PHYSICAL PHARMACY AND PHARMACEUTICAL DOSAGE FORMS WITH

BIOPHARMACEUTICS
PHYSICAL PHARMACY
I. INTERMOLECULAR FORCES OF ATTRACTION
Repulsive forces
arise when dipolar molecules approach one another close enough positive to positive or
negative to negative, their electron cloud interpenetrate (repulsion).
Attractive forces
arise when dipolar molecules approach one another so that the positive pole of one is
close to the negative pole of the other (attraction occurs dipole-dipole interaction).
TYPES OF INTERMOLECULAR FORCES OF ATTRACTION
A. Van der Waals forces
1. Dipole-dipole interaction (Keesom forces)
2. Induced dipole-induced dipole interaction (London forces)
3. Dipole-induced dipole interaction (Debye induction forces)
B. Ion-ion, ion-dipole, and ion-induced dipole forces
C. Hydrogen bonds
II. STATES OF MATTER
A. GASES
Molecules in gaseous state travel in random and rapid motion, until they collide with other
molecules and with the walls of the container in which they are confined. These random
collisions are responsible for the pressure exhibited within the confined system.
Another important characteristics of a gas is volume
The interrelation among volume (V), pressure (P), and the absolute temperature (T) is
given by the ideal gas equation:
PV = nRT
PV = (g/MW)RT
Where n is the number of moles (g/MW) and
R is the molar gas constant (0.08205 L-atm/mole- oK
Pharmaceutical gases include:
A. Anesthetic gases (nitrous oxide and halothane)
B. Compressed gases (oxygen for therapy; nitrogen or carbon dioxide)
C. Liquefiable gases used as propellants in aerosol products (pressurized packaging)
D. Ethylene oxide used to sterilize or disinfect heat-labile objects
Vaporization phase change from liquid to gaseous state
Example:
1. Ether,
2. Halothane and
used as inhalation anesthetics
3. Methoxyflurane
4. Amyl nitrite , used as vasodilator in acute angina
Sublimation solid transform directly to gaseous, or vapor state without passing through
the liquid state (Example: Camphor, Iodine).
The intermolecular forces of attraction in gases are virtually nonexistent at room
temperature.

B. LIQUID
1. The inter molecular forces of attraction in liquids are:
1.1 Van der Waals forces and
1.2 hydrogen bonding
2. SURFACE AND INTERFACIAL TENSION
Surface tension or surface free energy
can be defined by the work required to increase the surface area of the liquid by 1
area unit (dynes/cm)
Surface tension of most liquids decreases with an increase in temperature.
Interfacial tension or free energy
is the work required to expand the interfacial area.
Force per unit length existing between 2 immiscible phases.

Interfacial tension reflects the extent of the intermolecular forces of attraction and
repulsion at the interface.

3. FLOW PROPERTIES
Rheology
study of flow properties of liquid and the deformation of solids.
It also involves the viscosity characteristics of powders, fluids and semisolids.
Viscosity
resistance to flow of adjacent layers of fluid.
units: in CGS, dyne/sec/cm2 or poise (0.01 poise = centipoise).
I. GENERAL CATEGORIES OF FLOW
A. Newtonian flow
is characterized by a constant viscosity, regardless of the shear rates applied.
(e.g. liquids of simple molecules and dilutes dispersions)
B. Non-Newtonian flow
characterized by a change in viscosity characteristics with increasing shear rates.
3 TYPES OF NON-NEWTONIAN FLOW
1. Dilatant (shear thickening) viscosity increases with an increase in shear force
Displayed by suspensions of small deflocculated particles that have a high contents of
solids.
2. Psuedoplastic (Shear thinning) viscosity decreases with an increasing rate of shear.
Exhibited by polymer solutions, e.g., gums (natural and synthetic).
3. Plastic (Bingham body) show no apparent response to low-level stress.
Flow begins only after a limiting yield stress is exceeded.
Exemplified by flocculated particles in concentrated suspensions
(gels, semisolids like creams, ointments, pastes, cerates and cataplasms.)
Other types of flows
Thixotropy gel-sol transformation
Negative thixotropy or antithixotropy sol-gel transformation
C. SOLIDS
1. Intermolecular forces of attraction are stronger than liquids or gases.
2. Solids are either crystalline or amorphous.
CRYSTALLINE
AMORPHOUS
1. Fixed molecular order
1. Randomly arranged molecules
2. A distinct melting point
2. Non-distinct melting points

3. Anisotropicity

3. Isotropicity

3. Polymorphism
is the condition wherein substances can exist in more than one crystalline form.

Different polymorphs of a drug can have different properties.

Examples: steroids, excipients like cocoa butter

4. Melting point and heat fusion.

Melting point
is the temperature at which the solid is transformed to a liquid.
Latent heat of fusion
the heat absorbed when 1 gram of solid is heated and melts.
III. PHYSIOCHEMICAL BEHAVIOR

A.

HOMOGENOUS SYSTEMS
1. Solution
a homogenous system in which the solute is molecularly dispersed, or dissolved in a
solvent.
Saturated solutions
are solutions which, at a given temperature and pressure, contain the maximum amount
of solute that can be accommodated by the solvent.
A. Solvent present in greatest quantity.
B. Solute can be gases, liquids, or solids, and nonelectrolytes or electrolytes.
1. Nonelectrolytes
do not form ions when dissolved in water.
Their aqueous solutions do not conduct electric current.
Examples: estradiols, glycerin, urea and sucrose.
2. Electrolytes
do form ions in solution, thus conduct electric current.
3. Strong electrolytes
completely ionized in water.
Examples: sodium chloride, hydrochloric acid
4. Weak electrolytes
partially ionized in water.
Example: Aspirin, Atropine
2. Colligative properties of solution depend mainly on the number of particles in solution.
2.1 Lowering of vapor pressure
Raoults Law
The partial vapor pressure of each volatile component in a solution is equal to the
product of the mol fraction of the component in the solution and the vapor pressure of the pure
component.
Vapor pressure
is the pressure at which an equilibrium is established between the molecules of A in the
liquid state and the molecules of A in the gaseous (vapor) state in a close, evacuated
container.
2.2 Elevation of boiling point
Boiling point
is the temperature at which the vapor pressure of a liquid equals an external
pressure of 760 mmHg.
2.3 Depression of freezing point

Freezing point is the temperature at which the solid phase of the pre solvent and the liquid
phase of the solution are in equilibrium under a pressure of 1 atm.
2.4 Osmotic pressure
Osmosis
is the process by which solvent molecules pass through a semipermeable membrane
from a region of dilute solute to one of more concentrated solution.
Osmotic pressure
is the pressure that must be applied to the solution to prevent the flow of pure solvent
into the concentrated solution.
3 Solubility
(quantitative) is defined as the concentration of solute in a saturated solution at
certain temperature .
(qualitative) is defined as the spontaneous interaction of two or more substances to
form a homogenous molecular dispersion.
Factors affecting the solubility of drugs
(1) Physicochemical properties of the solute and the solvent
(2) Temperature
(3) Pressure
(4) pH of the solution
(5) presence of other substance to aid solubility
DESCRIPTIVE TERMS OF APPROXIMATE SOLUBILITY
DESCRIPTIVE TERM
PARTS OF SOLVENT REQUIRED TO
DISSOLVE 1 PART OF SOLUTE
Very soluble
Less than 1 part
Freely soluble
1 10
Soluble
10 30 parts
Sparingly soluble
30 100 parts
Slightly soluble
100 1,000 parts
very slightly soluble
1,000 10,000 parts
Practically insoluble or insoluble
More than 10,000 parts
4 Electrolyte solution and ionic equilibria
A. Acid base equilibira
(1) Arrhenius Dissociation Theory
An acid is a substance that liberates H+ in aqueous solution.
A base is a substance that liberates hydroxyl ions (OH+) in aqueous solution.
(2) Lowry Bronsted Theory
An acid is a substance (change or unchanged) that capable of donating a proton.
A base is a substance (change or unchanged) that is capable of accepting a proton from
an acid. The dissociation of an acid (HA) always produces a base (A -)
HA
H+ + A HA and A are a conjugate acid-base pair (an acid and a base that exist in equilibrium
and differ in structure by a proton).
The proton of an acid does not exist free in solution, but combines with the solvent. In
the water, the hydrated proton is a hydronium ion (H 3O+)
(3) Lewis theory
An acid molecule or ion that accepts an electron pair from another atom and a
base is a substance that donates an electron pair to be shared with another atom.
B. H+ concentration
Expressed in exponential notation as pH.

 pH is the logarithm of the reciprocal of the H + concentration.

H +

pH = log
1

pH = -log [H+] or [H+] = 10-pH

As pH decreases, H+ concentration increases exponentially.
C. Dissociation constant
Ionization is the complete separation of ions in crystal lattice when the salt is dissolved.
Dissociation is the separation of ions in solution when the ions are associated by interionic
attraction.
(1) For weak acids
Dissociation in water is expressed as:

H+ + A-

HA

Equilibrium expression for the dissociation of a weak acid is:

H +

A
Ka =

The acid dissociation constant is:

pKa = -log [Ka]

(2) For weak bases
Dissociation may be expressed as:
(I)
Conjugate acid of the base

BH+ <-> H+ + B
Dissociation constant for this reaction is:
H +

[B]

Ka =
BH +

(II)

For a base that contains a hydroxyl group

B + H2O <-> OH + BH+

Dissociation constant for this reaction is expressed as:
OH

BH +
Kb =

The base dissociation constant is:

pKb = -log[kb]
D. Henderson-Hasselbalch equation
Described the relation between the ionized and unionized species of a weak electrolyte.
(1) For weak acids
[salt ]
pH = pKa + log [ acid]
(2) For weak base

pH = pKa + log
E. Degree of ionization ()

BH +

[B]

the fraction of a weak electrolyte that is ionized in solution, and is calculated as:
[I ]
= [ I ] +[U ]
when the pH of the solution is numerically equal to the pKa of the weak electrolyte,
whether a weak base or a weak acid,
[I] = [U] and the degree of ionization = 0.5 (50% of the solute is ionized).

Solubility of a weak electrolyte (varies as a function of pH)

for weak acids, solubility increases with an increasing pH.
for weak bases, solubility decreases with increasing pH.

(4)

G. Buffers and buffer capacity

(1) Buffer
a mixture of salt with acid base that resists changes in pH when small quantities
of acid or base are added.
It is usually a combination of a weak acid and its conjugate base (salt) or a
combination of a weak base and its conjugate acid (salt).
(2) Buffer equation
a. For a weak acid and its salt
pH = pKa + log [salt]/[acid]
b. For a weak base and its salt
pH = pKw pKb + log [base]/[salt]
(3) Buffer action is the resistance to a change in pH.
Buffer capacity is the ability of a buffer solution to resist changes in pH.
a. Buffer capacity is the number of gram equivalent in an acid or base that
changes the pH of 1 L buffer solution by 1 unit.
b. Buffer capacity equation ()
H +

Ka+ 2
= 2.3 C

Ka+

c. Maximum buffer capacity occurs when pH = pKa, and is represented by:

= 0.576 C
(5) Biological buffer system
a. Primary buffers
carbonic acid/bicarbonate buffer system found in plasma
b. Secondary buffers
hemoglobin/Oxyhemoglobin and
acid/alkali potassium salts of phosphoric acid.
(6) Pharmaceutical buffers
a. Important in ophthalmic preparation
b. Examples:
boric acid and sodium bicarbonate; Mixtures of salts of sodium
phosphate.
H. Isotonic solutions
Cause no swelling or contraction of the tissues with which they come in contact, and produce
no discomfort when instilled into the eye, nasal tract, blood or other tissues.
Isotonic with blood solution has the same salt concentration as the RBC content.
Isoosmotic with blood solution has the same osmotic pressure as the RBC.
HYPOTONIC cause cells to swell; water enter the cells resulting to hemolysis.
HYPERTONIC cause cells to shrink because of the outward passage of water.
Methods of adjusting tonicity
(1) Cryoscopic method/freezing point depression method
(2) Sodium chloride equivalent method
(3) White Vincent method

B.

HETEROGENEOUS (DISPERSE) SYSTEM

I. COARSE DISPERSIONS
1. Suspension
A. it is a two-phase system that is composed of a solid material dispersed in an
oily or aqueous liquid.
B. the particle size is usually greater than 0.5mm.
2. Emulsion
A. it is a heterogeneous system that consist of at least one immiscible liquid that is
intimately dispersed in another in the form of droplets.
B. Droplet diameter usually exceeds 0.1 m.
C. the third component of the system is an emulsifying agent. This agent prevents
coalescence and maintains the integrity of the individual droplets.
D. Inherently unstable system.
II. DISPERSION STABILITY
1. Ideal dispersion
A. Particles do not interact.
B. Participles are uniform in size and exhibits Brownian movement.
2. Real dispersion
A. Particles are not uniformly sized
B. Particles are subjected to particular aggregation, of clumping, and become more
heterogeneous with time.

3. Interfacial properties of the suspended particles

A. Flocculation a process of forming a light, fluffy conglomerates that are held together
by weak Van der Waals forces.
I. Flocculated system
Particles settle rapidly, but can easily be resuspended.
Particles do not form a cake.
II. Deflocculated system
Particles dont settle rapidly, so more stable.
Particles aggregated to form a hard cake
B. Aggregation a process where particles adhere by stronger forces with the resultant
formation of a hard cake.
C. Caking growth and fusing together of crystals in the precipitate to produce a solid
aggregates.
4. Stroke Law
A. The rate of setting of the dispersed phase in the dispersion medium is a function of:
I. Particle size
II. Viscosity of the dispersion medium
III. Difference in density between the dispersed phase and the dispersion
medium.
B. Sedimentation rate = d2g(p1-p2)

18
d = particle diameter
g = acceleration due to gravity
= viscosity of the dispersion medium
(p1-p2) = difference in density between the density of the particles (p 1) and the
density of the dispersion medium (p2).
5. Stabilization of dispersion

A. Particle size should be as small as possible.

B. High particulate (dispersed phase) concentrations.
C. Avoidance of particle-particle interactions.
I. If the particles have similar electrical charge.
II. The dispersion is deflocculated (high zeta, , potential).
III. Manipulated of densities.
IV. Increased viscosity of the dispersion medium.
6. Emulsion stability
A. Coalescence
the liquid particles of the dispersed phase merge to form larger particles.
This is prevented by the interfacial film of the surfactant around the droplet.
B. Creaming
is the reversible separation of a layer of emulsified particles.
Mixing or shaking can be reverse the process.
C. Phase inversion, or emulsion-type reversal
involves the reversion of an emulsion from an o/w to a w/o form, or vice-versa.
It can change the consistency or texture of the emulsion cause further
deterioration in its stability.
III. COLLOIDAL DISPERSION
1. Characteristics of particles
A. May be deflected under ultramicroscope; visible in electron microscope.
B. Pass through filter paper but do not pass through semipermeable membrane.
C. Diffuse very slowly
2. Properties of colloids
A. Faraday-Tyndall effect
B. Brownian movement
C. Electrophoresis
3. Methods of separating colloids
A. Dialysis
B. Ultrafiltration
C. Electrodialysis
4. Types of colloidal system
A. Lyophilic colloids solvent loving colloids
Interacts appreciable with the dispersion medium
Form colloidal dispersion of sols
Examples:
1. Hydrosol (water is the dispersion medium) acacia, gelatin,
Insulin, albumin;
2. Organosol (organic solvent is the dispersion medium) polysterene and
rubber;
3. Aerosol (dispersion of a solid or liquid in gaseous medium).
B. Lyophobic colloids solvent gating colloids
Materials with little or no attraction for the dispersion medium
Examples: Gold, silver, sulfur. Silver iodide
C. Association colloids (Amphiphilic)
Characterized by having tow distinct regions of opposing solution affinities
within the same molecule or ion.
Micelles aggregates of subcolloidal particles
C.

CHEMICAL KINETICS AND DRUG STABILITY

I. STABILITY is defined as the extent to which a product retains, within specified limits, and
throughout its period of storage and use (i.e., its shelf-life), the same properties and
characterized that is possessed at the time of its manufacture.
FIVE TYPES OF STABILITY
1. Physical the original physical properties, including appearance, palatability, uniformity,
dissolution and suspendability are retained.

2. Chemical each active ingredient retain its chemical integrity and labeled potency, within the
specified limits.
Important for selecting storage condition,
selecting the proper container, and
for anticipating interactions.
3. Microbiologic sterility or resistance to microbial growth is retained according to the specified
requirements.
Antimicrobial agents that are present retain effectiveness within specified limits.
4. Therapeutic the therapeutic effect remain unchanged.
5. Toxicology no significant increase in toxicity occurs.
Instability of drug products may give rise to the following consequences.
1. Substantial loss of the active ingredient from the dosage form.
2. Formation of a toxic product
3. Can cause decreased bioavailability
II. CHEMICAL KINETICS
Importance:
1. Stability
2. Expiration dating

RATES AND ORDERS OF REACTIONS

1. Reaction rate of degradation rate
A. It is the velocity with which the reaction occurs.
B. Expressed as dC/dt
C. Its application in the body is under pharmacokinetic principles.

2. Reaction order
A. Is the way in which the concentration of the drug or reactant in a chemical reaction affects
the rate.
B. Reaction order for pharmaceutical degradation can be:
(1) Zero-order reaction
The rate is independent of the concentration of the reactants.

C = kot + Co
(2) First-order reaction
Drug concentration decreases exponentially with time.
Half-life
is the period required for the concentration of a drug to decrease by onehalf (t1/2)

t1/2 = 0.693/k
Stability projections for shelf-life (t90)
the time required for 10% of the drug to degrade with 90& of the intact
drug remaining.
3. Factors affecting reaction rates
A. Temperature
An increased in temperature causes an increase in reaction rate.
B. Presence of solvent
(1) A change in the solvent system alters the transition state and the activity coefficients of
the reactant molecules.
(2) In some cases, additional reaction pathways are generated.
C. Change in pH
Affects specifically the magnitude of the rate of a hydrolytic reaction.
D. Presence of additives
(1) Buffer salts

 These salts can be affected the rate of degeneration primarily as a result of salt
increasing the ionic strength
Can also promote drug degradation through general acid or base catalysis
(2) Surfactants
Acceleration of degradation is caused by micellar catalysis
(3) Complexing agent
Can be improved drug stability as a result of the formation of a less reactive complex.
III. MODES OF PHARMACEUTICAL DEGRADATION
1. HYDROLYSIS
A. The most common type of degradation
B. H+ and OH- are most common catalysis.
C. Esters, amides and lactams usually undergo hydrolytic reactions that cause drug
instability
2. OXIDATION
A. Is usually mediated through reactions with atmospheric oxygen under ambient conditions
(auto-oxidation)
B. Medicinal compounds that undergo auto-oxidation at room temperature are affected by
oxygen dissolved in the solvent and in void space of their package. These compounds
should be package in an inert atmosphere
(e.g., nitrogen carbon dioxide) to exclude air from their containers.
C. Most oxidation reactions involve free radical mechanism and a chain reaction.
Free radicals tend to take up electrons from other compounds.
Antioxidants react with free radicals by providing electrons and easily available
hydrogen atoms.

Commonly used antioxidants include:

1. ascorbic acid,
2. butylated hydroxyanisole (BHA),
3. butylated hydroxytoluene (BHT),
4. propyl gallate,
5. sodium bisulfite,
6. sodium sulfite, and the
7. tocopherols.
3. PHOTOLYSIS is the degradation of drug molecules by normal sunlight or room light.
A. Photolytic degradation occurs on exposure to light wavelengths less than 400 nm.
B. Amber bottle or an opaque container prevent or retard photolysis by acting as barrier to
light.
IV. SHELF LIFE
The shelf life of a drug preparation is the amount of time that the product can be stored before
it becomes unfit for use, through either chemical decomposition or physical deterioration.
1. Storage temperature affects shelf life.
2. In general, a preparation is considered fit for use if it varies from the normal concentration
or dose by no more than 65%, provided that the decomposition products are more toxic or
harmful than the original material.
3. Shelf life testing
A. Samples are stored at approximately 3-5 oC and at room temperature (20-25 oC).
The samples are then analyzed at various intervals to determine the rate of decomposition.
Shelf life is calculated from this rate.
B. Accelerated stability testing
The rate constants obtained from these samples are used to predict shelf life.

 Temperature accelerated stability testing is not useful if temperature changes are

accompanied by changes in the reaction mechanism or by physical changes in the system.
Stability at room temperature can be predicted from accelerated testing date by the
Arrhenius equation:

Log k1 = Ea(T2-T1)
k2 2.303 RT2T1
k1 and k2
= rate constants at the absolute temperature T2 and T1, resprectively
R
= gas constant
Ea
= energy of activation
The length of time that the drug will maintain its required potency can also be predicted by
calculation of the t90%
V. MICROMETRICS
The science and technology of small particles
1. Methods of determining particle size
A. Microscopic method
B. Seiving method
C. Sedimentation technique
D. Permeation method
E. Adsorption method
F. Electronic sensing zone
G. Light Obstruction of powder
2. Derived properties of power
A. Porosity
B. Packaging arrangements
C. Densities of particles
D. Bulkiness
E. Flow properties
F. Dilantacy