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Dosage II > E2 L5 - Suspension > Flashcards

E2 L5 - Suspension Flashcards

1
Q

Liquid preparations that consist of solid particles dispersed throughout a liquid phase in which the particles are not soluble

A

Suspension

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2
Q

Biggest issue in solutions

A

Instability
Need to figure out how we prevent aggregation

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3
Q

Bismuth subsalicyclate

A

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)

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4
Q

Suspensions vs. Solutions:

A

Solubility

Chemical stability

Solution: first order

Suspension: zero order

Palatability (taste)

Eg. Erythromycin estolate oral suspension (more palatable than Erythromycin)

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5
Q

Suspensions vs. Tablets:

A

Flexibility of dose

Ease of swallowing

Dissolution rate

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6
Q

Suspensions compared to tablets/solutions

A

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

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7
Q

Suspension vs tablet dissolution

A

Suspension is MUCH quicker and much better dissolved as compared to tablet

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8
Q

Suspension vs Solution vs tablet excretion

A

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

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9
Q

Components of suspension

A

Active ingredient (solid particles)

Vehicle

Buffer

Preservative

Flocculating agent (Stabilize)

Structured vehicle system (stabilize)

Wetting agent (stabilize)

Antifoaming agent

Flavor and sweetener

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10
Q

Desirable properties suspension

A

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

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11
Q

Settling

A

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 -

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12
Q

Micropulverization

A

10-50 micrometer (most oral and topical suspensions)
High speed attrition or impact mills

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13
Q

Fluid energy grinding

A

<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

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14
Q

Spray drying

A

<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

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15
Q

Suspension formulation designs

A

Dispersed phase (solid particles)

Dispersion medium

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16
Q

Types of suspension

A

Dispersed suspension

Flocculated suspension

Structured vehicle system

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17
Q

Thermodynamic stability

A

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

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18
Q

Thermodynamic stability summary

A

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

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19
Q

Interparticle forces: Van Der Waals

A

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

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20
Q

Interparticle forces:
Hydration

A

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

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21
Q

Interparticle forces:
Electrostatic

A

repulsive force
Due to surface charge on particles. May be controlled by the formulation.

Dependent on pH – change surface charges to fix repulsive forces

22
Q

Interparticle forces:
Steric

A

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

23
Q

Net effect of interparticle forces

A

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

24
Q

Dispersed solution:

A

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

25
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)
26
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
27
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
28
Dispersed vs flocculated presentation
Dispersed looks cloudy because they are still trying to settle Flocculation is clear because they have already settled
29
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
30
Degree of flocculation
sediment volume of test suspension/sediment volume of dispersed suspension Asks how **effective the flocculating agent was**
31
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**
32
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
33
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
34
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
35
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
36
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
37
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)
38
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
39
Non Newtonian pseudoplastic
Typical of polymer solutions such as methyl cellulose, polyvinyl alcohol, sodium carboxymethylcellulose xanthan "Shear thinning"
40
Non Newtonian Dilatant
Exhibited by suspension having a high solids content "Shear thickening" -Apply shear stress (shake) - liquid becomes thicker - shear thickening
41
Thixotrophy definition
Thixis (stirring, shaking) + trepo (turning, changing)
42
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**
43
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)
44
Controlled flocculation simplified
Rapid rate of sedimentation Clear supernatant Large sediment volume Easily redispersed by shaking
45
Structured vehicle
May appear as a semi-solid when undisturbed but is fluid when shaken No sedimentation Thixotropic
46
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**
47
Contact angle
A high contact angle indicates **poor spreading** and that cohesive forces of the liquid is strong
48
Contact angle of water on different solids
Contact angle vs hydrophilicity of a solid Hydrophilic: <90 Hydrophobic: > 90
49
Hydrophobic angles
Polyethylene, high density Salicylic acid Magnesium stearate Chloramphenicol palmitate
50
Hydrophilic angles
Potassium chloride Sodium chloride Lactose Caffeine Acetaminophen Chloramphenicol Phenobarbitol Sulfadizine Aspirin Phenaceting Hexobarbitol
51
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**

Dosage II (25 decks)

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