suspensions -intro to formulations

list the advantages of oral suspensions

Suspended insoluble powders easier to swallow than tablets/capsules

• Uniform dispersal of disperse phase for more effective absorption after dosing

• Good for bulky insoluble powders e.g. Kaolin B.P.

• Insoluble derivative may be more palatable than soluble equivalent

• Insoluble derivative may be more stable in suspension than equivalent soluble salt - Superior chemical stability of dispersed drugs in comparison to solutions

What is Stoke's Law?

expresses the settling velocities of small spherical particles in a fluid medium.

define stokes law

based on stokes law what are some properties you should take into consideration to reduce sedimentation

-particle size

-density between particle size and liquid

-liquid viscoity

what should you do with particle size

Reduce particle size

Particle size may change on storage particularly if there is temperature fluctuation:

solubility may increase as temp. increases, on cooling drug will crystallise out.

what should you do with density difference between particle size and liquids

Reduce density difference between particle and liquid -

Increase liquid density

• Add sucrose, sorbitol, glucose, glycerol or other soluble, non-toxic materials - density modifiers (may also be viscosity modifiers)

what should you do with liquid viscocity

INCREASE IT

- Add a thickening or suspending agent

what is a diffusible solid

does not dissolve in the vehicle but may be mixed with vehicle so that, upon shaking, the powder is evenly diffused throughout the liquid for sufficient time to ensure uniform distribution in each dose.

examples of diffusible solids

light kaolin, light magnesium carbonate

what is an indiffusible solid

- a solid is regarded as indiffusible when it does not remain evenly distributed in the vehicle long enough to ensure uniformity of the measured dose

what must be done to the vehicle which contains an indifusable solid

increase the liquid's viscoity and use a suspending agent

list 5x things that a suspending agent/thickener must be

• Should readily dispersed when added to water

• Shouldn't interfere with dissolution or absorption of drug

• Should ensure uniform distribution of insoluble material

• Should be inert, non-toxic and free from incompatibilities

Free from microbial contamination

• Readily available and inexpensive

list 3x types of suspending agents

• Polysaccharides

Hydrated silicates • Carbopol

what are the 2 forms of a polysachharide thickener

-naturally occuring

-Water-soluble celluloses (semi-synthetic)

example of a naturally occuring polysaccharide that is used as a thickner

• Acacia gum (gum arabic, from acacia tree)

acacia gum

-often used for

-solubility

-sticky/not sticky

-dense powders or no

-

Often used as a thickening agent for extemporaneously prepared oral suspensions (in a concentration of 5-15% w/v)

- Soluble 1 in 2.7 water

- Very sticky - not used for external preps.

- Not very good for dense powders but often used in combination with other thickeners as in Compound Tragacanth Powder BP which contains acacia, tragacanth, starch and sucrose

what happens to acicia mucilage on storage

becomes acidic

example of a semi-synthetic suspending agent

xanthan gum

how is xanthan gum produced

(produced by fermentation of glucose or sucrose by the Xanthomonas campestris bacterium

what is xanthan gum comonly used in

Widely used in oral and topical products

xanthan gum

-stability at temp and pH

-solubility

-

- Good stability and viscosity over a wide temperature (10- 60oC) and pH (3-12) range

- Soluble in cold or warm water

What is mucilage?

a mucilage is a preprepared solution containing the powdered gum and water

-it contains no API,colouring or flavouring agents

-the mucilage can then be used to make up a solution

tragacanth is it a natural gum

yes

what products is tragacanth used for

internal and external products

tragacanth solubility

insoluble in water but swells rapidly in 10 times its own weight of hot or cold water to produce viscous colloidal sols or semigels

how long does it take tragacanth to achieve maximum viscocity after dispersion in water

7 days

What does thixotropic mean?

viscosity that decreases when a stress is applied

recovers over time

what should you first add tragacanth to to prevent clumping

disperse the powder in alcohol

This coats the outside of the particles and makes it easier for water to hydrate the individual paricles

how is tragacanth mucilage prepared

with alcohol and chloroform water (1.25% tragacanth) and the proportion used as a suspending agent is one-quarter of the volume of the mixture

what is thixotropy

a type of non-newtonian flow

what is newtonian flow

-rate at which is moves is dircelty proportinal to the

-sheer stress/force applie and sheer rate are dirclty protportional

what is pseudoplastic flow

• Rheogram starts at the origin, flows when stress is applied

• Viscosity decreases as shear stress increases

• Pseudoplastic flow called shear rate thinning.

• Viscosity can only be calculated from slope of tangent at a specific point of curve.

• Aqueous dispersions of suspending agents, emulsions

basic explaination of pseudoplastic flow

The more force you stress this mmaterial the lower the viscocity becomes

You are thining out the forulation when yiu increase the stress applied

This could be due to polymer presenc

what are the structural reasons for pseudoplastic flow

orientation

extension

deformation

destruction of aggregates

Thixotropy

If you shake a suspension formulation the longer you shake the lower the viscoity will decrease

If you remove the stress the viscocoty will recover

Fir a suspension formulation the viscocity will drop but not

Explain thixotropy

-

gel like when unsheared

▪ apply energy (shear stress) bonds break and viscosity falls (called gel-sol formation)

▪ remove stress - bonds reform

▪ time to reform will vary (minutes to days)

▪ time to reform related to the length of time material is subjected to shear stress (plus other factors)

what is alginic acid

Swells in water but does not dissolve - absorbs 200-300 its own weight of water -

Alginate mucilages must not be heated above 60 oC - depolymerization occurs with loss of viscosity

- Sodium alginate is the most widely used salt (1-5% w/v) - anionic - will be incompatible with cationic materials ; slowly soluble in water giving viscous colloidal solution

what is starch used with

One of constituents of Compound Tragacanth Powder • Can be used with sodium carboxymethylcellulose

list 4 water soluble celluloses

Methylcellulose

Hydroxyethylcellulose

Sodium carboxymethylcellulose

methylcellulose

2% solution of methylcellulose 20 has a kinematic viscosity of 20 cS while a 2% solution of methylcellulose 4500 has a kinematic viscosity of 4500 cS

- Concentration used depends on viscosity grade 0.5 - 2%

- More soluble in hot than cold water - often dispersed in warm water and on cooling with stirring a clear or opalescent viscous solution is produced -

Methylcellulose preparations are best prepared by dispersion in about one-third to one-half the total volume of hot water, followed by the addition of the remaining water as ice water or ice

hydroxylcellulose

-what is replaced

-solubility

- Hydroxyethyl instead of methyl on cellulose chains

- Soluble in both hot and cold water

- Similar to methylcellulose

Sodium carboxymethylcellulose

-clarity in solutions

-

- Clear solutions in hot and cold water

- Anionic- incompatible with polyvalent cations, acid precipitates at low pH

- Used at concentrations up to 1%

Name 3 hydrated silicates that can be used in pharmaceutical suspension and gel formulations.

Which of these can be used in oral formulations?

Bentonite

Magnesium aluminium silicate

Hectorite

magnesium aluminium sulphate

what is bentonite

- Clay-like mineral

- Naturally occurring hydrated aluminium silicate (Al2O3 .4SiO2 .H2O)

- Used externally

what is magnesium aluminium sulphate

Used internally and externally

Hectorite

Used externally

what is a carbomer

Synthetic crosslinked polymer of acrylic acid

-the more crosslinking and higher the molecular weight the greater the viscoity of the molecule

what are 3x carbomers

Carboxypolymethylene,

polyacrylic acid,

carboxyvinyl polymer

can you use carbomers externallty and internally

Externally and internally (some grades)

what else can be added to a suspension

buffer

colours

flavours,sweetening agents

preservutes

antioxidants

wettinmg agents

what is a wetting agents used for -such as surfactants

- to aid dispersion of suspending agent and/or medicament

- Decrease angle of contact between solid and liquid

-improve contact between suspending agent and improve wetabbility

-if you improve the wetability of the suspendied solid the individiual paricles are nicely dispersed within the liquid and wont have the tendency to lump/clump

suspending agents and suspensions

Surfactants may be used in the formulation to aid dispersion of the solid particles in the liquid.

• This is particularly important if the powder is not readily wetted by the liquid vehicle.

• Surfactants can reduce the interfacial tension between the solid particles and the liquid vehicle.

• The advancing contact angle is reduced, and wetting of the solid particles promoted. Such a system is said to be deflocculated.

What is a deflocculated suspension?

particles aren't close together to begin with, over time break energy barrier and fuse to form cakes

what is a flocculated suspension

the particles clump together

what happens to particles in a suspension

Particles dispersed in a liquid medium may become charged in one of two main ways.

how do particles disperesed in a liquid medium become chagred

Ionic species present in solution may be adsorbed at the surface or, alternatively charges on the surface may arise due to ionization of groups (such as carboxyl groups for example) which may be located at the surface.

what does the surface charge of the particle show

The surface charge will influence the distribution of ions in the aqueous medium surrounding the solid particles.

what is the electric doubkle layer

If the surface charge is negative, immediately adjacent to the surface will be a region of tightly bound solvent molecules and positive counter ions. Thus, the first layer is tightly bound, while the second layer (which still contains an excess of positive ions) is more diffuse.

floculation and net charge

The state of the suspension is determined by how the particles interact with one another.

• If the net force is repulsive, the particles stay suspended; if the net force is attractive, the particles will clump together

• As two particles approach each other in aqueous medium, a weak attractive force exists just beyond the range of the double layer-repulsive forces. This region is responsible for the particle interaction termed ''flocculation.

what happens if repulsion is lowered

If repulsion is lowered, particles will tend to fall into the secondary minimum instead of staying far away from one another, BUT this increases the chances of reaching irreversible aggregation in the primary minimum.

• The more you decrease repulsion, the more particle-particle interaction will occur.

define a flocculation agent

s carry an electrical charge opposite to that of the net zeta potential of the suspended particles.

what does the addition of the flocculating agent cause

The addition of the flocculating agent, at some critical concentration, negates the surface charge on the suspended particles and allows the formation of floccules or clusters, as particles are held loosely together by weak van der Waals forces.

• Since the particles are linked together only loosely, the entrapment of liquid within the flocs increases the sedimentation volume, flocs will not cake and the sediment is easily redispersed by a small amount of agitation/shaking of the suspension.

• Floccules have approximately the same size particles; therefore a clear boundary is seen when the particles settle.

why do you add a flocculating agent

• Since the particles are linked together only loosely, the entrapment of liquid within the flocs increases the sedimentation volume, flocs will not cake and the sediment is easily redispersed by a small amount of agitation/shaking of the suspension.

what is the advantage of flocculation

less tendency of the particles to cake

Explain the process of controlled flocculation using electrolyte as a flocculating agent.

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.

• The absence of caking in the suspensions correlates with the maximum sedimentation volume, which reflects the amount of flocculation.

can a surfactant be used as a flocculating agent

yes

must be used at the right concnetration

surfactants and controlled flocculation

An electrostatic attraction of surfactant ions to oppositely charged sites on the particle surface results in a lowering of the electrical energy barrier to the close approach of two particles to each other.

- Flocculation may also occur by a bridging mechanism. A long (usually polymeric) surfactant molecule containing functional groups at various sites may adsorb onto sites on the surface of adjacent particles, holding the particles together in a loose arrangement.

- Or, if the surfactant molecules adsorb in such a manner that the molecule extends into the liquid phase, interaction of the extended portions of surfactant molecules adsorbed to different particles result in bridging of those particles.

under what circumstances would an emergency suspsnesion need to be formulated

Compounders may be required to produce a suitable liquid preparation for patients who cannot swallow capsules or tablets

• The pure drug powder (API) may not be readily available

• If liquid formulation is not available may have to compound liquid formulation from available dosage forms

• Crushing of tablets or opening capsules to provide powdered drug to formulate suspension

what are 3 substances you can use to make a suspension

1-injection

2-crushing of tablets

3-tablet dispersion in the suspension

why might a drug be in an injectable form

The form of the drug in the injectable may not be orally availabledoesnt get absorbed by the body- broken down in GIT

-may need to be an injection as the drug needs to go directly into the blood stream

what happens if the injectable form of the drug is the same as the oral form

IF the injectable form of the drug is the same as the oral form (e.g. same salt form) it can be assumed that the drug will be absorbed from the injectable formulation BUT may get more rapid absorption and higher peak blood levels compared to slower absorption from solid dosage form

-your rate of adsorbtion may vary

-there may be a faster/slower rate of adsorbtion

injectable form of the drug and first pass metabolisism

The oral use of the injectable form of a drug which is subjected to extensive first pass metabolism, resulting in poor bioavailability, may be impractical due to the large volume required

cost and the injectable form of the drug

The cost of giving the injectable form orally may be prohibitive

what is the crushing of tablets

- Crush tablets or open capsules and add the powder to a palatable drink or sprinkle onto solid food - There are few circumstances when this method is appropriate or necessary • Difficult to ensure complete dose has been taken • Practice of nurses or carers handling powdered drug may present health concerns

what is the most frequenct method for emergency suspension formulation

- The most frequently used method is to grind the required number of tablets to a fine powder in a mortar and form a slurry by adding a small volume of water(concentrated suspension)

what do you add to the ground tablet forms

Excipients such as antimicrobial preservatives, suspending agents and flavouring agents are added to make a final product

- Other agents sometimes include buffer systems to provide the pH for drug stability or activity of the antimicrobial preservati

why is it important to make a suspension and not a solution from dissolved tablets

ltration may remove significant amounts of drug if extraction from tablets is incomplete

-