In the preparation of
suspensions, particle size is reduced. There is an increase in the specific
area, which cause an increase in surface free energy. These parameters are
expressed in the following relationship:
ΔF
= γΔA Where ΔF = increase in free energy
γ
= interfacial tension
ΔA
= increase in surface area.
With large F, the particles are
highly energetic and tend to regroup so as to reduce the total area. Thus
suspensions like other dispersed systems are thermodynamically unstable. The
particles tend to flocculate, i.e. form light, fluffy conglomerates, held
together by weak Van der Waal’s forces of attraction. But they may adhere
firmly to form aggregates, which grow and fuse to form a solid. The suspension
is then said to have undergone caking or forming a cake.
The smaller the ΔF the more the
thermodynamic stability. ΔF can be reduced by reducing γ (e.g. using wetting
agents or surfactants) or by reducing ΔA. γ cannot be reduced to zero, thus
particles although deflocculated, settle slowly, forming a hard cake
eventually, which is difficult to re-disperse. ΔA is reduced by deliberately
formulating loose aggregates or flocs which although settle rapidly, they do
not pack tightly at the bottom due to porous nature. They form a loose mass
that can be redistributed with minimum agitation.
Question:
A hypothetical
suspension contain 103 spherical particles of diameter d = 10-3
cm. (a)Assuming that the interfacial
tension between the solid and the liquid is γSL = 100 dyne/cm,
compute the total surface free energy, ΔF. (b) The solid particles are
divided to obtain 100 particles from
each initial particle. Compute the increase in total surface area and the total
surface free energy ΔF’ for the divided particles. (HINT: Compute the volume of
a particle to get its new radius and surface area. Assume that the density of
the particle is unity.
FORMULATION OF SUSPENSIONS:
Formulation of suspensions calls
for a compromise between:
1. Keeping
the particles in a suspension as long as possible and having a cake on
standing.
2. Deliberately
forming agglomerates which although settle rapidly are easy to re-disperse.
RECALL
i.
Forces acting between two articles in a disperse
system (resultant of attractive and repulsive forces, DLVO theory).
ii.
Particles are charged (How do particles in a
dispersed system acquire a charge? How can we ascertain that particles in a
disperse system are charged?)
iii.
Factors affecting zeta potential and their
effect on stability of dispersed systems.
iv.
What are the secondary minimum and its
importance in the formulation of suspensions?
Deflocculation:
Zeta potential is reflective of the potential at the
surface of a particle (Nernst Potential). When ξ potential is high, repulsive
forces are higher than attractive forces. Particles are deflocculated. Slowly
sedimentation occurs, forming a closely packed arrangement, smaller particles
filling the voids of larger ones. Lowermost articles are pressed together, the
energy barrier is overcome and particles touch. The particles remain attracted
to each other and form a hard cake.
Flocculation.
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Addition of a preferentially adsorbed ion, having a charge
opposite to that of the particle, neutralizes the surface potential and
progressively lowers the ξ potential, thus lowering repulsive forces. When
attractive forces still dominate, the particles approach each other more
closely forming aggregation called flocs. The system is flocculated. The
added substance is called flocculating agent. Addition of more
flocculating agent can increase the zeta potential to opposite direction
leading to deflocculation again.
Settling:
This one aspect of instability.
In order to control it let us see the factors involved:
SEDIMENTATION RATE:
1. Stoke’s law:
ν = 2r2 (δ – δ0 )g Where g = acceleration due to gravity
9 η0
ν =The velocity of
sedimentation,
r = radius of a spherical
particles
δ = density of particles
δ0 = density of medium
η0 = viscosity
To reduce the sedimentation
rate, we can reduce the particle size, r. (particles shall be deflocculated) or
increase viscosity (but should not impede flow).
Question: A coarse powder with a true density of 2.44
g/cm3 and a mean diameter d
of 100 µm was dispersed in a 2% carboxymethylcelulose dispersion having a
density ρ0 of 1.010 g/cm3. The viscosity of the medium at
low shear rate was 27 poises. Using Stoke’s law, calculate the average velocity
of sedimentation of the powder in cm/sec.
2. Brownian motion:
Particles lower than 2μ show
Brownian movement and the rate of sedimentation is lower than would be expected
from Stoke’s law and may even remain suspended for prolonged periods of time
due to this phenomenon. But this effect is eliminated when high viscosity
liquids are used e.g. glycerin.
3. Effect of flocculation
In deflocculated systems, large
particles settle faster than smaller particles. Very small particles remain
suspended longer such that no distinct boundary between the supernatant and the
sediment. In flocculated systems, flocs tend to fall together, producing a
distinct boundary between sediment and the supernatant liquid. The supernatant
is clear, showing that very fine particles have been incorporated in flocs.
Here we use the term subsidence rather than sedimentation.
SEDIMENTATION PARAMETERS
Sedimentation volume, F
F = ratio of equilibrium or
final volume of the sediment, Vu to the original volume of the
suspension, Vo.
F
= Vu F ranges from 0-1
Vo
F is only a qualitative
representation, but no meaningful reference. A more useful parameter is the
degree of flocculation. The ideal suspension has F=1. This means there is no
sedimentation or caking and the suspension is esthetically appealing.
Degree of Flocculation, β
This is more meaningful. For a
completely deflocculated suspension,
F∞
= V∞
Vo
V∞ is very small.
Degree of flocculation d relates
the sedimentation volume of the flocculated suspension, F to the sedimentation
volume of the deflocculated suspension, F∞.
β = F
F∞
That is β = Vu/
Vo = Vu
V∞/ Vo V∞
That is if β = 5, the volume of
sediment in flocculated system is 5X that in a deflocculated system. If β
= 7, it is more preferable.
FORMULATION OF SUSPENSIONS
In the formulation of a stable
suspension,
1. We
need a structured vehicle to maintain deflocculated particles in suspension.
2. Principles
of flocculation are applied to produce flocs which although settle rapidly are
easily resuspended.
Structured vehicles are plastic or pseudoplastic,
frequently associated with thixotropy. They act by entrapping the deflocculated
particles so that settling is discouraged. Though sedimentation occurs to some
degree due to shear thinning property of the vehicles, a uniform dispersion is
reformed easily on application of shear. (remember flocculated systems cake on
standing). The principle then is to
formulate flocculated particles in a structured vehicle of hydrophilic colloid
and hence principles of controlled flocculation are applied.
How is controlled flocculation achieved?
1.
The first step is to reduce the particle size. Use
mortar and pestle, agitators, homogenizer, colloid mills etc
2.
Particles must be wetted. Some particles are not
easily wettable and will not remain in vehicle long enough to ensure uniformity
of dosage. Here wetting agents are needed as well as thickening agents to
increase viscosity and delay sedimentation. Such materials are called indiffusible
solids, e.g. sulfur, charcoal magnesium stearate. Their angle of contact is approximately 90º.
They are hydrophobic. Surfactants reduce surface tension and therefore
lower angle of contact. Also glycerin and other hydroscopic materials can be
used to improve wetting properties. Some powders however are easily wetted (eg
light kaolin, Ca carbonate, Zinc Oxide, Talc). They show small or no angle of
contact and sink. They easily mix with water and on shaking diffuse evenly
through liquid. These are diffusible or dispersible substances.
3.
Controlled flocculation
Electrolytes, surfactants and polymers are used to
control flocculation to avoid caking. They are known as flocculating agents.
Electrolytes:
They lower the electrical barrier between particles
(decrease the zeta potential), and form a bridge between particles to link them
in a loosely arranged structure. For example, bismuth subnitrate (positively
charged particles) is deflocculated (due to repulsive forces between
particles). Addition of potassium acid phosphate (KH2PO4), which is negatively
charged, decreases zeta potential due to adsorption of KH2PO4 on bismuth
subnitrate. Progressively zeta potential is reduced to zero and then reverts to
negative. At a certain zeta potential maximum flocculation occurs. At this
point, there is maximum degree of flocculation. Flocculation exists until zeta
potential is sufficiently negative to cause deflocculation again and subsequent
caking.Similarly, Aluminium chloride (positively charged)
added to sulfamerazine (negatively charged) would bring about the same effect.
Surfactants:
Both ionic and non-ionic surfactants can bring about
flocculation. Since they also act as wetting agents their concentration is
crucial.
Polymers
The long chain high molecular weight compounds have
active groups along their chain. Part of the chain is adsorbed on particle
surface and the other part projects in the dispersion medium. By bridging
between the latter portions flocs are formed. Hydrophilic polymers act as
protective colloids and hence reduce the caking tendency. They also exhibit
pseudoplastic flow (eg gelatin). Sodium sulfathiazole is negatively charged in
aqueous solution. If it is precipitated from acid solution in presence of
gelatin it is positive, free flowing and does not cake. This is because gelatin
is positive and is coated on sulfathiazole. The coated particles are
flocculated and do not cake. The strong negative charge has been replaced by
small positive charge.
Flocculation in structured vehicle.
Suspending agents.
Controlled flocculation alone results in unsightly
preparations. Thus suspending agents are used to retard sedimentation of flocs
which would make the preparation unsightly. They try to make the sedimentation
volume F close to 1. For example, carboxymethyl cellulose (CMC) carbapol 934,
veegum, tragacanth, bentonite or combination. But addition of suspending agents
may lead to problems of incompatibilities. For example, if a positively charged
particles are dispersed and flocculated
by a correct negatively charged electrolyte, there is no problem when
the hydrocolloid is used to improve physical stability. This is because most
hydrocolloids are negatively charged. But if the particles were negatively
charged and cationic electrolyte is used for stabilization, addition of
hydrocolloid will cause incompatibility. Therefore to overcome such a problem,
we use protective colloid to change the sign from negative (ve-) to positive
(ve+). For example non-toxic fatty acid amine is used so that on addition of
hydrocolloid (anionic) there is no problem.
Types of thickening agents.
Polysaccharides
·
Natural: Acacia, tragacanth, starch, sodium
alginate
·
Semisynthetic: methylcellulose, hydroxymethyl
cellulose, sodium carboxy methyl Cellulose
Inorganic agents:
Clay, bentonite, Aluminium magnesium silicate,
Aluminium
hydroxide.
Synthetics: Carbomer (carboxy nvinyl polymer), colloidal
silicon dioxide
Rheological
considerations
Viscosity studies are very important in suspensions.
Viscosity affects
§ Settling
of particles
§ Flow
properties on shaking, pouring and spreading qualities of lotions and Flow
properties during manufacturing.
§ Passage
of suspensions in syringe needle.
An ideal suspending agent should have high viscosity
at negligible shear (during storage when the only shear is due to settling of
particles) and low viscosity at high shear rate 9that it free flowing during
agitation, pouring and spreading. Hence it should be pseudoplastic and preferably
thixotropic. Sometimes suspending agents are combined to give better properties
eg bentonite and CMC are combined and give average properties: bentonite has
marked hysteresis loop and CMC is thixopropic.
Preparation of suspensions
Small scale.
The insoluble matter is ground or levigated t a
smooth paste with a vehicle containing the dispersion stabilizer. The remaining
liquid phase in which any soluble drugs may be dissolved is gradually added.
Volatile ingredients are also dissolved in the vehicle. The slurry is
transferred to a tared container; the mortar is rinsed with successive portions
of the vehicle. Finally the dispersion is brought to final volume.
Large scale:
Mills are used ( ball mill, colloid mill, pebble
mill). Dough mixer or pony mixer may be needed as well. The colloid mill has a
cone shaped high velocity rotor centered in a stator at a small adjustable
clearance. The materials are fed through a hopper to the rotor by gravity, and
here they are sheared between the rotor and the stator., and forced out below
the stator, where it may be recycled or drawn off. The efficiency of the mill
depends on the clearance of discs, velocity of rotor and viscosity of
suspension.
