E2 L5 - Suspension Flashcards
Liquid preparations that consist of solid particles dispersed throughout a liquid phase in which the particles are not soluble
Suspension
Biggest issue in solutions
Instability
Need to figure out how we prevent aggregation
Bismuth subsalicyclate
INSOLUBLE SALT – of salicylic acid linked to bismuth caution
Water insoluble salt
Pre grind solid into very fine particles, and suspend into liquid
Benzoic acid – preservative
Magnesium Aluminum silicate – small particle – emulsion (stabilizer)
Suspensions vs. Solutions:
Solubility
Chemical stability
Solution: first order
Suspension: zero order
Palatability (taste)
Eg. Erythromycin estolate oral suspension (more palatable than Erythromycin)
Suspensions vs. Tablets:
Flexibility of dose
Ease of swallowing
Dissolution rate
Suspensions compared to tablets/solutions
Suspension – extra steps to be available to body
Takes time to dissolve into molecular level
Chemical stability: Suspension is still small solid particles – More stable - still a solid
Zero order – independent – slow - suspension
First order – Degrades MUCH quicker - solution
Suspension vs tablet dissolution
Suspension is MUCH quicker and much better dissolved as compared to tablet
Suspension vs Solution vs tablet excretion
Measured in 1 hr
Patients were given same drug in 3 different dosage forms
For a drug to be excreted, it must have been absorbed – best absorption = solution (most quickly)
Tablet most slowly
Take urine 6hrs later – may be different
Solution absorbed fast – already excreted
Tablet might need time to leave – still present
Components of suspension
Active ingredient (solid particles)
Vehicle
Buffer
Preservative
Flocculating agent (Stabilize)
Structured vehicle system (stabilize)
Wetting agent (stabilize)
Antifoaming agent
Flavor and sweetener
Desirable properties suspension
The suspended material should not settle rapidly
The particles that settle to the bottom of the container must NOT form a hard cake, but should be readily redispersed into a uniform mix when the container is shaken
Easy to administer:
The suspension must NOT be too viscous to pour freely from the orifice of the bottle or to flow through a syringe needle
IN THE CASE of an external lotion, the product must be fluid enough to spread easily over the affected area and yet must not be so mobile that it runs off the surface to which it is applied
Particle size remains constant during storage
Settling
Settling
(Stokes law)
Density of what’s suspended (particles) (ps)
(p1) Density of the liquid
How quickly will it drop?
Function of diameter of droplets
Raw suspended phase – raw liquid *(function of gravity) / (18 * n (viscosity of liquid)
- sign means floating
Solid vs liquid – density diff large – settle down quickly
Solid less dense than liquid – will float
Denominator is large -
Micropulverization
10-50 micrometer (most oral and topical suspensions)
High speed attrition or impact mills
Fluid energy grinding
<10 micrometer (Parenteral or ophthalmic suspensions)
Jet milling, micronizing
Shearing action of high-velocity compressed airstreams on the particles in confined space
-Sheer force to break down particles
Spray drying
<5 micrometers
Spray dryer: A cone-shaped apparatus into which a solution of a drug is sprayed and rapidly dried by a current of warm dry air circulating in the cone
Suspension formulation designs
Dispersed phase (solid particles)
Dispersion medium
Types of suspension
Dispersed suspension
Flocculated suspension
Structured vehicle system
Thermodynamic stability
Thermodynamic stability
A suspension is stable when deltaG = 0. This can never be reached in a suspension because we usually want small particles (high deltaA) for rapid dissolution. Over time, a suspension moves toward delta G = 0 by two processes that reduce the surface area (DeltaA) I.e. increase of particle size
Aggregation
Crystal growth
Thermodynamic stability summary
Leave the suspension alone, the system will do its best to bring it to deltaG as possible (aggregates)
Cannot really change this one – intrinsic properties based on liquid/solid
What we CAN do – change surface area
Even if it is aggregating, we try to make aggregation as resistant as possible
Interparticle forces: Van Der Waals
Attractive force
Operates at moderate distance from the surface, but becomes VERY strong close to the surface Formulation factors do not affect van der Waals force
Cannot do too much because they are there by nature
Interparticle forces:
Hydration
Repulsive force
Due to adsorbed water molecules at the surface of a particle. Formulation factors do not affect the hydration repulsive force
Repulsive lead to hydration is there – cannot change that
Interparticle forces:
Electrostatic
repulsive force
Due to surface charge on particles. May be controlled by the formulation.
Dependent on pH – change surface charges to fix repulsive forces
Interparticle forces:
Steric
Repulsive force
Due to adsorbed layer of neutral polymer at the surface of a particle. May be controlled by the formulation.
Can manipulate:
Wrap forces – generated by additional polymer
Net effect of interparticle forces
Y-axis – force between particles
X-axis – distance between particles
Repulsive or attractive force (very small)
Opposite forces
What forces these interparticle forces are made of
Forces are made of repulsive and attractive forces
Two particles – there are both attractive and repulsive forces – the balance depends on how particles will interact, as well as the distance
Dispersed solution:
Make repulsive forces dominant
The particles repel each other and do not aggregate
Problem: particles settle as individual particles. This leads to a dense, compact sediment (cake) which may be difficult to resuspend
**Two schools of thought:*
Perpetual suspension – keep distance as far as possible, make them HATE each other (dispersion)
Repulsive – shaking does not help
Controlled flocculation
Repulsive and attractive forces are in balance
Particles are attracted to each other at the secondary minimum to form aggregates, which are known as floccules
The floccules settle to produce a sediment with a high volume
The type of sediment is easy to redisperse
Floccular suspension – compromise
Bound to get together; cannot beat, just join
Compromise
Not possible to avoid particles getting together – secondary minimum
Net forces are negative signs (attractive) but the extent of force is small (weak)
Floccules
Particles are hanging out, stuck at certain distance, not motivated to come closer, cluster – Flocculation
Because they are clusters, if you leave on the shelf they will all settle down because they are fine
Settle down = large volume
Weak attractive forces – if you shake – will fall apart very easy
Dispersion
Large volume
Particles will all settle down as cluster
Liquid part is clear (supernatant)
See If liquid is cloudy or clear – Clear floc
Look for volume of sediment – sediment large – flocculation
Dispersed vs flocculated presentation
Dispersed looks cloudy because they are still trying to settle
Flocculation is clear because they have already settled
Sediment volume
Not actually volume – a fraction so there is NO unit
Final volume of sediment/volume of suspension
^^Any suspension can have sediment volume
Dispersed Sediment volume: 15 Total: 100 = 15/100 = .15
Floc: 75/100 = .75
Degree of flocculation
sediment volume of test suspension/sediment volume of dispersed suspension
Asks how effective the flocculating agent was
Flocculating agents
The choice depends on the type of drug and type of product
Clay (diluted bentonite magma)
Fine particles
Oral suspension
Appearing on surfaces
Effecting dispersion and attract forces
Alteration in the pH of the suspension (to the region of minimum drug solubility
Parenteral solution
Electrolytes
-Strong barrier
Non ionic or ionic surface active agents
RELISTEN TO GRAPH WITH ALL COMPONENTS
X axis – part of buffering agent – changes pH of solution
Y axis – shows what charges the particles assume
0 axis – shows the sedimentation
Right is showing sediment volume
Positive forces repel each other
Sediment volume is relatively low
Forms a dense cake
Ph is increasing = changes the charges
Starting to become neutral, neutral particles (no longer have positive charges)
Repulsive forces decreasing = balances changing
Particles are no longer repelling based on charges – neutral = BECOME FLOCCULAR
THEREFORE – sediment volume becomes HIGHER
Structured vehicle system
Even if it is possible to resuspend floccules, it is not desirable that a suspension settles too rapidly
-Hinders accurate measurement of dosage
-Esthetically not good
Structured Vehicle
Thicken the dispersion medium and help suspend particles
Polymer: carboxy methylcellulose (CMC), methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, xanthan gum
Clay: Bentonite, magnesium aluminum silicate
Should not interfere with availability of the drug
Should not make the suspension too viscous to agitate pour
Study of flow characteristics
Liquid in shape of cube
Apply force from side
How quickly the liquid will flow
Dv – velocity
Dr – How far the distance travels
Shear rate (how quickly, how far)
(dv/dr)
Force – shear force (F)
More force, more movement
Relatively proportional between shear force and shear rate
Rheology
Newtonian flow
Non-Newtonian flow
-Plastic
-Pseudoplastic
-Dilatant
High shear stress – flow very quickly
Not going when shear rate is very low
Pseudoplastic flow does not have shear stress
Plastic
Pseudoplastic relevant
Lower shear stress – leaving on the shelf not doing anything – thick but not flowing
Start to shake, start to flow
Deviates from linear flow
Newtonian flow
Slope =1/n =1/viscosity
F = F’/A = n*dv/dr
n: viscosity
Ex:
Castor oil (highest viscosity)
Chloroform
Ethyl alcohol
Glycerin 93%
Olive oil
Water (low viscosity)
Non Newtonian - plastic
Typical of flocculated suspensions
f (yield value): Threshold of shear stress necessary to initiate flow. This represents the strength of the attractive force of the secondary minimum “Shear thinning”
Apply shear stress - liquid becomes thinner
Non Newtonian pseudoplastic
Typical of polymer solutions such as methyl cellulose, polyvinyl alcohol, sodium carboxymethylcellulose xanthan
“Shear thinning”
Non Newtonian Dilatant
Exhibited by suspension having a high solids content
“Shear thickening”
-Apply shear stress (shake) - liquid becomes thicker - shear thickening
Thixotrophy definition
Thixis (stirring, shaking) + trepo (turning, changing)
Thixotrophy properties
The ability of a system that was disturbed by an applied shear stress to return to its undistributed structure
Plastic and pseudoplastic (ie. shear thinning) fluids show thixotrophy
At rest, the fluid forms a rigid matrix resembling a gel, which will stabilize suspensions
As shear is applied (by shaking), the matrix relaxes and forms a sol with the characteristics of a liquid dosage form for ease of use
Upon removal of the stress, the sol is returned to the undisturbed gel structure
Dispersed suspension (Stokes law approach) simplified
Aim to achieve very slow rate of sedimentation
Cloudy suspension
Dense sediment
May form non-suspendable sediment
(V=d^2(ps-pi)980/18n)
Controlled flocculation simplified
Rapid rate of sedimentation
Clear supernatant
Large sediment volume
Easily redispersed by shaking
Structured vehicle
May appear as a semi-solid when undisturbed but is fluid when shaken
No sedimentation
Thixotropic
Wetting
Displacement of air from the surface of a particle by the vehicle
Consider water-based (aqueous) vehicle
Consider hydrophilicity or hydrophobicity of the drug particles
Particles are not smooth – very rough surfaces
Air pockets and then particles
Because of air pockets – will float
Density
Rough particle added into water – do not get fully engaged with liquid – air pocket – particle floats
How to fix? Add surfactant
Contact angle
A high contact angle indicates poor spreading and that cohesive forces of the liquid is strong
Contact angle of water on different solids
Contact angle vs hydrophilicity of a solid
Hydrophilic: <90
Hydrophobic: > 90
Hydrophobic angles
Polyethylene, high density
Salicylic acid
Magnesium stearate
Chloramphenicol palmitate
Hydrophilic angles
Potassium chloride
Sodium chloride
Lactose
Caffeine
Acetaminophen
Chloramphenicol
Phenobarbitol
Sulfadizine
Aspirin
Phenaceting
Hexobarbitol
Wetting agent ext.
If a solid has a rough surface with many small pores. Aqueous vehicle will not enter the pores. The pores will remain filled w/air; the particles will float
The best solution is to reduce the surface tension of the aqueous vehicle to allow the water to enter the pore and displace the air
A surface-active agent added to reduce the surface tension = known as a Wetting agent (eg. polysorbate 80)
Molecule in suspension is hydrophobic - air present
Wetting agent is needed
