Suspensions as Dosage Form

dispersed systems

These are a two-phase system and consist of both a liquid outer phase (dispersing phase/dispersion medium/external phase) with an internal phase (solid or liquid, aka dispersed phase)

suspensions

two-phase systems where the external dispersing phase is a liquid while the internal dispersed phase is a fine powder solid

• heterogenous mixture

• particles range in size from 10-50 µm

• components can settle or be filtered

emulsions

two-phase system where the external dispersing phase is a liquid and the internal dispersed phase is fine liquid droplets that are immiscible in the dispersing phase

• type of colloid

• both phases are liquid & immiscible

• particles range from 100nm-10um and can’t be filtered

solution

comprised of a solute fully dissolved in a solvent forming a homogeneous mixture that cannot be filtered

particle size in suspension

10-50 µm

nanosuspension

a specific type of suspension where the particles range from 1-100 nm

colloid

comprised of undissolved particles (dispersed phase) in a dispersing phase forming a heterogeneous mixture where the particles can be either solids, liquids, or gasses and they range in size from 1-500 nm and the components do not settle and cannot be filtered

nanoemulsion

specific type of emulsion where the particles range from 1-100 nm

advantages of nanosuspensions

offer improvements in both absorption of specific drugs and can provide drug delivery benefits.

In the case of pharmaceutical suspensions, the particles in the internal phase are typically _________ soluble drug particles in a liquid dosage form (external phase).

poorly

why do patients shake up suspensions?

to disperse the particles as homogeneously as possible throughout the external phase to allow for measuring out an accurate dose of the mixture before the particles settle

why are powder used?

for drugs that are not stable for extended periods in solution to prevent degradation prior to being given to a patient

properties a suspension should have

• slow enough settling rate to allow a pt to get an accurate dose of the drug after shaking

• drug should be easily redispersed into the external phase after it settles

• particles in suspension need to remain same size over time w/o growing crystals in storage

• suspension needs to be able to pour easily to allow a pt to easily measure the correct dose

why avoid allow particles to settle & form a solid cake at bottom of container?

makes it harder to redisperse into suspension when another dose is needed

how do solid cakes form?

• particles settle to bottom

• weight of liquid slowly compacts them & pushes water out bw particles

• eventually allows particles to fuse & form crystals which makes the suspension exceptionally hard to redisperse

how to resolve problem of solid cake formation in suspension

1. deflocculated suspensions (use a viscous medium to prevent fast settling of the particles)

2. flocculated suspensions (use flocs to prevent the formation of solid cakes)

deflocculated suspension

the viscosity of the dispersion medium is increased to prevent particles from settling to the bottom quickly

• since the dispersion medium is viscous and is both less fluid and coats the particles, it makes it harder for the dispersion medium to be pushed out from between the particles to allow a cake to form

what determines particle settling rate in deflocc suspensions?

particle size

larger particles will settle ________ than smaller particles

faster

flocculated suspension

particles are clumped together in flocs, loosely held together by weak forces (such as van der Waals forces which are weak electrostatic attractions between atoms) to form these flocs

do flocs or particles in a deflocculated suspension settle faster?

flocs

flocs form a _________ that redisperses easily upon shaking

very loose sediment

do flocs group together to form cakes/crystals?

no, since there will be dispersion medium bw flocs

supernatant

clear layer above the flocs if left alone

• contains no particles

• typically similar to water if suspension is an aqueous suspension

• can contain dissolved solutes but won’t contain suspended particles

sedimentation volume

liquid below the supernatant that contains the flocs

how to calc sedimentation volume

calculated by taking the ultimate volume of the sediment (Vu ) over the original volume of the sediment (Vo) to determine the ratio (F) which is the sedimentation volume

what determines the stability of the suspension?

How much the sedimentation volume changes over time

flocs are formed by….

electrostatic interactions and/or by interaction of suspended particles with a polymer.

• Electrostatic interactions arise from charges that develop on particle surfaces, either through ionization of surface groups, selective ion adsorption, or the addition of ionic surfactants

effect of surface charges on particle surface in floc

cause an electrical double layer to form around each particle with a tightly bound layer of counter-ions plus a more diffuse outer layer (zeta potential)

zeta potential

electric potential at the boundary of electrical double layer on particle surfaces in floc

what does zeta potential determine?

how strongly particles repel one another

a high zeta potential keeps particles ________ in a deflocculated suspension

apart

to produce a flocculated suspension, a __________ is added to neutralize or compress the double layer

flocculating agent

effect of adding a flocculating agent

lowers zeta potential enough that repulsive forces are reduced and weak van der Waals attraction can pull particles into loosely bonded floc structures, which remain easily redispersed

flocs can also form via ________

polymer bridging

polymer bridging

coiled polymer chains adsorb onto multiple particles simultaneously, physically linking them together into flocs

stokes’ law

can be used to help us understand the settling rate of particles in a deflocculated suspension. While Stokes’ law is designed around an idealized scenario where all particles are identical perfect spheres and the suspension has very little solid matter suspended, it is still useful to understand the factors that contribute to settling rate

factors that contribute to settling rate according to Stokes’ law

• vertical distance that a particle falls in time

• rate at which the particle falls

• diameter of particle

• density of particles

• density of dispersion medium

• gravity

• viscosity of dispersion medium

the greater the diff bw densities of particles & dispersion medium, the ________ the settling rate

faster

if densities are similar, particles will settle __________

more slowly

particles that are more dense will settle _______ than particles that are less dense

faster

greater viscosity of dispersion medium _________ particles settling in suspension

slows

In order to produce drug particles in the 10-50 µm size range, particles are…

micronized through milling where particles are typically accelerated until they collide with other particles fragmenting them and making them smaller

commonly used viscosity enhancers

● Carboxymethylcellulose (CMC)

● Methylcellulose

● Microcrystalline cellulose

● Polyvinylpyrrolidone

● Xanthan gum

● Bentonite

dissolved drugs may interact w _________ agents or __________ agents prventing them from being absorbed

suspending / flocculating

3 factors w potential to decrease bioavailability of drug by mitigating absorption

1. dissolvability

2. diffusion/transport across intestinal membrane

3. drug interaction w suspending or flocculating agent

rheology

study of flow of materials

• Flow rate carries particular importance for pharmaceutical liquids as a high enough flow rate is needed to shake, mix, and remove a dose of drug from a pharmaceutical liquid

dosage forms such as gels must be more __________ in order to be effective

viscous

key factors when considering use of viscosity enhancers

1. greater density of suspended particles → more support needed to not settle quickly w/in soln (more dense particles will need more viscosity enhancer)

2. if there are more suspended particles, more viscosity enhancing agent will be needed to keep them suspended

wetting agent (aka surface active agent or surfactant)

facilitates particles of insoluble drug moving into & dispersing throughout dispersion medium rather than clumping/floating to urface

• often needed when preparing suspensions of insoluble particles in an aqueous suspension medium

typically, a surfactant will be added to the drug particles in order to ensure…

they are all properly coated

steps of preparing suspension w surfactant

• add surfactant to drug particles

• add resulting mixture to dispersion medium

what wetting agent should not be used for infants?

ethanol

common surfactants

• ethanol

• propylene glycol

• glycerin

preparation of suspension

1. all of the necessary components will be weighed

2. soluble components will be added to the dispersion medium first and insoluble particles will be added to the drug powder

3. wetting agent will be applied to the insoluble particles

4. the dispersion medium will be added to these particles to start forming the suspension before adding all of the dispersion medium and creating the final suspension.

what happens if a suspension needs to be created from a drug tablet/capsule rather than a powder?

the drug powder will either need to be emptied from a capsule or ground in a mortar and pestle from a tablet.

common examples of suspension vehicles

● Ora-Sweet

● Ora-Sweet SF

● Oral-Plus

why must suspension storage be considered?

to prevent degradation of drug in suspension over its lifetime

storage of suspensions

airtight and light-resistant containers and then refrigerated

what systems are typically used for sustained-release suspensions?

resin

ion exchange resins

form a complex w the drug

• this complex is then coated w polyethylene glycol to create plastic exterior & coated w a rate-controlling polymer like ethylcellulose

drug release via sustained-release ion exchange resin is dependent on exchanging _____ for the drug

Na+ or H+

effect of making drug release dependent upon exchanging Na + or H

keeps the drug from being released during storage, but allows slow drug release in gastric acid (H + rich)

liquid crystalline phases in sustained-release suspensions

particles then must be dissolved in order to be absorbed and this allows slow release due to slow dissolution. This is most commonly used for injections in areas with low aqueous fluids (like IM injections) where this process will occur slowly

when are liquid crystalline phases (sustained-release suspensions) commonly used?

injections in areas w low aqueous fluids (like IM injections) where process occurs slowly

Since suspensions need to be shaken, containers for suspensions should always have _________ to allow for good mixing of the suspension when shaken

air space