multiphasic liquid dosage forms suspensions

what are disperse systems (dispersions)?

they are heterogeneous systems - systems containing particulate matters or globules distributed throughout a medium

-particles in liquid = solutions

-globules in liquid = emulsions

• contains two phases:

  • dispersed phase (internal phase)

    • usually the suspended particles

  • continuous phase (dispersing phase/dispersion medium)

    • usually the suspension liquid

• black dots are the drug (dispersed phase)

• the blue is water (continuous phase)

classification of liquid dispersion systems

molecular dispersion

• < 1 nm

• particles invisible in electron microscope, undergo rapid diffusion

• ex: glucose solution, saline

classification of liquid dispersion systems

colloidal dispersion

• 1-500 nm

• particles invisible in ordinary microscope but seen under electron microscope, diffuse very slowly

• ex: milk, fog, paint, colloidal polymer, dispersions

classification of liquid dispersion systems

fine dispersion

• 0.5-10 µm

• particles visible under microscope, particles do not diffuse

• ex: magmas and gels

classification of liquid dispersion systems

coarse dispersion

• 10-50 µm

• particles visible under microscope, particles do not diffuse

• ex: blood, suspensions and emulsions

-pharmaceutical suspensions typically fall under this category

what are suspensions?

a dispersion of finely divided solid materials suspended in a liquid medium in which the drug has minimum solubility

• ex: ibuprofen and amoxicillin

suspensions: pharmaceutical applications

oral suspensions

have 2.5-10% (w/v) of solids e.g. antacids, antibiotics

suspensions: pharmaceutical applications

externally used suspensions

have 20% (w/v) of solids e.g. calamine lotion

suspensions: pharmaceutical applications

parenteral suspensions

are generally used for intra-muscular injections and have 0.5-30% (w/v) solids e.g. antibiotics, steroids

suspensions: pharmaceutical applications

topical suspensions

used for delivery of drugs to the eye e.g. anti-inflammatory drugs (Nevanac suspension)

suspensions: pharmaceutical applications

rectal suspensions

used for radiologicals and for treating intestinal disorders

suspensions: pharmaceutical applications

aerosols

formulated as suspensions - solid particles dispersed in a volatile propellant

what are the advantages of suspension dosage forms?

• for insoluble drugs

• reasonably smaller volume than solutions

• greater stability against hydrolysis and oxidation compared to aq solutions

• masking of disagreeable taste of drug

• easier to swallow compared to solid dosage forms (e.g. tablets)

• depot therapy - for sustained effect

  • depot: like a warehouse; if you inject a drug into body, it forms a warehouse and slowly releases the drug over a period of time

• topical dosage form for water insoluble drugs

how can you have greater stability against hydrolysis and oxidation in a suspension dosage form?

• solutions are more prone to oxidation and hydrolysis

• suspensions are less prone to oxidation and hydrolysis

  • reactions do not take place in solids because there is no molecular mobility

  • in suspensions, the drug is a solid, so not soluble

    • because it is solid, hydrolysis cannot attack the drug because the drug is not in liquid form. the same goes for oxidation.

what are the disadvantages of suspension dosage forms?

• difficulty maintaining uniformity and accuracy of doses

• sedimentation followed by compaction of particles

• loss on storage and transport

• usually more difficult manufacturing process compared to simple dosage forms

• major problem associated with suspensions:

  • inadequate dispersion of the particles in the vehicle

  • settling of the dispersed particles

  • caking of these particles in the sediment that resists re-dispersion

what are the desired features of suspensions?

• should settle slowly but re-disperse quickly upon only mild shaking

  • ideally, you don’t want any settling

    • second best is it settling slowly, but it must re-disperse quickly

• should avoid forming hard cake

• easy to pour (from bottle), easy to spread (on the skin) or easy to flow (through syringe needle)

• must remain sufficiently uniform for at least the period between shaking the container and removing the required doses

• sufficient physical, chemical and microbiologic stability

• pleasant taste

which of the following route of administration typically does not involve application of pharmaceutical suspensions?
a) topical

b) intramuscular

c) intravenous

d) rectal

c

which of the following is NOT a desired feature of pharmaceutical suspensions?

a) settle slowly and redisperses quickly

b) cakes quickly

c) uniformity

d) sufficient physical & chemical stability

b

flocculation and deflocculation

• focus on the height of sedimentation

• for flocculated suspension, the particles settle fast, and is not as compact as the deflocculated suspension

• for deflocculated suspension, while it takes more time for the sediments to settle, they are more compact

is flocculation desirable in preparation of suspension?

desirable

• there is no caking

• flocculation = settle quickly, less compacting

types of suspensions

flocculated suspensions

• particles are in the form of flocs or aggregates (close to one another but not touching each other)

• weakly bonded

• rapid sedimentation

• easily resuspendable

• resists complete settling

• less prone to compaction

types of suspension

deflocculated suspensions

• particles are in a finely divided state

• settle slowly

• closely packed arrangement

• form hard cake

• difficult to redisperse if caking occurs

properties of suspension

what is viscosity (η)?

is the ratio of force applied (shearing stress, F) to the rate of flow (rate of shear, G) of a liquid

η = F/G

G = F/η

• viscosity influences the physical stability of suspensions

classification of flow

newtonian flow

slope = 1/η

larger the slope, lower the viscosity

• ex: water

classification of flow

non-newtonian plastic flow

B>A

you have to provide a certain minimum force for the liquid to move/flow

• ex: ointments

  • when you invert an ointment (will not move)

    • you use your finger(s) to spread it on skin that it moves(flows)

    • when you stop spreading the ointment, the ointment remains on the part of the skin it was left on without moving (force)

classification of flow

non-newtonian pseudoplastic flow

B>A

there is no minimum force to begin with, but it just starts going and going

• ex: cream

  • when inverting cream in a jar, it will most likely not flow out

    • but applying only the slightest of force will make it flow

classification of flow

non-newtonian diatant flow

A>B

when you first apply force, it goes linearly, but then you apply too much, it starts to plateau

• ex: toothpaste

  • has high solid contents

    • when trying to make toothpaste, you should not apply too much force as it can make the material resist the flow (converting the material into a hard solid mass)

what kind of flow does most flocculated suspensions demonstrate?

non-newtonian pseudoplastic flow

what kind of flow does most deflocculated suspensions demonstrate?

non-newtonian dilatant flow

the greater the slope…..

the smaller the viscosity

• makes the flow nicer (better)

• essentially, B should be greater than A to be better

what is thixotropic flow?

gel → sol

• when force (shear stress) is applied, it will convert into a liquid with time

sol → gel

• when leaving the sol alone (on standing), it will convert back into gel with time

THIXOTROPIC IS A DESIRABLE PROPERTY IN SUSPENSIONS

what are the methods of preparation for suspension formulation?

1. deflocculated suspension: using a suspending agent to prepare deflocculated suspensions

2. controlled flocculation using flocculating agents

3. flocculated suspension in a structured vehicle

the main steps in the preparation of suspension

1. reduce the particle size (fine particle size)

2. add wetting agent to disperse the suspended particles

• wetting agent: to reduce the surface tension of water so that it spreads, wets, and penetrates surfaces instead of beading up and running off

  • helps it disperse into the surface

after adding the wetting agent and dispersing the particles, one of three things can happen

1. addition of suspending agent

• the job of suspending agent is to increase the viscosity

  • in doing so, it will dispense nicely and dispense slowly (deflocculated suspension)

2. addition of flocculating agent

• this agent causes flocculating formation

  • creates flocculated suspension from that formation

3. addition of flocculating agent then addition of suspending agent

• essentially a flocculated suspension in a structured vehicle

  • means there will be an increase in viscosity of flocculated suspension

    • flocculated suspensions are desirable because they give you stable suspensions

      • the addition of suspending agent makes the suspension more desirable by having the settlement of sedimentation be slower

which of the following accurately characterizes colloidal dispersions?

a) particles diffuse very rapidly

b) particles diffuse very slowly

c) particles invisible in electron microscope

d) particles visible in ordinary microscope

e) particle size range is 0.5-10µm

b

the graph shown below is an example of __________

a) newtonian flow

b) plastic flow

c) pseudoplastic flow

d) dilatant flow

c

what are wetting agents?

wetting: vehicle completely touching solute particles

contact angle (ϴ)

• angle between a liquid and the surface over which it spreads

• ranges from 0 to 180 degrees

• low contact angle means high wetting

• wetting is most important for the initial dispersion during the preparation of an insoluble powder in a vehicle

• e.g. alcohol, glycerin, surfactants

  • alcohol and glycerin occupy the air spaces (top example)

    • alcohol can dissolve both organic phase and aq phase

      • means that alcohol and glycerin can interact with the particle and interact with the water (pulling the particle inside, towards water)

what is the point of suspending agents?

• to reduce the rate of sedimentation

• to enhance the appearance of the suspension

• the concentration of suspending agents is usually 0.5-5% w/v

• the suspending agent should preferably exhibit pseudoplastic flow and thixotropy

types

• natural hydrophilic polymers e.g. tragacanth, xanthum gum, acacia

• synthetic hydrophilic polymers e.g. methyl cellulose, carboxyl methyl cellulose

• clays e.g. bentonite, veegum

what is controlled flocculation?

• flocculating agents are added to reduce and control the particle surface charge to an optimum level

  • assures particle dispersion for sufficient period of time and prevent formation of a compact sediment that is difficult to redisperse

• flocculating agents:

  • electrolytes

  • surfactants

  • polymers

1. electrolytes as flocculating agents

• electrolytes act by reducing the electrical barrier between the particles

  • sodium phosphate, potassium chloride

• important points when choosing flocculating agents:

  • the surface charge of the drug particles

  • the valency of the electrolyte

  • electrolyte concentration

• you can bring the particles closer together by reducing the charge density on the particle

2. polymers as flocculating agents

• high molecular weight compounds

• particularly useful for drugs that do not carry a charge

• acts as flocculating agents by the adsorption of the polymer chains on the particle surface while the remaining parts of the polymer chain project outside. interaction between these protect polymer chains forms a bridge leading to flocs

• can mark the charge on the particles, if the drug particle is charged

  • ex: xanthum gum and polycrylamide

3. surfactants as flocculating agents

• ionic surfactants act as flocculating agents by reducing the charges on the particle surface similar to electrolytes e.g. docusate sodium

• non-ionic surfactants as a flocculating agents by forming a protective layer around to particles e.g. tweens or spans

oral suspension - antacid aluminum hydroxide

aluminum hydroxide gel use?

drug

oral suspension - antacid aluminum hydroxide

sorbitol solution use?

sweetener and viscosity modifier

oral suspension - antacid aluminum hydroxide

syrup use?

sweetener and viscosity modifier

oral suspension - antacid aluminum hydroxide

glycerin use?

wetting agent

oral suspension - antacid aluminum hydroxide

methylparaben use?

preservative

oral suspension - antacid aluminum hydroxide

propylparaben use?

preservative

oral suspension - antacid aluminum hydroxide

flavor use?

flavoring agent

oral suspension - antacid aluminum hydroxide

purified agent use?

vehicle

evaluation of suspensions - Stoke’s Law

rate of sedimentation

where:

• d is the diameter of dispersed particle

• η is the viscosity of the dispersion medium

• g is the gravitational acceleration (m/s²)

• ⍴_s is the mass density of the particles (the dispersed phase) (kg/m³)

  • suspended media

• ⍴_o is the mass density of the fluid (the dispersion medium) (kg/m³)

  • outside media

Stoke’s law and rate of sedimentation

as diameter of particles, d increases …..

V (sedimentation rate) increases, faster sedimentation

Stoke’s law and rate of sedimentation

as density of internal phase, ⍴_s increases …

V (sedimentation rate) increases, faster sedimentation

Stoke’s law and rate of sedimentation

as density of external phase, ⍴_o increases …

V (sedimentation rate) decreases, slower sedimentation

Stoke’s law and rate of sedimentation

as viscosity of medium, η decreases …

V (sedimentation rate) decreases, slower sedimentation

suspension stability

• the suspension should be redispersible on shaking

• a relatively narrow particle size distribution forms a good stable suspension

  • if we were to have a broad particle size distribution, it will create gaps which is not good because it create cake compact. that’s why we want narrow.

• drugs in suspension can undergo polymorphic conversion on storage

• change in pH of the dispersion medium can cause precipitation

  • pH must be kept in certain range so the particle does not dissolve

• drastic change in temperature can alter suspension stability

  • at high temps, molecular mobility is higher

    • might cause the particles to bombard each other and even grow in size

  • at low temps, the particles will be trapped

    • trapped in ice, so flocculation formation (if you have any) will be lost

packaging and storage

• all suspensions should be packaged in wide-mouth containers having adequate airspace above the liquid to permit thorough mixing by shaking and ease of pouring

• most suspensions should be stored in tight containers protected from freezing, excessive heat, and light

• it is important that suspensions be shaken before each use to ensure a uniform distribution of solid in the vehicle and thereby uniform and proper dosage

correctly identify the mechanism by which polymers acts as flocculating agents.

a) by reducing the electric barrier between the suspended particles

b) by adsorption on the particle surface

c) by forming a protective layer around the particles

d) by increasing the electric barrier between the particles

b