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Physical Pharmacy

application of physical chemistry in pharmacy

study of physiochemical properties of substances used in drug


formulation

FORCES OF ATTRACTION
Intramolecular Forces

forces of attraction within the molecule

Types Ionic & Covalent Bonds


o Ionic Bond

Transfer of electrons between a non metal


& a metal

observed in formation of salts


o Covalent Bond

sharing of electrons between two non


metals

observed in organic compounds

Intramolecular Forces

forces of attraction between molecules

Types Binding & Attractive Forces


o Binding Forces

Cohesion similar molecules

Adhesion different molecules

Repulsive prevent molecules from


annihilating each other
o Attractive Forces

Van der Waals

Hydrogen Bond

Ion-Dipole

Ion-induced Dipole

Van der Waals Forces

weak forces that involve the dispersion of charge across a


molecule called a dipole
o Keesom Forces (orientation effect)

Dipole-dipole

molecules are polar with permanent polar


dipoles

Ex. water, HCl, ethanol, acetone, phenol


o Debye Forces (induction effect)

Dipole-induced dipole

transient dipole induced by a permanent


dipole

polar molecules produces temporary


electric dipole in nonpolar molecules

Ex. Ethyl acetate, methylene chloride, ether


o London Forces (dispersion effect)

Induced dipole- induced dipole

induce polarity between non polar


molecules

responsible for liquefaction of gases


Ex. Carbon disulfide, CCl2, hexane

Hydrogen Bond

electrostatic interaction of H with highly electronegative


atoms (S,N,Cl,F,O)

accounts for unusual properties of water

Ion-Dipole Interaction

polar molecules are attracted to either positive or negative


charges

occurs when salt is dissolved in a polar solvent

solubility if crystalline substances in H2O

quaternary ammonium + tertiary amine

Ion-Induced Dipole

induced by close proximity of a charged ion to a non polar


molecule

responsible for the solubility of non polar molecules

Ex. Iodine complex with salts

PHYSICAL PROPERTIES OF MATTER


Additive

depends on the total contribution of the atoms in the


molecules

Ex. MW, Mass

atoms = MW = Mass

Constitutive

depends on the arrangement of the number & kind of atoms


within a molecule

Ex. Refactive Index, Optical Rotation

Colligative

function of the number of species or particles present in a


given solution

Ex. Osmotic pressure elevation, Vapor Pressure lowering,


Freezing Point Depression, Boiling Point Elevation

TYPES OF PROPERTIES
Intensive

independent of the amount of the substance in the system

Ex. Temperature, Pressure, Density, Viscosity, Surface


tension, Specific Gravity

Extensive

depends on the quantity of substance in the system

Ex. Mass, Length, Volume

Lorenzo Dominick Cid 2015

P1 & P2 = vapor pressures at T1 & T2


Hv = molar heat of vaporization
R = 1.987 cal/mole deg

STATES OF MATTER
The Gaseous State
Gas Laws

refers to an ideal situation where no intermolecular


interactions exist and collisions are perfectly elastic

there is no energy exchanged upon collision

Boyles Law
o relates volume and pressure
o constant temperature
o PV = k

Gay-Lussac and Charles Law


o states that the volume and absolute temperature of
a gas at constant pressure are directly proportional
o V = kT
Ideal Gas Law
o PV = nRT
o R = 0.08205 liter.atm/mole.K or 8.314 joules/mole.K
or 1.987 cal/mole deg
o n = number of moles

The Solid State

have fixed shapes

nearly incompressible

have strong intermolecular forces

very little kinetic energy

atoms vibrate fixed positions about an equilibrium position, &


so there is very little transitional motion

Crystalline Solids

Solids whose structural units are arranged in a fixed geometric


pattern or lattices

definite shape

orderly arrangement of units

definite and sharp melting points

6 Distinct Critical Systems Based on Symmetry


o Cubic Sodium Chloride
o Tetragonal Urea
o Hexagonal Iodoform
o Monoclinic Sucrose
o Rhombic I2
o Triclinic Boric Acid

Kinetic Molecular Theory

Gases are composed of particles called atoms or molecules,


the total volume of which is so small as to be negligible in
relation to the volume of the space in which the molecules are
confined

The particles of the gas do not attract one another, but


instead move with complete independence

The particles exhibit continuous random motion owing to


their kinetic energy

glasses or supercooled liquids

molecules are arranged in a random manner

The molecules exhibit perfect elasticity

no definite melting points

faster dissolution rate

The Liquid State

Critical temperature temperature above which a liquid can


no longer exist
Critical Pressure
o pressure required to liquefy a gas a critical
temperature
o highest vapor pressure of a liquid

Polymorphism

condition where substances can exist in more than 1


crystalline form

polymorphs have different melting points, x-ray crystals and


diffraction patterns and solubility

Theobroma Oil Polymorphs (Melting Points)

Boiling Point the temp at which the vapor pressure of the


liquid equals the external and atmospheric pressure

Unstable form 18C

form 22C

Latent Heat of Vaporization


o the quantity of heat taken up when a liquid
vaporizes
o it is liberated when a vapor condenses with a liquid

prime form 28C

Stable form 34C

Clausius-Clapeyron Equation

Amorphous Solids

relationship of vapor pressure and absolute temperature of


a liquid

log

Types of Polymorphism
o Enantiotropic reversible
o Monotropic unidirectional transition

Freezing Point

temperature at which liquid solid

melting point of a pure crystalline compound

P1 Hv (T2 -T1 )
=
P2 2.303 RT1 T2

Lorenzo Dominick Cid 2015

Latent Heat of Fusion

Energy absorbed when 1g of a solid melts

Heat liberated when it freezes

Liquid Crystalline State

liquid crystals intermediate between liquid and solid states

may result from the heating of solids (thermotropic) or from


the action of certain solvents on solids (lyotropic liquid
crystals)

Two Main Types of Liquid Crystals

Smectic
o Soaplike or greaselike
o molecules are mobile in 2 directions
o rotates in 1 axis
Nematic
o
o
o
o

threadlike
molecules are mobile in 3 directions
rotates in 1 axis
Cholesteric special type of nematic

Supercritical Fluids

THERMODYNAMICS

deals with the quantitative relationships of interconversion of


the various forms of energy

System a well defined part of the universe under study

Surroundings the rest of the universe from which the


observations are made

Boundaries physical or virtual barriers that separate a


system from the surroundings

Types of Systems

Open energy and matter can be exchanged with the


surroundings

Closed energy can be exchange with the surroundings but


not matter

Isolated neither matter not energy can be exchanged with


the surroundings

First Law of Thermodynamics

Energy cannot be created nor destroyed, it can only be


transformed into a different form

Adiabatic constant heat

Isothermic constant temperature


Isochoric constant volume
Isobaric constant pressure

properties intermediate between those of liquids and gases

formed from the gaseous state where the gas is held under a
combination of temperatures and pressures that exceed the
critical point of a substance

Second Law of Thermodynamics

Refers to the probability of the occurrence of a process based


on the tendency of a system to approach a state of energy
equilibrium

Entropy

THE PHASE RULE (GIBBS PHASE RULE)

relates the effect of the least number of independent variables


(T, P & C) among the various phases (S,L & G) that can exist in
an equilibrium system containing a given number of
components

Third Law of Thermodynamics

=+
F = no. of degrees of freedom
C = no. chemical components
P = no. of phases
X = variable dependent upod considerations of the phase diagram

F least number of intensive/independent variables that must


be fixed to describe the system completely

C smallest number of constituents by which the composition


of each pase in the system at equilibrium can be expressed in
the form of a chemical formula or equation

P number of homogenous physically distinct portion of a


system that is seperated from other portions of the system by
bounding surfaces

1 Phase F=2 Bivariant

2 Phases F=1 Univariant

3 Phases F=0 Invariant

The entropy of a pure crystalline substance is zero at absolute


zero because the crystal arrangement must show the greatest
orderliness at this temperature

CONDENSED SYSTEMS

S & L phases only

the vapor state is disregarded with an assumption of working


at a pressure at 1atm
o 2 Components liquid phases
o 2 Components S & L eutectic mixtures
o 3 Components

Two Component System Containing Two


Liquids

Binodal Curve area within the curve which represent a 2


phase system

Upper Consolute/Critical Solution Temperature max.


temperature at which two phase region in the phase diagram
of a two-component system containing two liquids will exist

Lorenzo Dominick Cid 2015

Tie line
o
o

Sedimentation
line from which a system seperates into phases of
constant composition
approximates proportion of components in a
particular temperature

Conjugate Phases
o phases of constant composition that separate when
a mixture is prepared within the boundary of the 2phase system

Two Component System Containing Solid and


Liquid

Eutectic Point
o minimum temp. where both exist in liquid form
o point where solid A, solid B & the liquid phase coexist

Three Component System

Andreasen apparatus

Sedimentation rate = Particle size (direct proportionality)

follow the Stokes Law

Particle Size Determination

Coulter Counter

HIAC/Royco

Gelman Counter

Derived Properties
Porosity of Voids

Porosity measure of a void volume in a powder material

Bulk Volume total volume of the material

Void Volume difference between bulk and true volume

Density

Ternary system

True Density density of actual particle

2 liquids that are miscible + 3rd component (co-solvent) with


affinity to both layers

Granule Density volume of particles together with


intraparticulate spaces

has 4 degrees of freedom

Bulk Density
o mass of powder divided by the bulk volume
o USP Method 1 Graduated Cylinder
o USP Method 2 Scott Volumeter
o USP Method 3 Vessel

MICROMERITICS

study of small particles

Fundamental properties
o defined individually
o Ex. particle size & shape, particle size distribution,
surface area

Flow Properties

Derived properties
o computed
o dependent on fundamental properties
o Ex. Porosity, Density, Flow properties, Packing
arrangement

Particle Size Determination


Optical Microscopy

Angle of Response
o maximum angle possible between the surface of a
pile of power and the horizontal plane

h = height of cone
r = radius of base cone
o

AOR = Flow Property

Tapped Density
o measured using a tapped density tester by repeated
tapping until a consistent tapped volume is achieved

microscope

individual particles can be seen

tedious and 2D image is only seen

Ferret Diameter measure of the distance between tangents


parallel to some fixed directions

LIQUIDS

Projected Area Diameter diameter of a circle with the same


area of the particle

less kinetic energy than gases

occupy definite volume

Martin Diameter length of the line that bisects the particle

take the shape of contaniners

denser than gases

not compressible

Sieving

use of sieves

official method USP Method

mesh number refers to number of openings per inch

Solutions of Electrolytes & Non-Electrolytes


True Solutions

Mesh Number = Particle Size (inverse proportionality)

molecular dispersions

Lorenzo Dominick Cid 2015

particle size = <1nm

Electrolytes

Hypertonic Solutions

more solutes compared to cell concentrations

freeze lower than -0.52C

form ions in solution

causes creanation of the cell

electrical conductance

5% NaCl solution

Strong Electrolytes
o completely ionized in solution
o NaCl, HCl, H2SO4

Hypotonic Solutions

Weak Electrolytes
o partial ionization
o CH3COOH and most drugs

Non-Electrolytes

do not form ions in solution

no electrical conductance

sucrose, glycerin, urea

Colligative Properties of Solutions


Vapor Pressure Lowering

pressure of saturated vapor above a liquid escape of liquid


molecules

non volatile solute + volatile solvent decreased escape


tendency

vapor pressure is lowered proportional to relative number of


added solutes

Ex. Dextrose + Water VP of water

less solutes compared to cell concentrations

freeze higher than -0.52C

causes lysis of the cell

distilled water

Methods of Adjusting Tonicity and pH

Class I Methods
o NaCl or some other subtance is added to the
solution of the drug to make it isotonic

Freezing Point Depression/Crysoscopic Method


o FPD used to calculate the amount of solute to add in
making an isotonic solution

Class II Methods
o water is added to the drug isotonic solutions

White Vincent Method V = w x E x 111.1

Sprowls Method V = 0.3g x E x 111.1

Theories of Acid & Bases


Theory
Arrhenius

Boiling Point Elevation

temperature where VP of liquid = external atmospheric


pressure

non volatile solute in solution = BP of solution

Freezing Point Depression

Base
Liberates OH in aq.
soln
Proton acceptor
Electron donor

Classification of Solvents

Melting or Freezing Point


o temp at which S & L phases are at equilibrium under
1 atm
o indicator of purity

Protophillic (Basic Solvents) capable of accepting protons


from solute

Protogenic (Acidic Solvents) proton donating

Aprotic neither accepts nor donates

Solutions have FPD than pure substances

Ionization of Weak Acids & Bases

Osmotic Pressure

Bronsted-Lowry
Lewis

Acid
Liberates H3O in aq.
soln
Proton donor
Electron acceptor

pressure required to prevent the movement of water through


a semipermeable membrane from region of high to low
concentration

Tonicity of Solutions
Isotonic Solutions

living cell does not gain or loss water

same osmotic pressure with body fluids

0.9% NaCl solution, normal saline, D5W

Ionization complete separation of ions in a crystal lattice


when a salt is dissolved

Dissociation separation of ions in solution when the ions


are associated by interionic attraction

Henderson-Hasselbalch Equation

aka pH or buffer equation

preparation of drug solutions at a desired pH using both the


neutral and the salt forms of a drug

determine percentage of neutral and ionized forms at a given


pH

determination of pKa of an acid or a base

Lorenzo Dominick Cid 2015

Surface & Interfacial Tension

For acid and its salt :


[]
= + log
[]

For base and its salt :


= + log

Interface Tension
o force per unit length excisting at the interface
between 2 immiscible liquids

Wetting Phenomenon

compound or a mixture of compounds which has the ability to


resist changes in pH when small amounts of acids and bases
are added

Buffer Capacity

Surface Tension
o
force that pulls molecules of the interface together
& contracts the surface

[]
[]

Buffers

contact angle that a droplet of the liquid makes with the solid
surface at the point of contact

Contact Angle = wetting

180 = complete non wetting

SURFACTANTS (SURFACE ACTIVE AGENTS)

buffer efficiency or buffer index

B = represents the small increment in gram equivalents per liter


of strong base or acid added to the buffer solution to produce
a change in pH

Solubility

long chain molecules

affinity for both polar and non polar solvents

reduces interfacial tension

based on Hydrophile Lipophile Balance (HLB) Values


Type

Anionic

Cationic

concentration of a saturated solution in which the dissolved


solute is in equilibrium with its solid phase at constant

Intrinsic Solubility

Apparent Solubility

Kinetic Solubility

Thermodynamic Solubility

Amphoteric

Non-Ionic

Factors Affecting Solubility

Dissolution Rate of Solute

Temperature

Addition of Salt

Complex Formation

Salt Formation

Amorphous Form

HLB Values
1-3

Descriptive Term

Parts of Solvent for One Part of


Solute

Very soluble
Freely Soluble
Soluble
Sparingly Soluble
Slightly Soluble

<1
1-10
10-30
30-100
100-1000

Description

Examples

Long chain molecules of


carboxylates, sulfates or
sulfonates
Interactions with negatively
charged surfaces such as cell
membranes; cytotoxic
antimicrobial preseratives
Naturally occuring surfactants
Zwitterions
Long but contains a small
alcohol base (eg. propylene
glycol), sorbitan or glucerol to
which fatty acids are attached
to form fatty acid esters
Utilities
Antifoaming agent

3-6

W/O Emulsifying Agents

7-9

Wetting & Spreading Agents

8-18

O/W Emulsifying Agents

13-16

Detergents

15-20

Solubilizing

Sodium lauryl sulfate

Benzalkonium chloride

Polypeptides, Proteins
Alkyl bentanes
Lecithin, Cephalins
Fatty alcohols (lauryl,
cetyl, stearyl)
Steroid alcohols
Glyceril esters
Examples
Mineral Oil
Fatty Alcohol
Wax
Span 80
Lanolin
Brij 30
Docusate sodium
Twean 20
Cremophor A25
Alkyl Benzenes
Sulfonates
Sodium Lauryl Sulfate

Interfacial Phenomenon

attributed to the effect of the properties of molecules located


or close to the boundary between immiscible phases

Interface boundary between 2 distinct phases

Lorenzo Dominick Cid 2015

Electric Properties of Interfaces

Nerst Potential Electrothermodynamic

Zeta Potential Electrokinetic

Streaming potential -- potential created by forcing a liquid


to flow through a plug or bed of particles

COARSE DISPERSION

COLLOIDAL DISPERSIONS
Lyophillic

Emulsion

Suspensions

Semisolid preparations gels, jellies, suppositories &


ointments

Solvent loving

dispersed phase consists generally or large organic molecules


lying within a colloidal range

Molecules of the dispersed phase are solvated they are


associated with the molecule comprising the dispersion
medium

Instability of Coarse Dispersion


Emulsions

Creaming upward movement of internal phase

Spontaneously disperse to form colloidal dispersion

Sedimentation downward movement of internal phase

thermodynamically stable

Flocculation reversible aggregation of droplets

Coalescence/Cracking/Breaking complete fusion of


droplets (irreversible)
Inversion change in the type of emulsion (W/O O/W or
O/W W/O)

Association

Ampiphillic

dispersed phase consists of micelles or small organic


molecules or ions whose size individually is below the
colloidal range

Suspension

Hydrophillic or lipophillic portion is solvated depending on


whether the dispersion medium is aq. or non aq.

colloidal aggregates are formed spontaneously when the


concentration of the ampiphile exceeds critical micelle
concentration

Lyophobic

solvent hating

dispersed phase consists of materials that have little


attraction for the dispersion medium

material does not spontaneously form a dispersion

Properties of Colloids
Kinetic Properties

Brownian Movement particles appear as tiny points of light


in constant motion

Diffusion movement of particles from high to low


concentration until equilibrium is achieved

Optical Property

Tyndall Effect ability to scatter or disperse light

Faraday Effect

Electrokinetic Effect

Caking compaction of suspended particles at the bottom of


the container

Gels, Jellies, Suppositories & Ointments

Syneresis shirking of gel structure caused by loss of liquid

Bleeding liberation of liquid from the base

Swelling/Imbibition absorption of liquid into the structure

Swelling increase in volume

Imbibition no increase in volume

RHEOLOGY

study of the flow of liquids

viscosity is the expression of the resistance of a fluid to flow

F = shearing stress (dyne/cm2) amount of force per unit area


required to cause a liquid to flow
G = rate of shear (rev/min) velocity of the system that leads to
the deformation of the liquid
=

Viscosity
Units of Measurement

Electrophoresis movement of a charged particle through a


liquid

Absolute viscosity centipoise/poise

Kinematic viscosity centistoke/stoke

Electroosmosis movement of a liquid through plug or


membrane across which a potential is applied

Relative viscosity unitless

Sedimentation creation of a potential when particles


undergo sedimentation

Lorenzo Dominick Cid 2015

Measurement of Viscosity

Dilatant Flow

Capillary Tube Viscometers


o measure the time required for a given volume of
liquid to flow through a capillary
o
o
o

Time = Viscosity
Ex. Ostwald & Ubbelohde viscometers
Follows Poiseulles Law :

!
8

r = radius of capillary
t = time to flow
P = pressure in dyne/cm2
l = length of capillary
v = volume of liquid flowing

Rotational Viscometers
o makes use of a bob or spindle w/c is immersed in the
in the liquid whose viscosity is to be determined
o Rotating Bob Brookfeil, Rotovisco, Stormer
o Rotating Cup MacMichael

Factors Affecting Viscosity

Temperature
o

T = viscosity in liquids ; in gases

Shear Rate

Time

Concentration of Solution

Newtonian Systems

direct relationship between shearing stress & rate

constant viscosity with increasing rate

eg. water, ethanol, acetone, glycerine, benzene

Non-Newtonian Systems
Plastic Flow

bingham bodies

curve does not pass through the origin but rather intersects
the shearing stress axis at a particular point (yield value)

shear thickening systems

reverse effects of pseudoplastic flow

viscosity increases with increases shear rate

Ex. starch in H2O, conc. suspension of inorganic pigments in


H2O, Zinc Oxide, Barium sulfate or Titanium oxide in H2O

Thixotropy

decrease in viscosity with time when flow is applied to a


sample previously at rest and the recovery of viscosity in time
when flow is continued

Ex. aq. bentonite magma

Rheopexy

refers to the phenomenon that the gel formation of a system


may be facilitated by tapping or low shear compared to
keeping the sample at rest

time dependent increase in viscosity during flow

Ex. Bovine synovial fluid, serum albumin due to protein,


Sodium hyalorunate

Antithixotropy

time dependent increase in viscosity during flow caused by


reversible aggregation of particles

reversed hysteresis loop

Ex. magnesia magma

GASES

have kinetic energy that produces rapid motion

held together by weak intermolecular forces

capable of filling all available spaces

easily compressible

Gas Laws
Gas Law

Equation

Constant
Variable

Boyles Law

! ! = ! !

Temperature

Gay-Lussacs Law

Volume

a yeild value must be overcome before the system begins to


flow

! !
=
! !

Charles Law

Pressure

Ex. Flocculated suspension, gels, ointments, pastes,


surfactants, polymeric substances

! !
=
! !

Combined Gas Law

! ! ! !
=
!
!

Ideal Gas Equation

Pseudoplastic Flow

shear thinning systems

curve begins at the origin

no yeild value

viscosity decreaes w/ increasing shear rate

Ex. Polymer solution, Na alginate, Perityl cellulose, PEG

Avogadros Principle

equal volume of gases at constant temperature & pressure


contain the same number of molecules

N 6.02 x 1023 molecules/mole

Lorenzo Dominick Cid 2015

o
o
o

Ideal Gas Law

no molecular interactions

elastic collisions

no exchange of energy

Photodegredation
PV = nRT

n = number of mole/s (n = g/MW)


R = molar gas constant
0.08205 L.atm/mole.K
1.987 cal/mole.K

Van der Waals Equation


(P +

!
)( ) =
!

a = force of attraction between molecules


b = size of molecules

sensitivity of drug to UV light

prevention light resistant / opaque containers

Hydrolysis & Acid-Base Catalysis

effect of pressure in solubility of a gas in liquid

in dilute solution, the partial vapor pressure of a solute is


proportional to the mole ratio of the solute to that of the
solvent in solution
2 !
=
1
!
P2 = partial vapor pressure of the has
PT = total vapor pressure
k = solubility coefficient

Grahams Law

Reaction Rates

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


from a given reaction

velocity with which the reaction occurs

Influenced by:
o Concentration
o Temperature
o Change in pH
o Presence of additives
o Presence of solvents
o Radiation
o Catalytic Agents or Enzymes

Order of Reactions
Zero Order

concentration independent kinetics

elimination of a reactant will be linear with time

Ex. suspension

speed of diffusion of 2 different gases is inversely


proportionality to the square root of their densities

Raoults Law

degredation of esters, amindes, lactams to carboxylic acid

CHEMICAL KINETICS

Henrys Law

Chemical Properties and Composition


Microbiological Sterility
Therapeutic Activity

vapor pressure lowering due to effects of electrolytes or


solutes in solution
the partial vapor pressure of the solvent of an ideal solution is
equal to the product of the mole fraction of the solvent and its
vapor pressure in pure state
= ! + !
PA = Vapor pressure x mole fraction of component A
PB = Vapor pressure x mole fraction of component B
MF of A + MF of B = 1

DRUG PRODUCT STABILITY

extent to which a preparation retains the same properties that


it had at the time of formulation

It is concerned with :
o Physical Properties

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 decresing at a rate proportional to the


square of the amount of drug remaining

uncommon

Order
Integrated
Rate Law

Half Life

Unit of K

Zero Order

First Order

Second Order

!/! =

!/! =

0.683

1
1
=
+
[]

!/! =

!! !!

Lorenzo Dominick Cid 2015

Lorenzo Dominick Cid 2015