Corresponding

Angles of Repose
Angle of Repose (𝜭) Flow Character
< 30 Excellent (very free)
31 - 35 Good
36 - 40 Fair – aid not needed
41 – 45 Passable – may hang up
46 - 55 Poor – must agitate, vibrate
56 - 65 Very poor
> 66 Very, very poor
Reference: Carr, R.L. Evaluating Flow Properties of Solids. Chem.
Eng. 1965, 72, 163–168.
Micromeritics
Problem:
Calculate the angle of
repose of the given
powder.
𝒉 4.00 cm
𝒓
𝟒. 𝟎𝟎
𝟑. 𝟐𝟓
𝜭 = 𝟓𝟎. 𝟗𝟏𝒐
6.50 cm
F3. Densities of Powders
- Part F -
MICROMERITICS
Micromeritics
Voids (Spaces)
Intraparticulate
voids
Micromeritics
Densities of Particles
• TRUE DENSITY
- density of material itself EXclusive of inter- and
intraparticular voids
• GRANULAR DENSITY
- density of material itself including intraparticular
voids
- BULK DENSITY
- density of material itself INclusive of inter- and
intraparticular voids
• TAPPED DENSITY
- a.k.a. COMPRESSED BULK DENSITY
- Obtained after compaction by tapping or vibration
Micromeritics
Determination of Bulk Density
• Method I –
Graduated Cylinder
𝒈𝒔𝒂𝒎𝒑𝒍𝒆
𝝆𝒃𝒖𝒍𝒌 =
𝒎𝑳𝒖𝒏𝒕𝒂𝒑𝒑𝒆𝒅
𝜌 → ”𝑟ℎ𝑜”
• Method II –
Scott Volumeter
Micromeritics
Determination of Tapped Density
• Mechanical tapping is
achieved by raising the
cylinder and allowing it to
drop under its own weight
𝒈𝒔𝒂𝒎𝒑𝒍𝒆
𝝆𝒕𝒂𝒑𝒑𝒆𝒅 =
𝒎𝑳𝒕𝒂𝒑𝒑𝒆𝒅
Micromeritics
Starch Citric Acid
𝟏𝟏 𝒎𝑳 𝟏𝟎. 𝟓 𝒎𝑳
𝟏𝟕 𝒎𝑳
𝟐𝟑 𝒎𝑳
Before Tapping After Tapping Before Tapping After Tapping

Micromeritics
Talc Activated Carbon
𝟒𝟐 𝒎𝑳 𝟐𝟗 𝒎𝑳
𝟏𝟒 𝒎𝑳
𝟗 𝒎𝑳
Before Tapping After Tapping Before Tapping After Tapping

Micromeritics
Problem:
Calculate the bulk density and tapped density of

starch powder if a 10-gram sample has volumes of
23 mL before tapping, and 17 mL after tapping.
𝒈𝒔𝒂𝒎𝒑𝒍𝒆 𝒈𝒔𝒂𝒎𝒑𝒍𝒆
𝝆𝒃𝒖𝒍𝒌 = 𝝆𝒕𝒂𝒑𝒑𝒆𝒅 =
𝒎𝑳𝒖𝒏𝒕𝒂𝒑𝒑𝒆𝒅 𝒎𝑳𝒕𝒂𝒑𝒑𝒆𝒅
𝟏𝟎 𝒈 𝟏𝟎 𝒈
𝝆𝒃𝒖𝒍𝒌 = = 𝟎. 𝟒𝟑𝟒𝟕𝟖 𝝆𝒕𝒂𝒑𝒑𝒆𝒅 = = 𝟎. 𝟓𝟖𝟖𝟐𝟒
𝟐𝟑 𝒎𝑳 𝟏𝟕 𝒎𝑳
Micromeritics
Compressibility (Carr’s) Index
• Carr reported that the more a material is

compacted in a compaction or tap bulk
density test, the poorer are its flow
properties.
𝝆𝒕𝒂𝒑𝒑𝒆𝒅 − 𝝆𝒃𝒖𝒍𝒌
𝑪. 𝑰. = 𝒙 𝟏𝟎𝟎
𝝆𝒕𝒂𝒑𝒑𝒆𝒅
Learning Micromeritics: From Laboratory-Based to Home-Based Approach
Table 2. Scale of Flowability
Compressibility
Flow Character
(Carr’s) Index (%)
< 10 Excellent
11-15 Good
16-20 Fair
21-25 Passable
26-31 Poor
32-37 Very poor
> 38 Very, very poor
Reference: Carr, R.L. Evaluating Flow Properties of Solids. Chem.
Eng. 1965, 72, 163–168.
Micromeritics
Voids (Spaces)
Intraparticulate
voids
F4. Porosity
- Part F -
MICROMERITICS
Micromeritics
Voids (Spaces)
Intraparticulate
voids
Micromeritics
Porosity
• A measure of the air spaces or voids in a

material 𝜺 → ”𝒆𝒑𝒔𝒊𝒍𝒐𝒏”
𝑽𝒗𝒐𝒊𝒅 = 𝑽𝒃𝒖𝒍𝒌 − 𝑽𝒕𝒓𝒖𝒆
𝑽𝒗𝒐𝒊𝒅
𝑷𝒐𝒓𝒐𝒔𝒊𝒕𝒚 (𝜺) = 𝒙 𝟏𝟎𝟎
𝑽𝒃𝒖𝒍𝒌
F5. Packing Geometry
- Part F -
MICROMERITICS
Packing Geometry
It is defined as the ratio of the void volume to
bulk volume of the powder packing.
A. True volume
B. Bulk density
C. Specific bulk volume
D. Porosity
E. All of the above
REFERENCE:
Physical Pharmacy
It is defined as the ratio of the mass of the powder
and its bulk volume.
A. True density
B. Granule density
C. Bulk density
D. Void density
E. Either B or C
REFERENCE:
Physical Pharmacy
It is defined as the maximum angle possible between
the surface of a pile of powder and the horizontal
plane.
A. Cosine of an angle
B. Cotangent of an angle
C. Sine of an angle
D. Angle of repose
E. Both A and C
REFERENCE:
Physical Pharmacy
This method is used to quantify particle size
distribution in a powder.
A. Microscopic technique
B. Sedimentation of sieving technique
C. Sieving technique
D. All of the above
REFERENCE:
Physical Pharmacy
- Part G -
G. RHEOLOGY
G1. Rheology
- Part G -
RHEOLOGY
Rheology
Rheology
• The study of deformation and flow properties of

matter
• Main components:
1. Viscosity
- resistance to flow
- property of liquids
2. Elasticity
- stickiness or structure
- property of solids
G2. Newtonian Fluids
- Part G -
RHEOLOGY
Rheology
Temperature Dependence of
Viscosity
For liquids: ↑ temperature ↓ Viscosity
* Due to decrease in the IMFA
For gases: ↑ temperature ↑ Viscosity
Newtonian Fluids
• Examples are simple liquids, either pure
chemicals or solutions, water
• Viscosity is independent on the rate of shear.
G3. Non-Newtonian Fluids
- Part G -
RHEOLOGY
Rheology
• Non-Newtonian System
The majority of fluid

pharmaceutical products are not
simple liquids and do not follow
Newton's law of flow. When non - Newtonian materials
These systems are referred to as are analyzed in a rotational
non - Newtonian. Non- Newtonian viscometer and results are plotted,
behaviour is generally exhibited by results will be various consistency
liquid and solid heterogeneous curves, representing three classes
dispersions such as of flow:
• colloidal solutions • Plastic
• emulsions • Pseudoplastic
• suspensions • Dilatant
• ointments
Time-Independent Non-Newtonian Fluids
• Non-Newtonian
• Plastic Flow
• known as Bingham bodies

• does not begin to flow until
shearing stress corresponding to
the yield value is exceeded. A
certain amount of force must be
applied to the fluid before any flow
is induced; this force is called the
“yield value”
• a yield value exists because of the
contacts between adjacent
particles (bound by Van der
Waals), which must be broken
down before flow occurs.
Non-Newtonian
Plastic Flow
• this type of flow is associated with
the presence of flocculated
particles in concentrated
suspensions.
• the more flocculation, the greater
is the yield value.
• hand cream, grease, tomato
paste, toothpaste
• Non-Newtonian Flow
• Pseudoplastic Flow
• known as shear –thinning systems
• viscosity of a pseudoplastic
substance decreases with
increasing rate of shear.
• decrease in viscosity brought
about by increase shear stress is
due to the shearing action on long
chain molecules of materials
(polymers). It also results in
release of solvent.
• Non-Newtonian Flow
• Pseudoplastic Flow
• exhibited by polymers in solution,
liquid dispersion of natural and
synthetic gums such as
tragacanth, sodium alginate,
methylcellulose, and sodium
carboxymethyl cellulose.
• hand sanitizer, ketchup
• Non-Newtonian
• Dilatant Flow
• termed shear-thickening systems or
dilatants
• increase in the rate of shear results
in an increase in viscosity; when the
shear stress is removed, the system
will return to its original state of
fluidity.
• represented by substances that are
suspensions containing a high
concentration of small, deflocculated
particles.
Rheology
Time-Independent Non-Newtonian
Fluids
PLASTIC PSEUDOPLASTIC DILATANT
FLOW FLOW FLOW
Does not begin to flow until a The viscosity of a substance The viscosity of a substance
shearing stress decreases with increasing increases with increasing
corresponding to the rate of shear. rates of shear.
yield value is exceeded. As shear stress is increased,
the bulk of the system
expands.
a.k.a. Bingham bodies “Shear-thinning system” “Shear-thickening system”
Exhibited by concentrated Exhibited by many Exhibited by highly

flocculated suspensions, pharmaceutical products, concentrated deflocculated
and semisolid dosage e.g. liquid dispersions of suspensions
forms natural & synthetic gums
Rheology
Non-Newtonian
Thixotropy
• an isothermal and comparative slow
recovery, on standing of a material,
of a consistency lost through
shearing.
 breakdown of structure does
not reform immediately when stress
is removed or reduced.
Rheopexy - the longer the fluid
undergoes shearing force, the higher
its viscosity.
G4. Determination of Rheologic

Properties
- Part G -
RHEOLOGY
Rheology
TYPES OF VISCOMETER
CAPILLARY
VISCOMETER
(Ostwald viscometer)
• The viscosity of a
Newtonian liquid can be
determined by
measuring the time
required for the liquid to
pass between two marks
as it flows by gravity
through a vertical
capillary tube.
Rheology
TYPES OF VISCOMETER
FALLING SPHERE VISCOMETER

(Hoeppler viscometer)
• A glass or steel ball
rolls down an almost
vertical glass tube
containing the test
liquid at a known
constant temperature.
The rate at which a ball
of a particular density
and diameter falls is an
inverse function of the
viscosity of the sample.
Rheology
Rheology
TYPES OF VISCOMETER
CUP-AND-BOB VISCOMETER
• the sample is sheared in the
space between the outer wall of a
bob and the inner wall of a cup
into which the bob fits.
Couette type – MacMichael

Viscometer
• Rotating bob, nd rotating cup
Searle type – Brookfield and

Stormer Viscometer
• Rotating bob, stationary cup
Rheology
Brookfield
Viscometer
Rheology
Viscosity Spindle
number
Speed
% torque
Rheology
TYPES OF VISCOMETER
CONE-AND-PLATE VISCOMETER
(Ferranti-Shirley Viscometer)
• the sample is placed at the center of
the plate, which is then raised into
position under the cone.
• A variable-speed motor drives the
cone, and the sample is sheared in
the narrow gap between the
stationary plate and the rotating
cone.
Rheology
Coaxial
cylinder
Cone and Plate Plate and Plate
It is a phenomenon in which the material exhibits an
increase in resistance to flow with increasing rate of
shear.
A. Dilatancy
B. Thixotropy
C. Rheopexy
D. Hysteresis
REFERENCE:
Physical Pharmacy
Which of the following instruments is/are used for
Newtonian Systems?
A. Capillary movements
B. Falling and rising body apparatus
C. Either A or B
D. Neither A nor B
REFERENCE:
Physical Pharmacy
It is an example of a rotational cone and plate
viscometer.
A. Cup and Bob viscometer

B. Maxwell viscometer
C. Couette type – MacMichael Viscometer
D. Ferranti-Shirley viscometer
E. Brookefield viscometer
REFERENCE:
Physical Pharmacy
- Part H -
H. COMPLEXATION
- Part H -
COMPLEXATION
H1. COMPLEXATION OR
COORDINATION COMPOUNDS
Results from a donor-acceptor mechanism
or Lewis acid-base reaction between two
or more different chemical constituents.
Lewis Electronic Theory
 - Electron Donor e.g. non-metal/ ionic compound
 - Electron Acceptor e.g. metal/ neutral atom
Complexation and Protein Binding
Complex or Coordination
Compounds
Types:
1. Metal ion
2. Organic Molecular
3. Inclusion/Occlusion
H2. TYPES OF COMPLEXES
COMPLEXATION
2) Chelating agents –
• from thecontains 2 or more donor groups (LIGAND) combined with a metal
(e.g. chlorophyll, hemoglobin, albumin)
• organic compounds that can assimilate and fix metallic ions and thus remove
them body. They are useful in cases of poisoning and tissue damage from
metals.
EDTAethylenediaminetetraac BAL, British Anti-
etic acid Lewisite
COMPLEXATION
Classification of Complexes
B. Organic Molecular Complexes
1. 1. Drug complexes
Organic Molecular Complexes
formed as a result of noncovalent interactions
between ligand and substrate.
the interaction occurs through electrostatic
forces, van der Waals forces, charge transfer,
hydrogen bonding, or hydrophobic effects.
COMPLEXATION
Drug Complexes
Drug complexes examples
1. Caffeine + organic acid anions – forms insoluble
complexes making caffeine less soluble which
provides caffeine in a form that masks its normal bitter
taste.
Such as
caffeine + gentisic acid (organic acid) = insoluble complex
or less soluble caffeine, masking the bitter taste of
caffeine and serve as a suitable state for chewing
caffeine tablets.
These chewable caffeine tablets also provide an
extended-release form of the drug with improved taste.
COMPLEXATION
B. Organic Molecular Complexes
1. 2. Polymer type
Polymer Complexes
Example
 Povidone (polyvinylpyrrolidone)polymer + iodine = povidone -iodine
 Povidone (polyvinylpyrrolidone, PVP) is used in the pharmaceutical industry as
a synthetic polymer vehicle for dispersing and suspending drugs.
 Povidone’s most common use is in the topical povidone-iodine solution
(Aerodine, Betadine), where iodine is released as an antiseptic.
COMPLEXATION
C. Inclusion Compounds
1. Channel Lattice Type
2. Layer Type
3. Clathrates
4. Cyclodextrins
Inclusion compounds or complexes

formed between interacting molecules in which
guest molecules are entrapped in a host molecule
through the unique molecular architecture of the
host.
Inclusion Compounds
1. Clathrates
• a molecule of a ‘guest’ compound gets entrapped within the
cage-like structure formed by the association of several
molecules of a ‘host’
• E.g. Warfarin Sodium
Complexation and Protein Binding
2. Channel Lattice Complexes

• Host component
crystallizes to form a
channel-like structure
into which the guest
molecule can fit
• E.g. Cholic acid
Inclusion Compounds
3. Monomolecular Inclusion Compounds
 entrapment of guest molecules into the cagelike structure
formed form a single host molecule.
 E.g. cyclodextrin
4. Macromolecular Inclusion Compounds or Molecular
Sieves
 Examples: synthetic zeolites, dextrans, silica and related
substances
5. Layer-Type or Intercalation Compounds
 the guest molecule is diffused between the layers of carbon
atom, hexagonally oriented to form alternate layers of guest
and host molecules.
 Examples:
1. montmorillonite – principal component of bentonite
2. graphite
- Part I -
I. CHEMICAL KINETICS
AND STABILITY
- Part I -
CHEMICAL KINETICS AND STABILITY
I1. Chemical Kinetics
- Part I -
Chemical Kinetics and Stability
Introduction
To ensure that the patient receives the

correct dose of a drug,
the rate of degradation must be known.
Degradative reactions are chemical in

nature and take place at definite rates.
Chemical Kinetics
• the study of rate of a chemical reaction
Reaction rate
- speed of a chemical reaction
Chemical Kinetics
•Deals with the stability of drugs and

the mode of action of their
degradation through the examination
of rate of reaction.
•Can provide predictive information

to anticipate stability problems
I2. Order of Reaction

The way or the description in which the
concentration of the drug or reactant
affects the rate of a chemical reaction.
- Part I -
Chemical Kinetics
Orders of Reactions
•Zero-Order Reactions
Amt Amt ∆
The loss of drugs is independent of (mg) (mg)
the concentration of the 0 time 500
reactants and constant with respect 2 mon 450 50
to time. 4 mon 400 50
6 mon 350 50
𝑑𝐶 8 mon 300 50
− = 𝑘[𝐶][𝑊]
𝑑𝑡
Remaining
Concentration (mg/mL)
40
30
20
10
Y-axis
1 2 3 4
Time (hr)
x-axis
Straight line  follows

zero-order kinetics
The equation of the line:
𝒚 = 𝒎𝒙 + 𝒃
𝒎 → 𝒔𝒍𝒐𝒑𝒆
𝒃 → 𝒚 − 𝒊𝒏𝒕𝒆𝒓𝒄𝒆𝒑𝒕
𝑪 = −𝒌𝒕 + 𝑪𝟎
𝒌 → 𝒓𝒂𝒕𝒆 𝒄𝒐𝒏𝒔𝒕𝒂𝒏𝒕
𝑪𝟎 → 𝒊𝒏𝒊𝒕𝒊𝒂𝒍 𝒄𝒐𝒏𝒄𝒆𝒏𝒕𝒓𝒂𝒕𝒊𝒐𝒏
𝑪 = −𝒌𝒕 + 𝑪𝟎
𝒎 → −𝒌 𝒌 = −𝒎
𝐶2 − 𝐶1
𝒎=
𝑡2 − 𝑡1 Select the last
two points.
𝒃 → 𝑪𝟎 = 𝐶2 + 𝑘𝑡2
Chemical Kinetics
Orders of Reactions
• Shelf-life for Zero
Order Kinetics
• Half-life for Zero Order The time required for
Kinetics 10% of the drug to
The time required for one-half of the disappear, 𝑡0.90
drug to disappear. 𝑡1 or 𝑡0.5 . Equation for 𝑡0.90
2
Equation for 𝑡1
2
𝐶𝑡 = 𝐶0 − 𝑘𝑡 𝐶𝑡 = 𝐶0 − 𝑘𝑡
𝒕𝟏 = 𝑪𝟎 /𝟐𝒌𝟎 𝟎. 𝟏𝑪𝟎
𝟐
𝒕𝟎.𝟗𝟎 =
What will the remaining quantity of
𝒌 𝒐
a 500 mg drug after 1 year if its’ half What will the remaining
life is 1 year?
quantity of a 100 mg drug
Answer = 250 mg after 3 years if its’ shelf
life is 3 yearS?
Answer = 90 mg
Drug Y degrades by a zero-order process with a rate
constant of 5 mg/mL per year at room temperature. If a
1 % w/v solution is prepared and stored at room
temperature.
1.What concentration will remain after 18 months?

Formula:
Given
k = 5mg/mL per year 𝑪𝒕 = 𝑪𝟎 − 𝒌𝒕
𝐶0 = 1 % w/v convert to mg/mL
1𝑔 𝑥 Substitution:
𝐶0 = = = 𝐶𝑡 = 𝐶0 − 𝑘𝑡
100𝑚𝐿 1𝑚𝐿
0.01𝑔 1000𝑚𝑔
𝑥= × = 𝐶𝑡 = 10𝑚𝑔 −(
5𝑚𝑔
𝑝𝑒𝑟 𝑦𝑒𝑎𝑟 ×
𝑚𝐿 1𝑔 𝑚𝐿 𝑚𝐿
𝐶0 = 10 mg/ mL 1.5 𝑦𝑒𝑎𝑟)
𝑦𝑒𝑎𝑟 Answer:
𝑡 = 18 𝑚𝑜𝑛𝑡ℎ𝑠 × 1 𝑚𝑜𝑛𝑡ℎ𝑠
12 𝑪𝒕 = 2.5 mg per mL after
= 1.5 𝑦𝑒𝑎𝑟
1.5 year or 18 months
Drug Y degrades by a zero-order process with a rate
constant of 5 mg/mL per year at room temperature. If a 1
% w/v solution is prepared and stored at room
temperature.
2. What is the half-life of the drug? 3. What is the shelf life of drug Y?
Formula: Formula:
𝟎. 𝟏𝑪𝟎
𝑪𝟎 𝒕𝟎.𝟗𝟎 =
𝒕𝟏 = 𝒌
𝟐 𝟐𝒌
Given Given
k = 5mg/mL per year k = 5mg/mL per year
𝑪𝟎 = 10 mg/ mL 𝑪𝟎 = 10 mg/ mL
Substitution: Substitution:
10𝑚𝑔 0.1 ×10𝑚𝑔
𝐶0 𝑚𝐿 𝑡0.90 =𝟎.𝟏𝑪 𝟎
== 𝑚𝐿
𝒕𝟏 = = 𝑚𝐿 𝒌 𝑚𝐿
5𝑚𝑔 𝑝𝑒𝑟𝑦𝑒𝑎𝑟
𝟐 2𝑘 2 ×5𝑚𝑔 𝑝𝑒𝑟
𝑦𝑒𝑎𝑟
Answer Answer
𝒎𝒐𝒏𝒕𝒉𝒔
𝒕𝟏 = 1 year 𝒕𝟎.𝟗𝟎 = 0.2 year × 𝟏𝟐
𝟏𝒚𝒆𝒂𝒓
= 𝟐. 𝟒 𝒎𝒐𝒏𝒕𝒉𝒔
𝟐
Chemical Kinetics
Orders of Reactions
•First-Order Reactions
The loss of the drug is
directly proportional to
the concentration
remaining with respect
to time.
𝑑𝐷
− = 𝑘[𝐷][𝑊]
𝑑𝑡
First-Order Elimination
• the amount of drug eliminated per unit of time decreases as

the amount of drug in the body decreases
• the fraction or percentage of a drug in the body eliminated
over a given time remains constant
First-order Kinetics
• A plot of the remaining drug concentration, C versus t,

gives a curved line.
• However, a plot of natural logarithm of drug concentration,

ln C vs t, gives a straight line with a slope equal to -k.
𝒍𝒏𝑪 = −𝒌𝒕 + 𝒍𝒏𝑪𝟎
𝒎 → −𝒌 𝒌 = −𝒎
𝑙𝑛𝐶2 − 𝑙𝑛𝐶1 Select the last

𝒎=
𝑡2 − 𝑡1 two points.
𝒃 → 𝒍𝒏𝑪𝟎 = 𝑙𝑛𝐶2 + 𝑘𝑡2

Determine the rate constant, k.
𝑙𝑛𝐶2 − 𝑙𝑛𝐶1 Time (hr) Concentration (M)

𝒎= 0 1.0005
𝑡2 − 𝑡1 5 0.505
11 0.255
𝑙𝑛0.063−𝑙𝑛0.130
𝒎= 17 0.130
23ℎ𝑟−17ℎ𝑟
23 0.063
−0.72440
𝒎= = −0.12073 𝒉𝒓−𝟏 𝒌 = −𝒎
6ℎ𝑟
𝒌 = − −0.12073𝒉𝒓−𝟏 = 𝟎. 𝟏𝟐𝟎𝟕𝟑 𝒐𝒓 𝟎. 𝟏𝟐 𝒉𝒓−𝟏

Determine the half-life and shelf-life of

the drug in the previous problem.
(a) Half-life:
𝟎. 𝟔𝟗𝟑 𝟎. 𝟔𝟗𝟑
𝒕𝟏/𝟐 = 𝒕𝟏/𝟐 = −𝟏
= 𝟓. 𝟕𝟒 𝒉𝒓
𝒌 𝟎. 𝟏𝟐𝟎𝟕𝟑 𝒉𝒓
(b) Shelf-life:
𝟎. 𝟏𝟎𝟓 𝟎. 𝟏𝟎𝟓
𝒕𝟗𝟎 = 𝒕𝟗𝟎 = −𝟏
= 𝟎. 𝟖𝟕 𝒉𝒓
𝒌 𝟎. 𝟏𝟐𝟎𝟕𝟑 𝒉𝒓
The concentration of drug Q is aqueous solution drops by 0.05 % per month when
stored at room temperature. If the degradation occurs by the first order, what
concentration will remain if a 100 mg/mL solution of the drug is stored under the
same conditions for 3 months?
Given Formula:
𝑘 = 0.05 % per month convert to mg/mL ln𝐶𝑡 = 𝑙𝑛𝐶0 − 𝑘𝑡
0.05𝑔 𝑥
k= =
100𝑚𝐿 1𝑚𝐿 Substitution:
𝑥=
0.0005𝑔
×
1000𝑚𝑔
=0.5 mg/mL per month ln𝐶𝑡 = 𝑙𝑛𝐶0 − 𝑘𝑡
𝑚𝐿 1𝑔
𝑐0 = 100 mg/ mL
ln𝐶𝑡 = 𝑙𝑛100 − (0.5 × 3)
𝑡 = 3 𝑚𝑜𝑛𝑡ℎ𝑠
ln𝐶𝑡 = 3.11
Answer:
𝑪𝒕 = 22.32 mg/mL will remain after 3 months
Zero-order First-order
Equation 𝑪 = −𝒌𝒕 + 𝑪𝟎 𝒍𝒏𝑪 = −𝒌𝒕 + 𝒍𝒏𝑪𝟎
Rate 𝒌=−
𝑪𝟐 − 𝑪𝟏
𝒌=−
𝒍𝒏𝑪𝟐 − 𝒍𝒏𝑪𝟏
constant 𝒕𝟐 − 𝒕𝟏 𝒕𝟐 − 𝒕𝟏
𝑪𝒐𝒏𝒄𝒆𝒏𝒕𝒓𝒂𝒕𝒊𝒐𝒏 𝟏
Unit for k 𝒕𝒊𝒎𝒆 𝒕𝒊𝒎𝒆
𝟎. 𝟓𝑪𝒐 𝟎. 𝟔𝟗𝟑
Half-life 𝒕𝟏/𝟐 =
𝒌
𝒕𝟏/𝟐 =
𝒌
𝟎. 𝟏𝑪𝒐 𝟎. 𝟏𝟎𝟓
Shelf-life 𝒕𝟗𝟎 =
𝒌
𝒕𝟗𝟎 =
𝒌
Shelf Life and Expiration Dating
•Shelf life
- the time period during which a drug product is
expected to remain within the approved
specification for use, provided that it is stored
under the conditions defined on the container label.
- the time required for 10% of the material to
disappear
•Expiration Date
- the date placed on the container label of a drug
product designating the time prior to which a batch of
the product is expected to remain within the
approved shelf-life specification
Determination of Shelf-life
1. Arrhenius Equation
- used to predict temperature stability
2. Q10 Method
- can estimate the effect of a
10° rise in temperature on the
stability of pharmaceuticals
I3. Evaluation of Stability of Drug

products
- Part I -
Evaluation of Stability of Drug products
•Accelerated Stability Studies

- designed to increase the rate of chemical
degradation or physical change of a drug or
drug product by using exaggerated storage
conditions
• Stress Testing
- carried out under more severe conditions
than those used for accelerated testing
- High temperature, humidity, high or low pH
I4. Decomposition Processes of

Pharmaceuticals
- Part I -
Decomposition and Stabilization of
Pharmaceuticals
Thank you for listening…
Dr Ana Marie L. Rubenicia

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Integrated Pharmaceutical Sciences 1

Ana Marie L. Rubenicia, PhD, RPh

Application of physical, chemical, and

Physical Chemical Biological

A1. Binding Forces Between

Binding Forces Between Molecules

Binding Forces Between Molecules

When molecules interact with each other,

Intermolecular Binding Forces

There are four main types of intermolecular attractive forces:

Intermolecular Binding Forces

• Occur when polar molecules

Intermolecular Binding Forces

• Occur when polar molecules

Intermolecular Binding Forces

Intermolecular Binding Forces

Intermolecular Binding Forces

Intermolecular Binding Forces

Hydrogen bond can be

A2. States of Matter

Flows and Fills any

Thus, to develop a drug product it is

A3. The Gaseous State

The Gaseous State

• Gas exerts pressure.

Combined Gas Laws

General Ideal Gas Law

This equation is correct only for 1 mole

𝑁 = 6.02 × 1023 molecules / mole

Ideal Gas Law

𝑹 → 𝒎𝒐𝒍𝒂𝒓 𝒈𝒂𝒔 𝒄𝒐𝒏𝒔𝒕𝒂𝒏𝒕

Ideal Gas Law

Calculation of Molecular Weight using

A. Boyle’s law equation

Kinetic Molecular Theory (KMT)

Elastic bodies and

Kinetic Molecular Theory

where P – pressure; V - volume occupied by any number n of molecules of mass m

Root Mean Square Velocity

Graham’s Law , who showed that a lighter gas

van der Waals Equation for Real Gases

Ideal gas vs Real gas

• Real gas molecules;

( P + a n2) (V – nb) = nRT

van der Waals Equation for Real Gases

When the volume of gas is large

States that the concentration of dissolved gas is proportional to the

Root Mean Square Velocity

A4. The Liquid State

• Possess less kinetic energy than gases

Temperature and Pressure

Gaseous state Liquid state

If the temperature is elevated suficiently, a value

The critical temperature of water is 374 °C or 647 K, its critical pressure r

AEROSOL is a liquid mixture

• An aerosol is a suspension of fine solid

Vapor Pressure of Liquids

• Some molecules subsequently return to the liquid state.