Polymorphism

Powder Flow
Surface Properties

Presented By:-
Shayana Gora
M.Pharm
Quality Assurance
1st Semester
 What is Polymorphism?
C h e m ic a l C o m p o u n d ICH Definition
on Polymorphism

H a b it In t e r n a l S t r u c t u r e
Disordered
Ordered C r y s t a llin e A m o rp h o u s arrangement
arrangement

S in g le E n t it y M o le c u la r A d d u c t s
P o ly m o r p h s

N o n s t o ic h io m e t r ic S t o ic h io m e t r ic
In c lu s io n C o m p o u n d s S o lv a t e s ( H y d r a t e s )

Channel Layer Cage

( C la t h r a t e )
 POLYMORPHISM
 Many drug substance can exist in more than
one crystalline form with different space lattice
arrangements.
 Classified into two form-

1. Enantiotropic e.g. Sulfur

2. Monotropic e.g. glyceryl stearate
 Polymorphic solids have different unit cells.
 In general, the stable polymorph exhibits the
highest melting point , the lowest solubility, and
the maximum chemical stability.
 Itis important to identify the polymorph that is stable at room
temperature.

 To determine whether the polymorpic transition are possible

within the temp. range used for stability studies & during
processing(drying,milling).

 The particular polymorph formed by a drug depends on the

 conditions of crystallisation; for example, the solvent used,
 the rate of crystallisation and the temperature.
 Pharm. Properties Exhibited
by Different Polymorphs

 Melting Point
 Hygroscopicity
 Chemical and Physical Stability
 Apparent Solubility and Dissolution
 Bioavailability and Bioequivalence
 Manufacturability
 When some compounds crystallise they may
entrap solvent in the crystal. Crystals that
contain solvent of crystallisation are called
crystal solvates, or crystal hydrates when
water is the solvent of crystallisation.
 Crystals that contain no water of
crystallisation are termed anhydrates.
 There are two main types of crystal solvate:
1. Polymorphic solvates
2. Pseudopolymorphic solvates
 The particular solvate formed by a drug depends on the
conditions of crystallisation, particularly the solvent used.
 The solvated forms of a drug have different physicochemical
properties to the anhydrous form:
 The melting point of the anhydrous crystal is usually higher
than that of the hydrate.
 Anhydrous crystals usually have higher aqueous solubilities
than hydrates.
 The rates of dissolution of various solvated forms of a drug
differ but are generally higher than that of the anhydrous form.
 There may be measurable differences in bioavailabilities of the
solvates of a particular drug; for example, the monoethanol
solvate of prednisolone tertiary butyl acetate has an absorption
rate in vivo which is nearly five times greater than that of the
anhydrous form of this drug.
• Clathrates or inclusion compounds:- A chemical
substance consisting of a lattice of one type of
crystal structure trapping and containing a
second type of molecule. Therefore, a clathrate
is a material which is a weak composite, in
which molecules of suitable size are captured in
spaces in the crystal lattice.
• Molecules of one substance are completely
enclosed within the crystal structure of another.
 Formulation problems
• Polymorphs with certain crystal habits may be
difficult to inject in suspension form or to
formulate as tablets.
• Transformation between polymorphic forms
during storage can cause changes in crystal
size in suspensions and their eventual caking.
• Crystal growth in creams as a result of phase
transformation can cause the cream to become
gritty.
• Changes in polymorphic forms of vehicles such
as theobroma oil, used to make suppositories,
could cause products with different and
unacceptable melting characteristics

Analytical issues
• Difficulties in identification arise when samples
that are thought to be the same substance give
different infrared spectra in the solid state
because they exist in different polymorphic
forms
.
• Change in polymorphic form can be caused by
grinding with potassium bromide when samples
are being prepared for infrared analysis.

• Changes in crystal form can also be induced by

solvent extraction methods used for isolation of
drugs from formulations prior to examination by
infrared spectroscopy – these can be avoided
by converting both samples and reference
material into the same form by recrystallisation
from the same solvent.
 Bioavailability differences
• The difference in the bioavailability of different
polymorphic forms of a drug is usually
insignificant but is a problem in the case of the
chloramphenicol palmitate, one (form A) of the
three polymorphic forms of which is poorly
absorbed.
• High M.P. Strong lattice hard to
remove a molecule Low Dissolution rate

• Amorphous > metastable > crystalline

order of dissolution rate

• Since the metastable forms have higher

aqueous stability, they show better
bioavailability therefore they are preffered in
formulation
 Techniques for studies of
crystals

 Microscopy
 Hot Stage Microscopy
 Thermal analysis
 X-ray diffraction
 MICROSCOPY
 Materials with more than one refractive index
are anisotropic and appear bright with brilliant
colours against black polarised background.

 The color intensity depends upon crystal

thickness.

 Isotropic material have single refractive index

and this substance do not transmit light with
crossed polarising filter and appears black.
Advantage
By this method, we can study crystal
morphology and difference between
polymorphic form.

Disadvantage
This require a well trained optical
crystallographer,as there are many possible
crystal habit and their appearance at different
orientation.
 Hot Stage Microscopy

 The polishing microscope fitted with hot stage

is useful for investigating polymorphism,
melting point and transition temperature.

Disadvantage
 In this technique, the organic molecule can
degrade during the melting process and
recrystallization of the melt may not occur.
 THERMAL ANALYSIS
 Differential Scanning Calorimetry (DSC) and
Differential Thermal Analysis (DTA) are
particularly useful in the investigation of
polymorphism.
 It measures the heat loss/gain resulting from
physical/chemical changes within a sample as
a function of temperature.
 For characterising crysatl forms, the heat of
fusion can be obtained from the area under
DSC for melting endotherms.
 Similarly, heat of transition from one polymorph
to another may be calculated.
 A sharp symmetric melting endotherm can
indicate relative purity of molecule.
 A broad asymmetric indicates presence of
impurities.

Disadvantage

Degradation during thermal analysis may

provide misleading results.
 X – RAY diffraction
 Working:- When beam of non homogenous X-
ray is allowed to pass through the crystal, X-ray
beam is diffracted and it is recorded by means
of photographic plate.
 Diffraction is due to crystal which acts as 3D
diffraction grating toward X-ray.
 Random orientation of crystal lattice in the
powder causes the X-ray to scatter in a
reproducible pattern of peak intensities.
 Mixtures of different crystalline forms can be
analyzed using normalized intensities at
specific angles, which are unique for each
crysatlline form.

 An amorphous form doesnot produce a pattern.

 Single- crystal X-ray provide the most complete

information about the solid dtate.
Powder Flow
 When we are concerned with the flow of any material it relates with
Rheology.

 Powders are classified into

1. Free flowing
2. NON free flowing(cohesive powder)

 If not of proper density then are densified by SLUGGING

 Fundamental properties:- properties that relates to the individual

particle .
 Derived properties:- They are dependant on fundamental properties
& well defines the basic factors relating to measurements.
 Good flow properties are a prerequisite for the successful
manufacture of both tablets and powder-filled hard gelatin
capsules.

 It is a property of all powders to resist the differential movement

between particles when subjected to external stresses.

 This resistance is due to the cohesive forces between particles.

 Three principal types of interparticle forces have been

identified:-

 forces due to electrostatic charging

 vander Waals forces

 forces due to moisture

• Powders with particles below 50 µm will
generally exhibit irregular or no flow due
to vander Waals forces.

• Particle shape is also important; for

example, the force between a sphere and
plane surface is about twice that between
two equal sized spheres.
 POROSITY (Є) or VOIDS:- It is the space between the particle.

 It is the ratio of void volume to the bulk volume of the packing.

Є = (Vb-Vp)/Vb

= 1- (Vp/Vb)

% porosity = Є ˣ 100

Where ,
Vp = true volume

Vb = bulk volume

V = void volume
 Theoretical porosity of powder consist of
uniform sphere in
 Closest packing- 26%
 Loosest packing- 48%
 Real powder have porosity in between 30 to
50%.
 In suspension, porosity may be above the
theoretical max limit 48%.
 Crystalline materials porosity- <1% (under force
10000 lb/in2)
 Three types of densities
 DENSITY - Universally defined as weight per unit volume.

 1. True density:- it is the weight of material itself

 2.Granule density:-
Granule density = granule weight
granule volume

 Measured by mercury displacement method.

 Mercury fills the voids, but fails to penetrate internal particles

as it has non weighting properties.

 Granule volume related to weight of the mercury that displaced

by granules in pycnometer.
 Bulk density:-

 Bulk density = mass of the powder (w)

bulk volume (Vb)

 When particle are loosely packed ,there are lots of

gaps in between particles, bulk volume increases
making powder light.
 Powder classified as ‘light’or ‘heavy’
 “Light powder have high bulk volume”
 ‘Bulk density apparatus’ is used to determine bulk
volume.
34
• Minimum bulk density is when the volume of
the powder is at a maximum, caused by
aeration, just prior to complete
breakup of the bulk.

• Poured bulk density is when the volume is

measured after pouring powder into a cylinder,
creating a relatively loose
structure.

• Tapped bulk density is, in theory, the

maximum bulk density that can be achieved
without deformation of the particles.
Changes in Bulk Density:

 Ratios of the poured to tapped bulk

densities are expressed in two ways to
give indices of flowability.

 1.Hausner Ratio
 2.Carr’s compressibility index
• Hausner Ratio = tapped density
bulk density

• The Hausner Ratio varies from about 1.2 for a free-

flowing powder to 1.6 for cohesive powder

• less than 1.25 (equivalent to 20% carr′s) indicates

good flow.

• Greater than 1.5(equivalent to 33% carr′s)indicates

poor flow.

• Between 1.25 & 1.5- added glidant – improves flow

 Angle of Repose
• Maximum angle possible between the surface
of a pile of powder and the horizontal plane.
• It is a function of the surface roughness.
• The angle of repose is determined by allowing
a mass of powder to flow freely through an
orifice from a height and form a conical heap on
the horizontal surface.
• As the heap is formed, the particles slip and roll
over each other until the mutual friction
between the partcles just balance the
gravitational force.
By definition,
tan ɵ = h/r
ɵ = tan-1(h/r)

where, h = height of pile

r =radius of base of the pile
Ɵ =angle of repose
Flow Angle of repose Carr’s
Relationship between flow, angle of index
(%)
repose, Carr’s index .
Excellent <25 5-15
Good 25-30 12-16
Fair to 30-40 18-21
passable
Poor > 40 23-35
Very Poor 33-38

Extremely Poor >40

 Effect on angle of repose of various
procedure

 decrease particle size- higher angle of repose

Fines (up to 15%)-increase angle of repose

Lubricants at low concentration- ↓ angle of repose

Rough & irregular surface- higher angle of repose

Lower the angle of repose- better the flow property

 Higher the moisture content greater the cohesion &
adhesion.

 Flow properties can be improved by following

methods-

1. Altering the particle size

2. Removal or Addition of Fines ( upto 15% )
3. Altering the particle shape and texture
4. Altering the surface forces
5. Removing extra moisture
6. Adding flow activators or Glidants
Surface Properties
• When two phases are in contact with each other, the
boundary between them is referred to as interface.
• If one of the two phases is a gas or vapor, the term
surface is generally used instead of interface.
• Molecules at the surface do not have their attraction
forces properly balanced. They experience an inward
force of attraction towards the bulk of the liquid. The
surface of a liquid therefore gets contracted and
molecules at the interface are pulled together. The
force which has to be applied to counterbalance
exactly this inward pull is known as the surface
tension.
• Interfacial tension is the force acting between two
immiscible liquid phases.
 ADHESIONAL FORCES COHESIONAL FORCES

1. Forces which act 1. Forces which act

between molecules of between molecules of
different phases. the same phase.

2. Tend to increase the 2. Tend to keep the

affinity of two phases. phases separate.
 Measurement of Surface and
Interfacial Tension

I. Capillary Rise Method

II. Drop Weight and Drop Count Methods

III. Wilhelmy Plate Method

IV. Ring Detachment Method ( Du Nouy

Tensiometer)
• If small quantity of an immiscible liquid is placed on
the surface of another liquid, it will either spread as a
film on the surface of the other liquid or remain as a
drop or lens.

• Which of the two applies generally depends on the

achievement of a state of minimum free energy.

• The ability of one liquid to spread over another can be

assessed in terms of spreading coefficient whose
value should either be positive or zero for spreading to
occur.
• The spreading coefficient is the difference between
the
 work of adhesion and the work of cohesion.
(Wa-Wc).
• This implies that if work of adhesion is more
than the work of cohesion, spreading will occur.

• where γgw is the sublayer liquid surface

tension, γgo is the spreading liquid surface
tension and γow is the interfacial tension
between the two layers
• Surfactants are compounds that lower the surface
tension of a liquid, allowing easier spreading, and
lowering of the interfacial tension between two
liquids, or between a liquid and a solid.

• Classification
a) Anionic surfactants:- alkali soaps, amine soaps
b) Cationic surfactants:- quaternary ammonium
compounds such as cetrimide, benzalkonium
chloride
c) Ampholytic surfactants:- lecithin
d) Nonionic surfactants:- glycerl monostearate, macrogol
esters, tween,span
 HLB SYSTEM
1. Surfactant possess both hydrophilic and lipophilic
portions, so there must be some scale to measure the
balance between these two opposing tendencies.

2. Griffin (1949) developed an arbitrary scale to serve

as a measure of hydrophilic-lipophilic balance (HLB) of
surface active agents.

3. This HLB scale is numerical scale extending from 1

to 20.

4. The more hydrophilic surfactants have a high HLB

number > 10, while surfactants with an HLB < 10 are
considered to be lipophilic.

5. The HLB value helps in the selection of a proper

surfactant for a particular application.
6. The HLB of a number of polyhydric alcohols and
fatty acid esters such as glyceryl monostearate, can
be calculated by using the formula:
HLB = 20(1 - S/A)
saponification number for many substances like bees-
wax and wool-fat derivatives where S is the
saponification number of the ester and A is the acid
number of the fatty acid.
7. . But the saponification number for many
substances like bees-wax and wool-fat derivatives
cannot be easily estimated.
8. In such cases, the following relation is used, 
HLB = (E + P)/5
where E is the percent by weight of oxythelene chains
and P is the percent by weight of polyhydric alcohol
groups in the molecules.
9. Obviously, when the molecule consist only of
oxyethylene groups, equation becomes
HLB = E/5 10.

10.Davies calculated the HLB values for surface active

agents by splitting the various surfactant molecules
into their component groups, to each of which is
assigned a group number. 
11. The summation of the respective group number
permits the calculation of the HLB value according to
the equation

HLB = ∑ (hydrophilic group numbers) - (lipophilic

group numbers) + 7

HLB values and their applications

• A value from 0 to 3 indicates an anti-foaming agent
• A value from 4 to 6 indicates a W/O emulsifier
• A value from 7 to 9 indicates a wetting agent
• A value from 8 to 18 indicates an O/W emulsifier
• A value from 13 to 15 is typical of detergents
• A value of 10 to 18 indicates a solubiliser
or hydrotrope
• Wetting is the ability of a liquid to maintain
contact with a solid surface, resulting from
intermolecular interactions when the two are
brought together.

• The degree of wetting (wettability) is

determined by a force balance between
adhesive and cohesive forces.  

• Wetting and the surface forces that control

wetting are also responsible for other related
effects, including so-called capillary effects.
 DETERGENCY

 Ability of a detergent to lift soil (dirt and grease)

from a surface by displacing it with chemicals
(called surfactants) which adhere more readily
to the surface being cleaned than to the soil.

 Detergent functions in the cleaning process

• Removal of the soil from the substrate
• Prevention of its redeposition
 Electrical Properties of
Interfaces

Electrical Double Layer

 A double layer (DL, also called an electrical
double layer, EDL) is a structure that appears
on the surface of an object when it is placed
into a liquid.
 The object might be a solid particle, a gas
bubble, a liquid droplet, or a porous body.
 The DL refers to two parallel layers of charge
surrounding the object.
 The first layer, the surface charge (either
positive or negative), comprises
ions adsorbed directly onto the object due to a
host of chemical interactions.

 The second layer is composed of ions attracted

to the surface charge via the coulomb force,
electrically screening the first layer.

 This second layer is loosely associated with the

object, because is made of free ions which
move in the fluid under the influence of electric
attraction  and thermal motion rather than
 being firmly anchored. It is thus called the diffuse
layer.

NERNST and ZETA potential

 The difference in electric potential between the actual
surface of the particle and the electroneutral region is
referred to as Nernst potential.
 Thus, Nernst potential is controlled by the electrical
potential at the surface of the particle due to the
potential determining ions.
 the potential difference between the ions in the tightly
bound layer and the electroneutral region, referred to
as zeta potential.
Zeta potential governs the degree of repulsion
between adjacent, similar charged, solid
dispersed particles.
 If the zeta potential is reduced below a critical
value (which depends on the particular system
being used) the force of attraction between
particles supersede the force of repulsion, and
the particles come together.
 This phenomenon is referred to as flocculation
and the loosely packed particles are called
floccule.
 References
Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems,Loyd
V.Allen,Jr.,Nicholas G. Popovich,8th edition

Fast Track Physical Pharmacy, David Attwood, Alexander T. Florence, RPS

Publishing

Martin’s Physical Pharmacy and Pharmaceutical Sciences, Alfred N.

Martin,Lippincott Williams and Wilkins

A Textbook of Biopharmaceutics and Pharmacokinetics, Dr.Javed Ali, Dr. R.K.

Khar, Dr. Alka Ahuja, Birla Publications PVT. Limited

Pharmaceutical preformulation- The physiochemical properties of drug substance,

James I. Wells