Suspensions review questions

Question 1

Define suspensions, specific criteria for suspensions with respect to solubility of dispersed phase and classification according to size.

Answer 1

pharmaceutical suspension = fine or coarse suspension w/ finely divided insoluble material suspended in a liquid medium.

Particles are uniformly distributed & minimal solubility in the continuous phase.

The size distribution of the particles ranges from 1 - 100 μm

1 - 50 μm – fine dispersion

50 - 100 μm – coarse dispersion

Question 2

Why formulate suspensions – advantages disadvantages?

Answer 2

Advantages

• Alternative to solid dosage form
• Suitable for patients unable to swallow capsules or tablets
• Solubility- Used to delivery poorly soluble drugs
• Palatability-Used to deliver drugs having unpleasant taste Improved drug stability
• Improved bioavailability compared to solid dosage forms
• Provide sustained release – since it must undergo a dissolution step

Disadvantages

• Sedimentation may occur
• Manufacturing difficulties (large mixing vessels, uniformity of product difficult to maintain)
• Bulkiness of final product (handling and shipping bottles, heavy boxes difficult)

Question 3

Provide the required qualities of suspensions.

Answer 3

Fine uniform sized particles
Uniform distribution of particles in vehicle Slow sedimentation rate

Easily redispersible
i.e., does not form a “hard cake”

Appropriate viscosity
Readily pourable or able to flow through a needle

Question 4

classification os suspenstions by pharmaceutial use

Answer 4

Oral Suspensions: i.e., antibiotics, antacids, radiopaque suspensions

Topical Suspensions: calamine lotion

Parenteral Suspensions [sterile]: i.m., s.c.

Sterile Topical Suspensions: ophthalmic suspensions Cosmetic

Question 5

classification of suspensions by physical structure

Answer 5

Defloculated

• Dispersed particles are small, discrete units.
• The smaller the particle size, the slower the gravitational settling.
  
  • Bc of slow settling, no liquid trapped between particles.
• sediment is compacted and very difficult to redisperse
  
  • “caking” (claying) is a serious physical stability problem.
• The supernatant remains cloudy even after settling occurs.
• recommended for products which must be stored for a long period of time

Flocculated

• Dispersed particles form loose aggregates (flocs).
  
  • repulsive forces are low, particles settle as flocs
• rate of sedimentation is relatively rapid.
• sediment contains trapped liquid between flocs volume of sediment large and “fluffy” (a hard cake doesn’t form).
• The loosely packed sediment is easily redispersed by moderate agitation
• .The supernatant is relatively clear after settling occurs (due to rapid settling).

Question 6

List the essential components of suspensions and their properties. Provide examples for different types of internal and external phases.

Answer 6

Internal Phase (drug, active, or disperse phase)

• Hydrophilic Solids - readily wetted by water
  
  • clays (bentonite, kaolin, talc, magnesium aluminum silicate)
  • hydroxides and oxides of calcium, magnesium, zinc, aluminum & titanium
• Hydrophobic solids - not wetted by water, wetted by oils
  
  • most pharmaceutical substances, charcoal, sulfur, aspirin, phenobarb

External phase (dispersion medium)

• polar, non polar liquids or structured behicles

Question 7

Define structured vehicle. Provide examples and explain how it works.

Answer 7

aqueous solutions of polymeric substances

· protective colloids at low concentrations, while they function as viscosity-inducing agents at higher concentrations

· reduce the sedimentation rate of dispersed particles according to Stoke’s Law

Question 8

Provide examples for polar liquids (hydrophilic solvents) used in suspensions, their approximate usage level and potential issues when used in suspensions.

Answer 8

Water: up to 100%

Alcohol: 3-10%, could solublize drug

Polyols (glycerin): 5-15%, could impart hot acrid taste at higher levels

Glycols (proyplene glycol): 5-10%, unpleasent taste

simple syrup (sucrose): 50-100%: may cause cap locking

Cheryr syrup: 50-100%: May cause cap locking

Sorbitol: 5-10%: improved flavour bodying agent, helps to retard cap locking tendency

Question 9

Define suspending agent. List the different types of suspending agents, their properties and main mechanism of action in suspensions

Answer 9

Excipients that are used to help incorporate solid particle into a liquid vehicle and achieve appropriate physical stability of a suspension

Wetting agents
Deflocculating agents

Flocculating agents

Thickeners

Question 10

Define wetting agent and provide examples.

Answer 10

These can be surfactants, protective colloids or solvents
The purpose for all three types of wetting agents is to allow incorporation of a solid into a liquid by displacing air from the powder surface;

only surfactant can lower the interfacial tension

ex: Glycerine and propylene glycol, alcohol can be used to wet hydrophobic solvents

Question 11

Why use wetting agents to prepare suspensions.

Answer 11

Determine whether the drug particles are hydrophobic or hydrophilic

Hydrophobic drugs, when suspended, will float on the surface of the vehicle. Hydrophobic materials can be wetted by use of a surfactant, which can adsorb at the powder – liquid interface.

-

Question 12

What is the proper method to use wetting agents?

Answer 12

common mistake during compounding of suspensions is to use too much of the suspending liquid in the initial wetting step.

High shear is critical in the initial wetting step.

This is most easily accomplished through a localized high viscosity system (i.e. a thick paste).

After thoroughly wetting the solids with minimal wetting agent, the suspension can be diluted with further portions of the vehicle. Remember, in your initial wetting step, keep it thick!

Question 13

Define deflocculating agent and basis of use in suspensions.

Answer 13

deflocculating agents alter the surface charge of particles by physical adsorption causing repulsion among particles but have no influence on interfacial tension

Question 14

Define flocculating agent, types and basis of use in suspensions.

Answer 14

Electrolytes, ionic surfactants or polymers that can be used to achieve loose aggregation of suspended particles to provide a fluffy, high volume sediment that is easily redispersible (pharmaceutically stable)

Question 15

Define thickeners and basis of use in suspensions. Provide examples.

Answer 15

thickeners = hydrophilic (or protective) colloids

• function to increase the strength of the hydration layer formed around the suspended particles and provide steric hindrance to keep particles uniformly suspended.

The degree of viscosity induced by these agents is concentration-dependent (i.e. the concentration must be high enough to produce a thick preparation)

ex: Polysaccharides: acacia gum, tragacanth, alginates

Ex: water soluble cellulose derivates: methylcellulose, hydroyethylcellulose, sodium carboxymethylellulose, microcrystlaine cellulose

Question 16

thickening agents

Answer 16

* protective colloids, can alter viscosity

Polysaccahides acacia gum tragacanth alginates (only extemporaneous comp bc increases suscpetibility to mmicrobial growth)

water colble cellulose derivates: methylcellulose, hydroxyethylcellulose
sodium carboxymethylcellulose, microcrystalline cellulose

Question 17

Why is wetting necessary for the incorporation of solids into suspensions?

Answer 17

Proper wetting is the first step in the preparation of suspensions.

The liquid must displace the air at the surface of the solid particle before the particle will become wetted.

Question 18

Define contact angle and how it is related to the degree of wetting of solids.

Answer 18

The degree of wetting can be described by the contact angle (θ). Lowering the contact angle indicated better wetting of the solid.

Question 19

Define θ and the interfacial tensions that exist when a droplet is placed on a solid surface

Answer 19

large angle = hydrophobic surface, poor wetting

small angle = hydrophillic surface, better wetting

Question 20

a. Indicate which drop has the highest and lowest contact angle.

Answer 20

highest = C, lowest = b

Question 21

Indicate which drop is most hydrophobic and most hydrophilic.

Answer 21

most hydrophobic = C

most hydrophillic = b

Question 22

Indicate which drop has highest and lowest wettability.

Answer 22

highest wettability = b

lowest wettability = c

Question 23

Indicate how a wetting agent would influence the drop shape.

Answer 23

round drop will faltten and cover surface

Question 24

Explain the influence of interfacial tension and total surface area of the particles on Gibbs surface free energy.

Answer 24

∆ F = γSL ∆ A

The smaller the ∆ F, the more thermodynamically stable the suspension will be at equilibrium.
Surfactant can lower γSL, thereby ↓ lower surface free energy and ↑ stability of the suspension

• to ↓ ∆F: ↓ interfacial tension and /or ↓ interfacial area

Question 25

Identify and explain the changes in energies of interaction between particles and particle behavior/distribution in a suspension with respect to physical stability in context of DLVO theory.

Answer 25

Panel A: attractive forces predominate (primary minimum) particles irreversibly aggregate (coagulate)

Panel B: repulsive forces predominate (primary maximum) within the electrical double layer; particles remain separated and colloidally stable

Panel C: weak attractive forces cause flocculation of particles (secondary minimum); particles loosely aggregate but redispersible (pharmaceutically stable

Question 26

Identify three strategies for the formulation of physically stable suspensions. Which one is the most reliable and practical approach? Why?

Answer 26

• incorporate deflocculated particles into a structured vehicle
• controlled flocculation of particles
• combination of both flocculation and incorporation into structured vehicle
• the combination of flocculation and structured vehicle (of suitable viscosity) is a reliable choice – this provides improved stability by reducing sedimentation as well as good redispersibility

Question 27

What are the requirements for a well-formulated suspension?

Answer 27

• After shaking, the dispersed phase must stay in suspension at least long enough to remove the correct dose for oral preparations and the correct proportion for topical preparations.
• The sediment must be easily resuspendible with moderate agitation.
• The viscosity of the preparation must be low enough to allow for ready removal from the container. (Good flow properties)
• The suspended particles should be uniformly small to appear esthetically smooth and not gritty.

Question 28

When assessing the stability of a suspension which specific parameters are important and how are they determined (only briefly).

Answer 28

1. Physical stability

• Rate of sedimentation
• sedimentation VOlume (V_u/V_o)
• Ease of re-dispersion

2. Rheological assessemnt

• viscosity
• consistency of product

3. Assessment of crystal growth
   * temp cycling produces a stress condition for the suspension

Question 29

In the compounding of suspensions there are several practical considerations that provide guide to achieve a well-formulated product.

List the most important steps

Answer 29

drug particle size

wetting

flocculation

other considerations

Question 30

why is it important to consider drug particle size when formulating suspensions?

Answer 30

• the two most important factors are i) average particle size, and ii) distribution of particle sizes - small average size (1-50μm) and narrow size range is necessary

Question 31

why is wetting important for formulation suspensions

Answer 31

• determine if hydrophobic or hydrophilic (most drugs hydrophobic)
• hydrophobic drugs will float on surface of vehicle, can be wetted by use of surfactants that abs at powder-liq interface

* keep to minimal amount of surfactant bc foaming/ bas taste

• use high sheer in wetting step to create thcik paste

Question 32

describe flocculation in the formulation os suspensions

Answer 32

• want floccualted particles for optimum physical stbaility and uniform drug distribution
• to flocculate suspended particles:
  a) use surfactant
  b) use long chain, high MW polymers Iadsorb by the drug particles to produce surface films capable of binding with each other to form flocs)

* do NOT reduce interfacial and surface tension, so can use surfactants to enhance their functionality

*also act as protective colloids (adsorbed by and coat the particles)

c) Electroyltes, reduce electrical barrier between particles -> DEC Zeta potnetial and allows loose aggregation to form stable floc (last resort)

Question 33

other considerations when formulating suspensions

Answer 33

• microbial stability: some consumers may want without preservatives, can do if only a few days supply and kept in fridge

wide temp ranges can cause recrystalization, solubility fluctuates with temp and can cause caking *keep either refridgerated or at room temp at all times

*chem degredation can happen at elevated temps, check if fridge sticker

*always need shake well label fo suspensions, consider using oversized bottle if have a viscous product

Question 34

What is the reason for caking and what steps would you take to prevent caking of a suspension?

Answer 34

reason :Deflocculated particles

remedy: Induce flocculation, Add flocculating agent Incorporate into a viscous vehicle

Question 35

What is the reason for crystal growth (Ostwald ripening) and what steps would you take to prevent crystal growth in a suspension?

Answer 35

reason: temp fluctuations, heterogenous particle size
remedy: avoid temp fluctuations, make homogenous size

Question 36

What is the reason for flotation of suspended particles and what steps would you take to prevent this in a suspension?

Answer 36

Reason: high interfacial tension, large contact angle

remedy: add surfactant (wetting agent)

Question 37

Explain the reasons for poor redispersibility in a suspension and provide preventative and remedial steps to avoid/fix this major problem.

Answer 37

Reasons: caking, crystla growth, viscosity of vehicle too high (diff to redisperse when shaking)

Remedy: flocculate particles, make sure particle size is unifrom distribution, use optimum viscosity