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Pharmaceutical suspensionPharmaceutical suspension
BY
NGENDA WAMUNYIMA-
Dip Pharm
IntroductionIntroduction
A Pharmaceutical suspension is a disperse system in
which internal phase is dispersed uniformly as finely
divided insoluble particles throughout the external
phase.
The internal phase consisting of insoluble solid
particles having a specific range of size which is
maintained uniformly throughout the suspending
vehicle with aid of single or combination of
suspending agent.
The external phase (suspending medium) is generally
aqueous in some instance, may be an organic or oily
liquid for non oral use.
Introduction continuedIntroduction continued
 The term "Disperse System" refers to a system
in which one substance (The Dispersed Phase) is
distributed, in discrete units, throughout a
second substance (the continuous Phase or
vehicle).
Each phase can exist in solid, liquid, or gaseous
state .
. Most suspensions are classified as a coarse
suspension which is a dispersion of particles with
a mean diameter greater than 1µm (1 to 100 µm.
A colloidal suspension is a dispersion of particles
with a mean diameter of less than 1µm (0.5µm to
1µm).
The Difference BetweenThe Difference Between
Solution & SuspensionsSolution & Suspensions
When the 2 substances totally mix it is
called a solution.
E.g. Solute + Solvent = Solution
 (sugar) + (water) = Solution

We then say sugar is soluble in water, it
has dissolved.
The Difference BetweenThe Difference Between
Solution & SuspensionsSolution & Suspensions
. The particles in a suspension are insoluble
Sometimes when we mix substances they
stay in clusters. We therefore say it is
insoluble in water.
E.g. Chalk + Water = Suspension

Eventually the particles sink to the bottom
to form sediment.
Types of insoluble solidsTypes of insoluble solids
There are two types of insoluble solids
which constitute the internal or dispersed
phase. These are
1.Diffusible solids – these sediment
sufficiently slowly to enable satisfactory
dose removal after redispersion.eg. Light
kaoline, magnesium tricilicate
Types of insoluble solidsTypes of insoluble solids
INDIFFUSIBLE SOLIDS- eg.
sulphadimidine and chalk. These sediment
too rapidly and require the addition of
other materials to reduce sedimentation
rate to an acceptable level.
SedimentationSedimentation
This is a phenomenon which occurs in
dispersed system where the dispersed
particles settle to the bottom of the
container. This occurs because the
particles are too large to remain
permanently suspended in the vehicle.
Therefore suitable suspending agents are
added to retard this process.
SUSPENDING AGENTSSUSPENDING AGENTS
Suspending agents are substances that are used
to keep finely divided insoluble materials
suspended in a liquid media by preventing there
agglomeration (coming together) and by
imparting viscosity to the dispersion media so
that the particles settle more slowly. Care must
be taken when selecting a suspending agent for
oral preparations as the acid environment of the
stomach may alter the physical characteristics of
the suspension and therefore the rate of release
of the drug from suspension.
They are various types of suspending agents
Types of suspending agentsTypes of suspending agents
1. NATURAL AGENTS
This class consists of those from.
a. Animal source eg Gelatine
b. Plant source eg. Accacia, Tragacanth, Starch, sea weed
(Alginates)
c. mineral sources.eg Bentonite, Kaoline
2. SEMI-SYNTHETIC AGENTS
These consist of substituted cellulos (minerals) eg.
Hydroxyethylcellulose , Sodium Carboxymethylcellulose ,
methylcellulose, Microcrystalline cellulose
3. SYNTHETIC AGENTS.
They are synthetic polymers eg carboxypolymethylene
(carbopol), Polyvinyl Alcohol, Polyvinyl Pyrolidone iodine
complex (PVC)
Types of suspending agentsTypes of suspending agents
continued…..continued…..
Most suspending agents perform two functions
i.e. besides acting as a suspending agent they also
imparts viscosity to the solution. Suspending
agents form film around particle and decrease
interparticle attraction.
A good suspension should have well developed
thixotropy.
At rest the solution is sufficient viscous to
prevent sedimentation and thus aggregation or
caking of the particles. When agitation is applied
the viscosity is reduced and provide good flow
characteristic from the mouth of bottle.
Classification of suspensionsClassification of suspensions
 Based On General Classes
Oral suspension
Externally applied suspension
Parenteral 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)
Coarse suspension (>1 micron)
Nano suspension (10 ng)
FORMULATION OFFORMULATION OF
SUSPENSIONSSUSPENSIONS
The three steps that can be taken to ensure
formulation of an elegant pharmaceutical
suspension are:
1.CONTROL PARTICLE SIZE. On a small
scale, this can be done using a mortar and a
pestle to grind down ingredients to a fine
powder.
2. Use thickening agent to increase viscosity of
the vehicle by using suspending agents or
viscosity increasing agents
3. Use of a wetting agent/ surfactants
Pharmaceutical Applications ofPharmaceutical Applications of
suspensionssuspensions
Suspensions may be used pharmaceutically for a number of reasons. Some
are given bellow;
 Suspension is usually applicable for drug which is insoluble or poorly
soluble. E.g. Prednisolone
 suspension To prevent degradation of drug or to improve stability of drug.
E.g. Oxytetracycline suspension
 To mask the taste of bitter or unpleasant drug when formulated in solution
form. Drugs are formulated in as suspesnion which will be more palatable
E.g. Chloramphenicol palmitate suspension
 Suspension of drug can be formulated for topical application e.g. Calamine
lotion.
Pharmaceutical Applications of suspensionsPharmaceutical Applications of suspensions
 Suspension can be formulated for parentral application in order to
control rate of drug absorption, E.g. penicillin procaine
 Vaccines as a immunizing agent are often formulated as
suspension.E.g. Cholera vaccine
 X-ray contrast agent are also formulated as suspension.
E.g. Barium sulphate for examination of alimentary tract
 If the drug is unstable when in contact with the vehicle, suspensions
should be prepared immediately prior to handing out to the patient
in order to reduce the amount time that the drug particles are in
contact with the dispersion medium. Eg Amoxicilin suspension
Pharmaceutical Applications of suspensionsPharmaceutical Applications of suspensions
Drugs which degrade in aqueous solution may be
suspended in a non-aqueous phase. eg.
Tetracycline hydrochloride is suspended in a
fractionated coconut oil for ophthalmic use.
Lotions containing insoluble solids are formulated
to leave a thin coating of medicament on the skin.
As the vehicle evaporates, it gives a cooling effect
and leaves the solid behind.eg calamine lotion and
sulphur lotion compound.
Bulky, insoluble powders can be formulated as a
suspension so that they are easier to take eg
Kaolin or chalk
ADVANTAGES OF SUSPENSIONSADVANTAGES OF SUSPENSIONS
Suspension can improve chemical stability of certain
drug. E.g. Procaine penicillin G
Drug in suspension exhibits higher rate of
bioavailability than other dosage forms. bioavailability
is in following order,

Solution > Suspension > Capsule >
Compressed Tablet > Coated tablet
Duration and onset of action can be controlled. E.g.
Protamine Zinc-Insulin suspension
Suspension can mask the unpleasant/ bitter taste of
drug. E.g. Chloramphenicol palmitate
DISADVANTAGEDISADVANTAGE
Physical stability, sedimentation and
compaction can causes problems.
 It is bulky, therefore sufficient care
must be taken during handling and
transport.
 It is difficult to formulate
 Uniform and accurate dose can not be
achieved unless suspension are packed in
unit dosage form
Basic requirements of suspensionBasic requirements of suspension
1. The suspended particles should not settle
rapidly and sediment produced, must be
easily re-suspended by the use of moderate
amount of shaking.
2.Satisfactory pourability.
3. Should have an elegant smooth appearance.
4. After gentle shaking, the medicament stays
in suspension long enough for a dose to be
accurately measured.
5. Constant particle size and size distribution
so that the product is free from a gritty
texture.
Theory of SuspensionsTheory of Suspensions
Sedimentation Behaviour
Sedimentation means settling of particle or
floccules
occur under gravitational force in liquid
dosage form.
Theory of Sedimentation
The factors affecting the rate of
sedimentation of a particle are
described in Stoke’s equation
 V= 2r2
(ρ s- ρo ) g or V= d2
(ρ s- ρo ) g
 9η 18η
Stokes equationStokes equation
Where, vsed. = sedimentation velocity in cm
/ sec
d = Diameterof particle
r = radius of particle
ρ s= density of disperse phase
ρo= density of disperse media
g = acceleration due to gravity
η= viscosity of disperse medium in poise
Stokes equationStokes equation
The basic consequences of the stokes equation
are that the rate of fall of a suspended particle in
a vehicle of a given density is greater for larger
particles than it is for smaller particles. Also the
greater the difference in density between the
particles and the vehicle, the greater will be the
rate of sedimentation. Increasing the viscosity of
the dispersion medium will reduce the rate o
sedimentation. Thus decrease in the rate of
sedimentation of particles in a suspension may be
achieved by reducing the size of the dispersed
particles and by increasing the density and
viscosity of the dispersion/continuous phase.
Factors AffectingFactors Affecting
SedimentationSedimentation
1. Particle size diameter (d)
 V dα 2
 Sedimentation velocity (v) is directly proportional to the
square of diameter of particle.
2. Density difference between dispersed phase and
dispersion media (ρs - ρo)
 V (α ρs - ρo)
 Generally, particle density is greater than dispersion medium
but, in certain cases particle density is less than dispersed
phase, so suspended particle floats & is difficult to distribute
uniformly in the vehicle.
 If density of the dispersed phase and dispersion medium are
equal, the rate of settling becomes zero.
Factors AffectingFactors Affecting
SedimentationSedimentation
Viscosity of dispersion medium ( )η
V 1/α ηo
Sedimentation velocity is inversely
proportional to
viscosity of dispersion medium.
 So increase in viscosity of medium,
decreases settling, so the particles achieve
good dispersion system but greater increase
in viscosity gives rise to problems like
pouring, syringibility and redispersibility of
suspensoin.
Advantages and DisadvantagesAdvantages and Disadvantages
due to viscosity of mediumdue to viscosity of medium
Advantages
High viscosity inhibits the crystal growth.
High viscosity prevents the transformation of
metastable crystal to stable crystal.
High viscosity enhances the physical stability.
Disadvantages
High viscosity hinders the re-dispersibility of the
sediments
High viscosity retards the absorption of the drug.
High viscosity creates problems in handling of the
material during manufacturing.
The Sedimentation Behavior of Flocculated andThe Sedimentation Behavior of Flocculated and
Deflocculated Suspensions:Deflocculated Suspensions:
Flocculated Suspensions
Flocculation is a condition which occurs as a result of
the lowering of electrical forces of repulsion in a
dispersed system , so that the force of attraction
predominate. Systems under this condition reduced
repulsive forces the dispersed particles to approach
each other more closely and form aggregates known as
flocs
In flocculated suspension, formed flocs (loose
aggregates) will cause increase in sedimentation rate
due to increase in size of sedimenting particles. Hence,
flocculated suspensions sediment more rapidly.
Flocculated suspension continuedFlocculated suspension continued
 Here, the sedimentation depends not only on the size
of the flocs but also on the porosity of flocks. In
flocculated suspension the loose structure of the
rapidly sedimenting flocs tends to preserve in the
sediment, which contains an appreciable amount of
entrapped liquid. The volume of final sediment is thus
relatively large and is easily redispersed by agitation.
 Most stable pharmaceutical suspensions are flocculated.
 The suspension appear somehow unsight (unappealing)
due to its rapid sedimentation and it presents an
obvious clear supernatant. This can be minimised by
enlarging the volume of the sediments by the use of
flocculating agents eg starch, alginates and carboxyvinyl
polymers.
 Since the sediment is loosly structured, caking or
claying does not occur.
Deflocculated suspensionsDeflocculated suspensions
A deflocculated suspension is one in which the electrical repulsive
forces between particles exceeds the attractive forces, the
particles are kept apart as individuals affected only by the
suspending vehicle. Even when brought together by random
motion, they resist collision due to the high surface tension.
 In deflocculated suspension, individual particles are settling, so rate
of sedimentation is slow which prevents entrapping of liquid
medium which makes it difficult to re-disperse by agitation.
 This phenomenon also called ‘cracking’ or ‘claying’.
 In deflocculated suspension, smaller particles settle slowly and
therefore remaining supernatant liquid so supernatant appears
cloudy and has a pleasing granular appearance whereby in
flocculated suspension, even the smallest particles are involved in
flocs, so the supernatant does not appear cloudy.
Flocculating AgentsFlocculating Agents
Flocculating agents decreases zeta potential
of the suspended charged particle and thus
cause aggregation (flock formation) of the
particles.
Examples of flocculating agents are:
Neutral electrolytes such as KCl, NaCl.
Surfactants
Polymeric flocculating agents
Sulfate, citrates, phosphates salts
Neutral electrolytes e.g. NaCl, KCl besides
acting as flocculating agents, also decreases
interfacial tension of the surfactant solution.
If the particles are having less surface charge
then monovalent ions are sufficient to cause
flocculation e.g. steroidal drugs.
For highly charged particles e.g. insoluble
polymers and poly-electrolytes species, di or
trivalent flocculating agents are used.
Method of Floccules FormationMethod of Floccules Formation
The different methods used to form
floccules are mentioned below:
1 . Electrolytes
Electrolytes decrease electrical barrier
between the particles and bring them
together to form floccules. They reduce zeta
potential near to zero value that results in
formation of bridge between adjacent
particles, which lines them together in a
loosely arranged structure.
Method of Floccules FormationMethod of Floccules Formation
If we disperse particles of bismuth
subnitrate in water we find that based on
electrophoretic mobility potential because
of the strong force of repulsion between
adjacent particles, the system is peptized or
deflocculated. By preparing series of bismuth
subnitrate suspensions containing increasing
concentration of monobasic potassium
phosphate co-relation between apparent
zeta potential and sedimentation volume,
caking, and flocculation can be
demonstrated.
Method of Floccules FormationMethod of Floccules Formation
The addition of monobasic potassium phosphate to
the suspended bismuth subnitrate particles causes the
positive zeta potential to decrease owing to the
adsorption of negatively charged phosphate anion.
With continued addition of the electrolyte, the zeta
potential eventually falls to zero and then increases in
negative directions.
Only when zeta potential becomes sufficiently
negative to affect potential does the sedimentation
volume start to fall.
Finally, the absence of caking in the suspensions
correlates with the maximum sedimentation volume,
which, as stated previously, reflects the amount of
flocculation.
SurfactantsSurfactants
 Both ionic and non-ionic surfactants can be used to
bring about flocculation of suspended particles.
 Optimum concentration is necessary because
these compounds also act as wetting agents to
achieve dispersion.
 Optimum concentrations of surfactants bring down
the surface free energy by reducing the surface
tension between liquid medium and solid particles.
This tends to form closely packed agglomerates.
 The particles possessing less surface free energy
are attracted towards to each other by van der-
waals forces and forms loose agglomerates.
PolymersPolymers
Polymers possess long chain in their
structures.
Starch, alginates, cellulose derivatives,
carbomers, tragacanth
The part of the long chain is adsorbed on
the surface of the particles and remaining
part projecting out into the dispersed
medium.
Bridging between these later portions, also
leads to the formation of flocs.
Viscosity of SuspensionsViscosity of Suspensions
 Viscosity of suspensions is of great importance for stability and pourability
of suspensions. As we know suspensions have least physical stability
amongst all dosage forms due to sedimentation and cake formation.
 So as the viscosity of the dispersion medium increases, the terminal settling
velocity decreases thus the dispersed phase settle at a slower rate and they
remain dispersed for longer time yielding higher stability to the suspension.
 On the other hand as the viscosity of the suspension increases, it’s
pourability decreases and inconvenience to the patients for dosing
increases.
 Thus, the viscosity of suspension should be maintained within optimum
range to yield stable and easily pourable suspensions.
Different Approaches To IncreaseDifferent Approaches To Increase
The Viscosity of SuspensionsThe Viscosity of Suspensions
Various approaches have been suggested to
enhance the viscosity of suspensions. Few of
them are as follows:
1. Viscosity Enhancers
Some natural gums (acacia, tragacanth), cellulose
derivatives (sodium CMC, methyl cellulose),
clays(bentonite, veegum), carbomers, colloidal
silicon dioxide (Aerosil), and sugars (glucose,
fructose) are used to enhance the viscosity of the
dispersion medium. They are known as
suspending agents.
ThixotropyThixotropy
Thixotrophy is a phenomenon or property
exhibited by highly floculated preparation in
which a preparation is sem-solid at rest (in the
absence of shearing forces) but becomes so fluid
when tapped or shaken and resumes its original
structure after only a few minutes of rest.
A thixotropic suspension is the one which is
viscous during storage but loses consistency and
become fluid upon shaking.
A well-formulated thixotropic suspension would
remain fluid long enough for the easy dispense of
a dose but would slowly regain its original
viscosity within a short time.
Other Formulation AspectsOther Formulation Aspects
Introduciton
A perfect suspension is one, which provides content
uniformity. The formulator must encounter
important problems regarding particle size
distribution, specific surface area, inhibition of crystal
growth and changes in the polymorphic form. The
formulator must ensure that these and other
properties should not change after long term storage
and do not adversely affect the performance of
suspension.
 Choice of pH, particle size, viscosity, flocculation,
taste, color and odor are some of the most
important factors that must be controlled at the time
of formulation.
Formulation ComponentsFormulation Components
The various components, which are used in suspension formulation, are as follows.
 API ………….Active drug substances
 Wetting agents ………They are added to disperse solids in
continuous liquid phase.
 Flocculating agents ………They are added to floc the drug particles
 Thickeners …………They are added to increase the viscosity of
suspension.
 Buffers and pH adjusting agents ………They are added to stabilize
the suspension to a desired pH range.
 Osmotic agents ………They are added to adjust osmotic pressure
comparable to biological fluid.
 Coloring agents ………..They are added to impart desired color to
suspension and improve elegance.
 Preservatives ……….They are added to prevent microbial growth.
 External liquid vehicle ………They are added to construct structure
of the final suspension.
wetting Agentswetting Agents
Hydrophilic materials are easily wetted by water while
hydrophobic materials are not. However hydrophobic materials
are easily wetted by non-polar liquids. The extent of wetting by
water is dependent on the hydrophillicity of the materials. If the
material is more hydrophilic it finds less difficulty in wetting by
water. Inability of wetting reflects the higher interfacial tension
between material and liquid. The interfacial tension must be
reduced so that air is displaced from the solid surface by liquid.
 Non-ionic surfactants are most commonly used as wetting
agents in pharmaceutical suspension. Non-ionic surfactants having
HLB value between 7-10 are best as wetting agents. High HLB
surfactants act as foaming agents. The concentration used is less
than 0.5 %. A high amount of surfactant causes solubilization of
drug particles and causes stability problem.
 Ionic surfactants are not generally used because they are not
compatible with many adjuvant and causes change in pH.
SurfactantsSurfactants
Surfactants decrease the interfacial tension between
drug particles and liquid and thus liquid is penetrated
in the pores of drug particle displacing air from them
and thus ensures wetting.
Surfactants in optimum concentration facilitate
dispersion of particles. Generally we use non-ionic
surfactants but ionic surfactants can also be used
depending upon certain conditions.
Disadvantages of surfactants are that they have
foaming tendencies.
Further they are bitter in taste. Some surfactants such
as polysorbate 80 interact with preservatives such as
methyl paraben and reduce antimicrobial activity.
SurfactantsSurfactants
Polysorbate 80 is most widely used
surfactant both for parenteral and oral
suspension formulation.
Polysorbate 80 is also adsorbed on drug
particle and decreases its zeta potential. This
effect of polysorbate80 stabilizes the
suspension.
Polysorbate 80 stabilized suspensions
through steric mechanism. At low
concentration of polysorbate 80,only partial
stabilization of suspension was observed.
SurfactantsSurfactants
In absence of polysorbate 80, difficulty was
observed in re-dispersion of sedimented
particles.
Polysorbate 80 is most widely used due to its
following advantages
It is non-ionic so no change in pH of medium
No toxicity.
Safe for internal use.
Less foaming tendencies however it should be
used at concentration less than 0.5%.
Compatible with most of the adjuvant.
Hydrophilic ColloidsHydrophilic Colloids
Hydrophilic colloids coat hydrophobic
drug particles in one or more than one
layer. This will provide hydrophillicity to
drug particles and facilitate wetting.
They cause deflocculation of suspension
because force of attraction is declined.
e.g. acacia, tragacanth, alginates, guar
gum, pectin, gelatin, wool fat, egg yolk,
bentonite, Veegum, Methylcellulose etc.
SolventsSolvents
The most commonly used solvents used are alcohol,
glycerin, polyethylene glycol and polypropylene glycol.
The mechanism by which they provide wetting is that
they are miscible with water and reduce liquid air
interfacial tension. Liquid penetrates in individual
particle and facilitates wetting.
Co-solvents Used in suspensions
Some solvents which themselves have high viscosity
are used as co-solvents to enhance the viscosity of
dispersion medium:
Glycerol, propylene glycol, sorbitol.
MIXING PROCEDURESMIXING PROCEDURES
THE DISPENSING OF SUSPENSIONSTHE DISPENSING OF SUSPENSIONS
 The method of dispensing suspensions is the same for most,
with some differences for specific ingredients.
1. Crystalline and granular solids should be finely powdered in
the mortar. The suspending agent should then be added and
mixed thoroughly in the mortar. Do not apply too much
pressure, otherwise gumming or caking of the suspending
agent will occur and heat of friction will make it sticky.
2. Add a little liquid vehicle to make a paste and mix well until
smooth and free of lumps. Continue with gradual additions
until the mixture can be poured into a bottle. Further liquid
is used to rinse all the powder into the bottle where it is
made up to volume.
3. When water is prescribed as a vehicle, use freshly boiled and
cooled water or potable water where permissible
VARIATIONSVARIATIONS
If the wettinng agents are included in the
formulation, add them before forming the paste
If syrup and/or glycerol are in the formulation,
use this rather than water to form the initial
paste
If soluble solids are being used, dissolve them in
the vehicle before or after making the paste
Leave addition of volatile components, colouring
or concentrated flavouring tinctures such as
chloroform spirit, liquid liquorice extract and
compound tartrazine solution until near the end
STABILITY OF SUSPENSIONSSTABILITY OF SUSPENSIONS
Factors that contribute to appreciable
stability of a suspension include:
a)Small particle size- reduse the size of the
dispersed particle increases the total surface
area of the solid. The greater the degree of
subdivision of a given solid the larger the
surface area. The increase in surface area means
also an increase in interface between the solids
and liquids leading to an increase in viscosity of
a system.
STABILITY OF SUSPENSIONSSTABILITY OF SUSPENSIONS
b). Increasing the viscosity – increasing the
viscosity of the continuous phase can lead to the
stability of suspensions. This is so because the rate of
sedimentation can be reduced by increase in viscosity.
Viscosity increase is brought about by addition of
thickening agents to the external phase. In water
these must be either soluble or swell. It is important
to note that the rate of release of a drug from a
suspension is also dependent on viscosity. Of a
product. The more viscous the preparation, the
slower is likely to be the release of a drug. Sometimes
this property may be desirable for depot
preparations.
STABILITY OF SUSPENSIONSSTABILITY OF SUSPENSIONS
C). TEMPERATURE.
Another factor which negatively affects the
stability and usefulness of pharmaceutical
suspensions is fluctuation of temperature.
Temperature fluctuations can lead to
caking and claying.
Quality Control of SuspensionsQuality Control of Suspensions
The following tests are carried out in the final quality control of suspension:
 Appearance Color, odor and taste
 Physical characteristics such as particle size determination and
microscopic photography for crystal growth
 Sedimentation rate and
 Zeta Potential measurement
 Sedimentation volume
 Redispersibility and Centrifugation tests
 Rheological measurement
 Stress test
 pH
 Freeze-Thaw temperature cycling
 Compatibility with container and cap liner
Special labels and advice forSpecial labels and advice for
suspensionssuspensions
All pharmaceutical suspensions should be
properly labelled.
The most important additional information in
addition to the product name and directions for
use is the inclusion of the direction “shake the
bottle well before use” as some sedimentation
of medicament would normally be expected.
Shaking the bottle will redisperse the
medicament and ensure that the patient can
measure the accurate dose.
Other labelling information include directions to
store in a cool place, expiry date.
CONTAINERS FORCONTAINERS FOR
SUSPENSIONSSUSPENSIONS
Choices of packaging of all
pharmaceutical products are extremely
important aspect of ensuring stability of
the product.
Suspensions should be packed in amber
coloured bottles- plain for internal use
and ribbed for external use. There should
be adequate air space above the liquid to
allow shaking and easy pouring. A 5ml
medicine spoon or oral syringe should be
given when the suspension is for oral use.
Ideal Requirements ofIdeal Requirements of
Packaging MaterialPackaging Material
It should be inert.
It should effectively preserve the product
from light, air, and other contamination
through shelf life.
It should be cheap.
It should effectively deliver the product
without any difficulty
THE ENDTHE END
With God all things
are possible- matt
19:26
It shall be well

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Pharmaceutical suspension

  • 2. IntroductionIntroduction A Pharmaceutical suspension is a disperse system in which internal phase is dispersed uniformly as finely divided insoluble particles throughout the external phase. The internal phase consisting of insoluble solid particles having a specific range of size which is maintained uniformly throughout the suspending vehicle with aid of single or combination of suspending agent. The external phase (suspending medium) is generally aqueous in some instance, may be an organic or oily liquid for non oral use.
  • 3. Introduction continuedIntroduction continued  The term "Disperse System" refers to a system in which one substance (The Dispersed Phase) is distributed, in discrete units, throughout a second substance (the continuous Phase or vehicle). Each phase can exist in solid, liquid, or gaseous state . . Most suspensions are classified as a coarse suspension which is a dispersion of particles with a mean diameter greater than 1µm (1 to 100 µm. A colloidal suspension is a dispersion of particles with a mean diameter of less than 1µm (0.5µm to 1µm).
  • 4. The Difference BetweenThe Difference Between Solution & SuspensionsSolution & Suspensions When the 2 substances totally mix it is called a solution. E.g. Solute + Solvent = Solution  (sugar) + (water) = Solution  We then say sugar is soluble in water, it has dissolved.
  • 5. The Difference BetweenThe Difference Between Solution & SuspensionsSolution & Suspensions . The particles in a suspension are insoluble Sometimes when we mix substances they stay in clusters. We therefore say it is insoluble in water. E.g. Chalk + Water = Suspension  Eventually the particles sink to the bottom to form sediment.
  • 6. Types of insoluble solidsTypes of insoluble solids There are two types of insoluble solids which constitute the internal or dispersed phase. These are 1.Diffusible solids – these sediment sufficiently slowly to enable satisfactory dose removal after redispersion.eg. Light kaoline, magnesium tricilicate
  • 7. Types of insoluble solidsTypes of insoluble solids INDIFFUSIBLE SOLIDS- eg. sulphadimidine and chalk. These sediment too rapidly and require the addition of other materials to reduce sedimentation rate to an acceptable level.
  • 8. SedimentationSedimentation This is a phenomenon which occurs in dispersed system where the dispersed particles settle to the bottom of the container. This occurs because the particles are too large to remain permanently suspended in the vehicle. Therefore suitable suspending agents are added to retard this process.
  • 9. SUSPENDING AGENTSSUSPENDING AGENTS Suspending agents are substances that are used to keep finely divided insoluble materials suspended in a liquid media by preventing there agglomeration (coming together) and by imparting viscosity to the dispersion media so that the particles settle more slowly. Care must be taken when selecting a suspending agent for oral preparations as the acid environment of the stomach may alter the physical characteristics of the suspension and therefore the rate of release of the drug from suspension. They are various types of suspending agents
  • 10. Types of suspending agentsTypes of suspending agents 1. NATURAL AGENTS This class consists of those from. a. Animal source eg Gelatine b. Plant source eg. Accacia, Tragacanth, Starch, sea weed (Alginates) c. mineral sources.eg Bentonite, Kaoline 2. SEMI-SYNTHETIC AGENTS These consist of substituted cellulos (minerals) eg. Hydroxyethylcellulose , Sodium Carboxymethylcellulose , methylcellulose, Microcrystalline cellulose 3. SYNTHETIC AGENTS. They are synthetic polymers eg carboxypolymethylene (carbopol), Polyvinyl Alcohol, Polyvinyl Pyrolidone iodine complex (PVC)
  • 11. Types of suspending agentsTypes of suspending agents continued…..continued….. Most suspending agents perform two functions i.e. besides acting as a suspending agent they also imparts viscosity to the solution. Suspending agents form film around particle and decrease interparticle attraction. A good suspension should have well developed thixotropy. At rest the solution is sufficient viscous to prevent sedimentation and thus aggregation or caking of the particles. When agitation is applied the viscosity is reduced and provide good flow characteristic from the mouth of bottle.
  • 12. Classification of suspensionsClassification of suspensions  Based On General Classes Oral suspension Externally applied suspension Parenteral 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) Coarse suspension (>1 micron) Nano suspension (10 ng)
  • 13. FORMULATION OFFORMULATION OF SUSPENSIONSSUSPENSIONS The three steps that can be taken to ensure formulation of an elegant pharmaceutical suspension are: 1.CONTROL PARTICLE SIZE. On a small scale, this can be done using a mortar and a pestle to grind down ingredients to a fine powder. 2. Use thickening agent to increase viscosity of the vehicle by using suspending agents or viscosity increasing agents 3. Use of a wetting agent/ surfactants
  • 14. Pharmaceutical Applications ofPharmaceutical Applications of suspensionssuspensions Suspensions may be used pharmaceutically for a number of reasons. Some are given bellow;  Suspension is usually applicable for drug which is insoluble or poorly soluble. E.g. Prednisolone  suspension To prevent degradation of drug or to improve stability of drug. E.g. Oxytetracycline suspension  To mask the taste of bitter or unpleasant drug when formulated in solution form. Drugs are formulated in as suspesnion which will be more palatable E.g. Chloramphenicol palmitate suspension  Suspension of drug can be formulated for topical application e.g. Calamine lotion.
  • 15. Pharmaceutical Applications of suspensionsPharmaceutical Applications of suspensions  Suspension can be formulated for parentral application in order to control rate of drug absorption, E.g. penicillin procaine  Vaccines as a immunizing agent are often formulated as suspension.E.g. Cholera vaccine  X-ray contrast agent are also formulated as suspension. E.g. Barium sulphate for examination of alimentary tract  If the drug is unstable when in contact with the vehicle, suspensions should be prepared immediately prior to handing out to the patient in order to reduce the amount time that the drug particles are in contact with the dispersion medium. Eg Amoxicilin suspension
  • 16. Pharmaceutical Applications of suspensionsPharmaceutical Applications of suspensions Drugs which degrade in aqueous solution may be suspended in a non-aqueous phase. eg. Tetracycline hydrochloride is suspended in a fractionated coconut oil for ophthalmic use. Lotions containing insoluble solids are formulated to leave a thin coating of medicament on the skin. As the vehicle evaporates, it gives a cooling effect and leaves the solid behind.eg calamine lotion and sulphur lotion compound. Bulky, insoluble powders can be formulated as a suspension so that they are easier to take eg Kaolin or chalk
  • 17. ADVANTAGES OF SUSPENSIONSADVANTAGES OF SUSPENSIONS Suspension can improve chemical stability of certain drug. E.g. Procaine penicillin G Drug in suspension exhibits higher rate of bioavailability than other dosage forms. bioavailability is in following order,  Solution > Suspension > Capsule > Compressed Tablet > Coated tablet Duration and onset of action can be controlled. E.g. Protamine Zinc-Insulin suspension Suspension can mask the unpleasant/ bitter taste of drug. E.g. Chloramphenicol palmitate
  • 18. DISADVANTAGEDISADVANTAGE Physical stability, sedimentation and compaction can causes problems.  It is bulky, therefore sufficient care must be taken during handling and transport.  It is difficult to formulate  Uniform and accurate dose can not be achieved unless suspension are packed in unit dosage form
  • 19. Basic requirements of suspensionBasic requirements of suspension 1. The suspended particles should not settle rapidly and sediment produced, must be easily re-suspended by the use of moderate amount of shaking. 2.Satisfactory pourability. 3. Should have an elegant smooth appearance. 4. After gentle shaking, the medicament stays in suspension long enough for a dose to be accurately measured. 5. Constant particle size and size distribution so that the product is free from a gritty texture.
  • 20. Theory of SuspensionsTheory of Suspensions Sedimentation Behaviour Sedimentation means settling of particle or floccules occur under gravitational force in liquid dosage form. Theory of Sedimentation The factors affecting the rate of sedimentation of a particle are described in Stoke’s equation  V= 2r2 (ρ s- ρo ) g or V= d2 (ρ s- ρo ) g  9η 18η
  • 21. Stokes equationStokes equation Where, vsed. = sedimentation velocity in cm / sec d = Diameterof particle r = radius of particle ρ s= density of disperse phase ρo= density of disperse media g = acceleration due to gravity η= viscosity of disperse medium in poise
  • 22. Stokes equationStokes equation The basic consequences of the stokes equation are that the rate of fall of a suspended particle in a vehicle of a given density is greater for larger particles than it is for smaller particles. Also the greater the difference in density between the particles and the vehicle, the greater will be the rate of sedimentation. Increasing the viscosity of the dispersion medium will reduce the rate o sedimentation. Thus decrease in the rate of sedimentation of particles in a suspension may be achieved by reducing the size of the dispersed particles and by increasing the density and viscosity of the dispersion/continuous phase.
  • 23. Factors AffectingFactors Affecting SedimentationSedimentation 1. Particle size diameter (d)  V dα 2  Sedimentation velocity (v) is directly proportional to the square of diameter of particle. 2. Density difference between dispersed phase and dispersion media (ρs - ρo)  V (α ρs - ρo)  Generally, particle density is greater than dispersion medium but, in certain cases particle density is less than dispersed phase, so suspended particle floats & is difficult to distribute uniformly in the vehicle.  If density of the dispersed phase and dispersion medium are equal, the rate of settling becomes zero.
  • 24. Factors AffectingFactors Affecting SedimentationSedimentation Viscosity of dispersion medium ( )η V 1/α ηo Sedimentation velocity is inversely proportional to viscosity of dispersion medium.  So increase in viscosity of medium, decreases settling, so the particles achieve good dispersion system but greater increase in viscosity gives rise to problems like pouring, syringibility and redispersibility of suspensoin.
  • 25. Advantages and DisadvantagesAdvantages and Disadvantages due to viscosity of mediumdue to viscosity of medium Advantages High viscosity inhibits the crystal growth. High viscosity prevents the transformation of metastable crystal to stable crystal. High viscosity enhances the physical stability. Disadvantages High viscosity hinders the re-dispersibility of the sediments High viscosity retards the absorption of the drug. High viscosity creates problems in handling of the material during manufacturing.
  • 26. The Sedimentation Behavior of Flocculated andThe Sedimentation Behavior of Flocculated and Deflocculated Suspensions:Deflocculated Suspensions: Flocculated Suspensions Flocculation is a condition which occurs as a result of the lowering of electrical forces of repulsion in a dispersed system , so that the force of attraction predominate. Systems under this condition reduced repulsive forces the dispersed particles to approach each other more closely and form aggregates known as flocs In flocculated suspension, formed flocs (loose aggregates) will cause increase in sedimentation rate due to increase in size of sedimenting particles. Hence, flocculated suspensions sediment more rapidly.
  • 27. Flocculated suspension continuedFlocculated suspension continued  Here, the sedimentation depends not only on the size of the flocs but also on the porosity of flocks. In flocculated suspension the loose structure of the rapidly sedimenting flocs tends to preserve in the sediment, which contains an appreciable amount of entrapped liquid. The volume of final sediment is thus relatively large and is easily redispersed by agitation.  Most stable pharmaceutical suspensions are flocculated.  The suspension appear somehow unsight (unappealing) due to its rapid sedimentation and it presents an obvious clear supernatant. This can be minimised by enlarging the volume of the sediments by the use of flocculating agents eg starch, alginates and carboxyvinyl polymers.  Since the sediment is loosly structured, caking or claying does not occur.
  • 28. Deflocculated suspensionsDeflocculated suspensions A deflocculated suspension is one in which the electrical repulsive forces between particles exceeds the attractive forces, the particles are kept apart as individuals affected only by the suspending vehicle. Even when brought together by random motion, they resist collision due to the high surface tension.  In deflocculated suspension, individual particles are settling, so rate of sedimentation is slow which prevents entrapping of liquid medium which makes it difficult to re-disperse by agitation.  This phenomenon also called ‘cracking’ or ‘claying’.  In deflocculated suspension, smaller particles settle slowly and therefore remaining supernatant liquid so supernatant appears cloudy and has a pleasing granular appearance whereby in flocculated suspension, even the smallest particles are involved in flocs, so the supernatant does not appear cloudy.
  • 29. Flocculating AgentsFlocculating Agents Flocculating agents decreases zeta potential of the suspended charged particle and thus cause aggregation (flock formation) of the particles. Examples of flocculating agents are: Neutral electrolytes such as KCl, NaCl. Surfactants Polymeric flocculating agents Sulfate, citrates, phosphates salts
  • 30. Neutral electrolytes e.g. NaCl, KCl besides acting as flocculating agents, also decreases interfacial tension of the surfactant solution. If the particles are having less surface charge then monovalent ions are sufficient to cause flocculation e.g. steroidal drugs. For highly charged particles e.g. insoluble polymers and poly-electrolytes species, di or trivalent flocculating agents are used.
  • 31. Method of Floccules FormationMethod of Floccules Formation The different methods used to form floccules are mentioned below: 1 . Electrolytes Electrolytes decrease electrical barrier between the particles and bring them together to form floccules. They reduce zeta potential near to zero value that results in formation of bridge between adjacent particles, which lines them together in a loosely arranged structure.
  • 32. Method of Floccules FormationMethod of Floccules Formation If we disperse particles of bismuth subnitrate in water we find that based on electrophoretic mobility potential because of the strong force of repulsion between adjacent particles, the system is peptized or deflocculated. By preparing series of bismuth subnitrate suspensions containing increasing concentration of monobasic potassium phosphate co-relation between apparent zeta potential and sedimentation volume, caking, and flocculation can be demonstrated.
  • 33. Method of Floccules FormationMethod of Floccules Formation The addition of monobasic potassium phosphate to the suspended bismuth subnitrate particles causes the positive zeta potential to decrease owing to the adsorption of negatively charged phosphate anion. With continued addition of the electrolyte, the zeta potential eventually falls to zero and then increases in negative directions. Only when zeta potential becomes sufficiently negative to affect potential does the sedimentation volume start to fall. Finally, the absence of caking in the suspensions correlates with the maximum sedimentation volume, which, as stated previously, reflects the amount of flocculation.
  • 34. SurfactantsSurfactants  Both ionic and non-ionic surfactants can be used to bring about flocculation of suspended particles.  Optimum concentration is necessary because these compounds also act as wetting agents to achieve dispersion.  Optimum concentrations of surfactants bring down the surface free energy by reducing the surface tension between liquid medium and solid particles. This tends to form closely packed agglomerates.  The particles possessing less surface free energy are attracted towards to each other by van der- waals forces and forms loose agglomerates.
  • 35. PolymersPolymers Polymers possess long chain in their structures. Starch, alginates, cellulose derivatives, carbomers, tragacanth The part of the long chain is adsorbed on the surface of the particles and remaining part projecting out into the dispersed medium. Bridging between these later portions, also leads to the formation of flocs.
  • 36. Viscosity of SuspensionsViscosity of Suspensions  Viscosity of suspensions is of great importance for stability and pourability of suspensions. As we know suspensions have least physical stability amongst all dosage forms due to sedimentation and cake formation.  So as the viscosity of the dispersion medium increases, the terminal settling velocity decreases thus the dispersed phase settle at a slower rate and they remain dispersed for longer time yielding higher stability to the suspension.  On the other hand as the viscosity of the suspension increases, it’s pourability decreases and inconvenience to the patients for dosing increases.  Thus, the viscosity of suspension should be maintained within optimum range to yield stable and easily pourable suspensions.
  • 37. Different Approaches To IncreaseDifferent Approaches To Increase The Viscosity of SuspensionsThe Viscosity of Suspensions Various approaches have been suggested to enhance the viscosity of suspensions. Few of them are as follows: 1. Viscosity Enhancers Some natural gums (acacia, tragacanth), cellulose derivatives (sodium CMC, methyl cellulose), clays(bentonite, veegum), carbomers, colloidal silicon dioxide (Aerosil), and sugars (glucose, fructose) are used to enhance the viscosity of the dispersion medium. They are known as suspending agents.
  • 38. ThixotropyThixotropy Thixotrophy is a phenomenon or property exhibited by highly floculated preparation in which a preparation is sem-solid at rest (in the absence of shearing forces) but becomes so fluid when tapped or shaken and resumes its original structure after only a few minutes of rest. A thixotropic suspension is the one which is viscous during storage but loses consistency and become fluid upon shaking. A well-formulated thixotropic suspension would remain fluid long enough for the easy dispense of a dose but would slowly regain its original viscosity within a short time.
  • 39. Other Formulation AspectsOther Formulation Aspects Introduciton A perfect suspension is one, which provides content uniformity. The formulator must encounter important problems regarding particle size distribution, specific surface area, inhibition of crystal growth and changes in the polymorphic form. The formulator must ensure that these and other properties should not change after long term storage and do not adversely affect the performance of suspension.  Choice of pH, particle size, viscosity, flocculation, taste, color and odor are some of the most important factors that must be controlled at the time of formulation.
  • 40. Formulation ComponentsFormulation Components The various components, which are used in suspension formulation, are as follows.  API ………….Active drug substances  Wetting agents ………They are added to disperse solids in continuous liquid phase.  Flocculating agents ………They are added to floc the drug particles  Thickeners …………They are added to increase the viscosity of suspension.  Buffers and pH adjusting agents ………They are added to stabilize the suspension to a desired pH range.  Osmotic agents ………They are added to adjust osmotic pressure comparable to biological fluid.  Coloring agents ………..They are added to impart desired color to suspension and improve elegance.  Preservatives ……….They are added to prevent microbial growth.  External liquid vehicle ………They are added to construct structure of the final suspension.
  • 41. wetting Agentswetting Agents Hydrophilic materials are easily wetted by water while hydrophobic materials are not. However hydrophobic materials are easily wetted by non-polar liquids. The extent of wetting by water is dependent on the hydrophillicity of the materials. If the material is more hydrophilic it finds less difficulty in wetting by water. Inability of wetting reflects the higher interfacial tension between material and liquid. The interfacial tension must be reduced so that air is displaced from the solid surface by liquid.  Non-ionic surfactants are most commonly used as wetting agents in pharmaceutical suspension. Non-ionic surfactants having HLB value between 7-10 are best as wetting agents. High HLB surfactants act as foaming agents. The concentration used is less than 0.5 %. A high amount of surfactant causes solubilization of drug particles and causes stability problem.  Ionic surfactants are not generally used because they are not compatible with many adjuvant and causes change in pH.
  • 42. SurfactantsSurfactants Surfactants decrease the interfacial tension between drug particles and liquid and thus liquid is penetrated in the pores of drug particle displacing air from them and thus ensures wetting. Surfactants in optimum concentration facilitate dispersion of particles. Generally we use non-ionic surfactants but ionic surfactants can also be used depending upon certain conditions. Disadvantages of surfactants are that they have foaming tendencies. Further they are bitter in taste. Some surfactants such as polysorbate 80 interact with preservatives such as methyl paraben and reduce antimicrobial activity.
  • 43. SurfactantsSurfactants Polysorbate 80 is most widely used surfactant both for parenteral and oral suspension formulation. Polysorbate 80 is also adsorbed on drug particle and decreases its zeta potential. This effect of polysorbate80 stabilizes the suspension. Polysorbate 80 stabilized suspensions through steric mechanism. At low concentration of polysorbate 80,only partial stabilization of suspension was observed.
  • 44. SurfactantsSurfactants In absence of polysorbate 80, difficulty was observed in re-dispersion of sedimented particles. Polysorbate 80 is most widely used due to its following advantages It is non-ionic so no change in pH of medium No toxicity. Safe for internal use. Less foaming tendencies however it should be used at concentration less than 0.5%. Compatible with most of the adjuvant.
  • 45. Hydrophilic ColloidsHydrophilic Colloids Hydrophilic colloids coat hydrophobic drug particles in one or more than one layer. This will provide hydrophillicity to drug particles and facilitate wetting. They cause deflocculation of suspension because force of attraction is declined. e.g. acacia, tragacanth, alginates, guar gum, pectin, gelatin, wool fat, egg yolk, bentonite, Veegum, Methylcellulose etc.
  • 46. SolventsSolvents The most commonly used solvents used are alcohol, glycerin, polyethylene glycol and polypropylene glycol. The mechanism by which they provide wetting is that they are miscible with water and reduce liquid air interfacial tension. Liquid penetrates in individual particle and facilitates wetting. Co-solvents Used in suspensions Some solvents which themselves have high viscosity are used as co-solvents to enhance the viscosity of dispersion medium: Glycerol, propylene glycol, sorbitol.
  • 47. MIXING PROCEDURESMIXING PROCEDURES THE DISPENSING OF SUSPENSIONSTHE DISPENSING OF SUSPENSIONS  The method of dispensing suspensions is the same for most, with some differences for specific ingredients. 1. Crystalline and granular solids should be finely powdered in the mortar. The suspending agent should then be added and mixed thoroughly in the mortar. Do not apply too much pressure, otherwise gumming or caking of the suspending agent will occur and heat of friction will make it sticky. 2. Add a little liquid vehicle to make a paste and mix well until smooth and free of lumps. Continue with gradual additions until the mixture can be poured into a bottle. Further liquid is used to rinse all the powder into the bottle where it is made up to volume. 3. When water is prescribed as a vehicle, use freshly boiled and cooled water or potable water where permissible
  • 48. VARIATIONSVARIATIONS If the wettinng agents are included in the formulation, add them before forming the paste If syrup and/or glycerol are in the formulation, use this rather than water to form the initial paste If soluble solids are being used, dissolve them in the vehicle before or after making the paste Leave addition of volatile components, colouring or concentrated flavouring tinctures such as chloroform spirit, liquid liquorice extract and compound tartrazine solution until near the end
  • 49. STABILITY OF SUSPENSIONSSTABILITY OF SUSPENSIONS Factors that contribute to appreciable stability of a suspension include: a)Small particle size- reduse the size of the dispersed particle increases the total surface area of the solid. The greater the degree of subdivision of a given solid the larger the surface area. The increase in surface area means also an increase in interface between the solids and liquids leading to an increase in viscosity of a system.
  • 50. STABILITY OF SUSPENSIONSSTABILITY OF SUSPENSIONS b). Increasing the viscosity – increasing the viscosity of the continuous phase can lead to the stability of suspensions. This is so because the rate of sedimentation can be reduced by increase in viscosity. Viscosity increase is brought about by addition of thickening agents to the external phase. In water these must be either soluble or swell. It is important to note that the rate of release of a drug from a suspension is also dependent on viscosity. Of a product. The more viscous the preparation, the slower is likely to be the release of a drug. Sometimes this property may be desirable for depot preparations.
  • 51. STABILITY OF SUSPENSIONSSTABILITY OF SUSPENSIONS C). TEMPERATURE. Another factor which negatively affects the stability and usefulness of pharmaceutical suspensions is fluctuation of temperature. Temperature fluctuations can lead to caking and claying.
  • 52. Quality Control of SuspensionsQuality Control of Suspensions The following tests are carried out in the final quality control of suspension:  Appearance Color, odor and taste  Physical characteristics such as particle size determination and microscopic photography for crystal growth  Sedimentation rate and  Zeta Potential measurement  Sedimentation volume  Redispersibility and Centrifugation tests  Rheological measurement  Stress test  pH  Freeze-Thaw temperature cycling  Compatibility with container and cap liner
  • 53. Special labels and advice forSpecial labels and advice for suspensionssuspensions All pharmaceutical suspensions should be properly labelled. The most important additional information in addition to the product name and directions for use is the inclusion of the direction “shake the bottle well before use” as some sedimentation of medicament would normally be expected. Shaking the bottle will redisperse the medicament and ensure that the patient can measure the accurate dose. Other labelling information include directions to store in a cool place, expiry date.
  • 54. CONTAINERS FORCONTAINERS FOR SUSPENSIONSSUSPENSIONS Choices of packaging of all pharmaceutical products are extremely important aspect of ensuring stability of the product. Suspensions should be packed in amber coloured bottles- plain for internal use and ribbed for external use. There should be adequate air space above the liquid to allow shaking and easy pouring. A 5ml medicine spoon or oral syringe should be given when the suspension is for oral use.
  • 55. Ideal Requirements ofIdeal Requirements of Packaging MaterialPackaging Material It should be inert. It should effectively preserve the product from light, air, and other contamination through shelf life. It should be cheap. It should effectively deliver the product without any difficulty
  • 56. THE ENDTHE END With God all things are possible- matt 19:26 It shall be well