GPAT ONLINE CLASSES
In collaboration with A.P govt.
Physical Pharmacy
Presented by
Dr. T.E.Gopala Krishna Murthy
Professor & Principal
Bapatla College of Pharmacy
Bapatla, Andhra Pradesh.
Topics to be covered in this session
1. Matter, properties of matter
2. Micrometrics and powder rheology
3. Surface and interfacial phenomenon
4. Viscosity and rheology
5. Complexation
6. Buffers
7. Solutions
1. Matter, properties of matter
–
–
–
–
–
–
–
–
–
–
Change in the state of matter
Latent heat and vapour pressure
Sublimation
Eutectic mixtures
Relative humidity
Liquid complexes
Liquid crystals
Glassy state
Crystalline and amorphous solids
Polymorphism
Change in the state of matter
• The enthalpy and entropy increases as the material
go from solid to liquid to gas
• Balance of enthalpy, entropy and temperature
determines the spontaneous process changes
• Latent heat in change of state. Heat of fusion and
heat of vaporization
Latent heat and vapour pressure
• Its depends on temperature not on the
amount of liquid
Sublimation
• Transformation of a solid to vapour without passage
through liquid state
• Solid sublimes only when the pressure of the vapour
is below the triple point of that substance
• Camphor,
naphthalene,
P-dichlorobenzene
iodine have triple point pressure below 1 atm.
and
Eutectic mixtures
• Thymol- salol, salol and camphor, camphor. Chloral
hydrate,
menthol-
acetaminophen.
betanaphthol
aspirin
and
Relative humidity
• Water of
hydration, crystallization, adsorption,
drying , production of effervescent products
Liquid complexes
• Creation of a solute structure with in a solvent
• Reduced rate of hydrolysis of benzocaine solution
containing caffeine
• Improved light stability of chlorpromazine
solutions containing saccharin
in
Liquid crystals
• The molecules in liquid are mobile in three directions and
rotate about three axes
• In solids, the molecules are immobile and rotations are
not possible
• Heating of lipids results intermediate liquid crystal
phases
• Biological systems lyotropic mesomorphism takes place
in presence of water
• Freedom to move, take many shapes and maintaining a
high degree of order
Liquid crystals
• Prepared by heat treatment (thermo tropic), by
adding controlled amount of water
• Molecules that form liquid crystals are
✓ Organic
✓ Elongated
✓ Rectilinear in shape
rigid
and
posses
polarisable groups
strong
dipoles
and
easily
• Nematic phase
– Parallel arrangements with restricted rotation about
at least one axis
– Might be to be thread or cable like
• Smectic phase or two dimensional crystal
– Molecular arrangement as layers
– Mobile in two directions, rotate about one axis
• Cholesteric phase
– Combination of smectic and nematic
– Thicker than smectic
Properties and significance
• Mobile and possess the property of birefringence
• Change in colour with temperature
• Nematic crystals are sensitive to electric field
• Smectic for solubilisation of hydrophobic materials
• Similar structure like cell membranes
• Gall stones and atherosclerosis
Glassy state
• Highly disordered or short range order
• Do not have specific melting points
• No decrease in volume at the crystallisation
temperature
Crystalline and amorphous solids
• Metallic, ionic, valence and molecular bonds are
involved in solids
• Arrangement in a regularly repeating pattern in
crystalline solids
• The units can be atoms, ions or molecules.
Covalent, electrostatic attractions, van der Walls
forces and hydrogen bonding are involved.
Crystalline and amorphous solids
• Cubic
(sodium
chloride),
tetragonal
(urea),
hexagonal (urea) , rhombic (iodine), monoclinic
(sucrose) and triclinic (boric acid)
• Amorphous solids are super cooled liquids with
random arrangement
• Amorphous and cubic crystals are isotropic
Polymorphism
• Exist in more than one crystalline form of chemically
identical components
• Differences in melting point, IR spectra solubility
and X-ray diffraction
• Depending on factors such as storage temperature,
recrystallization solvent, rate of cooling and rate of
recrystallization
2. Micromeritics and powder rheology
– Particle size and distribution
– Number and weight distribution
– Particle number
– Methods of determination of particle size
– Methods of determination of particle volume
– Methods of determination of particle surface area
Particle size and distribution
• Shape and surface area of individual particles and
size range & number or weight of particles present
are important in poly disperse sample
• Equivalent spherical diameter, volume diameter,
projected diameter and stokes diameter
General equation for average particle size
 nd
= 
f

nd

p+ f
d mean
1/ p



• P=1, 2, 3 corresponding to length, surface or volume
• P is positive for arithmetic and negative for harmonic
• Frequency
distribution
curve,
cumulative
percentage
frequency over size or under size
• The distribution may follow log normal distribution
• Log probability plot is employed for geometric mean and s.d
Number and weight distribution
• Number distribution from microscopy and weight
distribution from sieving and sedimentation
• Inter
conversion
by
using
the
Hatch-Choate
equation
'
log d in = log d − 5.757log  g
g
2
Particle number
• The number of particles per unit weight.
determined as follows.
6
N=
3
d cn 
It’s
Methods of determination of particle size
• Optical microscopy
– Range of 0.2 -100 µm
– Length and breadth are only possible
– Slow and tedious
– 300- 500 particles are counted
– Aggregates can be detected
• Sieving
– As fine as 44 µ
– Sieve loading, duration and intensity of agitation and attrition
of granular materials
Sedimentation
• The mean particle size is calculated with the
following equation
d st =
18o h
( s − o )gt
• Applicable to spherical shaped particles
• Free from aggregates, deflocculating agent is
required
• Flow of dispersion medium around particles is
laminar or streamline
Sedimentation
• Pipette method, balance method and hydrometer
method are available
• Specifications of Andreasen apparatus are 550
ml vessel, 10 ml pipette 2o cm below the
suspension surface and 1- 2% suspension at
constant temperature
Methods of determination of particle
volume
• Coulter counter is employed
• Capable of counting 4000 per second
• Particle growth and dissolution
• Effect
of
antibacterial
microorganisms
agent
on
growth
of
Methods of determination of particle surface
area
• Adsorption method
– Amount of a gas/liquid solute that is adsorbed on
to the sample of powder to form a monolayer
– Type II isotherm may be constructed
– Based on BET equation
(b − 1)p
p
1
=
+
V ( po − p ) Vmb Vmbpo
Methods of determination of particle surface
area
• Adsorption method
– Nitrogen gas is commonly employed and the
apparatus is quantasorb
– A plot of p/V (p-p0) against p/p0 is a straight line
with a slope and intercepts b and Vm
• Air permeability method
– The rate of penetration of a gas or liquid on to the
powder is related to resistance to the flow of a
liquid through a compact of powder
– Based on Kozeny- Carman equation
A Pt  3
V = 2.
.
2
S w KI (1 −  )
Fisher sub sieve sizer
1-1 Constant Pressure Regulator
1-2 Pressure Control
1-3 Air Filter
1-4 Air Pump
1-5 Dryer
1-6 Packed Powder Sample
1-7 Sample Tube
1-8 Range Control
1-9 Manometer
1-10 Calculator Chart
1-11 Manometer Level Control
Fisher-sub-sieve-sizer-principlepicture-1/HMK-22 Fisher Sub Sieve
Sizer
• Derived Properties of Powders
• Derived properties of powders
• Based on two fundamental properties size
distribution and surface area
– Porosity
– Packing arrangements
• The porosity of spherical uniform size particles
in closest and loosest packing is 26 and 48%
• Densities of particles
– Bulk density,
– granule density and
– true density
g
 int raparticle = 1 −

• In non porous solids, true and granule densities are
equal
• For nonporous solids, displacement of helium or
mercury, benzene or water is used
• Densities of particles
• For porous solids and for true density helium is used
• Mercury is used for granule density
• Intra particle, inter particle and total porosity
 int erspace
b
=1−
g
• Bulkiness
• Reciprocal of bulk density and influenced by
particle size and size distribution
• Flow properties
– High density, low internal porosity offers free
flowing
• Dustibility and stickiness
3. Surface and interfacial
phenomenon
• Contents:
–
–
–
–
–
–
–
–
–
–
Liquid interface
Surface and interfacial tensions
Surface free energy
Measurement of surface and interfacial tensions
Spreading coefficient
Adsorption and liquid interface
HLB classification
Surface active agents
Adsorption at solid interface
Electrical properties of films
• Liquid interface
– Cohesive forces in bulk and adhesive forces at
surface
• Surface and interfacial tensions
– The force per unit length applied parallel to the
surface/ interface
– Expressed in dyne/cm
• Surface free energy
– W=γ∆A
– Expressed in ergs
• Measurement of surface and interfacial tensions
– Capillary rise, DuNouy ring , drop weight, bubble pressure,
sessile drop, and Wilhelmy plate methods are used
– Choice of method depends on the parameter to be determined,
desired accuracy and convenience, available sample size and
the effect of time on surface tension
– Temperature control is necessary
– Capillary rise method is not suitable for surface tension
– γ=1/2 rhрg
– Force required detaching a platinum- iridium ring immersed at
the surface/ interface
• Spreading coefficient
– S=γ S –γ L-γ LS
• Adsorption and liquid interface
– Positive adsorption
– Negative adsorption
• Surface active agents
– Ions and molecules adsorbed at the interface
– Amphiphilic
• HLB classification
– 0-3 anti foaming agents, 3-8 W/O emulsifying agents, 7-9
wetting and spreading agents, 8-16 O/W emulsifying
agents, 13-16 detergents >16 solubiling agents
• Adsorption at solid interface
– Adsorption of gas on solid surface to remove
odour , gas masks
– Adsorption of liquid on solid in decolourisation,
chromatography, detergency and wetting
– Solid-gas interface
– Solid- liquid interface
• Solid-gas interface
– Physical adsorption is associated with van der Waals forces
and chemisorption's with irreversible chemical bonds
– Depends on chemical nature of the adsorbent, material used
to adsorb the gas, surface area of
the adsorbent,
temperature and partial pressure of the adsorbed gas
Freundlich isotherm
Langmuir isotherm
• Solid- liquid interface
✓Adsorption of drugs from solution
✓Wetting WS/L=γ L (1+cos ∅)
• Electrical properties of films
– Dispersed particles may have charge due to
– Selective adsorption of particular species of ions at
interface
– Ionization of groups situated at the surface of the particle
– Difference in dielectric constant between particle and
dispersion medium
– The potential at the solid surface due to potential
determining ions is called Nernst potential
– The difference in potential between the surface of the
tightly bound layer and electro neutral region of solution is
known as zeta potential.
4.
Viscosity
and
Rheology
–
–
–
–
–
–
Newtonian systems
Kinematic viscosity
Effect of temperature
Non- Newtonian systems
Thixotropy in formulations
Determination of viscosity
• Newtonian systems
– Law of flow
– Velocity gradient or rate of shear is directly proportional to
shearing stress
F'
dv
=
A
dr
– Unit in CGS system is dynes/cm2.scc-1 or gm/cm. s=poise
– In SI system, Newton/m2.s-1 or Pascal.sec=10 poise
• Kinematic viscosity
– The unit is stoke

Kinematicvis cosity =

• Effect of temperature
– Arrhenius equation
 = Ae
Ev / RT
• Non- Newtonian systems
– Flocculated suspensions exhibit plastic flow and polymer
dispersions exhibit pseudo plastic
– Viscosity of pseudo plastic systems decreases with
increasing rate of shear
– Increased volume with shear is noticed with dilatants
systems (>50% solid content)
– Pseudo plastic is shear thinning and dilatants are shear
thickening
– Time dependent and time independent non Newtonian
fluids
– Lower Newtonian or zero shear viscosity
Upper Newtonian viscosity
du
V = 0 + k
dy
 du 
 v = K  
 dy 
n'
'
K’= Flow consistency index
n’= Flow behavior index
n’<1 = For pseudo plastic
n’>1 = For dilatant systems
• Thixotropy in formulations
– Isothermal, comparatively slow recovery of a consistency
of a material lost through shearing
– Observed in plastic and pseudo plastic systems that are
shear thinning
– Measurement of thixotropy
• Determination of viscosity
– Single point and multi point instruments
– Capillary viscometer
– Based on Poiseuille's law
r 4tP
=
8lV
• Falling sphere viscometer
• Rotational viscometer
• MacMichael type, the torque is measured against
the rotating outer cup
• Storner type, cup is stationary and the bob or rotor
is driven
• Coaxial- cylinder viscometer
• Infinite gap viscometer
• Cone and plate viscometer
• Parallel plate viscometer
 = K (  B − L )
t
• Viscosity is calculated by means of Margules equation
• Applications of rheology in pharmacy
Rotational viscometer
Capillary
Falling ball
5. Complexation
5.1. Classification of complexes
✓
Metal ion complexes
✓
Organic molecular complexes (charge transfer
complexes)
✓
Inclusion or occlusion complexes
5.2. Methods of preparation
5.3. Analysis
5.4. Applications
5.1. Classification of complexes
• Metal ion complexes
– Inorganic type
– Chelates
– Olefin type
– Aromatic type pi, sigma and sandwich
– Coordination complex contains a central metal surrounded
by electron pair donor
– 4 and 6 is the commonly observed coordination number
– Uni dental and multi dental ligands
• Metal ion complexes
– Chlorophyll and hemoglobin are naturally occurring
chelates
– Platinum and silver are commonly used in metalolefin complexes
– The red solution of iodine in benzene is due to pi bond
– Sigma complex is noticed in Friedel- Crafts reaction
– Sandwich complex is observed between d orbital of
metal and molecular orbital of aromatic ring
• Organic molecular complexes (charge transfer
complexes)
– Quinhydrone type, picric acid type, caffeine and
other drug complexes and polymer type
– Electro static interactions and hydrogen bonding is
involved
– The bond distance is greater than 3A and the energy
is less than 5 kcal/mole
– Quinhydrone
concentrations
is
formed
of
by
alcoholic
mixing
eqimolar
benzoquinone
htdroquinone , salicylic acid forms complex
and
– Picric acid forms complex with weak bases
– Polymers containing nucleophilic oxygen can
form complexes
• Inclusion or occlusion complexes
– Channel, layer, clathrates, monomolecular and
macromolecular type
5.2. Methods of preparation
– Physical mixing
– Kneading
– Co precipitation
– Solvent evaporation
5.3. Analysis
– Continuous variation
– pH titration method
– Distribution method
– Solubility method
– Spectroscopy
– NMR and IR spectroscopy
– Polarography
– Circular dichroism
– DSC
– XRD
5.4. Applications
– In drug delivery
– In analysis (affinity and chiral
chromatography)
– Protein binding
– In therapeutics
6. Buffers
• Buffer equations
• Buffer capacity, buffer efficiency, buffer index, buffer value
• Buffers in pharmaceutical systems
• Preparation and stability
• Buffered isotonic solutions
• Measurement of tonicity
• Calculations and Methods of adjusting tonicity
• Buffer equations
– For weak acid and its salt

salt
pH = pKa + log
acid 
– For weak base and its salt

base
pH = pKw − pKb + log
salt
• Buffer capacity, buffer efficiency, buffer index,
buffer value
B
K a H 3O +
=
 = 2.3C
+ 2
pH
K a + H 3O
(
– Maximum buffer capacity


 max = 0.576C

)
Buffers in pharmaceutical systems
Composition
pH range
HCl and KCl
1.2-2.2
HCl and C8H5KO4
2.2- 4.0
NaOH and C8H5KO4
4.2-5.8
NaOH and KH2PO4
5.8-8.0
H3BO3, NaOH and
KCl
8.0-10
• Preparation and stability
– Selection of a weak acid
– Selection of ratio
– Selection of individual concentration 0.05-0.5 M with buffer
capacity 0.01-0.1
– Availability, sterility, stability and freedom from toxicity
• Buffered isotonic solutions
– Hypertonic solutions causes crenated and hypotonic
solutions causes hemolysis
• Measurement of tonicity
– Hemolytic method
– Colligative properties
• Calculations and Methods of adjusting tonicity
– Class I methods
• Cryoscopic method
• %w/v NaCl required=0.52-a/0.576
• Sodium chloride equivalent method
• E=17 L/M
– Class II methods
• White- Vincent method
• V=WxEx111.1
– Sprowls method
CHAPTER-7
SOLUTIONS
Contents
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Solubility
Solubility curves
Types of solutions
Effect of co-solvency, pH & other factors on
solubility
Solubility of gases in liquids
Solubility liquids in liquids
Solubility of solids in liquids
Critical solution temperature
Law of partitioning and its applications
Solute- solvent interactions
Expression of concentrations
Solubility
• Concentration of a solute in a saturated solution at a certain
temperature
– Phase rule F=C-P+2
– Rate of solution=DA/l (C1-C2)
– Particle size, stirring, solubility and viscosity of solvent affect rate of
solution
• Descriptive terms for solubility
Descriptive term
Part of solvent required per part of
solute
Very soluble
Less than 1
Freely soluble
From 1 to 10
Soluble
From 10 to 30
Sparingly soluble
From 30 to 100
Slightly soluble
From 100 to 1000
Very slightly soluble
From 1000 to 10,000
Practically insoluble
10,000 and over
Solubility curves
Types of solutions
• Solutions of solids in liquids
• Solutions of liquids in liquids
• Solutions of gases in liquids
• Solutions of solids in solids
O/W
W/O
W/O/W
Effect of co-solvency, PH & other factors on
solubility
• Co-solvent increases the solubility of un ionized
species by adjusting the polarity of the solvent
• It may decrease the dissociation of
a weak
electrolyte
• The solubility of week electrolyte is influenced by the pH
pH p = pK a + log
S − So
So
pH p = pK w − pKb + log
So
S − So
Solubility of gases in liquids
• Hcl, NH3, effervescent preparations and aerosols
• Depends on pressure ,temperature, salts and chemical
reaction
• Henrys law C2= σ р = product of solubility coefficient and
partial pressure of the gas
• Solubility decreases with temperature
• Salting out
• Henrys law not applicable in a chemical reaction
• Solubility of a gas in liquid is expressed by Henrys law
constant or Bunsen absorption coefficient α
Solubility liquids in liquids
• Divided in to complete and
partial miscibility systems
• Binary and ternary
systems
• Molecular connectivity (χ, zero, first and higher order). Sum of the
reciprocal of square root number
• Molecular surface area related properties like the total surface
area(TSA), hydrocarbon surface area(HYSA) and functional group
surface area(FGSA)
Solubility of solids in liquids
• With or without accompanying chemical reaction in the
solvent
• Effect of temperature
• Effect of salts salting in, salting out or no alteration
• Solubility of solutes containing two or more species
common ion effect
• Solubility following a chemical reaction
• In ideal solutions heat of solution is equal to heat of
fusion
Solubility of solids in liquids
• Solubility of a solid in ideal solution depends on
temperature, melting point and molar heat of fusion
• In ideal solutions, the slope of the line drawn between
log solubility (mole fraction) vs reciprocal of absolute
temperature is – ∆Hf/2,303R
• In non ideal solutions, the concentration is replaced with
activity, solubility parameter determined from heat of
vaporization, internal pressure and surface tension
• EHS Solubility approach
Critical solution temperature
Law of partitioning and its applications
K=c1/c2
• Effect of ionic dissociation and molecular
association on partition
• Extraction
• Solubility
• Preservative action
• Biological activity
Solute- solvent interactions
• Like dissolves like
• Dipole moment
• Hydrogen bond
• Difference in acidic and basic constituents
• Ratio of polar to non polar groups of the molecule
Expression of concentrations
• Volume of the solvent required to dissolve one gram of
solute (g/ml)
• Quantity of solute in grams dissolves in 100 ml
• Quantity of solute in grams dissolved in 100 gm
• Number of moles of solute in 1 liter of solvent
• 100 ml of saturated solution contains – gms of solute
• %w/w, %w/v, %v/v
• Molarity, molality and mole fraction