ReKm SUSPENSION

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Disperse systems

• Disperse systems consist of particulate matter


known as dispersed phase, dispersed
Suspension throughout a continuous or dispersion
medium.
PHR212: • Dispersed systems are classified according to
Pharmaceutical Technology I particle size:

Dr. Reatul Karim

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Suspension
Class Range of particle size Example
• A Pharmaceutical suspension is a coarse
dispersion in which internal phase
Molecular dispersion < 1 nm True solution (therapeutically active ingredient) is dispersed
Colloid dispersion 1 nm – 0.5 µm Colloidal Ag solution
uniformly throughout the external phase.
• The external phase (suspending medium) is
Coarse dispersion > 0.5 µm Suspension & emulsion
generally aqueous; in some instance, may be
an organic or oily liquid for non oral use.

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Classification of suspensions
3.Based on Electrokinetic Nature of Solid
1. Based on General Classes
Particles
➢Oral suspension
➢Flocculated suspension
➢Externally applied suspension
➢Deflocculated suspension
➢Parenteral suspension
4. Based on Size of Solid Particles
2. Based On Proportion of Solid Particles
➢Coarse suspension (>1 micron)
➢Dilute suspension (2 to 10% w/v solid)
➢Colloidal suspension (< 1 micron)
➢Concentrated suspension (50% w/v solid)
➢Nano suspension (10 nm)

Tetracycline hydrochloride (degraded in water) is suspended


• Application of Pharmaceutical Suspensions in a fractionated coconut oil for ophthalmic use.
➢ To mask the taste: to make more palatable. E.g.: Paracetamol
• Suspension is usually applicable for drug suspension.
which is insoluble or poorly soluble. E.g. ➢ Suspension of drug can be formulated for topical application.
E.g.: Calamine lotion.
Prednisolone suspension.
➢ Suspension can be formulated for parentral application in
• To overcome the instability of certain drug in order to control rate of drug absorption. E.g.: penicillin
procaine.
aqueous solution: Insoluble derivative
➢ Suspensions in aerosol inhalation therapy: suspension of
formulated as suspension. E.g.: (unstable) active agents in mixture of propellants.
oxytetracycline HCL  (stable) calcium salt. ➢ Vaccines as an immunizing agent are often formulated as
suspension. E.g.: Cholera vaccine.
➢ X-ray contrast agents are also formulated as suspension. E.g.:
Barium sulphate for examination of alimentary tract.

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Theoretic consideration of suspensions
• Decrease in the rate of sedimentation of particles
A) Theory of sedimentation: Sedimentation in a suspension may be achieved by reducing the
means settling of particle or floccules occur under size of the dispersed particles and by increasing
gravitational force in liquid dosage form. the density and viscosity of the
dispersion/continuous phase.
Velocity of sedimentation expressed by Stoke’s Particle size of any suspension is critical, because-
equation ➢ Larger particles will settle faster at the bottom of
the container. The particle size can be reduced by
d2 (ρs − ρl )g using mortar and pestle.
Sedimentation rate =
18η ➢ But very fine particles will easily form hard cake
at the bottom of the container.

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B) Zeta Potential
• Electrical double layer exists around each
particle which consists of two parts; an inner
region (Stern layer) where the ions are strongly
bound and an outer (diffuse layer) region
where they are less firmly associated. Within
this diffuse layer is a notional boundary within
which the particle acts as a single entity
(slipping or shear plane). The potential at this
boundary is the zeta potential.

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• Zeta potential has practical application in stability of Deflocculated Suspensions
• In a deflocculated suspension, the dispersed particles remain
systems containing dispersed particles. This potential as discrete separated units and settling will be slow. The
governs the degree of repulsion between the supernatant of this suspension will continue to remain
adjacent, similarly charged, dispersed particles. cloudy for an appreciable time after shaking, due to the very
slow settling rate of the smallest particles in the product.

If the zeta potential is reduced below a certain value, • The slow rate of settling prevents the entrapment of liquid
within the sediment, which thus becomes compacted and
the attractive forces exceed the repulsive forces, and can be very difficult to redisperse. This phenomenon is
the particles come together. This phenomenon is called caking (or claying) and is the most serious of all the
known as flocculation. The flocculated suspension is physical stability problems encountered in suspension.
one in which zeta potential of particle is -20 to +20
• Deflocculated suspensions have the advantage of a slow
mV. sedimentation rate, thereby enabling a uniform dose to be
taken from the container.

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Flocculated suspensions
• Formation of a loose aggregation of the particles held
together by weak Van der Waal's forces is termed a floc
or a floccule. The floccules have porous loose structure
and they can entrap a large amount of the liquid phase.
Therefore, the volume of the final sediment will still be
large and will easily be redispersed by moderate
agitation. Although flocs settle more rapidly than
individual discrete particles, flocculated particles
forming a type of lattice that resists complete settling
and thus are less prone to compaction and cake
formation than unflocculated particles.
Figure: a) deflocculated • In a flocculated suspension, the supernatant quickly
suspension and b) becomes clear, because of the large flocs that settle
flocculated suspension rapidly (inelegant appearance).
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Formulation Components of suspensions
• Active pharmaceutical ingredient
• Vehicle (suspending medium)
Structured vehicle: Controlled flocculation: to
Flocculation in structured • Wetting agents
vehicle: the product can
to maintain the
deflocculated
produce flocs that, although, they
settle rapidly are easily look unsightly if the • Flocculating agent
particles in redispersed with a minimum of
agitation.
sedimentation volume (F)
is not close to or equal to
• Suspending agent
suspension
1. So a suspending agent • Buffers
is added to retard
sedimentation of the • Other additives (Osmotic Agents, flavour,
flocs. colour, preservatives, etc.)

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2. Wetting agents: It is difficult to disperse solid


1. Structured vehicles: Structured vehicles are
vehicles containing thixotropic particles in a liquid vehicle due to the layer of
compounds/polymers like acacia which are adsorbed air on the surface.
pseudo-plastic in nature. • Inability of wetting reflects the higher
• Thixotropic compounds/polymers form a three- interfacial tension between material and
dimensional gel network structure which entrap liquid. The interfacial tension must be reduced
the particles so that, ideally, no settling occurs.
so that air is displaced from the solid surface
• During shaking the gel network is completely by liquid. The use of wetting agent allows to
destroyed, so that administration is facilitated.
The shear thinning property of these vehicles remove this air from the surface and to easy
does however facilitate the redispersion when penetration of the vehicle into the pores.
shear is applied.

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• Contact angle: The angle, the liquid makes with the solid
surface is called contact angle. Contact angle can be used
to measure wettability. Generally, if the water contact
angle is smaller than 90°, the solid surface is
considered hydrophilic and if the water contact angle is
larger than 90°, the solid surface is
considered hydrophobic. To reduce the contact angle
between solid and liquid; the following agents can be
tried out:
A) Surfactants (HLB value 7-9): They reduce the interfacial
tension between the solid particles and a vehicle. As a
result of the lowered interfacial tension, contact angle is
lowered, air is displaced from the surface of the particles,
and wetting is promoted. E.g.: Non ionic surfactant
polysorbates.
• Disadvantage: they have foaming tendencies.

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B) Solvents: Alcohol, glycerin, polyethylene glycol


3. Suspending agents/Viscosity modifier/Thickener
and polypropylene glycol flows into the voids Viscosity of suspensions is of great importance for stability and
between the particles to displace the air and pourability of suspensions.
reduce liquid air interfacial tension so that water ➢ When viscosity of the dispersion medium increases, the terminal
settling velocity decreases thus the dispersed phase settle at a
can penetrate and wet the individual particles. slower rate and they remain dispersed for longer time yielding
higher stability to the suspension.
C) Hydrophilic Colloids: Hydrophilic colloids coat ➢ On the other hand as the viscosity of the suspension increases,
hydrophobic drug particles it’s pourability decreases and inconvenience to the patients for
in one or more than one layer. This will provide dosing increases.
Therefore viscosity of suspension should be maintained within
hydrophillicity to drug particles and facilitate optimum range to yield stable and easily pourable suspensions.
wetting.
• Co-solvents: Some solvents which themselves have high viscosity
• They cause deflocculation of suspension because are used as co-solvents to enhance the viscosity of dispersion
force of attraction is declined due to their medium. For example: glycerol, propylene glycol, sorbitol etc.
coating. E.g.: acacia, tragacanth, bentonite,
Veegum, Methylcellulose etc.
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4. Flocculating Agents
• Although, structured vehicles reduce the A) Electrolytes: Dispersed solid particles in a suspension
may have charge in relation to their surrounding vehicle,
sedimentation of particles, not necessarily because of-
completely eliminate the particle settling. ➢ Selective adsorption of a particular ionic species present in the
Thus, the use of deflocculated particles in a vehicle
➢ Ionization of functional group of the particle
structured vehicle may form solid hard cake • Electrolytes acts as flocculating agents by reducing the
upon long storage. electrical barrier between the particles, thus, decrease the
zeta potential, this leads to decrease in repulsion potential
and makes the particle come together to form loosely
• The risk of caking may be eliminated by arranged structure (floccules).
controlled flocculation of the particles in a
structured vehicle. Controlled flocculation of • example: if we disperse particles of bismuth subnitrate in
water, we find that, they possess a large positive charge.
particles is obtained by adding flocculating Because of the strong forces of repulsion between adjacent
agents. Flocculating agents are added to particles, the system is deflocculated.
enhance particle re-dispersability, which are
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• The addition of monobasic potassium


phosphate to the suspended bismuth
subnitrate particles causes the positive zeta
potential to decrease due to the adsorption
of the negatively charged phosphate anion.

• With the continued addition of the


electrolyte, the zeta potential falls to zero
and then increases in a negative direction.
The flocculating power increases with the valency
of the ions. Calcium ions are more powerful than
sodium
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B) Surfactants: Both ionic and non ionic surfactants • C) Polymers: Polymers like starch, alginates,
could be used to control flocculation, e.g. Tween cellulose derivatives, carbomers, tragacanth are
80, Sodium lauryl sulfate. long chain, high molecular weight compounds
• The concentration of surfactants necessary to containing active groups spaced along their
achieve flocculation is critical since these length.
compounds may also act as wetting agents to • These agents act as flocculating agents because
achieve dispersion. Optimum concentrations of part of the chain is adsorbed on the particle
surfactants bring down the surface free energy by surface with the remaining parts projecting out in
reducing the surface tension between liquid the dispersion medium. Bridging between these
medium and solid particles. portions leads to the formation of floccules.
• The particles possessing less surface free energy • Polymers exhibit pseudo-plastic flow in solution
are attracted towards each other by van der- promoting the physical stability of suspension.
waals forces and forms loose aggregates.
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5. Suspending Agents
• Alginates
6. Buffers: To encounter stability problems all liquid
• Methylcellulose
formulation should be formulated to an optimum
• Hydroxyethylcellulose pH. Rheology, viscosity and other property are
• Carboxymethylcellulose dependent on the pH of the system. Most liquid
• Microcrystalline cellulose systems are stable at pH range of 4-10.
• Acacia • Most commonly used buffers are salts of week
• Tragacanth acids such as carbonates, citrates, gluconates,
• Xanthan gum phosphate and tartrates.
• Bentonite
• Carbomer • Na phosphate is most widely used buffer in
pharmaceutical suspension system. Citric acid is
Most suspending agents perform two functions i.e. besides acting most preferable used to stabilize pH of the
as a suspending agent they also imparts viscosity to the solution. suspension between 3.5 to 5.0. L-methionine is
Suspending agents form film around particle and decrease inter-
particle attraction. most widely used as buffering agent in parenteral
suspension.
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7. Osmotic Agents: They are added to produce osmotic
pressure comparable to biological fluids when suspension is Preparation of a suspension
to be intended for ophthalmic or injectable preparation.
Most commonly used osmotic agents for ophthalmic finely divided particles
suspensions are dextrose, mannitol and sorbitol.
particles are added to dispersion medium
• The tonicity-adjusting agents used in parenteral suspension
are sodium chloride, sodium sulfate, dextrose, mannitol
wetting agent is used
and glycerol.
deflocculated suspension
8. Preservatives: The naturally occurring suspending agents
such as tragacanth, acacia, xanthan gum are susceptible to
microbial contamination. If suspension is not preserved addition of structured vehicle flocculating agents flocculating agents
properly then the increase in microbial activity may cause are added are added
stability problem such as loss in suspending activity of deflocculated suspension
suspending agents, loss of color, flavor and odor, change in in structured vehicle flocculated suspension addition of structured vehicle
elegance etc. Antimicrobial activity is potentiated at lower
pH. flocculated suspension
in structured vehicle

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Evaluation of Suspensions
A) Sedimentation method: Two parameters are studied
for determination of sedimentation.
• 1. Sedimentation volume (F): sedimentation
volume of a suspension is expressed by the ratio of
the final volume of the sediment, Vu, to the original
volume, Vo of the suspension before settling.
F = Vu/Vo
• The value of F provides a qualitative knowledge
about the physical stability of the suspension.

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F= 1 This is the ideal condition. No
sedimentation, no clear supernatant.
• Degree of flocculation (β): degree of flocculation
F =0.5 50% of the total volume is occupied is the ratio of the sedimentation volume of the
by sediment flocculated suspension, F, to the sedimentation
volume of the deflocculated suspension, F∞.
F>1 Sediment volume is greater than the
original volume due to formation of F Vu /Vo
β= =
network of flocs which are fluffy and F V /Vo
loose. Therefore extra vehicle is
added. • The minimum value of β is 1. The degree of
flocculation is therefore an expression of the
increased sediment volume resulting from
flocculation. Suspension having the higher β
value is the preferred formulation.
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B) Re-disperseability: To quantitate this parameter D) Electro kinetic method: Measurement of Zeta-potential using Micro
to some extent, a mechanical shaking device may electrophoresis apparatus.
be used. It simulates human arm motion during • It shows the stability of a disperse system.

the shaking process.


E) Particle Size Changes: During storage or transport the product may experience a
• The smaller the number, the easier would be the fluctuation of temperature which may lead to crystal growth or physical
incompatibilities. Normally it may take time to check the stability regarding
re-dispersability of the sediment. A number crystal growth. So to accelerate this effect freeze-thaw cycle technique is
greater than 15 inversions indicates caking. particularly applicable.

C) Rheological method: Rheologic behavior can


• Freeze-Thaw studies put products through a series of extreme temperature
also be used to help determine the settling changes. An example of a freeze-thaw cycle is exposing the product to freezing
behavior and the arrangement of the vehicle and temperatures (approximately -15°C to -25°C) for 24 hours and then store it at a
higher temperature (approximately 25°C) for 24 hours. The sample is then
particle structural features for purposes of analyzed for significant changes. This completes one cycle. If no significant
comparison. changes are observed after three cycles one can be confident that the product is
sufficiently stable for transport.
• Brookfield viscometer is used to study the
viscosity of the suspension.
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Packaging and Storage of Suspensions
In Process Quality Control (IPQC) of Suspensions
➢Should be packaged in wide mouth containers • The tests are carried out during the manufacturing of
having adequate air space above the liquid. suspension to ensure a stable, safe and quality product.
These include:
➢Should be stored in tight containers protected • Appearance of Phases
from: freezing, excessive heat & light. • Viscosity of Phases
➢Label: "Shake Before Use" to ensure uniform • Particle Size of Dispersed Phase
• pH Test
distribution of solid particles and thereby • Pourability
uniform and proper dosage. • Zeta Potential Measurement
➢Stored in room temperature if it is dry powder • Centrifugation Test
(25 °C). • The product is checked for uniform distribution of
color, absence of air globules before packing

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• Final Quality Control of Suspensions • Innovations in Suspensions


The following tests are carried out in the final quality control of 1. Taste Masked Pharmaceutical Suspensions
suspension: • Un-palatability due to bad taste is a major concern in most of
• Appearance the dosage forms containing bitter drugs. In case of
• Color, odor and taste suspensions also taste masking is being applied to mask
• Physical characteristics such as particle size determination and bitterness of drugs formulated. The taste masking approaches
microscopic photography for crystal growth for suspensions can be summarized as
• Sedimentation rate and Zeta Potential measurement • A) Polymer Coating of Drugs: The polymer coat allows the
• Sedimentation volume time for all of the particles to be swallowed before the
• Redispersibility and Centrifugation tests threshold concentration is reached in the mouth and the taste
• Rheological measurement is perceived. Example: Ethyl cellulose, Eudragit etc.
• Stress test • Polymer coated drug powders are also used for preparation of
• pH reconstitutable powders that means dry powder drug
• Freeze-Thaw temperature cycling products that are reconstituted as suspension in a liquid
• Compatibility with container and cap liner vehicle such as water before usage. These reconstitutable
• Final Product Assay polymer coated powders have long shelf-life and once
reconstituted have adequate taste masking.
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B) Encapsulation with a Basic Substance: Here a basic substance is
mixed with a bitter tasting drug which is insoluble at high pH. The
mixer is then encapsulated with a polymer (cellulose derivative, • Nano-Suspension
vinyl derivative or an acid soluble polymer for example copolymer • Nano-suspension of potent insoluble active pharmaceutical ingredient will
of dimethyl ammonium methyl methacrylate). The drug after become improved drug delivery formulations when delivered to at sizes
encapsulation are suspended, dispersed or emulsified in suspending less than 50 nm.
medium to give the final dosage form.
• When delivered intravenously at sizes less than 50 nm, the suspension
C) Polymer Coated Drug with a Basic Substance: This method has
claimed to give stable taste masked suspensions on reconstitution particles avoids the normal reticuloendothelial filtration mechanisms and
(taste masked for prolonged period). circulates for long periods. The suspension particles may be insoluble API
particles or nano-particle polymeric carriers of soluble or insoluble drugs
and may be useful in delivering genetic therapeutic materials targeted to
D) Coating and pH Control: Those drugs which are soluble at high pH
are the cells.
preferably be maintained in a suspension at a low pH where the
drug exhibit maximum insolubility. Similarly drugs which are soluble • In transdermal delivery application, control of particulates in the 10-50 nm
at low pH are preferably maintained in suspension at a high pH size range should allow the formulation of API in formats that match
where the drug is insoluble. Also applying polymeric coating to the
drug substance for taste masking. requirements of delivery rates and for penetration depth target.

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• For oral delivery, nanometer size particles may allow delivery of API
through the intestinal wall into the blood stream, at desired rates
and with minimal degradation in the GI tract. Insoluble particles at
these sizes may be designed to be transportable across this barrier.
Another strategy involves encapsulation of active drugs in nano-
particulate degradable polymer structures.

3. Sustained Release Suspensions


• Sustained release is a method to increase only the duration of
action of drug being formulated without affecting onset of action.
In suspension, sustained release affected by coating the drug to be
formulated as suspension by insoluble polymer coating. The
polymer coating provides sustained release and also masks the
taste of the bitter drug.

• The polymer used for sustained release in suspension is Ethyl


cellulose, Eudragit, Cellulose acetate, etc.

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