Table of Specifications (TOS) for the Pharmacy Board

Examination
Physical Pharmacy Principles
• Define the 8 types of attractive forces between molecules and the mechanism for each type.
• Describe the magnitude of attraction for each type of force.
• Define the ideal gas law and the modified ideal gas law for real gas in equation form.
• Explain how the ideal gas law works on aerosol dosage form.
• Describe the principles of the kinetic molecular theory.
• Differentiate latent heat of vaporisation, vapour pressure and boiling point.
• Differentiate crystalline and amorphous solid.
• Apply the principles of polymorphism and eutectic point in the solubility of the drugs.
• Differentiate liquid crystal state from solid and liquid state.
• Discuss the significance of Phase diagram and calculate the degrees of freedom.
• Distinguish the utility of thermodynamics in dosage form and stability.
SOLUBILITY AND DISTRIBUTION PHENOMENA
• Differentiate solubility, saturated solutions; supersaturated solutions and subsaturated solutions.
• Enumerate the factors affecting solubility and understand the effects either on the solute/solvent.
• Understand quantitatively the theory and application of the phenomenon.
• Relate partition/distribution coefficient to solubility principles.
COLLOIDS
• Understand the theory and technology of dispersed system
• Identify the characteristics of colloids
• Differentiate the optical, kinetic and electric properties of colloids.
• Identify the different types of colloid and their application to pharmacy.
COARSE DISPERSION
• Differentiate suspension, emulsion, and other pharmaceutical semi solids
• Discuss the physical properties necessary in the preparation of suspension, emulsion and semi
solids.
• Understand the different theories in emulsification
• Discuss the drug kinetics and drug diffusion in coarse dispersed system.
BUFFER AND ISOTONIC SOLUTION
• Differentiate buffer and buffer action.
• Explain the importance of buffer and isotonic solution in pharmaceutical preparations.
• Compute the desired amount of buffer and tonic agent that is necessary to a pharmaceutical
preparation.
INTERFACIAL PHENOMENA
• Differentiate interface, interfacial tension and surface tension
• Identify the types of interface present in various pharmaceutical dosage forms.
• Differentiate the classes of surfactants and cite examples
• Calculate the HLB values and understand its application to emulsion stability.
MICROMERITICS
• Differentiate particle size, size distribution, particle shape, surface area and pore size
• Differentiate the methods for determining particle size and surface area
• Enumerate and describe the different derived properties of powders
RHEOLOGY
• Differentiate Newtonian and Non-Newtonian system
• Discuss the application of rheology in pharmaceutical formulation and analyses of emulsion pastes,
suppositories and creams
COMPLEXATION AND PROTEIN BINDING
• Know the classification of complexes and how they are formed
• Identify the different drugs or substances that act as complexing agent
• Integrate complexation to drug product formulation and protein binding to drugs' physiologic
properties
KINETICS
• Define chemical kinetics
• Differentiate the various rates and orders of decomposition
• Enumerate the different processes of drug product decomposition and identify approaches on how
to stabilize them
• Compute rate constants; half-life and shelf life.
 Solubility and Distribution Phenomena
SOLUBILITY and DISTRIBUTION PHENOMENA
SOLUTION is a homogenous system in which the solute is molecularly dispersed, or dissolved in
a solvent.
Components of solution:
• Solvent – present in greatest quantity
o Polar, Non-polar, Semipolar
• Solute – can be gases, liquids, or solids
a. Non-electrolytes – do not form ions when dissolved in water; do not conduct electric
current (Ex.: Estradiol, glycerin, urea and sucrose)
b. Electrolytes – Do form ions in solution, thus conduct electric current
o Strong electrolytes – completely ionized in water (Ex.: Sodium chloride, HCl)
o Weak electrolytes – partially ionized in water (Ex.: Aspirin, Atropine)

POLAR SOLVENTS
➔ Dissolve ionic solutes and other polar substance
➔ The solubility of various solutes in water may be due to;
• Dipole moment
• Hydrogen bonds (dissolves phenols, alcohols, aldehydes, ketones, amines and other O and N
containing compounds)
• Difference in acidic and basic character of the constituents
• Structural features such as the ratio of the polar to the non-polar groups of the molecule
Solubility of substances is affected by structural features
• As the number of non-polar chain of an aliphatic alcohol increases, solubility in water decreases
• Straight-chain monohydroxy alcohols, aldehydes, ketones, and acids with more than 4 or 5 C
cannot enter into the hydrogen bonded structure of water and hence are only slightly soluble
• Water solubility increases when additional polar groups are present in the molecule as found in
propylene glycol, glycerin and tartaric acid
• Branching of C-chain reduces the non-polar effect and leads to increase water solubility.
Mechanism of Solvent Action
1. High dielectric constant
2. Break covalent bonds of potentially strong electrolytes by acid-base reactions
HCl + H2O→H3O+ + Cl-
3. Capable of solvating molecules and ions through dipole interaction force, particularly H-bond
formation.
NON-POLAR SOLVENTS
• Hydrocarbons
• Unable to reduce attraction between ions of strong and weak electrolytes due to low dielectric
constant
• Aprotic solvents (neither accept nor donate protons), so cannot break covalent bonds and
ionize weak electrolytes
• Can dissolve non-polar solutes with similar internal pressures through induced-dipole
interactions
• Ionic and polar solutes are not soluble or are only slightly soluble
Examples:
 CCl4, benzene and mineral oil – dissolve oils and fats
 Alkaloidal bases and fatty acids – soluble in non-polar solvents
SEMIPOLAR SOLVENTS
• May act as intermediate solvents to bring out the miscibility of polar and nonpolar liquids
• Examples;
 Acetone – increases the solubility of ether in water
 Alcohol – increases miscibility of water-castor oil mixture
 Propylene glycol – increases miscibility of water and peppermint oil; water and
benzyl benzoate

FACTORS AFFECTING 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
SOLUBILITY
• Is defined as the concentration of solute in a saturated solution at certain temperature
(quantitative)
• Is defined as the spontaneous interaction of two or more substances to form homogenous
molecular dispersion (qualitative)

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 parts
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

Solutions and Solubility

A. Saturated solution
• is one in which the solute is in equilibrium with the solid phase (solute)
B. Unsaturated or subsaturated solution
• is one containing the dissolve solute in a concentration below that necessary for complete
saturation at a definite temperature.
C. Supersaturated solution
• is one that contains more of the dissolved solute that it would normally contain at a definite
temperature, were the undissolved solute is present

SOLUBILITY OF GASES IN LIQUIDS

• Pharmaceutical solutions of gases include;
 HCl
 Ammonia water
 Effervescent preparations

FACTORS AFFECTING SOLUBILITY OF GASES:

1. EFFECT OF PRESSURE Expressed by Henry’s Law
“The weight of gas dissolved by a given amount of a liquid at a given temperature is
proportional to its pressure.”
SOLUBILITY of gas in a liquid can be expressed either by:
o Inverse Henry’s Law constant, δ (delta)
▪ Solubility coefficient
▪ δ = C2 (g/L)/p(mmHg)
o Bunsen Absorption coefficient, α (alpha)
▪ The volume of gas in liters (reduced to STP conditions) that dissolves in one liter
of solvent under a partial pressure of 1 atm of the gas at a definite temperature
▪ α p = Vgas, STP / Vsoln; so, a = Vgas, STP / Vsoln p
2. EFFECT OF TEMPERATURE
As the temperature increases, the solubility of a gas in liquids decreases.
More gas is present in a solution with a lower temperature compared to a solution with a higher
temperature.
3. SALTING-OUT
A phenomenon where gases are often liberated from solutions in which they are dissolved by
the introduction of an electrolyte (NaCl) and sometimes by a non-electrolyte (sucrose)
May also occur in solutions of liquid-liquid or solid-liquid.
4. EFFECT OF CHEMICAL REACTION
o Gases that can chemically react with solvents such as HCl, ammonia, and CO2 are more
soluble than those that do not react with the solvent.
o HCl is about 10,000 times more soluble in water than oxygen

SOLUBILITY OF LIQUIDS IN LIQUIDS

Liquid-liquid pharmaceutical solutions include;
 Spirits  Collodions  Elixir  Aromatic waters

IDEAL AND REAL SOLUTIONS

IDEAL SOLUTION
• When both components in a binary solution obey Raoult’s Law
RAOULT’S LAW
• “The vapor pressure of a volatile component of an ideal solution is equal to the mole fraction of
that substance in solution times its vapor pressure in the pure state at the temperature of the
solution.”
• It is true only for ideal solutions and ideal gases
REAL/NON-IDEAL SOLUTION
• Do not adhere to Raoult’s law throughout the entire range of composition
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
dissolved state
 Examples: water-ether; water-phenol

FACTORS AFFECTING THE MISCIBILITY OF LIQUIDS IN LIQUIDS

1. INFLUENCE OF FOREIGN SUBSTANCE
• If the added material is soluble in only one of the two components or if the solubilities in the two
liquids are markedly different, the mutual solubility of the liquid pair is decreased.
• When the third substance is soluble in both of the liquids to roughly the same extent, the mutual
solubility of the liquid pair is increased.
 Example: Glycerin in phenol-water system
BLENDING
• is the increase in mutual solubility of two partially miscible solvents by another agent.
2. DIELECTRIC CONSTANT
3. MOLECULAR CONNECTIVITY
4. MOLECULAR SURFACE AREA

SOLUBILITY OF SOLIDS IN LIQUIDS

IDEAL SOLUTION
• Is one in which there is no change in the properties of the components, other than dilution,
when they are mixed to form the solution
• No heat is evolved or absorbed during the mixing process
• The solubility of solids depends on;
o Temperature
o Melting point
o Molar Heat of Fusion – the heat absorbed when the solid melts
• The Heat of solution is equal to the heat of fusion.
NON-IDEAL SOLUTION
• The heat of solution has a positive (energy absorbed) or negative (energy liberated) value
• A negative heat of solution favours solubility while a positive heat works against dissolution
SOLUBILITY OF STRONG ELECTROLYTES
The process of dissolution is generally accompanied by;
1. ABSORPTION OF HEAT (Endothermic)
• The solution becomes cold
• Increase in temperature, increases solubility
• Dissolution of Na2SO4.H2O
2. EVOLUTION OF HEAT
• Exothermic, so the solution is hot
• Solubility decreases with an elevation of the temperature
• Dissolution of anhydrous Na2SO4
Sodium chloride does not evolve or absorb heat when it dissolves in water, thus its solubility is not
altered much by a change of temperature, and the heat of solution is zero.
Effect of Temperature on Solubility
• Decrease in solubility with temperature (exothermic)
• Increase in solubility with temperature (endothermic)

SOLUBILITY OF SLIGHTLY SOLUBLE ELECTROLYTES

• SOLUBILITY PRODUCT, Ksp
o Describes the solubility of slightly soluble electrolytes to form a saturated solution
Ksp = [A+]a[B-]b
Example: The Ksp of Calcium carbonate is 9 x 10-9 at 25°C where the dissociation equation at saturation
is CaCO3® ---> Ca+2 + CO3-2
3. COMMON ION EFFECT
• Reduces the solubility of a slightly soluble electrolytes
• When the common ion forms a complex with the salt, the net solubility may be increased
• Example: If an ion common with AgCl (e.g. Ag+ or Cl-) is added, the equilibrium is altered
 AgCl + NaCl AgCl-
▪ Some of the AgCl precipitates due to the increase in Cl ion concentration

SOLUBILITY OF WEAK ELECTROLYTES

WEAK ELECTROLYTES SOLUBILITY
CARBOXYLIC ACIDS WITH MORE THAN 5 o Insoluble in water
CARBONS o Forms soluble salts with the addition of
NaOH
FATTY ACIDS WITH MORE THAN 10 o Soluble in solvents with low dielectric
CARBONS constant (alcohol and ether)
(Oleic acid, C17H33COOH) o Form soluble soap with alkali metal and
insoluble soap with other metal
ACIDS (Tartaric acid and citric acid) o Soluble in water through their OH-
AROMATIC ACIDS o Form precipitate with acids
o Form water-soluble salts with dilute
alkalies
ALKALOIDS, SYMPATHOMIMETIC AMINES, o Soluble in dilute acid solution
ANTIHISTAMINES, LOCAL ANESTHETICS
SULFONAMIDES o Form slightly soluble weak acids and
water-soluble salts in alkaline solution

BARBITURATES o Soluble in alkalies

o Precipitated as free acid in strong acid

SOLUBILITY OF WEAK ELECTROLYTES AS INFLUENCED BY pH

WEAK ELECTROLYTES pH
Salt of weak acids precipitate in lower pH • Na phenobarbital precipitates at pH
below 8.3
Salt of weak base precipitate when the pH is • Codeine sulfate precipitates at an
elevated alkaline pH
Influence of Solvents on the Solubility of Weak • Weak acids and weak bases with high
electrolytes MW are not soluble in water
• Cosolvents such as alcohol, propylene
glycol, and polyethylene glycol or mixed
solvent systems are required for their
solubility

SOLVENT EFFECTS ON THE SOLUBILITY OF WEAK ELECTROLYTES IN BUFFER SOLUTION

1. Addition of alcohol increases the solubility of the unionized species by adjusting the polarity of
the solvent to a more favourable value
2. Alcohol decreases dissociation of weak electrolytes, and solubility of the drug goes down as the
dissociation constant is decreased
Calculating the solubility of weak electrolytes as influenced by pH
pHp = pKa + log S – S0
S0
Where;
• pHp = the ph below which the drug separates from solution as the undissociated acid
• pKa = ionization constant
• S = initial molar concentration
• S0 = Molar solubility of the undissociated acid
Influence of other factors on the solubility of solid
• Particle size – Solubility increases with a decrease in particle size
• Configuration of molecule and the kind of arrangement in the crystal
 a-alanine – solubility is 1.66 moles/L
 a-amino-n-butyric acid – solubility is 1.8 moles/L
 Less compact crystal has high solubility

Distribution Coefficient
PARTITION LAW states that;
“A solute will distribute itself between two immiscible solvents so that the ratio of its concentration in
each solvent is equal to the ratio of its solubility in each one.”
Kd = C0/Cw
Where;
C0 = molar concentration in organic layer
Cw= molar concentration in aqueous layer
Kd = partition coefficient or distribution constant
Application of Distribution Concepts
• Preservation of emulsions
• Drug action
• Drug absorption
pH partition hypothesis
• Drug absorption is a function of pH for weak electrolytes because pH changes ionization
• Only the unionized form of weak acids and bases is absorbed readily
• pKa determines whether the drug is predominantly dissociated or undissociated in biological
fluids and plasma
 Dispersion System
Dispersed System
Consist of particulate matter, known as dispersed phase, distributed throughout a continuous or
dispersion medium.
Three types of dispersed system
1. Molecular dispersion
2. Colloidal dispersion
3. Coarse dispersion
Characteristics of Particles of Molecular Dispersion
• Particle size is less than 1 nm
• Invisible in electron microscope
• Pass through ultrafilter and semipermeable
• Undergo rapid diffusion
• Examples include oxygen molecules, ordinary ions, glucose

Colloidal Dispersions
COLLOIDAL DISPERSION
• Particle size is 1 nm to 0.5 mm
• May be detected under ultra-microscope and visible in electron microscope
• Pass through filter paper but do not pass through semipermeable membrane
• Diffuse very slowly
METHODS OF SEPARATION
1. DIALYSIS – Uses semipermeable membrane that permits the passage of small molecules but not the
colloidal particles
 Electrodialysis – best way of purifying colloids
2. ULTRAFILTRATION – Uses hydraulic pressure to force the solvent and small particles to pass through
the filter leaving colloidal particles

TYPES OF COLLOIDAL SYSTEM

I. LYOPHILIC COLLOIDS
• Solvent-loving
• Interacts appreciably with the dispersion medium
• Form colloidal dispersions or SOLs
 Ex.: Hydrosol – acacia, gelatin, insulin Organosol – polysterene Aerosol –
solid/liquid in gaseous medium
II. LYOPHOBIC COLLOIDS
• Solvent hating colloids
• Materials with little or no attraction for the dispersion
 Ex.: Gold, Silver, Sulfur, Silver iodide
SPECIAL METHODS TO PREPARE LYOPHOBIC COLLOIDS
• DISPERSION – coarse particles are reduced in size
• CONDENSATION--Materials of subcolloidal dimensions are caused to aggregate into
particles within the colloidal size range
III. ASSOCIATION COLLOIDS
• Amphiphilic
• Characterized by having two distinct regions of opposing solution affinities within the same
molecule or ion.
• Aggregates of subcolloidal particles are called MICELLES
MICELLES
• Aggregates of 50 or more monomers
• The concentration of monomer at which micelles form is termed as Critical Micelle
Concentration (CMC)
• The number of monomers that aggregate to form a micelle is known as the Aggregation
Number
Amphiphiles
• May be anionic, cationic, nonionic, or ampholytic (zwitterionic)
• Shapes of micelles are;
(a) spherical in aqueous solution,
(b) reversed in nonaqueous medium,
(c) laminar, formed at higher amphiphile concentration, in aqueous media
Gegenions – are sodium ions attracted to the surface of the micelle, thus reducing the
overall negative charge.

OPTICAL PROPERTIES OF COLLOIDS

1. FARADAY-TYNDALL EFFECT
When a strong beam of light is passed through a colloidal sol, a visible cone, resulting
from the scattering of light by the colloidal particles, is formed.
2. LIGHT SCATTERING
• This property depends on the Faraday-Tyndall effect
• Widely used for determining the MW of colloids
• Can be used to obtain information on the size and shape of colloidal particles
• Scattering can be described in terms of TURBIDITY
• QELS (Quasi-elastic light scattering), a new technique that uses laser light and can
determine diffusion coefficients and particle sizes of macromolecules in solution.
KINETIC PROPERTIES OF COLLOIDS
1. BROWNIAN MOTION
• Caused by the erratic movement of particles as large as 5 mm
• Velocity of particles increases with decreasing particle size
• Increasing viscosity of the medium (addition of glycerin) decreases and finally stops the
Brownian movement
2. DIFFUSION
• A direct result of Brownian movement
3. SEDIMENTATION
• If the particles are subjected to the force of gravity, the lower size limits of particles obeying
Stoke’s equation is about 0.5 mm.
• The sedimentation of colloidal particles are accomplished by the use of ultracentrifuge
4. VISCOSITY
• An expression of resistance to flow of a system under an applied stress
• The viscosity of colloidal dispersion is affected by the shapes of particles
o Spherocolloids form dispersion of low viscosity
o Linear particles form more viscous dispersions

ELECTRICAL PROPERTIES OF COLLOIDS

ELECTROPHORESIS
• If an electric potential is applied to a colloid, the charged colloidal particles move toward the
oppositely charged electrode

STABILITY OF COLLOIDS
Stability of colloids is accomplished by two means;
• Providing the dispersed particle with an electric charge
• Surrounding each particle with a protective solvent sheath that prevents mutual adherence
when particle collides as a result of Brownian movement
Significant only in lyophilic sols
PROTECTIVE COLLOID
• Hydrophilic sol added to the hydrophobic particles (hydrophile is adsorb at the surface)
• The protective property of colloids is expressed in terms of GOLD NUMBER
• Gold Number – is the minimum weight (in mg) of the protective colloid required to prevent a
color change
• Protective colloids are gelatin, albumin, acacia, sodium oleate and tragacanth
SOLUBILIZATION
The property of association colloids to increase the solubility of materials that are normally
insoluble or only slightly soluble in the dispersion medium used
Factors influencing solubilization
1. Chemistry of the surfactants and the location of drugs in the micelles
2. pH

PHARMACEUTICAL APPLICATIONS OF COLLOIDS

• Colloidal Silver chloride, Colloidal Silver iodide, and Colloidal Silver proteins – Germicides
• Colloidal Copper – used in the treatment of cancer
• Colloidal Mercury – for syphilis
• Polymers
o Starch and cellulose – pharmaceutical adjuncts
o Hydroxyethyl starch (HES) – plasma substitute
o Other synthetic polymers – applied as coatings to protect drugs
• Colloidal electrolytes – used to increase solubility, stability, and taste of certain compounds in
aqueous and oily preparations
Colloid based Delivery Systems
• HYDROGELS
• MICROPARTICLES
• MICROEMULSIONS
• LIPOSOMES
• MICELLES
• NANOPARTICLES
• NANOCRYSTALS
Coarse dispersion – Suspensions
COARSE DISPERSION
• Particles size is greater than 0.5 mm.
• Particles are visible under microscope
• Particles do not pass through normal filter paper and dialyze through semipermeable
membrane
• Particles do not diffuse
• Examples are pharmaceutical suspensions and emulsions
SUSPENSION
• A coarse dispersion in which insoluble solid particles are dispersed in a liquid medium
• Particles have diameter greater than 0.1 mm
• Particles exhibit Brownian motion if the dispersion has a low viscosity

3 GROUPS OF PHARMACEUTICAL SUSPENSION

1. ORAL SUSPENSIONS
 Oral antibiotics, antacid and radiopaque suspensions
2. EXTERNALLY APPLIED SUSPENSIONS
• Designed for dermatologic, cosmetic and protective purposes
• Concentration of dispersed phase may exceed 20%
3. PARENTERAL SUSPENSIONS
• Contain 0.5 to 30% solid particles
• Viscosity and particle size are significant factors because they affect the ease of injection and
availability of drugs in depot therapy

DISPERSION STABILITY
IDEAL DISPERSION
• Particles do not interact
• Particles are uniform in size and exhibits Brownian movement
REAL DISPERSION
• Particles are not uniformly sized
• Particles are subject to particular aggregation, or clumping, and become more heterogeneous
with time
Interfacial properties of the suspended particles;
1. FLOCCULATION – a process of forming a light, fluffy conglomerates that are held together by weak
Van der Waals forces.
2. AGGREGATION – a process where particles adhere by stronger forces (compacted cake)
3. CAKING – growth and fusing together of crystals in the precipitate to produce a solid aggregates
Flocculation and Deflocculation
I. Flocculated system
• Particles form loose aggregates or floccules
• Particles settle rapidly, but easily resuspended
• Particles do not form a cake
• After settling, a clear boundary exists between the sediment and the supernatant
SETTLING IN SUSPENSIONS
• The velocity of sedimentation is expressed by STOKE’S LAW
• Free settling occurs in dilute suspensions (contains less than 2 g/100 mL)
• Concentrated suspensions (5 g/100 mL) exhibit hindered settling and do not obey Stoke’s law.
SUBSIDENCE – describe settling in flocculated system

STOKES’ LAW
The rate of settling of the dispersed phase in the dispersion medium is a function of:
• Particle size
• Viscosity of the dispersion medium
• Difference in density between the dispersed phase and the dispersion medium
Sedimentation rate = d2g(r1-r2)/18h

SEDIMENTATION PARAMETERS:
I. SEDIMENTATION VOLUME (F)
• Ratio of the equilibrium volume of the sediment, Vu, to the total volume of suspension Vo.
F= Vu /Vo
• The ideal F value is 1 (value ranges from 0 to 1)
II. DEGREE OF FLOCCULATION (β)
• Relates the sedimentation volume of the flocculated suspension, F, to the sedimentation
volume of suspension when deflocculated, Fµ.
β = F/Fµ
• The aim of a formulation is to produce as flocculated products as possible

FORMULATION OF SUSPENSIONS
Two approaches commonly used in the preparation of physically stable suspensions
I. The use of structured vehicle to maintain deflocculated particles in suspension
• Structured vehicles are pseudoplastic and plastic in nature
• Act by entrapping the particles so that no settling occurs
 • Example is hydrophilic colloid
II. The application of the principles of flocculation to produce flocs that easily settle and resuspend with
minimum agitation

Wetting of particles
• The initial stage in the preparation of dispersions
• Hydrophobic powders (ex.: sulfur, charcoal, magnesium stearate) are not easily wetted due
to large contact angle
• Hydrophilic powders (ex.: ZnO, Talc , Magnesium carbonate) have low contact angle so are
easily wetted
WETTING AGENTS – are surfactants that lower the advancing contact angle so can facilitate wetting of
powders.

Materials used to control flocculation;

1. ELECTROLYTES
• Act as flocculating agents by reducing the electric barrier between the particles
2. SURFACTANTS
• Ionic and Nonionic; used to bring about flocculation
3. POLYMERS
• Hydrophilic polymers exhibit pseudoplastic property that promotes the physical stability of
suspensions

STABILIZATION OF DISPERSION;
• Particle size should be as small as possible
• High particulate concentrations
• Avoidance of particle-particle interaction;
a. Particles have similar charge
b. Deflocculated
c. Manipulation of densities
d. Increased viscosity of the dispersion medium
Coarse Dispersion – Emulsions
EMULSION
• A heterogeneous system that consists of at least one immiscible liquid that is intimately
dispersed in another in the form of droplets
• Droplet diameter usually exceeds 0.1mm
• The third component of the system is an emulsifying agent. This agent prevents coalescence
and maintains the integrity of the individual droplets
• A thermodynamically unstable system

EMULSION TYPES:
1. OIL-IN-WATER
• Oil is dispersed as globules throughout an aqueous continuous phase
• Medicinal emulsion for oral administration
• Requires the use of o/w emulsifiers (nonionic surfactants, acacia, tragacanth and gelatin
2. WATER-IN-OIL
• the oil phase serves as the continuous phase
• Example: salad dressing, butter

METHODS OF DETERMINING THE TYPE OF EMULSION

1. DYE SOLUBILITY TEST – uses methylene blue or brilliant blue
➔ the dye is dissolve and uniformly diffuse – O/W
➔ the particle of the dye lie in dumps on the surface – W/O
2. DILUTION TEST
➔ freely mixes with water – O/W
➔ not diluted with water – W/O
3. ELECTRIC CONDUCTIVITY TEST
➔ O/W conducts electric current
➔ W/O do not conduct electric current

Pharmaceutical applications of emulsions;

• O/W types are used conveniently for the administration of oil-soluble vitamins
• Intravenous emulsions are indicated for patients who are unable to assimilate materials
administered orally
• Radiopaque emulsions used in diagnosis
• Cosmetic lotions and creams
• Emulsification is used for the rapid formation of foams
THEORIES OF EMULSIFICATION
1. SURFACE-TENSION THEORY
The use of surfactants results in the lowering of interfacial tension between two immiscible
liquids
2. ORIENTED WEDGE THEORY
This theory assumes monomolecular layers of emulsifying agent curved around a droplet of the
internal phase
3. PLASTIC OR INTERFACIAL FILM THEORY
This theory places the emulsifying agent at the interface between the oil and water,
surrounding the droplets of the internal phase as a thin layer of film adsorbed on the surface of the
drops

EMULSIFYING AGENTS
1. SURFACE ACTIVE AGENTS
• Adsorbed at oil-water interfaces to form monomolecular films and reduce interfacial tension
2. HYDROPHILIC COLLOIDS
• Form multimolecular film around the dispersed droplets of oil in an o/w emulsion
3. FINELY DIVIDED SOLID PARTICLES
• Adsorbed at the interface between two immiscible liquid phases

HLB SYSTEM
Used to classify surfactants
HYDROPHILIC SURFACTANTS LIPOPHILIC SURFACTANTS

• High HLB values (>10) • Low HLB values (1-10)

• Form O/W emulsion • Form W/O emulsion

Application of Surfactants is for PHYSICAL STABILITY OF EMULSION

• FLOCCULATION AND CREAMING
• COALESCENCE AND BREAKING
• MISCELLANEOUS PHYSICAL AND CHEMICAL CHANGE
• PHASE INVERSION (Emulsion-type reversal)
o O/W to W/O form or vice-versa
o Can change the consistency or texture of emulsion
 CREAMING is a reversible process
UPWARD CREAMING
• Observed in O/W type where the dispersed phase is less dense than the continuous phase
DOWNWARD CREAMING
• Observed in W/O type where the internal phase is heavier than the continuous phase, so the
globules settle
Prevention of creaming:
1. Initially by agitation
2. Addition of viscosity improvers and thickening agents
3. Homogenation
4. Adjusting the external and internal phase densities

COALESCENCE AND BREAKING

• An irreversible process
• Simple mixing fails to re-suspend the globules since the film surrounding the particles has been
destroyed and oil tends to coalesce
• A 50-50 phase volume ratio of oil:water forms a stable emulsion

RHEOLOGIC PROPERTIES OF EMULSION

• Most emulsions, except dilute ones, exhibit NON-NEWTONIAN flow.
• NEWTONIAN flow is exhibited by emulsion with low volume concentration (less than 0.05) of
the dispersed phase
• Pseudoplastic flow is exhibited when the volume concentration is increased and when
sufficiently high, becomes plastic flow

MICROEMULSION
• Thermodynamically stable system
• Optically transparent isotropic mixture of a biphasic O/W system stabilized with surfactants
• Diameter of particle: 100 Å (10 mμ) to 1000 Å
Coarse Dispersion – Gels
GELS
are semisolid systems consisting of either suspension made up of small inorganic particles or large
organic molecules enclosed and interpenetrated by a liquid
CLASSES OF GELS
As to composition: As to dispersion medium used:
• INORGANIC GELS – two-phase system • HYDROGEL
• ORGANIC GELS – single phase system • ORGANOGEL

CLASSES OF GELS
SINGLE PHASE GEL – Macromolecules are distributed in the dispersion medium in such manner that no
apparent boundaries exist between them
TWO-PHASE GEL – Consist of floccules of small distinct particle and frequently called MAGMA or MILK

TERMINOLOGIES RELATED TO GELS

IMBIBITION – taking up a certain amount of liquid without a measurable increase in volume
SWELLING – taking up of a liquid by a gel with an increase in volume
SYNERESIS – the dispersion medium is squeezed out in droplets upon standing, and the gel shrinks
XEROGEL – A gel in which the liquid is removed and only the framework remains
Examples are acacia tears, tragacanth ribbons and gelatin sheets
 Buffer and Isotonic Solution

Buffers
Buffers
are compounds or mixture of compounds that by their presence in solution resist changes in pH upon
the addition of small quantities of acid or alkali.
BUFFER ACTION
Resistance to a change in pH
Mechanism of buffer action:
➔ Strong acids are buffered by weak base
➔ Strong bases are buffered by weak acid
ACETIC ACID-SODIUM ACETATE BUFFER PAIR
• CH3COOH + OH- → CH3COO- + H2O
• CH3COO- + H3O+ → CH3COOH + H2O
AMMONIA-AMMONIUM CHLORIDE BUFFER PAIR
• NH3 + H3O+ → NH4+ + H2O
• NH4+ + OH- → NH3 + H2O

BUFFER EQUATION OR HENDERSON-HASSELBALCH EQUATION

For a weak acid and its salt;
pH = pKa + log [salt]/[acid]
For a weak base and its salt;
pH = pKw – pKb + log [base]/[salt]

FACTORS INFLUENCING THE pH OF THE BUFFER SOLUTION

1. ADDITION OF NEUTRAL SALTS TO BUFFERS
• Changes the pH of solution by altering the ionic strength
2. DILUTION/ADDITION OF WATER
• May cause a small positive or negative deviation because it alters activity coefficient and water
itself can act as a weak acid or base
DILUTION VALUE – is the change in pH on diluting the buffer solution to half its original strength
➔ Positive dilution value – pH rises with dilution
➔ Negative dilution value – pH decreases with dilution
3. TEMPERATURE
Temperature Coefficient of pH – is the change in pH with temperature
Acetate buffers – pH increase with temperature
Boric acid-Sodium borate buffers – pH decrease with temperature
The temperature coefficient of acid buffers was relatively small, the pH of most basic buffers was found
to change more markedly with temperature owing to Kw.

BUFFER CAPACITY
• Also known as buffer efficiency, buffer index, and buffer value
• Is the magnitude of resistance to pH changes
• Is the number of gram equivalents in an acid or base that changes the pH of 1 L buffer solution
by 1 unit
The buffer capacity equation (β)
β = 2.3 C Ka + [H+] /[Ka + (H+)]2
¡ Where C is the total buffer concentration (sum of the molar concentrations of the acid and the salt)

Maximum Buffer capacity

• Maximum buffer capacity occurs when pH = pKa, and is represented by:
βmax = 0.576C

BIOLOGICAL BUFFER SYSTEM

BLOOD is maintained at a pH about 7.4 by the;
1. PRIMARY BUFFERS (in the plasma)
• Carbonic acid/bicarbonate buffer system
• Acid/alkali sodium salts of phosphoric acid
• Plasma proteins behaves as acid and can combine with bases and so act as buffers
2. SECONDARY BUFFERS (in the erythrocytes)
• Hemoglobin/Oxyhemoglobin
• Acid/alkali potassium salts of phosphoric acid
Buffer capacity of the blood
• pH 7.0 to 7.8
o Hgb and other constituents (exclusive of bicarbonate)
▪ about 0.025 gram equivalents per liter per pH unit
o Bicarbonate system
▪ 003 gram equivalents per liter per pH unit
o Total buffer capacity
▪ = 0.025 + 0.003 = 0.028
 o It is life threatening if the pH of the blood is below 6.9 and above 7.8
OTHER BIOLOGICAL BUFFERS
• LACRIMAL FLUID
o pH is about 7.4 with a range of 7 to 8 or slightly higher
o Found to have a great degree of buffer capacity
o Allows dilution of 1:15 with neutral distilled water before alteration of pH is noticed
• URINE
o Average pH range is 6.0 units
o As low as 4.5 or as high as 7.8
o pH below normal values, hydrogen ions are excreted by the kidneys
o pH above normal values, hydrogen ions are retained

PHARMACEUTICAL BUFFERS:
➔ Important in ophthalmic preparation
➔ Also find application in colorimetric determination of pH

• Gifford’s
o Boric acid + Monohydrated sodium carbonate, in various proportions yield solutions
with pH values 5 to 9
• Sorensen’s
o Mixture of salts of sodium phosphate of pH 6 to 8
o Sodium chloride is added to make it isotonic with the body fluids
• Palitzsch, Hind and Goyan
o Consist of boric acid, sodium borate, and sufficient sodium chloride to make mixture
isotonic
o Used for ophthalmic solutions in the pH range of 7 to 9
• Clark-Lubs Mixture
o HCl and KCl, pH 1.2 to 2.2
o HCl and potassium hydrogen phthalate, pH 2.2 to 4.0
o NaOH and potassium hydrogen phthalate, pH 4.2 to 5.8
o NaOH and KH2PO4, pH 5.8 to 8.0
o H3BO3, NaOH, and KCl, pH 8.0 to 10.0

BUFFERED ISOTONIC SOLUTION

• Pharmaceutical solutions that are meant for application to delicate membranes should be
adjusted to approximately the same osmotic pressure as that of the body fluids
• Nasal, ophthalmic and parenteral solutions
A. 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.
B. HYPOTONIC – cause cells to swell; water enters the cell resulting to hemolysis.
C. HYPERTONIC – cause cells to shrink because of the outward passage of water.
Measurement of tonicity:
(1) HEMOLYTIC METHOD
• Based on the appearance of RBC suspended in the various solutions of the drug
• Hypotonic solution liberates oxyhemoglobin
(2) Based on any methods that determine colligative properties
• FREEZING POINT DEPRESSION (Δtf)
o The tf of human blood and tears is -0.52°C, thus the Δtf is 0.52°C
o The tf 0.9% NaCl solution is -0.52°C also, thus is isotonic with blood and tears
o Hypotonic solution has a tf between 0 and - 0.52°C
o Hypertonic solution has a tf below - 0.52°C
CLASS I METHODS
I. CRYOSCOPIC METHOD
Amount of NaCl needed = [0.9 x (0.52-Δtf sol)]
in 100 mL 0.52
II. SODIUM CHLORIDE EQUIVALENT METHOD
E = NaCl equivalent; “tonicic equivalent”, is the amount of NaCl that is equivalent to 1 g of the
drug
E = 17(Liso/MW)
Step 1: E x (amount of drug in solution) = X
Step 2: (0.9 g/100 mL) x Vsoln in mL = Y
Step 3: Y – X = amount of NaCl needed
If NaCl is not to be used;
Step 4: Amount of NaCl___ = Amount of the tonicic agent
E of the tonicic agent
CLASS II METHODS
• Involve the addition of water to the drug to make an isotonic solution, followed by the addition
of an isotonic diluting vehicle.

V = [Σ (w x E)]x 111.1
I. WHITE-VINCENT METHOD
II. SPROWL’S METHOD
V values (Sprowl’s volume)
o based on 1 [Link] (30 mL) of a 1% solution, so the weight of the drug (W) is 0.3 g.
 Interfacial Phenomena
SURFACE TENSION
• The force per unit length that must be applied parallel to the surface so as to counterbalance the
net inward pull
• Surface tension decreases with an increase in temperature
• Unit: dyne/cm

INTERFACIAL TENSION
• Is the force per unit length existing at the interface between two immiscible liquid phases
• Reflects the extent of the intermolecular forces of attraction and repulsion at the interface
• Unit: dyne/cm

INTERFACES
• The boundary existing between two phases
CLASSIFICATION TYPES
Gas – Liquid Liquid surface
Gas – Solid Solid surface
Liquid – Liquid Liquid-liquid interface
Liquid – solid Liquid-solid interface
Solid – Liquid Solid-solid interface

TYPES OF INTERFACES
• LIQUID INTERFACES
o Liquid – liquid
o Liquid – gas
• SOLID INTERFACES
o Solid – gas
o Solid – liquid

SIGNIFICANCE OF INTERFACIAL PHENOMENA

• Absorption of drug onto solid adjuncts in dosage form
• Penetration of molecules through biologic membrane
• Emulsion formation and stability
• Dispersion of insoluble particles in liquid media to form suspension
METHODS OF MEASURING SURFACE / INTERFACIAL TENSION
CAPILLARY RISE METHOD
• The force of adhesion between the liquid molecule and the capillary wall is greater than the
cohesion between the liquid molecules, so the liquid spread over it and rise in the tube
DU NOUY RING METHOD
• Used to measure surface and interfacial tensions
• The principle is based on the force necessary to detach a platinum-iridium ring immersed at the
surface/interface is proportional to the surface/interfacial tension.

ADSORPTION AT LIQUID INTERFACES

• Surfactants are molecules that are adsorbed at interfaces
• The other term for surface-active agents is AMPHIPHILE (molecule or ions having certain
affinity for both polar and nonpolar solvents).

ADSORPTION AT SOLID INTERFACES

• Takes place from either adjacent liquid or gas phase
• The study of adsorption of gases is concerned with;
o Removal of objectionable odor from room and food
o Operation of gas mask
o Measurement of particle dimension of powders

THE SOLID-GAS INTERFACE

• ADSORBENT – the material used to adsorb the gas
• ADSORBATE – the substance being adsorbed
TYPES OF ADSORPTION
I. PHYSICAL or VAN DER WAALS ADSORPTION
➔ The adsorbate can be removed from the adsorbent by increasing the
temperature (Desorption)
II. CHEMICAL ADSORPTION
➔ Irreversible; the adsorbate is attached to the adsorbent by primary chemical
bonds

SOLID-LIQUID INTERFACE
• Dyes, alkaloids, fatty acids, organic acids and bases may be adsorbed from solution onto solids
such as charcoal and alumina
• Adsorption of diphtheria toxin by various clays
• Attapulgite and kaolin adsorb intestinal contents
FACTORS AFFECTING ADSORPTION
1. SOLUBILITY OF THE ADSORBATE – The extent of adsorption of a solute is inversely proportional to
its solubility in the solvent from which adsorption occurs.
2. pH – Adsorption increases as the ionization of the drug is suppressed.
3. NATURE OF ADSORBENT – The extent of adsorption is proportional to the specific surface area.
4. TEMPERATURE – Increase in temperature decreases the amount adsorbed

Principles which uses solid/liquid adsorption

• DECOLORIZING SOLUTION
• ADSORPTION CHROMATOGRAPHY
• DETERGENCY
• WETTING

DETERGENCY
• A complex process involving the removal of foreign matter from surfaces
• DETERGENTS are surfactants that are used for the removal of dirt
• The process includes;
1. Initial wetting of the dirt and of the surface to be cleaned
2. Deflocculation and suspension, emulsification or solubilization of the dirt particles
3. Foaming of the agent for entrainment and washing away of the particles
WETTING
• WETTING AGENT – a surfactant that when dissolved in water, lowers the advancing contact
angle and aids in displacing an air phase at the surface and replacing it with a liquid phase.
• CONTACT ANGLE – the angle between a liquid droplet and the surface over which it spreads.
Applications of Wetting
• Displacement of air from sulfur, charcoal, and other powders for the purpose of dispersing these
drugs in liquid vehicles
• Displacement of air from the matrix of cotton pads and bandages so that medicinal solutions may
be absorbed for application to various body areas.
• Displacement of dirt and debris by the use of detergents in the washing of wounds
• The application of medicinal lotions and sprays to the surface of the skin and mucous membrane
Applications of Surface-Active Agents
• Emulsifying agents • Foaming agents – stabilize gas-in-liquid dispersion
• Detergents • Antifoaming agents – break the foam
• Wetting agents • Antibacterial agents – Quaternary Ammonium compounds
• Solubilizing agents • Aids the absorption of drugs in the body
• Protective agents
 Micromeritics
MICROMERITICS
The science and technology of small particles
Fundamental properties of particles:
1. Size of particle
2. Surface area of the particle (particle shape)
POLYDISPERSE SYSTEM
• Collection of particles of more than one size
• Properties can be described in terms of:
1. Shape and surface area of individual particles
2. The size range and number or weight of particles
MONODISPERSE SYSTEM- Particles of approximately uniform size
USES:
• Diagnostic tests
• Particle size standards for particle analyzers
• For accurate determination of pore size in filters
• As uniformly sized surfaces upon which antigens may be coated for effective immunization
• For instrument calibration and quality control in the manufacture of submicron-sized products
such as liposomes, nanoparticles, and microemulsions

METHODS OF DETERMINING PARTICLE SIZE

OPTICAL MICROSCOPY; SIEVING; SEDIMENTATION and PARTICLE VOLUME MEASUREMENT
1. OPTICAL MICROSCOPY
• Uses an ordinary microscope for particle measurement in the range of 0.2 mm to 100 mm.
• Presence of agglomeration and particles of more than one component may be detected
• The diameter is obtained only from two dimensions: length and breadth, the thickness/depth in not
measured.
2. SIEVING
• Uses standard sieves
• Generally used for grading coarser particles
• May be employed for screening materials as fine as 44 mm (No. 325 sieve)
CAUSES OF ERRORS:
• Sieve loading
• Duration and intensity of agitation
Disadvantage: “Attrition” of particles (rubbing together/pulverization)
POWDERS OF VEGETABLE AND ANIMAL DRUGS ARE OFFICIALLY DEFINED AS:
 VERY COARSE (#8) – all particles pass through no.8 sieve and not more than 20 % through
sieve no. 60.
 COARSE (#20) – all particles pass through no.20 sieve and not more than 40 % through sieve
no. 60.
 MODERATELY COARSE (#40) - all particles pass through no.40 sieve and not more than 40 %
through sieve no. 80.
 FINE (#60) - all particles pass through no.60 sieve and not more than 40 % through sieve no.
100.
 VERY FINE (#80) – all particles pass through a no. 80 sieve. There is no limit as to greater
fineness.
POWDERS OF CHEMICAL DRUGS ARE OFFICIALLY DEFINED AS:
 COARSE (#20) – all particles pass through no.20 sieve and not more than 40 % through sieve
no. 60.
 MODERATELY COARSE (#40) - all particles pass through no.40 sieve and not more than 60 %
through sieve no. 60.
 FINE (#80) - all particles pass through no.80 sieve and there is no limit as to greater fineness.
 VERY FINE (#120) – all particles pass through a no. 120 sieve. There is no limit as to greater
fineness.
3. SEDIMENTATION
• The particles size may be obtained by gravity sedimentation as expressed by STOKE’S LAW.
• Uses Andreasen pipet

4. PARTICLE VOLUME MEASUREMENT

• Uses Coulter Counter
☺ An instrument used to measure the volume of particles
☺ Capable of counting particles at the rate of approximately 4000 per second, thus both gross
counts and particle size distributions are obtained in relatively short period of time
Average Particle size determination;
a. BY WEIGHT
• Sieving method
• Light scattering
• Sedimentation
b. PARTICLE SHAPE
• Sphere
• Affects the flow and packing of a powder
 c. SURFACE AREA
• Determined by the shape of particles
• Affects adsorption and dissolution rate
SPECIFIC SURFACE – surface area per unit volume or per unit weight

METHODS OF DETERMINING SURFACE AREA

1. ADSORPTION METHOD – Uses Quantasorb
2. AIR PERMEABILITY METHOD – Uses Fisher subsieve sizer
Powders of large surface area are good adsorbents

DERIVED PROPERTIES OF POWDERS

1. POROSITY (VOIDS) is defined as the ratio of the void volume to the bulk volume of the packing
Void volume = volume of spaces
Bulk volume = volume occupied
etotal = (Vb – Vp)/Vb
eintraparticle = (Vg – Vp)/Vg
einterspace = (Vb – Vg)/Vb
POROSITY CALCULATIONS
A. Calculate the porosity of a sample of aluminum oxide having a true density of 4.0 g/cm3.
When 75 g of the powder was placed in a graduated cylinder, The Al2O3 was found to have a bulk
volume of 62 cm3.
e = Vb –Vp
Vb
B. The true density of Aspirin is 1.37 and the granule density is 1.33. What is the porosity or
percent void spaces within the granules?
eintraparticle = Vg – Vp
Vg
eintraparticle = 1 – granule density
true density
C. A 1-g sample of a granular powder has a true volume of 0.3 cm3; volume of intraparticle pores
= 0.1 cm3; volume of spaces between particles = 1.6 cm3. Calculate the interspace porosity.
Vg = 0.3 + 0.1 = 0.4 cm3
Vb = 0.3 + 0.1 + 1.6 = 2.0 cm3

einterspace = Vb – Vg =1- bulk density___

Vb granule density
2. PACKING ARRANGEMENT
Two ideal packing arrangements
A. CLOSEST PACKING (OR RHOMBOHEDRAL)
• angles of 60° and 120° are common
• porosity is 26%
B. MOST OPEN, LOOSEST, OR CUBIC PACKING
• Packed at 90° to each other resulting to a porosity of 47-48%
3. DENSITIES OF PARTICLES
• TRUE DENSITY – is the density of the actual solid, exclusive of voids and intraparticle pores
• GRANULE DENSITY – density of the powder particles together with their intraparticle pores.
• BULK DENSITY – density of material as determined from the bulk volume and weight of a dry
powder
4. BULKINESS
• Or BULK, is the specific bulk volume
• Reciprocal of bulk density
• An important consideration in packaging powders
• Bulkiness increases with a decrease in particle size
5. FLOW PROPERTIES
Flow properties exhibited by POWDERS
o PLASTIC FLOW
o DILATANT FLOW
FACTORS AFFECTING FLOW PROPERTIES
A. PARTICLE SIZE AND SHAPE
• 250-2000mm = free flowing
• 75 – 250 mm = flow freely or cause problem depending on shape
• Very fine particles (less than 10 mm) = do not flow freely as large particles
Particle shape and flow properties
• Spherical shape flow better than needle particles
• Elongated or flat particles tend to pack resulting to high porosity powders
B. POROSITY AND DENSITY
• High density, low porosity = FREE FLOWING
C. SURFACE ROUGHNESS
• Leads to poor flow characteristics
 ANGLE OF REPOSE
• A technique for estimating the flowability of a powder
• Measures the frictional forces in a loose powder
• The maximum angle possible between the surface of a pile of powder and the horizontal
plane

tan θ = h/r
Where;
h = height of the powder cone
r = radius of the powder cone
tan θ = 3.3cm/ 4.5 cm
tan θ = 0.7333333
= arc tan 0.73333
= 36.25°
Powders of low repose angles are FREE FLOWING; high angle of repose poorly flow and has low
bulk density
FREE FLOWING POWDERS are haracterized by “ dustibility’
Examples:
 Talcum= 57%
 Potato starch = 27%
 Fine charcoal = 23%
COHESIVE POWDERS where, Cohesiveness may be a result of:
• Presence of “fines”
• Presence of moisture
Materials used to improve flow properties are called GLIDANTS LIKE;
 Magnesium stearate
 Starch
 talc
6. Compaction/ DILATANCY
• Dilatancy is the expansion of powder under the influence of stress
• Porosity of powders increases upon compression
• Important in pharmaceutical tableting
 Rheology
RHEOLOGY
➔ Study of flow properties of liquids and the deformation of solids
➔ Also involves the viscosity characteristics of powders, fluids and semisolids
VISCOSITY
• Resistance to flow of adjacent layers of fluids
• Units: in CGS – dyne/sec/cm2 or poise (0.01 poise = 1 centipoise)
Importance of Rheology in Pharmacy
• Mixing and flow of materials
• Packaging into containers
• Removal of product prior to use
o Pouring from bottle
o Extrusion from collapsible tube
o Passage thru syringe needle
The rheology of certain products can affect;
1. Patient’s acceptability
2. Physical stability
3. Biologic availability

GENERAL CATEGORIES OF FLOW

I. Newtonian Flow
• Characterized by a constant viscosity, regardless of the shear rates applied
• Exhibited by liquids of simple molecules and dilute dispersions
II. Non-Newtonian
• Characterized by a change in viscosity characteristics with increasing shear rates
• Substances that fail to follow Newton’s equation of flow
• Composed of liquid/solid heterogeneous dispersion such as;
o Colloidal sols
o Emulsion
o Liquid suspension
o Ointments
1. PLASTIC FLOW
• “ Bingham bodies”
• Does not begin to flow until the shearing stress is exceeded
• Exhibited by gels, pastes, creams, ointments, cataplasms, and cerates
2. DILATANT FLOW
• “ Shear Thickening Sytem”
• Viscosity increases with an increase in shear force
• Exhibited by suspensions of high percentage of dispersed solids
3. PSEUDOPLASTIC FLOW
• “Shear Thinning System”
• Viscosity decreases with an increase rate of shear
• Exhibited by polymers in solution, e.g., natural and synthetic gums

THIXOTROPY
• Defined as the isothermal slow reversible conversion of gel to sol
Negative Thixotropy And Rheopexy
NEGATIVE THIXOTROPY
• is a time dependent increase in the viscosity at constant shear
• the equilibrium form is SOL
• Exhibited by suspensions containing 1 to 10% of dispersed solids
RHEOPEXY
• is the phenomenon where sol forms a gel more rapidly when gently shaken than when
allowed to form the gel by keeping the material at rest
• The equilibrium state is gel

FACTORS AFFECTING RHEOLOGICAL PROPERTIES AND MEASUREMENT OF VISCOSITY OF

LIQUIDS AND SEMISOLIDS
• Temperature
• Shear rate
• Time
• Measuring conditions
• Pressure
• Composition and additives

DETERMINATION OF RHEOLOGIC PROPERTIES:

VISCOMETERS – determine viscosity of Newtonian system; Viscometers with variable stress control of
shear can be used for non-Newtonian system
1. Capillary Viscometer
2. Falling Sphere Viscometer
3. Cup and Bob Viscometer
4. Cone and Plate
VISCOELASTICITY
• A phenomenon observed in materials that exhibit both elastic behavior and viscous flow
• Exhibited by pharmaceutical products such as;
o Ointments and creams
o Suppositories
o Suspensions and colloidal dispersing, suspending, and emulsifying agents
• Observed also in biologic fluids like;
 Blood  Sputum  Cervical and synovial fluids
PSYCHORHEOLOGY

• Involves feel, spreadability, color, odor and other psychologic and sensory characteristics that
must be met by topical preparations in addition to desirable pharmaceutical and
pharmacological properties
• 3 classes of ointments as to rheologic properties:
o Class I – soft; for ophthalmic use
o Class II – medicated ointment of intermediate consistency
o Class III – stiff protective product for use in ulcerative conditions
 Complexation and Protein Binding
COMPLEX/COORDINATION COMPOUND
Results from a donor accept mechanism of Lewis acid-base reaction between two or more different
constituent
CLASSIFICATION OF COMPLEXES:
1. Metal ion complex
• Inorganic complexes
• Consist of a central metal ion (substrate) bonded to an electron pair donor ( a base, the ligand)
Types of ligands
I. Unidentate/monodentate ligand
• single base group capable of bonding to the metal ion
II. Multidentate ligand
• having more than one accessible binding site (bidendate, tridendate, hexadendate)
 EDTA – a hexadendate ligand
CHELATE is a special type of complex containing two or more donor groups to combine
with a metal ion
Two geometric forms;
a. cis isomer- 2 like ligands are adjacent
 Ex.: alcohol dehydrogenase enzymes (contains Zinc)
b. trans isomer- 2 like ligands are opposite each other
 Ex.: vitamin B12 and hemeproteins
2. ORGANIG MOLECULAR COMPLEXES
• Consists of constituents held together by weak forces of the donor-acceptor type or
by hydrogen bonds
Ex.:
 disulfiram, clomethiazole, tolnaftate – charge transfer complexes
 Quinhydrone of salicylic acid – quinhydrone complex
 Butesin picrate – a 2:1 complex of butesin and picric acid (Picric acid complex)
 Caffeine-gentisic acid complex – used in chewable tablet formulation
 Polymer complexes
 INCLUSION/OCCLUSION COMPOUND
➔ Consist of a macrocyclic molecule (host) and a small molecule (guest) that can enter the cavity
of the host molecule

TYPES OF INCLUSION/OCCLUSION COMPOUNDS:

A. Channel lattice type

B. Layer type
C. Clathrate - a cage like lattice in which the coordinating compound is entrapped
 Ex.: Warfarin sodium, USP
D. Monomolecular inclusion compounds - host molecules are represented by cyclodextrins
CYCLODEXTRINS
o β and γ cyclodextrins are the most useful in pharmacy
o Used as solubilizing agents
o Also used to improve the taste of oral liquid formulations
E. Macromolecular inclusion compounds - commonly called molecular sieves
 Ex.: Zeolite, dextrins, silica gels
 Chemical Kinetics, Stability & Degradation
REACTION KINETICS
The study of the rate of chemical change and the way this are influenced by conditions of concentration
of the reactants, products and chemical species that may be present, and by factors such as solvent,
pressure and temperature.
Importance of reaction kinetics
• Decomposition and stabilization of drug products
• Expiration dating or determination of shelf-life

RATES AND ORDERS OF REACTIONS

REACTION RATE or DEGRADATION RATE
• The velocity with which the reaction occurs
REACTION ORDER
• Is the way in which the concentration of the drug or reactant in a chemical reaction affects the
rate

ZERO-ORDER REACTION
• The loss of drug is independent of the concentration of the reactants and constant with respect
to time
• Unit is concentration/time (i.e., mg/mL/hr)
C = -k0t + C0
where;
ko is the zero-order rate constant
Co is the initial concentration of the drug
FIRST-ORDER REACTION
• The loss of the drug is directly proportional to the concentration remaining with respect to time
• Unit of k is reciprocal time (hr-1, min-1)
log C = -kt/2.303 + log C
• In natural log form
ln C = -kt + ln C0
SECOND ORDER REACTION
• Rate of bimolecular reactions,
A + B → products
• When the speed of the reaction depends on the concentrations of A and B with each term raised
to the first power, the rate of decomposition of A is equal to the rate of decomposition of B, and
both are proportional to the product of the concentrations of the reactants

APPARENT OR PSEUDO-ORDER
• Describes a situation where one of the reactants is present in large excess or does not effect the
overall reaction and can be held constant
• Second-order reaction behaves like a first-order is called apparent or pseudo-first-order
• Apparent zero-order kinetics is exhibited by suspensions
HALF-LIFE
• Is the period required for the concentration of a drug to decrease by one-half (t ½)
Zero order half-life: t ½ = 0.5A0/k0
First order half-life: t ½ = 0.693/k
Second order half-life : t ½ = 1/ak

STABILITY PROJECTIONS FOR SHELF-LIFE (t90)

• The time required for 10% of the drug to degrade with 90% of the intact drug remaining.

DETERMINATION OF ORDER
• SUBSTITUTION METHOD
• GRAPHIC METHOD
➔ If a straight line results when C is plotted against t, the reaction is ZERO ORDER.
➔ The reaction is FIRST ORDER if log C vs t gives a straight line.
• HALF-LIFE METHOD
➔ Zero order - half-life is not constant
➔ First order – half-life is constant

FACTORS AFFECTING REACTION RATES

1. TEMPERATURE
• An increase in temperature causes an increase in reaction rates
2. PRESENCE OF SOLVENT
• A change in the solvent system alters the transition state and the activity coefficients of the
reactant molecules
• In some cases, additional reaction pathways are generated
3. CHANGE IN pH
• Affects specifically the magnitude of the rate of hydrolytic reaction
4. PRESENCE OF ADDITIVES
• Buffer salts – due to increase ionic strength
– also promote degradation through general acid or base catalysis
• Surfactants – acceleration of degradation is caused by micellar catalysis.
• Complexing agent – can improve drug stability as a result of the formation of a less reactive
complex.

MODES OF PHARMACEUTICAL DEGRADATION

[Link]
• The most common type of degradation
• H+ and OH- are the most common catalysts
• Esters, amides, and lactams usually undergo hydrolytic reactions that cause drug instability
2. OXIDATION
• Is usually mediated through reaction with atmospheric oxygen under ambient conditions (auto-
oxidation)
• Compounds that undergo auto-oxidation are affected by oxygen dissolved in the solvent and in
void space of their package
REMEDY: Exclude air from the package by replacing oxygen with inert gas like nitrogen or carbon dioxide

OXIDATION REACTION
• Involves 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 anti-oxidant
 Ascorbic acid
 Butylated hydroxyanisole (BHA)
 Butylated hydroxytoluene (BHT)
 Propyl gallate
 Sodium bisulfite
 Sodium sulfite
 Tocopherols
PHOTOLYSIS
o The degradation of drug molecules by normal sunlight or room light
o Photolytic degradation occurs on exposure to light wavelengths less than 400 nm
o Amber bottle or an opaque container prevent or retard photolysis by acting as barrier to light
SHELF-LIFE
• The amount of time that the product can be stored before it becomes unfit for use through
either chemical decomposition or physical deterioration
• Affected by storage temperature
• In general, a preparation is considered fit for use if it varies from the nominal concentration or
dose by no more than 65%, provided that the decomposition products are not more toxic or
harmful than the original material
A. Shelf-life testing
Samples are stored at approximately 3-5°C and at room temperature (20-25°C).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
o Rate constants obtained are used to predict shelf-life
o Conducted for 6 months at 40°C and 75% relative humidity or 30°C and 60% relative humidity
C. Stability at room temperature
o Can be predicted from accelerated testing data by the Arrhenius equation
D. t90%
o Used to predict the length of time that the drug will maintain its require potency

STABILITY
• Is defined as the extent to which a product retains, within specified limits, and throughout its
period of storage and use, the same properties and characteristics that it 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 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
• Antimicrobial agents that are present retain effective within specified limits
4. THERAPEUTIC
• The therapeutic effect remain unchanged
5. TOXICOLOGIC
• No significant increase in toxicity occur
Instability of drug products may give rise to the following consequences

• Substantial loss of the active ingredient from the dosage form

• Formation of a toxic product
• Can cause decreased bioavailability

The Q10 method of shelf-life estimation

• Calculates estimates of shelf-life for a product that may have been stored or is going to be
stored under a different set of conditions

t90(T2) = t90(T1)/Q10(DT/10)
Where;
Q values = 2, 3, and 4
t90(T2) = is the estimated shelf-life
t90(T1) = is the given shelf-life at a given temperature
DT = is the difference in temperatures T1 and T2

SAMPLE PROBLEMS
• An antibiotic solution has a shelf-life of 48 hours in the refrigerator (5°C). What is the estimated
shelf-life at room temperature (25°C)?
• An ophthalmic solution has a shelf-life of 6 hours at room temperature (25°C). What would be
the estimated shelf-life if stored in a refrigerator (5°C)?
SOLUTION:
1. t90(T2) = 48/3[(25-5)/10]
= 48/32
= 5.33 hours
2. t90(T2) = 6/3[(5-25)/10]
= 6/3-2
= 6 x 32
= 54 hours