Definition
A
suspension is a two phase system composed of a solid material dispersed in a
liquid. The liquid can be oily or aqueous. However, most suspensions of
pharmaceutical interest are aqueous.
Advantages
Suspensions
offer distinct advantages _ they are as follows:
1. Stability: Some drugs are not stable in solution form. In such cases it is
necessary to prepare an insoluble form of that drug. Therefore drugs are
administered in the form of suspension. e.g. Procaine Penicillin G.
2. Choice of solvent: If the drug is not soluble in water and solvents other than water are
not acceptable, suspension is the only choice. e.g. Parenteral corticosteroid.
3. Mask the taste; In some cases drugs are made insoluble and dispensed in the form of
suspension to mask the objectionable taste. e.g. Chloramphenicol base is very
bitter in taste, hence the insoluble chloramphenicol palmitate is used which
does not have the bitter taste
4. Prolonged action: Suspension has a sustaining effect, because, before absorption the
solid particles should be dissolved. This takes some time. e.g. Protamine Zinc
Insulin and procaine penicillin G.
5. Bioavailability: Drugs in suspension exhibit a higher bioavailability compared to other
dosage forms (except solution) due to its large surface area, higher
dissolution rate. e.g. Antacid suspensions provides immediate relief from
hyperacidity than its tablet chewable tablet form.
Types of
suspensions
The
pharmaceutical suspension preparations are differentiated into suspensions,
mixtures, magmas, gels and lotions.
Suspensions
Simple
suspension is the insoluble solid dispersed in a liquid. The stability
considerations suggest that the manufacture of drugs in dry form is ideal. They
are reconstituted as suspensions using a suitable vehicle before
administration.
Few
examples are:
i)
Dispersible tablets of antibiotic, amoxycillin (e.g. PRESSMOX)
ii) Procaine penicillin G powder
(E.G. PENIDURE)
Gels
Gels
are semisolid systems consisting of small inorganic particles suspended in a
liquid medium. It consists of a network of small discrete particles. It is a
two-phase system. e.g. Aluminum hydroxide gel.
Lotions
Lotions
are suspensions which are intended to be applied to the unbroken skin without
friction. e.g. Calamine lotion, hydrocortisone lotion.
Magmas and Milks
Magmas and milk are aqueous suspensions of
insoluble, inorganic drugs and differ from gels mainly in that the suspended
particles are larger. when prepared they are thick and viscous and because of
this, there is no need to add a suspending agent. e.g. Bentonite magma, milk of
magnesia.
Mixtures
Mixtures
are oral liquids containing one or more active ingredients, dissolved,
suspended or dispersed in a suitable vehicle. Suspended solids may separate
slowly on standing, but are easily redispersed on shaking. e.g. Kaolin mixture
with pectin.
Classification of
suspensions
Based
on the proportion of solids, suspensions are empirically classified as dilute
or concentrated systems.
i)
Dilute suspensions : Solid content 2 - 10 %
e.g. Cortisone acetate and prednisolone acetate suspension.
ii) Concentrated suspensions: Solid content 10 - 50 % e.g. Zinc oxide suspension
for external use, Procaine penicillin G injection, Antacid suspension etc.
Depending
on the nature and behavior of solids suspensions are classified as flocculated
and deflocculated.
Deflocculated
suspension
In
this system, solids are present as individual particles.
Flocculated
suspension
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In
this system, particles aggregate themselves by physical bridging. These flocs
are light, fluffy conglomerate which are held together by weak van der Waal’s
forces of attraction.
If
the aggregate is an open network it is called floccule. They are fibrous, fluffy, open network of particles. It
is loosely packed after sedimentation.
If
the aggregate is a closed one - it is called coagule. They are tightly packed, produced by surface film bonding.
TABLE: Comparison between
Deflocculated and Flocculated System
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Deflocculated System
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Flocculated System
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i)
Pleasant appearance, because of uniform dispersion of particles.
ii)
Supernatant remains cloudy.
iii) Particles exist as
separate entities
iv) Rate of sedimentation is
slow, as the size of particles are small.
v)
Particles settle independently and separately
vi) The sedimentation is
closely packed and form a hard cake.
vii) The hard cake cannot be
redispersed.
viii)Bioavailability is higher due to large specific
surface area.
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i)
Somewhat unsightly sediment.
ii)
Supernatant is clear
iii) Particles form loose
aggregates.
iv) Rate is high, as flocs are
the collection of smaller particles having a larger size.
v)
Particles settle as flocs.
vi) Sediment is a loosely
packed network and hard cake cannot form.
vii) The sediment is easy to
redisperse.
viii)Bioavailability is comparatively less due to small
specific surface area.
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Factors affecting
the stability of a suspension
Settling in
suspensions
Brownian movement
Brownian
movement of particles prevents sedimentation. In general, particles are not in
a state of Brownian motion in pharmaceutical suspensions, due to
i)
larger particle size (Brownian movement is seen in particles having
diameter of about 2 to 5 mm (depending on the density
of the particles and the viscosity and the density of the suspending medium.
ii) and higher viscosity of the
medium.
Sedimentation
The
rate of sedimentation of particles can be expressed by the Stoke’s law, using
the following formula:
Where
d is the particle diameter
rs, r l are densities of a particle and liquid respectively.
g is the acceleration of gravity.
h
is the viscosity of the medium.
Stock’s
law is applicable if:
i)
particles are spherical; but particles in the suspension are largely
irregular.
ii) Particles settle freely and
independently.
In
suspensions containing 0.5 - 2 % (w/v) solid, the particles do not interfere
with each other during sedimentation - hence free settling occurs.
Most pharmaceutical suspensions
contain 5 - 10 % or higher percentages of solid. in this cases particles
interfere with one another as they fall - hence hindered settling occurs
and Stoke’s law no longer applies.
Stoke’s
law is applicable to deflocculated systems, because particles settle
independently. However, this law is useful in a qualitative manner in fixing
factors which can be utilized in formulation of suspensions.
1. Particle size
Rate
of sedimentation ¥ (diameter
of particle)2
So
smaller the particle size more stable the suspension. The particle-particle
interaction results in the formation of floccules or coagules where the sedimentation
rate increases. The particles are made fine either by dry milling prior to suspension or wet-milling of the final suspension in a colloid mill or a
homogenizer.
2. Viscosity of
the medium
According
to Stoke’s law:
Rate
of sedimentation ¥ 1 /
(viscosity of the medium)
The viscosity of suspension should
be optimum. Viscosity can be increased by adding suspending agents or
thickening agents. selection of high viscosity have both advantages and
disadvantages.
Advantages
i)
Sedimentation rate is retarded, hence enhances the physical stability
of the suspension.
ii) Inhibits crystal growth,
because movement of particles is diminished.
iii) Prevents the transformation
of metastable crystals to stable crystals.
Disadvantages
i)
Redispersibility of the suspension on shaking is difficult.
ii) Pouring out of the
suspension from the container may be difficult.
iii) Creates problems in the
handling of materials during manufacture.
iv) May retard absorption of
drugs from the suspension.
3. Density
Rate
of sedimentation ¥ (density
of solid - density of liquid medium)
Lesser the difference between the
densities of solid particles and liquid medium slower is the rate of
sedimentation. Since it is very difficult to change the absolute density of the
solid particles so the density of the liquid medium can be manipulated by
changing the composition of the medium. The addition of nonionic substances
such as sorbitol, polyvinylpyrrolidone (PVP), glycerin, sugar, or one of the
polyethyleneglycols or combination of these may be helpful in the manipulation.
If the density of the particles is
greater than the continuous medium the particles will settle downwards, the
phenomenon is known as sedimentation. If the density of particle is
lesser than that of the liquid medium then the particles will move upward - the
phenomenon is known as creaming.
Formulation of
suspensions
The
product must
1) Flow readily from the
container
2) Possesses a uniform
distribution of particles in each dose.
Two
approaches are commonly employed to secure the two requirements,
(i) the use of structured
vehicle t maintain deflocculated particles in suspension. Structured vehicles
are pseudoplastic and plastic in nature; it is frequently desirable that
thixotropy be associated with these two type of flow. Structured vehicles act
by entrapping the particles so that, ideally no settling occurs. In reality
some degree of sedimentation will usually take place. The shear thinning property of these vehicle does however facilitate
the redispersion when shear is applied.
(ii) and the application of the principles
of flocculation to produce flocs that, although, they settle rapidly are easily
redispersed with a minimum of agitation.
Wetting of
particles
The
initial dispersion of an insoluble powder in a vehicle is an important step in
the manufacturing process. Powders sometimes are added to the vehicle,
particularly in large scale operations, by dusting on the surface of the
liquid. It is frequently difficult to disperse the powder owing to an adsorbed
layer of air, minute quantity of grease and other contaminants.
Powders
those are not easily wetted by water and accordingly show a large contact
angle, such as sulfur, charcoal and magnesium stearate are said to be hydrophobic. Powders those are readily
wetted by water when free of adsorbed contaminants are called hydrophilic. e.g. zinc oxide, talc,
magnesium carbonate etc. belong to this category.
When a strong affinity exists
between a liquid and a solid, the liquid easily forms a film over the surface
of the solid. When this affinity is non-existent or weak, the liquid faces
difficulty in displacing the air or other substances surrounding the solid.
Hydrophilic solids usually can be incorporated into suspensions without the use of a wetting agent, but hydrophobic materials are extremely difficult to disperse and frequently float on the surface of the fluid owing to poor wetting of the particles or the presence of tiny air pockets on the surface of the solid particles.
To
reduce the contact angle between
solid and liquid (i.e. increase the wettability) the following agents can be
tried out:
1. Surfactants Solid-liquid interfacial
tension is reduced by incorporating a surfactant with a HLB value between 7 to
9. These are employed to allow the displacement of air from hydrophobic
material and permit the liquid, to surround the particles and provide a proper
dispersion. The surfactant is mixed with the solid particles if required by
shearing. The hydrocarbon chain is preferentially adsorbed to the hydrophobic
surface, with the polar part of the surfactant being directed towards the
aqueous phase.
2. Hydrophilic polymers such as sodium carboxymethyl cellulose, certain
water-insoluble hydrophilic material such as bentonite, aluminum-magnesium
silicates, and colloidal silica, either alone or in combination can be
incorporated in desired concentration. These materials are also used as
suspending agents and may produce a deflocculated system particularly if used
at low concentration.
3. Solvents such as alcohol, glycerol and glycols which are water miscible will
reduce the liquid / air interfacial tension. The solvent will penetrate the
loose agglomerates of powder displacing the air from the pores of the
individual particles thus enabling wetting by dispersion medium.
Method of
selection of a suitable wetting agent
In
order to select a suitable wetting agent Heistand has used a narrow trough,
several inches long and made of a hydrophobic material, such as Teflon, or
coated with paraffin wax. At one end of the trough is placed the powder and the
other end the solution of the wetting agent. The rate of penetration of the
wetting agent solution into the powder can then be observed directly. Greater
the rate of penetration of the solution into the powder better is the wetting
property of the solution.
Rheologic
considerations
Rheologic
consideration are important in
(i) the viscosity of a
suspension as it affects the settling of particles. As viscosity increases rate
of sedimentation of the particles reduces.
(ii) the change in flow
properties of the suspension when the container is shaken and when the product
is poured out off the bottle.
(iii) the spreading quality of the
lotion when applied to the affected area.
(iv) during the manufacture of
the suspensions.
Importance of
suspending agents
The
particles in a suspensions are experiencing bombardment constantly with each
other owing to the Brownian movement. During this type of inter-particular
interaction the particles may circumvent the repulsive force between them and
form larger particles which will then settle rapidly. Suspending agents reduce
this movement of the particles by increasing the viscosity of the medium.
According
to Stoke’s law rate of sedimentation is inversely proportional to the viscosity
of medium. So the settling of the particles , either in flocculated or
deflocculated system, can be slowed down by increasing the drag force on the
moving particles by increasing the viscosity of the medium.
Hydrophilic
polymers such as sodium carboxymethyl cellulose, certain water-insoluble
hydrophilic material such as bentonite, aluminum-magnesium silicates, and
colloidal silica, either alone or in combination can be incorporated in low
concentration as wetting agent.
Hydrophilic
polymers also acts as protective
colloids and particles coated in this manner are less prone to cake than
are uncoated particles.
Cellulose polymers e.g. sodium
carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose.
Proteins e.g. gelatin.
Synthetic polymer e.g. Polyacrylic acid
(Carbopol)
Clays essentially hydrated aluminum
and/or magnesium silicates are also useful in suspension formulation.
Characteristics of
ideal suspending agent
(i) An ideal suspending agent
should have a high viscosity at negligible shear; i.e. during shelf storage;
and it should have a low viscosity at high shear rates, i.e. it should be free
flowing during agitation, pouring and spreading
on the skin.
(ii) Suspending agents should
coat the particles which will be less prone to caking than the uncoated
particles.
Pseudoplastic
substances e.g. tragacanth, sodium alginate and sodium carboxymethylcellulose
show these desirable qualities. It is a shear thinning system, i.e. when this
type of system is shaken or agitated the viscosity diminishes.
A
suspending agent that is thixotropic as well as pseudoplastic should prove to
be useful since it forms gel on standing and becomes fluid when disturbed. e.g.
Bentonite - Carboxymethylcellulose has both pseudoplastic and thixotropic
behavior.
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Suspending agent
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Concentration in which
generally used
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Sodiumcarbxymethylcellulose
Tragacanth
Guargum
Carbopol
934
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0.5 - 2.5 %
1.25
%
0.5
%
0.3
%
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Controlled
flocculation
Assuming
that the powder is properly wetted and dispersed attention may now be given to
the various means by which controlled flocculation may be produced so as to prevent compact sediment which is difficult
to redisperse. Controlled flocculation can be described in terms of the
materials used to produce flocculation I suspensions, namely, (i) electrolytes,
(ii) surfactants, and (iii) polymers.
(i) Electrolytes act as flocculating agents
by reducing the electric barrier between the particles, as evidenced by a
decrease in the zeta-potential and formation of a bridge between adjacent
particles so as to link them together in a loosely arranged structure.
Example: When bismuth subnitrate is
suspended in water it has been found (by electrophoretic studies) that they
possess a large positive charge, or zeta potential. Because of the strong
forces of repulsion between adjacent particles, the system remains in deflocculated
(peptized) state. The addition of monobasic potassium phosphate (KH2PO4)
to the suspension causes the positive zeta-potential to decrease owing to the
adsorption of the negatively charged phosphate anion. The particles then can
come closer to form aggregates.
On
further addition of KH2PO4 the zeta potential eventually
falls to zero and then increases in a negative direction. Microscopic
examination of the various suspensions shows that at a certain positive zeta
potential, maximum flocculation occurs and will persist until the zeta
potential has become sufficiently negative for deflocculation to occur once
again. The onset of flocculation coincides with the maximum sedimentation
volume determined. F remains reasonably constant while flocculation persists,
and only when the zeta potential becomes sufficiently negative to effect
deflocculation.
(ii) Surfactants both ionic and nonionic,
have been used to bring about flocculation of suspended particles. The
concentration necessary to achieve this effect would appear to be critical
since these compounds may also act as wetting agents to achieve dispersion.
(iii) Polymers are long chain, high
molecular weight compounds containing active groups spaced along their length.
These agents act as flocculating agents because part of the chain is adsorbed
on the particle surface, with the remaining parts projecting out into the dispersion
medium. Bridging between these latter portions leads to the formation of flocs.
hydrophilic
polymers also acts as protective colloids and particles coated in this manner
are less prone to cake than are uncoated particles.
Flocculation in
structured vehicle
Although
the controlled flocculation approach is capable of fulfilling the desired
physical chemical requisites of a pharmaceutical suspension, the product can
look unsightly if F, the sedimentation volume, is not close to or equal to 1.
So a suspending agent is added to retard sedimentation of the flocs. Such
agents as carboxymethylcellulose (CMC), Carbopol 934, Veegum, tragacanth or
bentonite have been employed, either alone or in combination.
These
may lead to incompatibilities, depending on
(i) the initial particle charge
(ii) the charge carried by
flocculating agent and
(iii) the charge carried by
suspending agent.
Preparation of
suspensions
Method
of preparations can be subdivided into two broad categories:
Precipitation
method
There
are three methods
1. organic solvent
precipitation
2. precipitation effected by
changing the pH of the medium and
3. double decomposition
(i)
Organic solvent precipitation
Water
insoluble drugs can be precipitated by dissolving them in water-miscible
organic solvents (e.g. alcohol, acetone, propylene glycol and polyethylene
glycol) and then adding the organic phase to distilled water under standard
conditions produces a suspension having a particle size in the 1 to 5 mm range.
Example: Prednisolone is
precipitated from a methanolic solution to produce a suspension in water.
Disadvantage: Harmful organic solvents may be difficult to remove.
Advantage: In case of parenteral or inhalation therapy very
fine particles are required, which can be prepared by this method.
(ii)
Precipitation effected by changing the pH of the medium
A
drug may be readily soluble at a certain pH and precipitate at another pH. This
type of drug is first dissolved in the favorable pH and then the solution is
poured in another buffer system to change the pH of the medium and the drug
will form a suspension in the medium of the second pH.
Example 1: Estradiol suspensions can
be prepared by changing the pH of the of its aqueous solution; estradiol is
readily soluble in alkali as potassium or sodium hydroxide solutions. If a
concentrated solution of estradiol is thus prepared and added to a weakly
acidic solution of hydrochloric, citric or acetic acids, under proper
conditions of agitation, the estradiol is precipitated in a fine state of
subdivision.
Example 2: Insulin suspension may
also be prepared by pH change method. Insulin has an isoelectric point of
approximately pH5. When it is mixed with a basic protein, such as protamine, it
is readily precipitated when pH is between the isoelectric points of the two
components, i.e. pH 6.9 to 7.3. Protamine-Zinc-Insulin (PZI) contains an
excessive quantity of zinc to retard the rate of absorption. According to the
British Pharmacopoeia phosphate buffer is added to an acidified solution of PZI
so that the pH is between 6.9 to 7.3 to form the suspension.
(iii)
Double decomposition method
In
this method two water soluble reagent forms a water insoluble product.
Example: White Lotion NF is
prepared by slowly adding zinc sulfate solution in a solution of sulphurated
potash to form a precipitate of zinc polysulphide.
Dispersion method
In
this cases the powder form of the drug is directly dispersed in the liquid
medium. The liquid medium should have good power of wetting the powder.
1.
Small scale preparation method
A
suspension is prepared on the small scale by grinding or levigating the
insoluble material in the mortar to a smooth paste with a vehicle containing
the dispersion stabilizer and gradually adding the remainder of the liquid
phase in which any soluble drugs may be dissolved. The slurry is transferred to
a graduate, the mortar is rinsed with successive portions of the dispersion
medium is finally brought to the final volume.
2.
Large scale preparation method
On
large scale dispersion method the solid particles are suspended using ball,
pebble and colloid mills. Dough mixers, pony mixers and similar apparatus are
also employed.
Evaluation of
Suspension Stability
Sedimentation
volume
Since
redispersibility is one of the major considerations in assessing the
acceptability of a suspension, and since the sediment formed should be easily
dispersed by moderate shaking to yield a homogeneous system, measurement of the
sedimentation volume and its ease of redispersion are the two common evaluative procedures.
Definition: The sedimentation volume,
F, is defined as the ratio of the final, or ultimate volume of the sediment
(Vu), to the original volume of the suspension (Vo), before settling. Thus
F = Vu /
Vo
The
sedimentation volume can have values less than 1 to greater than 1. If the
volume of sediment in a flocculated system equals the original volume of
suspension, then F = 1. Such a product is said to be in ‘flocculation
equilibrium’.
Procedure: The suspension is taken in
a measuring cylinder upto a certain height and left undisturbed. The particles
will settle gradually. The value of F is determined from the ratio of the
volume of the sediment at that instant of time (Vu) and the original volume of
the suspension (Vo). The value of F is plotted against time (t). The plot will,
will start at 1.0. at time zero. The curve will either run horizontally or
gradually sloping downward to the right as time goes on.
One
can compare different formulations and choose the best by observing the line,
the better formulation obviously producing lines that are more horizontal
and/or less steep.
If
the suspension is highly concentrated then the suspension is diluted with the
continuous medium (liquid phase) and then the sedimentation volume is
determined.
Degree of flocculation
A
more useful parameter is the degree of flocculation, b.
Definition:
degree of
flocculation is the ratio of ultimate sediment volume of flocculated suspension to that of a deflocculated suspension.
sedimentation
volume of flocculated suspension (F)
b =
sedimentation
volume of deflocculated suspension (F¥)
F¥ = V¥ / Vo F¥ = sedimentation volume of deflocculated suspension
V¥ = ultimate sediment volume of deflocculated suspension
Vo =
original volume of suspension
F =
Vu / Vo F = sedimentation
volume of flocculated suspension
Vu =
ultimate sediment volume of flocculated
suspension
Therefore,
b = F / F¥
= (V¥ / Vo) / (Vu / Vo)
= (V¥ / Vu)
ultimate
sediment volume of flocculated
suspension (Vu)
b =
ultimate
sediment volume of deflocculated
suspension (V¥)
Redispersibility
The
evaluation of redispersibility is also important. To quantitate this parameter
to some extent, a mechanical shaking device may be used. It simulates human arm
motion during the shaking process and can give reproducible result when used
under controlled conditions.
Rheologic methods
Rheologic behavior can also be used to help
determine the settling behavior and the arrangement of the vehicle and particle
structural features for purposes of comparison. The structure of the suspension
changes during storage period. This structural changes can be evaluated by
rheologic method.
A practical rheologic method involves the use of a
Brookfield viscometer mounted on a helipath stand. The T-bar spindle is made to
descend slowly into the suspension, and the dial reading on the viscometer is
then a measure of the resistance the spindle meets at various level in the
sediment. In this technique, the T-bar is continually changing position and
measures undisturbed samples as it advances down in the suspension This
technique also indicates in which level of the suspension the structure is
greater, owing to the particle agglomeration, because the T-bar descends as it
rotates, and the bar is continually entering new and essentially undisturbed
material.
Thus using the T-bar spindle and the helipath, the
dial reading can be plotted against the number of turns of the spindle. The
result indicates how the particles are setting with time. In a screening study
the better suspensions show a lesser rate of increase of dial reading with
spindle turns, i.e. the curve is horizontal for a longer period.
Electrokinetic techniques
Instrument : Microelectrophoresis
apparatus.
Such instrument permit measurement of the migration
velocity of the particles with respect to the surface electric charge or the
zeta potential. Zeta potential correlated well with the visually observed
caking and certain zeta potential produced more stable suspensions because
aggregation was controlled and optimized.
Particle Size
Changes
During
storage or transport the product may experience a fluctuation of temperature
which may lead to crystal growth or physical incompatibilities. Normally it may
take time to check the stability regarding crystal growth. So to accelerate
this effect freeze-thaw cycling technique is particularly applicable. The
product is put into refrigerator and again brought into room temperature ¾ this type of temperature cycling promotes
the growth of particle size. The growth of particle and size distribution are
estimated by microscopic means.
Example(i) The crystal growth of
sulfathiazole in suspensions is found to accelerate after temperature cycling
Example(ii) the preservative and
protective colloid, may have a profound effect on the physical performance of a
suspension under freeze-thaw conditions. Two low solid content steroid
injectable preparations of following compositions underwent freeze-thaw
condition the first preparation showed intense caking while the latter was
unaffected.
Preparation Protective colloid Preservative Result after freeze-thaw
I sodium
carboxy benzyl alcohol Caked badly
methylcellulose
II carboxy
methyl methyl paraben, No caking
cellulose propyl paraben
Example (iii) Gelatin solidifies at low
temperature and methyl cellulose is precipitates in hot water.
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