Transcript pharmaceutical suspensions

Pharmaceutical Suspensions

Suspensions are heterogeneous systems consisting of
two phases.
 The continuous or the external phase is generally a
liquid or semisolid.
 The dispersed or the internal phase is made up of
particulate matter that is essentially insoluble in, but
dispersed throughout the continuous phase.

The insoluble matter may be intended for physiologic
absorption or for internal or external coating functions.

The dispersed phase may be composed of discrete
particles or it may be a network of particles resulting from
particle-particle interaction.
The system is thermodynamically unstable esp. for
hydrophobic drugs.

Classification

Based On rout of administration
Oral suspension (Antibiotics and antacids).
Externally applied suspension (Calamine lotion).
Parenteral suspension (Procaine penicillin G, Protamine Zinc-Insulin
suspension).

Based On Proportion Of Solid Particles
Dilute suspension (2 to10%w/v solid).
Concentrated suspension (50%w/v solid).

Based On Electrokinetic Nature Of Solid Particles
Flocculated suspension.
Deflocculated suspension.

Based On Size Of Solid Particles
Colloidal suspension (< 1 micron) (examples: aluminium hydroxide and
magnesium hydroxide suspensions).
Coarse suspension (>1 micron) A solid in liquid dispersion in which the
particles are above colloidal size is termed a coarse suspension.
Nano suspension (10 nm).
Applications

Drug in suspension exhibits higher rate of bioavailability than other dosage
forms. bioavailability is in following order:
Solution > Suspension > Capsule > Compressed tablet > Coated tablet.
Suspension have better bioavailability than solid dosage forms because of
the absence of the disintegration limiting step.

If the drug is insoluble or poorly soluble in a suitable solvent, such as water
(Hydrocortisone Acetate and Neomycin eye drops).

Some active ingredients are required to be present in the GI tract in a finely
divided form to provide a desired high surface area for adsorption of toxins
or to neutralize excess acidity (Kaolin, magnesium carbonate, magnesium
trisilicate).

Suspension can mask the unpleasant/ bitter taste of drug. E.g.
Chloramphenicol palmitate, particularly if the drug particles are coated E.g. :
cefuroxime (Zinnat ).

X-ray contrast agent are also formulated as suspension administered either
orally or rectally..
E.g. Barium sulphate for examination of alimentary tract. Due to the
relatively high atomic number (Z = 56) of barium, its compounds absorb Xrays more strongly than compounds derived from lighter nuclei.
Applications

Suspensions can improve chemical stability of certain drugs.
Drug highly degradable in the presence of water are easily and
rapidly degraded if formulated as solution because the drug is at the
molecular level, therefore the insoluble derivative can be formulated
as a suspension (insoluble calcium salt of oxytetracycline HCL in an
aqueous vehicle ).
Further improvement of drug stability can be achieved by dry or
reconstituted suspensions: dry powders to which a vehicle is added
at the time of dispensing, therefore the prolonged contact between
the solid drug particles and the dispersion medium can be
minimized thus enhancing stability (Amoxicillin trihydrate salt).
Furthermore, A drug that degrades in the presence of water may be
suspended in a non-aqueous vehicle (Phenoxymethylpenicillin,
Tetracycline HCL suspended in fractionated coconut oil for
ophthalmic use).
Applications

Duration and onset of action can be controlled.
E.g.Protamine Zinc-Insulin suspension and Isophane insulin.
Insulin when given IM solution shows rapid absorption and rapid
elimination from the body. When converted into insoluble form
and given as suspension it shows slow dissolution and
absorption and thus its action is prolonged with less frequency
of administration. Insluin forms insoluble complex with
protamine and zinc or with isophane. By varying the size of
dispersed particles the duration of activity can be controlled.
To prolong activity even further, the drug may be suspended in
fixed oils such as arachis or sesame oil.
Applications

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
Vaccines, for induction of immunity are often formulated as
dispersions of killed micro-organisms or toxoids adsorbed on to a
substrate of aluminium hydroxide or phosphate. Thus achieving a
prolonged antigenic stimulus resulting in a high antibody titre.
Patients having difficulty in swallowing solid dosage forms.
The adsorptive properties of fine powders are used in the
formulation of some inhalations. Volatile components such as
menthol and eucalyptus oil are adsorbed onto light magnesium
carbonate to have a more prolonged release.
Aerosol systems where the drug is suspended in a mixture of
propellants.
Suspensions of drugs can also be formulated for topical
application (Calamine Lotion BP).
Suspensions of semisolid consistency, where the drug is
suspended in a paraffin base (paste) or an emulsion base (Zinc
Cream BP).
Physical stability
• Almost all suspension systems separate on standing, and
the formulator’s main concern is not to eliminate
separation but rather to:
– Decrease the rate of settling.
– Permit easy resuspendability of any settled particulate matter.
• A satisfactory suspension must remain sufficiently
homogeneous for at least the period of time necessary to
remove and administer the required dose after shaking its
container.
Physical Stability
Flocculation: In which particles are
held to each other by weak forces,
in the form of loose agregate (flocs).

These are characterized by
a fibrous, fluffy, open
network of aggregated
particles.

The aggregates tend to
settle quickly to form a high
sediment height.

The sediments are easily
redispersible because the
particles constituting
individual aggregates are
sufficiently far apart from one
another to preclude caking.
Flocculated suspensions
The suspension shall form loose
networks of flocks that settle
rapidly, do not form cakes and
are easy to resuspend.
This form is inducted and desirable in the so
called flocculated suspensions because
particles can be easily redispersed by slight
shaking and thus it is pharmaceutically
acceptable.
Physical stability
Coagule (closed aggregate):
A coagule is a system of tightly
packed solid particles with very
small interparticulate distances,
thus resulting in strong
interparticulate attraction and
consequently cannot be
redispersed by slight
shaking. Accordingly, dosing
uniformity will not be achieved upon
using the same bottle as a result
of this aggregation. This form
could happen in the so
called deflocculated suspensions
and should be totally prevented.
In deflocculated suspensions:
Individual particles could
settles slowly with high
packing, which result in
formation of cakes that is
difficult or even impossible to
resuspend.
Because they are not reversible by
shaking, coagulation and caking
are not pharmaceutically
acceptable.
Physical Stability
Sedimentation:
Where,
Velocity of sedimentation vsed. = sedimentation
is expressed by Stoke’s
velocity in cm / sec.
equation:
d = diameter of particle
r = radius of particle.
ρs= density of dispersed
phase.
ρo= density of dispersing
media.
g = gravitational force.
ηo= viscosity of disperse
medium in poise.
Brownian movement (motion)
Brownian Movement: random movement in all
directions and is exhibited by small sized
particles.
Gravity
Brownian movement counteracts
sedimentation and sedimentation
equilibrium is achieved when gravity
is neutralized by Brownian movement
meaning no sedimentation.
2-5 m
Thermodynamic stability
Surface Energy (G): quantifies the
disruption of intermolecular bonds that
occur when a surface is created. The
surface energy may therefore be
defined as the excess energy at the
surface of a material compared to the
bulk.
= Surface Area (A)  Interfacial tension
()
Surface Energy (G)
Size reduction
Low surface area and
low G
High surface area and
high G
Thermodynamic stability

A system is in thermodynamic stability when surface
energy is zero. This would be achieved in suspensions
when the interfacial tension between the dispersed
particles is zero. However, because the interfacial
tension in suspensions is positive, free energy is
positive and thus suspensions are thermodynamically
unstable.

Drug solutions are thermodynamically stable because
of zero interfacial tension and thus the drug dissolves
because of this zero interfacial tension.
Factors affecting
thermodynamic stability
Particle size of the
dispersed phase
Interfacial tension
Thermodynamic
stability
Suspensions of
hydrophobic drugs
are less
thermodynamically
stable than of
hydrophilic drugs.
Coarse suspensions >
colloidal suspensions >
Nano-suspensions.
Thermodynamic stability

Any system tends to reduce the surface
free energy by reducing the surface area.
Which is achieved in suspensions by
agglomeration and particularly
coagulation. Thus when the suspension
settles to form a sediment, the system
becomes more thermodynamically stable
despite it becoming more pharmaceutically
unstable.
Thermodynamic stability
Thermodynamic
stability
Pharmaceutical
stability
Crystal growth

In a suspension, there is equilibrium between
molecules going into solution (dissolution) and
molecules going out of solution (crystallization). This is
particularly true if the drug at the set conditions is
slightly soluble (not practically insoluble). dissolution
tends to be faster from small particles because of their
high surface area than from large particles. On the
other hand crystallization tends to be more on the
coarse particles than on the small ones. This is
illustrated in the next slide. With time the small
particles get smaller (dissolution from them is higher
than crystallization on them), and they may ultimately
disappear; contrary to this, the large particles become
coarser. Thus, there will be a shift in particle size
distribution to a larger mean size with narrower
distribution.
For small particles
Crystallization
Dissolution
For coarse particles
Crystallization
Dissolution
Crystal growth is accelerated by the following:
1.
Wide size distribution.
2. Temperature fluctuations: the temperature fluctuations during storage is of
importance especially when suspensions are subjected to temperature
cyclings
of 20oC or more. This effect depend on:

The magnitude of temperature change.

The time interval (rate of heating and cooling).

The effect of temperature on the drug’s solubility and subsequent recrystallization.
3. Solid state: A change in the crystalline structure of the dispersed solid or a
change in the crystal habit may be the reason for crystal growth.

Amorphous to crystalline form.

Metastable to a more stable form.

Anhydrous to a hydrated form.
In addition amorphous and unstable polymorphs because of their higher
water solubility, they encourage crystal growth more than a stable
polymorph.
4.
Sedimentation enhances the potential for crystal growth by increasing the
particle concentration and decreasing the mean free diffusion path of the
solute molecules.
Prevention of crystal growth
Set the suspension conditions for minimal drug solubility. E.g.
Choose acidic pH for weakly acidic drug and alkaline pH for weakly
basic drugs for minimal drug ionization and solubility. The higher the
solubility, the higher the dissolution that is in equilibrium with high
crystallization rate.
 Try to narrow the size distribution as much as possible. Usually,
before dispersing the drug in a dispersing medium, the raw material
is size reduced. During size reduction use an equipment with
classifier. Suspension homogenization after preparation is also
helpful.
 Choose more stable polymorph than an amorphous or less stable
polymorph. This is for two reasons:
A. Solubility.
B. Polymorphic transformation.
 Avoidance of the use of high energy milling during particle size
reduction.
o Avoidance of temperature extremes during storage.

Prevention of crystal growth
When ingredient (s) are chosen for certain purpose. However,
such ingredients they can solubilize the drug. The
concentration of such ingredients should be limited to fit the
purpose. Excess concentration of such ingredients can
solubilize the drug and encourage crystal growth
E.g. 1. Wetting agents are added to prevent lump formation during
suspension production for hydrophobic drugs.
E.g. 2. Humectants in topical suspensions (Polyols).
o
Many pharmaceutical gums can get adsorbed on the surface
of the particles in the suspension and can be used to inhibit
crystal growth.
o
Incorporation of protective colloids (cellulose derivatives)
which form film barriers around the particles.
o
Increase the viscosity of the vehicle to retard particle
dissolution and subsequent crystal growth.

Electrical properties of solid-liquid interfaces
(Electrokinetics)

Particles dispersed in liquid media may become charged by
either of the following ways:

Selective adsorption of a particular ionic species present in
solution. This ion may be a part of an electrolyte (Na, K,
phosphate, Ca etc) that is added into solution or, in the case of
pure water, the hydronium or the hydroxyl ions produced by the
ionization of water.
Most particles in water acquire a negative charge due to the
preferential adsorption of hydroxyl ions.

Ionization of groups that are situated on the surface of the particle
(-COOH, -NH2, etc.) depending on the pKa of the group and the
pH of the medium.
Electrokinetics

If we considered a solid surface a-a' (figure next slide ) in contact
with an aqueous solution of an electrolyte and that some of the
cations (15 +ve) are adsorbed onto the surface giving it a positive
charge. These ions are referred to as primary ions or potential
determining ions. They give the surface charge of the solid
particles.

The rest of the solution will have the rest of the cations plus the total
number of anions added.

Near the positively charged surface, the anions are attracted to the
positive charge on the surface by electric forces while the cations
are being repelled at the same time. This is an attempt to achieve
electroneutrality. These ions in this layer are called counter ions, as
they have an opposite charge to the potential determining ions.
They are adsorbed into a liquid layer adjacent to the solid surface
a-a', which is called Stern layer (from a-a' to b-b' in the figure ) this
layer is tightly bound to the solid surface.
Electrokinetics
Assuming that anions with total
7 -ve have been adsorbed and
are present in the stern layer, did
the system achieve
electroneutrality at b-b'?
Answer is No, as at b-b', 8 +ve is
the net charge.
Electrokinetics
To achieve further electroneutrality, another liquid layer will
be formed and extend from b-b' to c-c'. This layer is called
diffuse layer and with the stern layer, both are called
electrical double layer. Unlike the stern layer this layer is
loose and not tightly bound to the stern layer. Ion
adsorption into the diffuse layer is governed by the
following:
A.
B.
Achieving electroneutrality: because electroneutrality was
not achieved at b-b', further anions (-ve) will be adsorbed
into the diffuse layer to achieve so.
Screen effect: the counter ions in the stern layer will act as
screen that would reduce the electrostatic attraction
between the charged solid surface and counter ions away
from the surface. Instead, the counetr ions in the stern
layer will bring into the diffuse layer positively charged
ions.
A and B will lead to mixed adsorption (+ve and -ve ions) into
the diffuse layer.
Electrokinetics
In the previous figure 12 -ve ions and 4 +ve ions were adsorbed
into the diffuse layer. Was electroneutrality achieve at c-c'. The
answer is Yes, as the 12 -ve neutralize the excess +8 at b-b' and
the 4 +ve in the diffuse layer. Thus the excess negative
adsorption into the diffuse layer brought electroneutrality at c-c'
It can be concluded from the previous case that when a suspended
particle acquires a charge, the system will neutralize this charge and
electroneutrality will be achieved at certain point from the solid
surface, that happened to be at c-c' in the previous example.
Beyond c-c' until reaching the bulk there will be even distribution of
negatives and positives with electroneutrality.
Electrokinetics

Despite the whole system in the previous example was
electroneutral, there are regions with excess charge (from a-a' to
c-c') with respect to the electroneutral regions. With excess charge
in these regions potentials exist at any point within these regions.
However, as we go from the solid surface potential decrease until
it becomes zero at c-c'.

The potential drops rapidly initially, followed by gradual decrease
as distance from the solid surface increases, this is because of the
screen effect.
Electrokinetics

The potential at the solid surface aa\ is called the
electrothermodynamic (Nernst) potential E.

E is defined as the difference in potential between the
actual surface and the electroneutral region of the
system.

The potential at the shear plane bb\ is called the
electrokinetic or zeta (ζ) potential.

ζ is defined as the difference in potential between the
shear surface of the solid and the electroneutral region of
the system.


Suppose that potentials in the
previous example can be calculated
based on the difference in the number
of ions, what are the values of Nernst
and Zeta? Answer: Nernst = +15 and
zeta = +8. In addition the potential at
c-c' is zero because of the
electroneutrality. A plot for potential
versus distance a way from the solid
particles for the previous example is
given in the slide.
Zeta potential is positive because counter ions
adsorbed onto the stern layer were insufficient to
neutralize the solid surface.
Effect of electrolyte

As the concentration of an electrolyte is increased in a
colloidal system, the screening effect of the
counterions is also increased and the potential falls off
rapidly with distance because the thickness of the
double layer shrinks.

When the valency of the counter ion is increased,
while the total concentration of the electrolyte is held
constant, the potential drop is fast and the double
electrical layer thickness decreases.

Both factors reduce the zeta potential.
Zero zeta potential

Suppose in the previous case the electrolyte concentration was
increased resulting in ion adsorption of 15 -ve into the stern layer. In
this case potential drops rapidly to zero at b-b' as zeta potential.
Nernst potential will remain the same, because the solid surface
charge was the same. The potential versus distance plot would be
as the following:
Excess counter ions adsorption

Suppose in the previous case the electrolyte concentration was
increased resulting in ion adsorption of 25 -ve into the stern layer. In
this case potential drops rapidly to zero before reaching b-b' and
then will further drop as a result of excess -ve adsorption beyond,
resulting in negative zeta potential. However, the system will
neutralize this excess negative charge at b-b' to achieve neutrality at
certain point away from b-b'. Again Nernst potential will remain the
same. The potential versus distance plot would be as the following:
When solid surface is negatively charged
nd
Significance of zeta potential

Because the tightly bound layer moves with the solid surface
(shear plane is not the solid surface), the net charge of the solid
surface and this layer (not the solid surface charge) is what
govern particle-particle repulsion as two particles approach each
others. Accordingly, Zeta potential has practical application in the
stabilization of systems containing solid particles, since this
potential, rather than the Nernst potential, governs the degree of
repulsion between dispersed particles. If the Zeta potential is high
(highly positive or negative), particles will experience high
electrical repulsion that would exceed the attractive forces, and
thus the dispersed particles will remain as monodispersed with no
flocculation. On the other hand, if it is low, repulsion would be
minimum, which would allow for attractive forces to slightly
exceed the repulsive forces. This will result in rapid flocculation
after shaking.
Flocculated and deflocculated
suspensions

When the absolute value of zeta potential is high (more than 25 mv
or less than -25 mv), repulsive forces highly exceed attractive
forces, thus deflocculated suspension is obtained. When zeta
potential is low and around zero (between –25 mv to 25 mv),
attractive forces slightly exceed repulsive forces an thus flocculated
suspension is obtained.
Real case on how controlled flocculation
can be achieved

Bismuth subnitrate particles acquire a positive charge in water at 0%
phosphate, and thus high positive zeta potential (around =90 mV)
was found for the suspension (see figure next slide). This
suspension is deflocculated with slow sedimentation and caking for
the formed sediment. When phosphate counter ions are added as
potassium phosphate into this suspension at increasing
concentrations zeta potential drops slowly with the increase in
counter ion concentration until reaching values between +25 mV
and -25mV (region B).

Within this region the low zeta potential values result in rapid
flocculation and large sediment volume with no caking. Thus region
B is the non caking zone. When zeta potential values are higher
than +25 mV (region A), the region is called caking zone. When
excessive concentration of phosphate are added zeta potential
drops below -25mV (region C) resulting in another caking zone.
A
B
C
Case study

A drug when formulated as
suspension in water acquired
a -ve charge on its solid
surface as a result of
carboxylate ionization. If the
zeta potential for this
suspension was -85 mv. If
NaCl was added as a source
for counterions at increasing
concentrations. The series of
suspensions with different
NaCl concentrations
prepared were measured for
zeta potential and the results
are shown in the right table.
Answer questions in the next
slide.
NaCl (mM)
Zeta potential
(mV)
0
-85
0.001
-67
0.01
-45
0.1
-13
0.2
+5
0.3
+35
0.4
+45
0.5
+69

What are the counter ions adsorbed into the tightly bound layer ?
Answer: Na+

What is the plot for zeta potential versus NaCl concentration?

What is the plot of potential versus distance a way from the solid
surface for suspension representing the beginning of region A of the
previous plot?
What is the plot of potential versus distance a way from the solid
surface for suspension representing the middle of region B of the
previous plot?
bound
What is the plot of potential versus distance a way from the solid surface
for suspension representing the far point of region C of the previous
plot?
If the experiment was repeated by using CaCl2 or AlCl3 as
sources for counterions. Compare the plots of zeta potential
versus electrolyte concentration with that of NaCl with
explanations.
Since Ca is divalent and Al is trivalent, while Na is monovalent,
as valency of counter ion is increased, potential falls more rapidly
and zero zeta potential values are achieved at lower electrolyte
concentration when valency is higher.
Deflocculated suspension

As a result of high zeta potential and high repulsion that highly
exceed attractive forces (such as Van der waals forces), particles
remain as separate entities (monodispersed). Particle show slow
sedimentation that is dependent on each individual particle size.
Coarse particles sediment first because of their large diameter.

As they reach the bottom they have voids among them. The voids
are filled with subsequently sedimented finer particles. The
sediment is formed slowly with short distance among the
sedimented particles (high-close packing). Close arrangement of
the sedimented particles and packing gives small sediment
volume relative to the volume of the whole suspension.

The supernatant is often cloudy due to presence of ultra fine
particle that remain suspended in the supernatant for long time
because of their very small diameter and brwonian movement.
Deflocculated suspension

Because of the small sediment volume and large-cloudy
supernatant with no distinct boundary between the
supernatant and the sediment, patient may not visually
detect sedimentation and in this case the appearance of
suspension is falsely appealing to him.

The coagulation of the particles in the small sediment likely
would result in cake formation. Cake formation is further
increased as the distance between particles would further
shorten due to the fact that particles lowest the sediment will
be pressed by the weight of the ones above. Caking can be
further worsen by dissolution and crystallization, both lead to
crystal bridging. In crystal bridging, particle surface crystal
growth occurs on two or more particles simultaneously and
results in the steady formation of crystal-linked particles.

This leads to the ultimate formation of a highly linked
sediment similar to concrete. Caking is not pharmaceutically
acceptable, because it is not reversible by shaking.
Flocculated suspension

Because of low zeta potential, attractive forces slightly exceed
repulsive force which induce rapid flocculation after shaking. The
formed floccules will engage all particle sizes (coarse and fine) and
thus sedimentation will depend on floccule size rather than
individual particle size.

Because floccule size is much larger than individual particle size
sedimentation is rapid. The rapid formation of loose floccule with
long interparticulate distance and the rapid sedimentation that will
not allow for close packing, both will lead to the formation of a
voluminous, spongy-highly porous sediment.
Flocculated suspension

The sediment will encompass most of the total suspension
volume. Because ultra fine particle will sediment as
floccules, the supernatant will be clear, however small,
distinct boundary would be present between the
supernatant and the sediment, which is not appealing to
the patient.

However, caking will not happen in the loose-voluminous
sediment which can be easily redispersed by shaking.
Thus sediment formation in flocculated suspension is
considered pharmaceutically acceptable, even with the
supernatant being clear.
Which suspension type is preferred
by formulators?

With controlled flocculation, the ultimate result for flocculated
suspension is rapid flocculation and fast sedimentation with an
easy reconstitution of the formed sediment.

When flocculation is prevented in deflocculated suspensions, any
sedimentation likely will lead to caking which is not acceptable.
Thus sedimentation has to be totally prevented in such
suspensions, which may be achieved by the following:
1. Reducing the particle size as much as possible.
2. Making the density of the suspended particle close to that of
the suspending medium. Density of most organic drug lies
between 1.1 and 1.5 g/ml, while the most widely used dispersing
medium, water, has a density of 1.0 g/ml. One way, though it is
not very practical, is to include vehicles which have higher density
than water, such as sorbitol solution (d = 1.29), Syrup (d = 1.31),
and high fructose syrup (d = 1.4). These ingredients also have
high viscosity, which would further retard drug sedimentation.



3. Increasing the viscosity of the dispersing phase.
Using suspending agent, of which the molecular structure entraps
the drug particles and severely retards their sedimentation, is known
as structured vehicle. This is particularly useful when the
suspending agent forms a thixotropic system meaning it forms gel
upon standing, while becomes thin by shaking (becomes fluid
enough) for pouring or injection.
The previous measures to prevent sedimentation in deflocculated
suspension may fail on shelf as a result of changes in the dosage
form such as crystal growth, precipitation of the suspending agent
with loss of viscosity due temperature or pH changes. For this
reason, deflocculated suspensions have been found not workable
by many investigators and flocculated suspension are preferred by
many formulators.
Ingredients used in pharmaceutical
suspensions

Drug:
A. Particle size:
•
Usually the drug raw material is subjected to particle
size reduction before suspension production. The most
efficient equipment for size reduction is fluid-energy
mill. It can achieve size as low as 10 micrometer.
•
When we need a size in the colloidal or nano region,
no size reduction equipment can achieve this small
size. To produce a colloidal or nanosuspension, a
process is performed which is called controlled
crystallization.
Ingredients used in pharmaceutical
suspensions
•
In controlled crystallization the drug is made as solution by
a reaction with strong base or strong acid. If the drug is
neither weak acid or weak base a drug solution can be
made in an anhydrous solvent.
•
The drug solution is dropped into a crystallization medium
containing a stabilizer (Surfactant, such as Tween 80 or
polymer, such as polyvinyl alcohol (PVA)) with stirring or
homogenization. The stabilizer makes a protective layer
around the formed layer to stabilize their size and prevent
aggregation.
•
By optimizing the crystallization conditions, which are rate
of addition, stirring rate of the crystallization medium,
stabilizer type, and stabilizer concentration, a controlled
crystal size can be achieved.
B. Wettabiltty:
 For a suspension to exist, there must be some degree of
compatibility between the external and internal phases.
 One aspect of that is the capacity of the external (continuous) phase
to wet the particulate matter of the internal (disperse) phase.
 When a strong affinity exists between a liquid and a solid, the liquid
easily forms a film over the surface of the solid.

When this affinity does not exist or is weak, the liquid has difficulty
displacing the air or other substances surrounding the solid.

As a result an angle of contact exists between the liquid and the
solid.

The contact angle θ is specific for any given system and results from
an equilibrium involving three interfacial tensions acting at interfaces
between liquid and vapor, solid and liquid, and solid and vapor
phases. These tensions are caused by unbalanced intermolecular
forces in the various phases.

As the drug is more hydrophobic the higher the contact
angle between its solid particles and the aqueous
dispersing medium because of the high interfacial
tension, and thus during suspension preparation the
drug will refuse to be dispersed as single particles and
will form large lumps. Accordingly for hydrophobic
drugs, the addition of wetting agents is usually a must.

On the other hand, hydrophilic drugs with low contact
angle and interfacial tension with the aqueous
dispersing medium are easily to be wetted and do not
require the addition of wetting agent.

List of hydrophilic and hydrophobic drugs are
listed in the following table. Notice in the table
that Talc is hydrophilic, but this does not mean it
is water soluble.
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Also notice that all the hydrophobic drugs are
organic, while all the hydrophilic drugs are clays,
such as antacids. The later substance usually
swell to high extent without being solubilized,
and thus they increase the viscosity of aqueous
suspensions. Contrary to this, organic
hydrophobic drugs do not.
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Wetting agents
•
Wetting agents lower interfacial tension and contact angle and
consequently there will be easier replacement of air among particles
with liquid, and easier spreading of liquid on the surface of individual
particles. Thus air is escaped from voids among drug particles and
the wetted drug would sink as individual wetted particle or wetted
mass for further wetting.
•
Wetting agents are usually Surfactants: The mechanism of action of
surfactants involve the preferential adsorption of the hydrocarbon
chain by the hydrophobic surface, with the polar moiety of the
surfactant being directed towards the aqueous phase.
•
The most widely used wetting agents. Anionic (SLS) or nonionic
surfactants (Tweens and pluronics) are used. Best surfactants are
with an HLB of 7-10. Most surfactants except pluronics have bitter
taste, nevertheless polysorbate 80 (Tween 80) is the most widely
used despite its bitter taste. The usual concentration of wetting
agents is from 0.05-0.5%. Higher concentrations my solubilze the
drug, which may enhance crystallization growth, and enhance
foaming.

The dispersion of hydrophobic solids is also improved by:
 Hydrophilic polymers such sodium
carboxymethylcellulose.
 Water insoluble hydrophilic materials (bentonite,
aluminum-magnesium silicate or colloidal silica either
alone or in combination).

These materials also exert viscosity-building effects
depending on the specific type and concentration used.
At higher concentrations an undesirable gelling may be
observed in the case of liquid suspensions in comparison
to the desired degree of viscosity or thixotropy.


Suspending agents (viscosity imparting agents or
thickening agents):
They are used in deflocculated suspension to prevent
sedimentation by increasing viscosity as much as
possible. Increasing viscosity beyond certain limit
may result in non-pourable liquid suspension or
difficult spreading and rubbing of a topical
suspension. In flocculated suspension they are used
at low concentration to maximize the sedimentation
volume ad thus minimize the clear supernatant. High
viscosity hinders the re-dispersibility of the
sediments.
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Suspending agents are classified as the following:
A. Natural: E.g. Acacia, tragacanth, alginic acid, carrageenan, locust
bean gum, guar gum, gelatin.
•
•
B. Cellulose derivatives (Semisynthetic):
Water soluble: Methylcellulose, HPMC and Hydroxypropyl
cellulose (which are non ionic), Sodium carboxymethyl cellulose
(anionic). They give high viscosity in water that is dependent on
concentration and molecular weight.
Water insoluble: Ethylcellulose (nonionic), its dispersion in water
is of low viscosity. Soluble in common organic solvents (e.g.
ethanol and glycerin) and thus used mainly in non-aqueous
suspensions.
C. Synthetic:
• Crabopol (Carbomer): polyacrylic acid (Polyanion).
Offered as fluffy, white, dry powders (100% effective). The
carboxyl groups provided by the acrylic acid backbone of
the polymer are responsible for many of the product
benefits. It forms a dispersion in water with low viscosity as
a result of low carboxylate ionization. When strong base,
such as triethanolamine or isopropanol amine is added to
this dispersion with stirring the polymer ionizes and dissolve
to give a clear gel. Crabopol is insoluble at pH <4.0 because
of low ionization.
•
•
Polyvinylpyrrolidone (PVP):
Non-ionic, soluble in water and some organic solvents
such as ethanol.
Polyvinyl alcohol (PVA):
Non ionic, water soluble, slightly soluble in ethanol.

Flocculating agents:
A. Electrolytes: the most widely used flocculating agents: valence
ions having an opposite charge to that of the suspended particles.
Proper use of electrolyte (conc. and type) can reduce Zeta
potential to around zero; thus shifting the interparticulate repulsion
toward attractive Van der Waal forces. Flocculation efficiency
increases with the increase in the valency of the ion. Trivalent
ions are more effective than divalent, and divalent are more
effective than monovalent (why?). For example Aluminum chloride
is more effective than Calcium chloride, which is more effective
than sodium chloride in reducing the Zeta potential of negatively
charged solid particles.
B. Polymers: at low concentration, hydrocolloids with high
molecular weight can bridge solid particle by adsorption at the
solid-liquid interface, and projecting into the bulk to attach to
another particle. However, at high concentration they would be
adsorbed as multimolecular film; they would act as protective
hydrocolloids against flocculation (steric hindrance against
flocculation). For example, the effect of concentration of ionic
polysaccharides on flocculation of sulfaguanidine suspension was
studied; it was observed that the sedimentation volume increased
as the polymer concentration was increased, but as concentration
was increased further, sedimentation volume was decreased.
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Humectants and Cosolvents: Glycerin, propylene glycol, low Mwt
PEGs and sorbitol.
-They prevent cap locking due to crystallization of sucrose on the
bottle nick in oral suspensions.
-Some of them act as sweetener, such as glycerin and sorbitol.
-Used as humectants in topical suspensions.
-They would also allow the incorporation of water insoluble inactive
ingredients, such as water insoluble preservatives and antioxidants
by acting as cosolvents for these ingredients.
-Excess concentration, however, should be avoided, because they
may solubilize the drug, and thus encourage crystal growth.
Sweeteners: Glycerin, sorbitol, sucrose and high fructose syrup.
They also increase viscosity of the suspension and thus act as
suspending agents. They also reduce the density difference
between the suspended particle and the vehicle.

Preservatives:
The naturally occurring suspending agents such as tragacanth,
acacia, xanthan gum are susceptible to microbial contamination. If
suspension is not preserved properly then the increase in microbial
activity may cause stability problem such as loss in suspending
activity of suspending agents, loss of color, flavor and odor, change
in elegance etc. Antimicrobial activity is potentiated at lower pH.
Preservatives are included in pharmaceutical dosage form to control
the microbial bioburden of the formulation.
Ideally, preservatives should exhibit the following properties:
* Possess a broad spectrum of antimicrobial activity encompassing
Gram-positive and Gram-negative bacteria and fungi.
* Be chemically and physically stable over the shelf-life of the
product.
* Have low toxicity.
* Should not be adsorbed on to the container.
* Should be compatible with other formulation additives.
* Its efficacy should not be decreased by pH.
Chemical structure and some properties of parbens commonly used as
preservatives are given next slide.
Parabens

Group of alkyl esters of p-hydroxybenzoic acid with
an effective pH range of 4.0 to 7.0.

Most active against yeast, molds, and gram positive bacteria.

Antimicrobial activity decreases above pH 7 due to the formation of
the phenolate anion.

Being esters, parabens undergo hydrolysis in weak alkaline and
strongly acidic solutions.

Parabens work more effectively in combinations.
As alkyl chain length of the paraben ester group increases,
antimicrobial activity increases but water solubility decreases
and oil solubility increases.
Based on animal data they estrogenic activity that may be
associated with breast cancer is a concern. This activity of
parabens increases with length of alkyl group.
Factors affecting preservative efficacy in oral suspension
1. The pH of the formulation: The pH of the formulation. In some
aqueous formulations the use of acidic preservatives, e.g. benzoic
acid, sorbic acid, may be problematic. Active form of preservative may
be ionized or unionized form. For example active form of benzoic acid
is undissociated form. The pKa of benzoic acid is 4.2. Benzoic acid is
active below pH 4.2 where it remains in unionized form. The activity of
the unionised form of the acid in this respect is due to the ability of this
form to diffuse across the outer membrane of the microorganism and
eventually into the cytoplasm. The neutral conditions within the
cytoplasm enable the preservative to dissociate, leading to
acidification of the cytoplasm and inhibition of growth. In antacid
suspensions, because the pH is 6-7, therefore parabens, benzoates
and sorbates become less active. In antacids other measures are
usually taken such as chlorination, ozonization of water or even
pasteurization of the suspension to ensure preservation.
2. The presence of micelles:
If the preservative exhibits lipophilic properties (e.g. the unionised
form of acidic preservatives, phenolics, parabens), then partition of
these species into the micelle may occur, thereby decreasing the
available (effective) concentration of preservative in solution.
Reconstitutable suspensions (Dry suspensions)

The most common reason for formulation of suspensions for
reconstitution is inadequate chemical stability of the drug in an aqueous
vehicle. Reconstituted suspension of penicillin has a maximum shelf life
of 14 days. The manufactured dry mixture, however, has shelf life of at
least 2 years. Another reason for reconstitution is to avoid problems of
physical stability, such as pH change, crystal growth and polymorphic
transformation. Nearly all of drugs formulated in this manner are
antibiotics. Ingredients used in such suspension are identical to those
used in liquid suspension. Other ingredients, may be necessary, such
as intragranular disintegrant when the suspension is manufactured
using wet granulation. The reconstituble suspension must be easily
reconstituted and poured by the patient, for example the drug and
suspending agent should disperse by hand shaking; carbomer and
methyl cellulose are not recommended. The combination of
microcrystaline cellulose and Na CMC (Known commercially as Avicel
RC 591 for FMC) is common suspending agent. Flocculating agents are
not commonly used in suspensions for reconstitution, because these
products are redispersed frequently enough to prevent caking; they do
not stand on shelf as liquid suspensions and the patients use them for
limited period of time with shaking every time of use.


Sucrose at concentration of 60% is usually included as suspending
agents and to aid the preservation (why?).
Anticaking agents, such as silica gel is usually included; the reason is
powder agglomeration due to moisture uptake, causing poor powder
flow, and even caking before reconstitution because of partial fusing of
particles, due to the presence of soluble ingredient, such as sucrose.
Consequently, dispersaibility of suspension upon reconstitution may
become a problem.
Production of suspension for reconstitution
They can be produced by granulation or dry blending.
Granulation is costly and may present the drug for degradation by
heat, however it would present less segregation and mixing
problems. Dry blending is more economical, and eliminates the
effect of heat of drug, however, more mixing problems, such as
segregation would happen. This is particularly true when the
particle size of drug is very different from the size of excepients.
Also the flow for granulated products is better, which would
facilitate filling during production and dispersability upon
reconstitution.