theory of suspension

1. Theory of suspension
By
Imran pasha
1st M.Pharm
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2. Contents
• Introduction
• Characteristics of suspension
• Surface and interfacial phenomenon
• Particle interaction
• Electrical properties of interface
• DLVO theory
• Wetting
• Adsorption
• Instabilities and stability concept
• Formulation additives 2

3. What is a suspension?
• A pharmaceutical suspension is a coarse
dispersion in which insoluble solid
particles are dispersed in a liquid medium.
• The particles have a diameter for most
part greater than 0.1µm.
• A suspension is a system that generally
consists of two phases of matter, although
number of components can be higher.
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4. Dispersed phase and dispersion
media
• Dispersed refers to the suspended particle
and dispersion media refers to the vehicle
or liquid in which the particles are
suspended.
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5. Characteristics of suspensions.
• Suspension should have optimum physical, chemical, and
pharmacological properties.
• Other concerns are;
a. Particle size distribution.
b. Specific surface area
c. Inhibition of crystal growth.
d. Changes in polymeric form
e. Sedimentation rate.
f. Flocculation
g. Solid liquid interface
a. Wetting
b. Contact angle
c. adsorption 5

6. Particle shape and distribution
analysis.
• Particles can exist in various shapes and geometry. The
most common shapes are spheres, cylinders, rods,
needles, and various crystalline shapes.
• Shape can be the factor in understanding the packaging
of sediment and settling characteristics.
• The size as well as their shape can influence on the
prospects for reversible change.
• Attraction between two dispersed particles will be
affected by the surface characteristics of the particles.
• Particles have the ability to exert attractive forces across
large surface will most likely result in greater attraction
and adhesion.
6

7. Contd……
• The particle shape of the suspended particles
(suspensoids) may have an impact on the packing of
sediment (e.g., packing density and settling
characteristics), and thus product’s resuspendability and
stability.
• Packing density is defined as the weight to volume ratio
of the sediment at equilibrium.
• A wide particle size distribution often results in a high-
density suspension, whereas widely differing particle
shapes (e.g., plates, needles, filaments, and prisms)
often produce low density slurries. Symmetrical barrel-
shaped particles of calcium carbonate were found to
produce stable suspensions without caking upon
storage, while asymmetric needle-shaped particles
formed a tenacious sediment cake, which could not be
easily redispersed
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8. Particle size
• Suspension having particle size greater than
1µm diameter are coarse suspension whereas
suspensions having particle size less than 1µm
are colloidal suspension.
• Determination of particle size
– Optical microscopy
– Sieving
– Sedimentation rate method
– Light energy diffraction.
– Laser holography
– Cascade impaction
– Coulter counter method.
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9. Contd…..
• Certain types of dosage forms require specific size
ranges; for example, suspension aerosols delivering
drugs into the respiratory tract should contain particles in
the order of 0.5 to 5 mm and no particles larger than 10
mm.
• The particle size data can be presented by graphical and
digital methods. When the number or weight of particles
lying within a certain size range is plotted against the
size range or mean particle size, a bar graph (histogram)
or a frequency distribution curve is obtained
• Alternatively, the cumulative percentage over or under a
particular size can be plotted against the particle size.
This results in a typical sigmoidal curve called
cumulative frequency plot. From these data, the mean
particle size, standard deviation, and the extent of
polydispersity may be determined.
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10. Settling of suspension
• One aspect of physical stability is concerned with keeping
the particles uniformly distributed throughout the
suspensions.
• where:
• g is the gravitational field strength (m/s2)
• R is the radius of the spherical particle (m)
• ρp is the mass density of the particles (kg/m3)
• ρm is the mass density of the fluid (kg/m3)
• μ is the dynamic viscosity (kg/m*s).
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11. Methods to determine settling
• Andreason pipette method
• Photo sedimentation-transmittance of light
is measured
• Cahn sedimentation method
• Centrifugal method- for particle size less
than 5micrometer
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12. • In a typical particle size analysis 3 factors
require calculation
1. Sedimentation time
2. Centrifugation time
3. Cumulative percent finer
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13. Surface and interfacial
phenomenon
• One of the most obvious properties of a disperse system
is the vast interfacial area that exists between the
dispersed phase and the dispersion medium .
• When considering the surface and interfacial properties
of the dispersed particles, two factors must be taken into
account: the first relates to an increase in the surface
free energy as the particle size is reduced and the
specific surface increased;
• the second deals with the presence of an electrical
charge on the particle surface.
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14. The interface
• An interface is defined as a boundary
between two phases. The solid-liquid and
the liquid-liquid interfaces are of primary
interest in suspensions and emulsions,
respectively.
• A large surface area of the dispersed
particles is associated with a high surface
free energy that renders the system
thermodynamically unstable.
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15. • The surface free energy, ΔG, can be
calculated from the total surface area, ΔA,
as follows:
• ΔG =γsl ΔA or ΔG= γLL ΔA
• where γsl and γLL are the interfacial
tensions between the solid particles and
the liquid medium and the liquid and liquid
mediums, respectively.
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16. • Very small dispersed particles are highly
energetic. To approach a stable state, they
tend to regroup themselves to reduce the
surface free energy of the system. An
equilibrium will be reached when ΔG =0.
This condition may be accomplished either
by a reduction of the interfacial tension or
by a decrease of the total surface area.
16

17. PARTICLE INTERACTION
• The interactions between similar particles,
dissimilar particles, and the dispersion medium
constitute a complex but essential part of
dispersion technology. Such interparticle
interactions include both attractive and repulsive
forces.
• These forces depend upon the nature, size, and
orientation of the species as well as on the
distance of separation between and among the
particles of the dispersed phase and the
dispersion medium, respectively.
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18. Contd……
• As the particles approach one another,
both attractive and repulsive forces are
operative. If the attractive forces prevail,
agglomerates result, indicating an
instability in the system.
• If repulsive forces dominate, a
homogeneously dispersed or stable
dispersion remains.
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19. Potential energy graph
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20. Types of forces existing betweem
the particles
• Various types of attractive interactions are
operating:
I. dipole-dipole or Keesom orientation forces,
II. dipole-induced dipole or Debye induction
forces,
III. induced dipole-induced dipole or London
dispersion forces,
IV. electrostatic forces between charged particles.
V.Vander waal’s forces of attraction.
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21. Contd ……..
• . The strongest forces are the electrostatic interactions
between charged particles. These forces, either
attractive or repulsive, are effective over a relatively long
range and dependent on the ionic charge and size of the
particle.
• Even though vander waals forces are relatively weak,
the van der Waals forces coupled with hydrogen bond
interactions are significant factors describing the
behavior of most nonionic compounds in liquids and
other dispersion media. These various types of attractive
interparticulate forces can lead to the instabilities of
disperse systems
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22. Electrical properties of the
interfaces
• Most insoluble materials, either solids or liquids, develop
a surface charge when dispersed within an aqueous
medium. These surface charges of particles may arise
from several mechanisms.
• For example, the ionization of functional groups present
at the surface of the particle, such as carboxylic acid or
amine groups, can be involved.
• Furthermore, surface charges can be developed due to
the adsorption or desorption of protons.
• A variety of colloidal systems (e.g., polymers, metal
oxides) fall into this group. For example, the surface
hydroxyl groups of aluminum hydroxide gel
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23. CONTD…….
• Surface charges can also be introduced by ionic
surfactants. For example, oil globules in an o/w emulsion
exhibit a surface charge if anionic or cationic surface-
active agents are used.
• The surfactant molecules are oriented at the oil-water
interface so that the charged hydrophilic groups are
directed toward the water phase. Ion deficiencies in the
crystal lattice or interior of the particles may also cause
surface charges.
• When a charged particle is dispersed within a dispersion
medium containing dissolved cations and anions, the
surface charges of the particle interact with the dissolved
ions in solution.
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24. DLVO THEORY
• Derjaguin, Landau, Verwey, and Overbeek developed a
theory giving insight into the energy of interaction
between suspended particles. This theory is thus often
referred to as the DLVO theory.
• It relates the stability of a disperse system to the
electrolyte content in the continuous phase and provides
an insight into the factors responsible for controlling the
rate at which particles in disperse systems come into
contact or aggregate.
• The process of aggregation subsequently accelerates
particle sedimentation and affects redispersibility of the
disperse systems
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25. Schematic form of the curve of total potential energy
(Vtotal) against distance of surface separation (H) for
interaction between two particles, with Vtotal= VA + VR.
25

26. CONTD…
• According to the DLVO theory, disperse systems
become unstable whenever their kinetic energy is
sufficient to overcome the primary maximum. Thus, the
instability of disperse systems increases when
decreasing the height of this energy barrier and when
increasing the kinetic energy of the particles.
• The reduction of the primary maximum can result from
the addition of substances, which
• (i) neutralize the surface particle charge or cause the
loss of the hydration layer;
• (ii) compress the electric double layer; and/or
• (iii) cause adsorbed species (e.g., surfactants) to desorb
from the particle surface.
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27. CONTD….
• . The primary factor determining the thickness of the
electric double layer is the potential energy drop-off. The
potential gradient strongly depends on the concentration
and charge of any electrolyte present in the dispersion
medium. In water at room temperature, the thickness of
the electric double layer ranges from 1 to 1000 A˚ ,
depending on the concentration of ions in the bulk
phase. Increasing electrolyte concentrations lead to
compressed double layers (decreasing double layer
thicknesses). Thus, the particles can approach each
other more closely, and the attractive forces become
more important. The concentration of foreign electrolytes
required to cause flocculation decreases as the valence
of the coagulating ion increases. For example, less Al3+
ions are required to flocculate a suspension than Na+
ions. 27

28. WETTING
• The wetting process is a primary concern particularly in
the preparation of a liquid disperse system in which the
internal phase is a solid (suspension).
• A solid material to be suspended must first be separated
into single particles, and the particles must be
individually wetted by the dispersion medium to achieve
a homogeneous distribution of the internal phase.
• Upon wetting, the air at the solid surface is replaced by
the liquid medium. Obviously, the tendency of a solid to
be wetted by a liquid is primarily determined by the
interaction between the three phases.
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29. CONTD…
• Experimentally, the degree of wetting of a powder can be
evaluated by observing the contact angle, θ, which is
defined by the boundaries of the solid surface and the
tangent to the curvature of the liquid drop.
• The contact angle results from an equilibrium involving
three interfacial tensions: those acting at the interfaces
liquid-gas, solid-liquid, and solid-gas. A contact angle of
00 indicates an extensive interaction between the solid
and the liquid phase.
• Thus, the solid is completely wetted by the liquid. Partial
wetting occurs when the contact angles are between 00
and 90 0.In contrast, contact angles greater than 900 are
classified as nonwetting situations in which the liquid
cannot spread over the solid surface spontaneously. If
the angle is close to 1800, the solid substance is called
“unwettable” by the liquid.
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30. CONTD….
• Hydrophilic substances are readily wetted by water or
other polar liquids because of the good interfacial
interaction resulting in small contact angles (Fig. 2).
Once dispersed, they may significantly increase the
viscosity of the liquid system. On the other hand,
hydrophobic substances repel water but can easily be
wetted by nonpolar liquids. They usually do not alter the
viscosity of aqueous systems. In pharmaceutical dosage
forms, aqueous vehicles or hydroalcoholic mixtures are
often used. Thus, proper wetting of hydrophobic drugs is
a necessary first step when preparing suspensions.
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31. • Hydrophobic materials are often extremely difficult to
disperse owing to poor wetting or presence of entrained
air pockets, minute quantities of grease, and other
contaminants. The powder may just float on the surface
of the liquid, despite its higher density. Fine powders are
particularly susceptible to this effect, and they may fail to
become wetted even when mechanically forced below
the surface of the suspending medium.
• To overcome this problem, to improve the wetting
characteristics of hydrophobic drug powders, often
anionic or nonionic surfactants are used. These
substances decrease the solid-liquid interfacial tension,
thus facilitating the wetting process. The mechanism of
surfactant action involves the preferential adsorption of
the hydrophobic part of the surfactant onto the
hydrophobic surface of the particle. The polar part of the
surfactant is directed toward the aqueous medium. 31

32. Adsorption
• Adsorption is the tendency of atoms, molecules, ions,
etc. to locate at a particular surface/ interface in a
concentration that is different from the concentrations in
the surrounding bulk media.
• Adsorption at the interface tends to increase with
increasing thermodynamic activity of the surfactant in
solution, until a complete monolayer is formed at the
interface, or until the active sites are saturated with
surfactant molecules.
• The adsorption of surfactants alters the properties at the
interface and promotes wetting of the dispersed phase in
suspensions. The reduction of the interfacial tension can
effectively decrease the resulting surface free energy
and hence the tendency for coalescence or aggregation.
Thus, the formation and stabilization of the disperse
systems can be significantly facilitated.
32

33. • The adsorption of ionic surfactants generally
increases the charge density on the surface of
the dispersed particles, thus improving the
stability of the dispersion.
• Protective colloids or polymeric materials can be
adsorbed onto the surface of the dispersed
phase. Polymer adsorption can be accomplished
simply by adding a solution of adsorbable
polymeric species into a slurry of the dispersed
particles
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34. INSTABILITIES AND
STABILITY CONCEPTS a
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35. • The content uniformity and long-term stability of
a pharmaceutical product are required for a
consistent and accurate dosing.
• Aggregation of dispersed particles and resulting
instabilities such as flocculation, sedimentation
(in suspensions), or creaming and coalescence
(in emulsions) often represent major challenges
in formulating pharmaceutical disperse systems.
35

36. • An instability of a dispersion may result from the
tendency of the system to reduce its surface free energy,
ΔG.
• “Flocculation” is generally understood as a process in
which particles are allowed to come together and form
loosely bound clusters, having an open type of structure.
• Deflocculation is the opposite, that is, breakdown of
clusters into individual particles.
• Although disperse systems are thermodynamically
unstable, certain systems can remain “stable” over a
prolonged period of time. Thermodynamically driven
changes to a lower energy state may be reversible or
irreversible.
36

37. • A disperse system remains stable as long as the
repulsive forces are sufficiently strong to
outweigh the van der Waals and/or other
attractive forces. These repulsive forces are
generally acquired through one or more of the
following mechanisms: (i) electrostatic Disperse
Systems repulsion, which arises from the
presence of an ionic charge on the surface of
the dispersed particles and (ii) steric repulsion,
which arises from the presence of uncharged
molecules on the surface of the particles.
37

38. Stabilization by Electrostatic
Repulsion
• The electrostatic repulsive forces can
prevent the dispersed particles having
surface charges of the same sign from
approaching each other, thus stabilizing
the dispersion against interparticle
attraction or coagulation.
38

39. • In suspensions, the addition of ions that are adsorbed
onto the surface of the dispersed particles generally
creates strong repulsion forces between suspended
particles and stabilizes the system.
• In contrast, the addition of water-miscible solvents (e.g.,
alcohols, glycerin, or propylene glycol) to aqueous
dispersions can lower the dielectric constant of the
medium.
• This results in a reduction of the thickness of the electric
double layer and the magnitude of the potential energy
barrier. Thus, the addition of these solvents tends to
cause instability or makes the system more sensitive to
coagulation 39

40. Stabilization by Steric
Repulsion
• When a strongly hydrated hydrophilic polymer is
adsorbed onto the surface of a hydrophobic solid particle
surrounded by an aqueous medium, the affinity of the
polymer for water can exceed the attractive forces
between the suspended particles. For example, a
hydrophilic polymer such as gelatin can increase the
strength of the protective hydration layer formed around
the dispersed particles. Water-soluble polymers, whose
adsorption stabilizes dispersions and protects them
against coagulation, are also called “protective colloids.”
• Adsorption of nonionic polymers (e.g., gums or water-
soluble cellulosic derivatives) or surfactants (e.g.,
polysorbate 80) of sufficient chain length can create
steric hindrance between adjacent particles 40

41. Formulation additives
• Surfactatnts
– Quaternary ammonium cpds, lecithin,
cetylmethylammonium bromide,etc..
• Protective colloids and viscosity imparting agents
– Gums, thickeners, and polymers.
• pH controlling agents
– Sodium chloride, disodium edetate
• Preservatives
– Benzalkonium chloride parabens
• Antioxidants
– Tocopherols,alkyl gallates, butylated hydroxy toulene
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42. Thank you
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