MODULE 5 PHARM 3

PHYSICAL PHARMACY
PHYSICAL PHARMACY responsible for the solubility of non-polar molecules
Ex. Iodine complex with salts
Application of physical chemistry in pharmacy
Study of physiochemical properties of substances used in PHYSICAL PROPERTIES OF MATTER
drug formulation
Additive
FORCES OF ATTRACTION depends on the total contribution of the atoms in the
molecules
INTRAMOLECULAR FORCES Ex. MW, Mass

Forces of attraction within the molecule

Constitutive
Types: depends on the arrangement of the number & kind of atoms
within a molecule
a. Ionic Bond Ex. Refractive Index, Optical Rotation
Transfer of electrons between a non-metal & a metal
observed in formation of salts Colligative
function of the number of species or particles present in a
b. Covalent Bond given solution
sharing of electrons between two non-metals Ex. Osmotic pressure elevation, Vapor Pressure lowering,
observed in organic compounds Freezing Point Depression, Boiling Point Elevation

INTERMOLECULAR FORCES TYPES OF PROPERTIES

forces of attraction between molecules Intensive

independent of the amount of the substance in the system
Types: Ex. Temperature, Pressure, Density, Viscosity, Surface
tension, Specific Gravity
a. Binding Forces
Cohesion similar molecules Extensive
Adhesion different molecules depends on the quantity of substance in the system
Repulsive prevent molecules from annihilating each other Ex. Mass, Length, Volume

b. Attractive Forces STATES OF MATTER

Van der Waals
Hydrogen Bond THE GASEOUS STATE
Ion-Dipole
Ion-induced Dipole Gas Laws
refers to an ideal situation where no intermolecular
Van der Waals Forces interactions exist and collisions are perfectly elastic
weak forces that involve the dispersion of charge across a there is no energy exchanged upon collision
molecule called a dipole

1. Keesom Forces (orientation effect) relates volume and pressure

Dipole-dipole constant temperature
molecules are polar with permanent polar dipoles PV = k
Ex. water, HCl, ethanol, acetone, phenol
2. Gay-
2. Debye Forces (induction effect) states that the volume and absolute temperature of a gas at
Dipole-induced dipole constant pressure are directly proportional
transient dipole induced by a permanent dipole V = kT
polar molecules produce temporary electric dipole in
nonpolar molecules 3. Ideal Gas Law
Ex. Ethyl acetate, methylene chloride, ether PV = nRT
R = 0.08205 liter.atm/mole.K or 8.314 joules/mole.K or 1.987
3. London Forces (dispersion effect) cal/mole deg
Induced dipole- induced dipole n = number of moles
induce polarity between non polar molecules
responsible for liquefaction of gases Kinetic Molecular Theory
Ex. Carbon disulfide, CCl2, hexane Gases are composed of particles called atoms or molecules,
the total volume of which is so small as to be negligible in
Hydrogen Bond relation to the volume of the space in which the molecules
electrostatic interaction of H with highly electronegative are confined
atoms (S, N, Cl, F, O) The particles of the gas do not attract one another, but
accounts for unusual properties of water instead move with complete independence
The particles exhibit continuous random motion owing to
Ion-Dipole Interaction their kinetic energy
polar molecules are attracted to either positive or negative The molecules exhibit perfect elasticity
charges
occurs when salt is dissolved in a polar solvent THE LIQUID STATE
solubility if crystalline substances in H2O
quaternary ammonium + tertiary amine Critical temperature
temperature above which a liquid can no longer exist
Ion-Induced Dipole
induced by close proximity of a charged ion to a non-polar
molecule

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Critical Pressure Supercritical Fluids
pressure required to liquefy a gas a critical temperature properties intermediate between those of liquids and gases
highest vapor pressure of a liquid formed from the gaseous state where the gas is held under a
combination of temperatures and pressures that exceed the
Boiling Point critical point of a substance
the temp at which the vapor pressure of the liquid equals the
external and atmospheric pressure

THE SOLID STATE relates the effect of the least number of independent
variables (T, P & C) among the various phases (S, L & G)
have fixed shapes that can exist in an equilibrium system containing a given
nearly incompressible number of components
have strong intermolecular forces Where: F = no. of degrees of freedom
very little kinetic energy C = no. chemical components
atoms vibrate fixed positions about an equilibrium position, & P = no. of phases
so there is very little transitional motion X = variable dependent upon considerations of
the phase diagram
Crystalline Solids F least number of intensive/independent variables that
Solids whose structural units are arranged in a fixed must be fixed to describe the system completely
geometric pattern or lattices C smallest number of constituents by which the
definite shape composition of each phase in the system at equilibrium can
orderly arrangement of units be expressed in the form of a chemical formula or equation
definite and sharp melting points P number of homogenous physically distinct portion of a
6 Distinct Critical Systems Based on Symmetry system that is separated from other portions of the system by
Cubic Sodium Chloride bounding surfaces
Tetragonal Urea 1 Phase F=2 Bivariant
Hexagonal Iodoform 2 Phases F=1 Univariant
Monoclinic Sucrose 3 Phases F=0 Invariant
Rhombic I2
Triclinic Boric Acid THERMODYNAMICS

Amorphous Solids deals with the quantitative relationships of interconversion of

glasses or supercooled liquids the various forms of energy
molecules are arranged in a random manner System a well-defined part of the universe under study
no definite melting points Surroundings the rest of the universe from which the
faster dissolution rate observations are made
Boundaries physical or virtual barriers that separate a
Polymorphism system from the surroundings
condition where substances can exist in more than 1
crystalline form TYPES OF SYSTEMS
polymorphs have different melting points, x-ray crystals and
diffraction patterns and solubility 1. Open energy and matter can be exchanged with the
Theobroma Oil Polymorphs (Melting Points) surroundings
18°C
22°C 2. Closed energy can be exchange with the surroundings but
28°C not matter
34°C
Types of Polymorphism 3. Isolated neither matter not energy can be exchanged with
Enantiotropic reversible the surroundings
Monotropic unidirectional transition
FIRST LAW OF THERMODYNAMICS
Freezing Point
temperature at which liquid solid Energy cannot be created nor destroyed, it can only be
melting point of a pure crystalline compound transformed into a different form
Adiabatic constant heat
Latent Heat of Fusion Isothermic constant temperature
Energy absorbed when 1g of a solid melt Isochoric constant volume
Heat liberated when it freezes Isobaric constant pressure

LIQUID CRYSTALLINE STATE SECOND LAW OF THERMODYNAMICS

liquid crystals intermediate between liquid and solid states Refers to the probability of the occurrence of a process
may result from the heating of solids (thermotropic) or from based on the tendency of a system to approach a state of
the action of certain solvents on solids (lyotropic liquid energy equilibrium
crystals) Entropy

Two Main Types of Liquid Crystals THIRD LAW OF THERMODYNAMICS

1. Smectic The entropy of a pure crystalline substance is zero at

Soap like or grease like absolute zero because the crystal arrangement must show
molecules are mobile in 2 directions the greatest orderliness at this temperature
rotates in 1 axis
CONDENSED SYSTEMS
2. Nematic
threadlike S & L phases only
molecules are mobile in 3 directions the vapor state is disregarded with an assumption of working
rotates in 1 axis at a pressure at 1atm
Cholesteric special type of nematic 2 Components liquid phases
2 Components S & L eutectic mixtures
3 Components

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 TWO COMPONENT SYSTEM CONTAINING TWO LIQUIDS Bulk Volume total volume of the material
Void Volume difference between bulk and true volume
Binodal Curve
area within the curve which represent a 2-phase system Density
True Density density of actual particle
Upper Consulate/Critical Solution Temperature Granule Density volume of particles together with
maximum temperature at which two phase region in the intraparticulate spaces
phase diagram of a two-component system containing two Bulk Density
liquids will exist mass of powder divided by the bulk volume
USP Method 1 Graduated Cylinder
Tie line USP Method 2 Scott Volumeter
line from which a system separates into phases of constant USP Method 3 Vessel
composition
approximates proportion of components in a particular Flow Properties
temperature
Conjugate Phases Angle of Response maximum angle possible between the
phases of constant composition that separate when a surface of a pile of power and the horizontal plane
mixture is prepared within the boundary of the 2-phase
system
Where: h = height of cone
TWO COMPONENT SYSTEM CONTAINING SOLID AND LIQUID r = radius of base cone

Eutectic Point Tapped Density measured using a tapped density tester

minimum temp. where both exist in liquid form by repeated tapping until a consistent tapped volume is
point where solid A, solid B & the liquid phase co-exist achieved

THREE COMPONENT SYSTEM LIQUIDS

Ternary system less kinetic energy than gases

2 liquids that are miscible + 3rd component (co-solvent) with occupy definite volume
affinity to both layers take the shape of containers
has 4 degrees of freedom denser than gases
not compressible
MICROMERITICS
SOLUTIONS OF ELECTROLYTES & NON-ELECTROLYTES
study of small particles
True Solutions
Fundamental properties molecular dispersions
defined individually particle size = <1nm
Ex. particle size & shape, particle size distribution, surface
area Electrolytes
form ions in solution
Derived properties electrical conductance
computed Strong Electrolytes
dependent on fundamental properties completely ionized in solution
Ex. Porosity, Density, Flow properties, Packing arrangement NaCl, HCl, H2SO4
Weak Electrolytes
PARTICLE SIZE DETERMINATION partial ionization
CH3COOH and most drugs
Optical Microscopy
microscope Non-Electrolytes
individual particles can be seen do not form ions in solution
tedious and 2D image is only seen no electrical conductance
Ferret Diameter measure of the distance between sucrose, glycerin, urea
tangents parallel to some fixed directions
Projected Area Diameter diameter of a circle with the COLLIGATIVE PROPERTY
same area of the particle
Martin Diameter length of the line that bisects the particle Vapor Pressure Lowering
pressure of saturated vapor above a liquid escape of
Sieving liquid
use of sieves molecules
official method USP Method nonvolatile solute + volatile solvent decreased escape
mesh number refers to number of openings per inch tendency
vapor pressure is lowered proportional to relative number of
added solutes
Sedimentation Ex. Dextrose + Water
Andreasen apparatus
Boiling Point Elevation
temperature where VP of liquid = external atmospheric
pressure
Particle Size Determination -
Coulter Counter
HIAC/Royco Freezing Point Depression
Gelman Counter Melting or Freezing Point
temperature at which S & L phases are at equilibrium
DERIVED PROPERTIES under1 atm
indicator of purity
Porosity of Voids

Porosity measure of a void volume in a powder material

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Osmotic Pressure Buffer Capacity
pressure required to prevent the movement of water through buffer efficiency or buffer index
a semipermeable membrane from region of high to low
concentration
B = represents the small increment in gram equivalents per liter of
TONICITY OF SOLUTIONS strong base or acid added to the buffer solution to produce a change
in pH
Isotonic Solutions
living cell does not gain or loss water SOLUBILITY
same osmotic pressure with body fluids
0.9% NaCl solution, normal saline, D5W concentration of a saturated solution in which the dissolved
solute is in equilibrium with its solid phase at constant
Hypertonic Solutions Intrinsic Solubility
more solutes compared to cell concentrations Apparent Solubility
freeze lower than -0.52°C Kinetic Solubility
causes crenation of the cell Thermodynamic Solubility
5% NaCl solution
Factors Affecting Solubility
Hypotonic Solutions Dissolution Rate of Solute
less solutes compared to cell concentrations Temperature
freeze higher than -0.52°C Addition of Salt
causes lysis of the cell Complex Formation
distilled water Salt Formation
Amorphous Form
Methods of Adjusting Tonicity and pH
Descriptive Term Parts of Solvent for One Part of Solute
Class I Methods Very soluble <1
NaCl or some other substance is added to the solution of the Freely Soluble 1-10
drug to make it isotonic Soluble 10-30
Sparingly Soluble 30-100
Freezing Point Depression/Crysoscopic Method Slightly Soluble 100-1000
FPD used to calculate the amount of solute to add in making
an isotonic solution INTERFACIAL PHENOMENON

Class II Methods attributed to the effect of the properties of molecules located

water is added to the drug isotonic solutions or close to the boundary between immiscible phases
White Vincent Method V = w x E x 111.1 Interface boundary between 2 distinct phases
Sprowls Method V = 0.3g x E x 111.1
Surface & Interfacial Tension
THEORIES OF ACIDS AND BASES
Surface Tension
Theory Acid Base force that pulls molecules of the interface together &
contracts the surface
Arrhenius Liberates H2O in aq. Liberates OH in
solutions aq.
solutions Interface Tension
Bronsted-Lowry Proton donor Proton acceptor force per unit length existing at the interface
between 2 immiscible liquids
Lewis Electron acceptor Electron donor
WETTING PHENOMENON
CLASSIFICATION OF SOLVENTS
contact angle that a droplet of the liquid makes with the solid
Photophilic (Basic Solvents) capable of accepting protons surface at the point of contact
from solute
Proteogenic (Acidic Solvents) proton donating 180° = complete non-wetting
Aprotic neither accepts nor donates
SURFACTANTS (SURFACE ACTIVE AGENTS)
Ionization of Weak Acids & Bases
long chain molecules
Ionization complete separation of ions in a crystal lattice affinity for both polar and non-polar solvents
when a salt is dissolved reduces interfacial tension
Dissociation separation of ions in solution when the ions based on Hydrophile Lipophile Balance (HLB) Values
are associated by interionic attraction
Type Description Examples
Henderson-Hasselbalch Equation Anionic Long chain molecules of Sodium lauryl sulfate
aka pH or buffer equation carboxylates, sulfates or
sulfonates
preparation of drug solutions at a desired pH using both the
neutral and the salt forms of a drug Cationic Interactions with negatively Benzalkonium chloride
charged surfaces such as cell
determine percentage of neutral and ionized forms at a given membranes; cytotoxic
pH antimicrobial preservatives
determination of pKa of an acid or a base Amphoteric Naturally occurring surfactants Polypeptides, Proteins
Weak acids = + Zwitterions Alkyl pentanes
Lecithin, Cephalins
Non-Ionic Long but contains a small Fatty alcohols (lauryl,
Weak bases = + alcohol base (e.g., propylene acetyl, stearyl) Steroid
glycol), sorbitol or glycerol to alcohols
BUFFERS which fatty acids are attached Glyceryl esters
to form fatty acid esters
compound or a mixture of compounds which has the ability
to resist changes in pH when small amounts of acids and
bases are added

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 HLB Values Utilities Examples INSTABILITY OF COARSE DISPERSION
1-3 Antifoaming agent Mineral Oil
Fatty Alcohol Emulsions
Wax Creaming upward movement of internal phase
3-6 W/O Emulsifying Agents Span 80
Sedimentation downward movement of internal phase
Lanolin Flocculation reversible aggregation of droplets
7-9 Wetting & Spreading Agents Brij 30 Coalescence/Cracking/Breaking complete fusion of
Docusate sodium droplets (irreversible)
Inversion change in the type of emulsion (W/O O/W or
8-18 O/W Emulsifying Agents Twean 20
Cremophor A25
13-16 Detergents Alkyl Benzenes Suspension
Sulfonates
Caking compaction of suspended particles at the bottom of
15-20 Solubilizing Sodium Lauryl Sulfate
the container
ELECTRIC PROPERTIES OF INTERFACES Gels, Jellies, Suppositories & Ointments
Syneresis shirking of gel structure caused by loss of liquid
Nernst Potential Electro thermodynamic
Bleeding liberation of liquid from the base
Zeta Potential Electrokinetic Swelling/Imbibition absorption of liquid into the structure
Swelling increase in volume
COLLOIDAL DISPERSIONS
Imbibition no increase in volume
Lyophilic
RHEOLOGY
Solvent loving
dispersed phase consists generally or large organic study of the flow of liquids
molecules lying within a colloidal range
viscosity is the expression of the resistance of a fluid to flow
Molecules of the dispersed phase are solvated they are
associated with the molecule comprising the dispersion
medium F = shearing stress (dyne/cm2) amount of force per unit area
Spontaneously disperse to form colloidal dispersion required to cause a liquid to flow
thermodynamically stable G = rate of shear (rev/min) velocity of the system that leads to
the deformation of the liquid
Association
Amphiphilic VISCOSITY
dispersed phase consists of micelles or small organic
molecules or ions whose size individually is below the Units of Measurement
colloidal range Absolute viscosity centipoise/poise
Hydrophilic or lipophilic portion is solvated depending on Kinematic viscosity centistoke/stoke
whether the dispersion medium is aq. or non aq. Relative viscosity unitless
colloidal aggregates are formed spontaneously when the Measurement of Viscosity
concentration of the amphiphile exceeds critical micelle Capillary Tube Viscometers
concentration measure the time required for a given volume of liquid
to flow through a capillary
Lyophobic
solvent hating Ex. Ostwald & Ubbelohde viscometers
dispersed phase consists of materials that have little Follows Law:
attraction for the dispersion medium
material does not spontaneously form a dispersion
r = radius of capillary
PROPERTIES OF COLLOIDS
t = time to flow
P = pressure in dyne/cm2
Kinetic Properties
l = length of capillary
Brownian Movement particles appear as tiny points of
v = volume of liquid flowing
light in constant motion
Diffusion movement of particles from high to low
Rotational Viscometers
concentration until equilibrium is achieved
makes use of a bob or spindle w/c is immersed in the in
the liquid whose viscosity is to be determined
Optical Property
Rotating Bob Brookfield, Rotovisco, Stormer
Tyndall Effect ability to scatter or disperse light
Rotating Cup McMichael
Faraday Effect
Factors Affecting Viscosity
Electrokinetic Effect
Temperature
Electrophoresis movement of a charged particle through
a liquid
Shear Rate
Electroosmosis movement of a liquid through plug or
Time
membrane across which a potential is applied
Concentration of Solution
Sedimentation creation of a potential when particles
undergo sedimentation
NEWTONIAN SYSTEMS
Streaming potential -- potential created by forcing a liquid
to flow through a plug or bed of particles
direct relationship between shearing stress & rate
constant viscosity with increasing rate
COARSE DISPERSION
E.g., water, ethanol, acetone, glycerin, benzene
Emulsion
NON-NEWTONIAN SYSTEMS
Suspensions
Semisolid preparations gels, jellies, suppositories &
a. Plastic Flow
ointments
Bingham bodies
curve does not pass through the origin but rather intersects
the shearing stress axis at a particular point (yield value)

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 a yield value must be overcome before the system begins to By manipulation of the equation, it can be used to determine the
flow following
Ex. Flocculated suspension, gels, ointments, pastes, Pressure
surfactants, polymeric substances Volume
Temperature
b. Pseudoplastic Flow No. of moles
shear thinning systems Weight
curve begins at the origin Molecular weight
no yield values Density
viscosity decrease w/ increasing shear rate
Ex. Polymer solution, Na alginate, Perityl cellulose, PEG

c. Dilatant Flow
shear thickening systems
reverse effects of pseudoplastic flow
viscosity increases with increases shear rate
Real Gas Equation
Ex. starch in H2O, conc. suspension of inorganic pigments in
H2O, Zinc Oxide, Barium sulfate or Titanium oxide in H2O
Van der Waal Equation for Real Gases
Thixotropy
decrease in viscosity with time when flow is applied to a
sample previously at rest and the recovery of viscosity in
Where:
time when flow is continued
a/V2 = internal pressure due to IMFA
Ex. aq. bentonite magma
b = excluded volume

Rheopexy NOTE
refers to the phenomenon that the gel formation of a system
may be facilitated by tapping or low shear compared to Real (Non-
keeping the sample at rest
time dependent increase in viscosity during flow
Ex. Bovine synovial fluid, serum albumin due to protein, 1 mole of ideal gas
Sodium hyaluronate

Antithixotropy
time dependent increase in viscosity during flow caused by
reversible aggregation of particles
reversed hysteresis loop
Ex. magnesia magma
The total pressure of the system, (PT) is the sum of the individual
GASES partial pressure of each component
have kinetic energy that produces rapid motion VAPOR PRESSURE OF SOLUTION
held together by weak intermolecular forces
capable of filling all available spaces Vapor Pressure
easily compressible A measure of escape
GAS LAWS
In ideal solution:
refers to an ideal situation where no intermolecular
The partial VP of each volatile constituent is equal to the VP
interactions exist and collisions are perfectly elastic
of the pure constituent multiplied by its more fraction in the
there is no energy exchanged upon collision
solution
Gay-Lussac and
PA = PA°(XA)
PB = PB°(XB)
P and V relationship V and T relationship V and n relationship Where: P = partial vapor pressure of solute
(Constant T, n) (Constant P, n) (Constant P, T) P° = vapor pressure of pure solute
Inverse: P 1/V Direct: V T Direct: n V

Combined Gas Law The speed of diffusion of a gas is relative to the MW or

density of the gas

NOTE: Gay- relationship

Ideal Gas Laws

The solubility of gas is directly proportional to pressure at
Ideal Gas Equation constant temperature
Equation of state of an ideal gas (theoretical gas behaving C=kP
ideally) Where: C = Concentration of gas in solution
PV = nRT P = pressure

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 VAPOR PRESSURE-TEMPERATURE VARIATION

Clausius-Clapeyron Equation
The relationship between the vapor pressure and the
absolute temperature of a liquid

Where P1 = initial vapor pressure

P2 = final vapor pressure
T1 = initial temperature in K
T2 = final temperature in K
R = gas constant (8.314 J/mol-K
NOTE: the molar heat of vaporization ( Hvap) is the energy required
to vaporize one mole of a liquid

DRUG PRODUCT STABILITY

extent to which a preparation retains the same properties

that
it had at the time of formulation
It is concerned with:
Physical Properties
Chemical Properties and Composition
Microbiological Sterility
Therapeutic Activity

Photodegradation
sensitivity of drug to UV light
prevention light resistant / opaque containers

Hydrolysis & Acid-Base Catalysis

degradation of esters, amides, lactams to carboxylic acid

CHEMICAL KINETICS

REACTION RATES

may refer to the rate of degradation or formation of a product

from a given reaction
velocity with which the reaction occurs
Influenced by:
Concentration
Temperature
Change in pH
Presence of additives
Presence of solvents
Radiation
Catalytic Agents or Enzymes

ORDER OF REACTIONS

Zero Order
concentration independent kinetics
elimination of a reactant will be linear with time
Ex. suspension

First Order
concentration dependent reaction
rate of reaction is proportional to the first power of the
concentration of a single reacting species
most drugs follow such order of reaction

Second Order
amount of drug is decreasing at a rate proportional to the
square of the amount of drug remaining
uncommon

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