Dr. Mohammad Javed Ansari, PhD. javedpharma@gmail.comContact info:

COLLEGE OF

PHARMACY

PHARMACEUTICS II

(PHT 312)

OBJECTIVES OF THE LECTURE

• At the end of this lecture, you will be aware of:

• What are disperse systems?

• What are various types of disperse systems?

• What are colloidal and coarse dispersions?

• What are suspensions?

• What are advantages / disadvantages of suspensions?

• What are various stability problems of suspensions?

• How suspensions are stabilized?

19:28

LECTURE OUTLINE

• Disperse system classification.

• Definition of pharmaceutical suspension.

• Advantages / disadvantages, rationale & application.

• Theory of suspension: sedimentation, stability & Brownian

motion.

• The Properties of ideal / optimal Suspensions.

• Classification.

• Formulation aspects.

• Difference between flocculated & deflocculated suspensions.

• Rheological Characteristics.

• Preparation.

• Evaluation.

• Stability.

• Packaging and Storage.

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19:28

Disperse systems 19:28

Pharmaceutical Suspension-Definition 19:28

Advantage/Application of Pharmaceutical Suspensions

• Insoluble drug or poorly soluble drugs which required to be

given orally in liquid dosage forms ( in case of children,

elderly, and patients have difficulty in swallowing solids

dosage forms)

• To over come the instability of certain drug in aqueous

solution: Insoluble derivative formulated as suspension

• (instable) oxytetracycline HCL (stable) calcium salt

A drug that degraded in the presence of water can be suspended in non- aqueous vehicles. Phenoxymethypencillin/ coconut oil and Tetracycline HCL/ oil

• To mask the taste: (to make more palatable)

Paracetamol suspension) and chloramphenicol palmitate.

• Some materials are needed to be present in the

gastrointestinal tract in a finely divided form, to increase

the surface area. Fore example, Mg carbonate and Mg trisilcate

are used to adsorb some toxins

1. Suspensions as oral drug delivery systems

19:28

2. Suspensions for topical administration

They can be fluid preparations, such as Calamine Lotion,

which are designed to leave a light deposit of the active

agent on the skin after quick evaporation of the

dispersion medium.

Some suspensions are semisolid in consistency, such as

pastes, which contain high concentrations of powders

dispersed.

It may also be possible to suspend a powdered drug in

an emulsion base, as in Zinc Cream.

Advantage/Application of Pharmaceutical Suspensions 19:28

3. Suspensions for parenteral use

Suspensions are formulated for parenteral administration in

order to control the rate of absorption of the drug.

By varying the size of the dispersed particles (rate of

dissolution) of active agent, the duration of activity can be

controlled.

In vaccines: e.g. Diphtheria and Tetanus vaccines

4. Suspensions for ophthalmic use: various eye drops

5. Suspensions in aerosol Inhalation therapy.

suspension of active agents in mixture of propellants

6. X-ray contrast media:

oral and rectal administration of propyliodone.

Advantage/Application of Pharmaceutical Suspensions 19:28

Physical stability of suspensions means particles

are uniformly distributed throughout the dispersion.

Settling/sedimentation of particle takes place

gradually over a prolonged period of time, due to

gravitational forces.

Settling/sedimentation can not be stopped

completely, hence factors should be known which

can minimize / slow the settling/sedimentation.

Theory of suspension: Sedimentation, Stability problem 19:28

Theory of suspension: Sedimentation

The velocity of sedimentation is expressed by Stoke’s law. v = d = the diameter of the particle in cm. s = the density of the dispersed phase (particles). o = the density of the dispersed medium. g = the acceleration due to gravity = the viscosity of the dispersion medium in poise.

Larger particles will settle faster at the bottom of

the container.

Thus to slow the sedimentation, particle size should

be reduced by using mortar and pastel.

But very fine particles will easily form hard cake at

the bottom of the container.

d2 (s - o) g 18 o

19:28

Theory of suspension: Brownian Movement

For particles having a diameter of about 2- 5 m

Brownian movement counteracts sedimentation to a

measurable extent at room temperature by keeping the

dispersed material in random motion.

19:28

No sedimentation: Ideally, the particles in a suspension

should not sediment at any time during the storage period.

Easily re-dispersed by gentle shaking and should have the

desired flow (Easy to pour yet not watery).

Homogenous: Must remain sufficiently homogeneous for at

least the period of time necessary to remove and administer

the required dose after shaking.

No Hard cake: The particles which settle to the bottom of the

container must not form a hard cake.

Should be free from gritting particles (external use)

Should be pleasant & Palatable (orally)

Should be chemically & physically stable(Temperature insensitive).

No cap-lock.

The Properties of ideal / optimal Suspensions 19:28

FORMULATION ASPECTS

INGREDIENTS of SUSPENSION

I - Insoluble drug.

II- Vehicle (suspending medium).

III- Wetting agents.

IV- Compounds allowing control of stability and sedimentation

(Flocculating, Suspending agent)

V - Additives used to regulate the flow behavior.

VI- pH regulators

VII- Other additives ( flavour, colour, taste preservatives).

19:28

I- The Insoluble Drug:

• Size of the particles

• Size distribution of the powder.

• Ease of wetting.

• Surface electric charge of the particles in suspension.

• Chemical stability of the drug, and possible interactions and

incompatibilities with other suspension constituents.

Work must be done to reduce solid to small particles and dispersed them in a continuous medium. • An increase in surface free energy W brought about by dividing

the solid into smaller particles and consequently increasing the

total surface area A is given by: W = SL . A

• SL = interfacial tension between the liquid medium and the solid

particles.

• In order to approach a stable state, the system tends to reduce the

surface free energy by decreasing surface area (agglomeration).

19:28

II- The Suspending Medium or Vehicle:

1 - Distilled water or deionized water.

2 - Water- alcohol

3 - Solution of glycerol.

4 – Non-aqueous vehicles (Topical use).

Structured vehicles

• Structured vehicles are vehicles containing thixotropic compounds/polymers like acacia which are pseudo-plastic or plastic in nature.

• Thixotropic compounds/polymers form a three-dimensional gel network structure which entrap the particles so that, ideally, no settling occurs.

• During shaking the gel network is completely destroyed (pseudoplastic and plastic in nature) so that administration is facilitated.

19:28

Structured vehicles 19:28

III- Wetting Agents

It is difficult to disperse solid particles in a liquid vehicle due

to the layer of adsorbed air on the surface.

Thus, the particles, even high density, float on the surface of

the liquid until the layer of air is displaced completely.

The use of wetting agent allows to remove this air from the

surface and to easy penetration of the vehicle into the pores.

Powders, which are not easily wetted by water and

accordingly show a large contact angle, such as sulfur,

charcoal and magnesium stearate are called hydrophobic.

Powders which are readily wetted by water are called

hydrophilic e.g. zinc oxide, talc.

The wettability of a powder may be ascertained easily by

observing the contact angle and spreading coefficient.

19:28

III- Wetting Agents…… 19:28

Sc = S - L - SL Sc = Spreading coefficient S = surface tension of solid L = surface tension of liquid SL= surface tension of solid - liquid interface.

• So for convenient wetting, the value of spreading coefficient

(Sc) should be positive. • This could be achieved by modification of the values of

surface tension of several surfaces involved until a positive value of the spreading coefficient is reached.

• How modification done?? • By adding Wetting agent (surfactant with HLB value 7-9) • Eg. Non ionic surfactant polysorbates

III- Wetting Agents…… 19:28

1 - Surfactants:

• They reduce the interfacial tension between the solid particles and

a vehicle (SL). As a result of the lowered interfacial tension the Sc

will be positive and the contact angle is lowered, air is displaced

from the surface of the particles, and wetting is promoted.

Disadvantages of surfactants are that they have foaming

tendencies.

All surfactants are bitter except Pluronics and Poloxamers.

Polysorbate 80 is most widely used surfactant both for parenteral

and oral suspension formulation.

It is non-ionic so no change in pH of medium

No toxicity.

Safe for internal use.

Less foaming tendencies.

Compatible with most of the adjuvant.

Decreases zeta potential thus stabilizes the suspension

III- Wetting Agents…… 19:28

2 - Glycerin and similar hygroscopic substances

• Alcohol, glycerin, polyethylene glycol and polypropylene glycol

flows into the voids between the particles to displace the air

and reduce liquid air interfacial tension so that water can

penetrate and wet the individual particles.

3-Hydrophilic Colloids

• Hydrophilic colloids coat hydrophobic drug particles

in one or more than one layer.

• This will provide hydro-phillicity to drug particles and facilitate

wetting.

• As most of hydrophylic colloids are negatively charged, they cause deflocculation of suspension because force of attraction is declined. e.g. acacia, tragacanth, alginates, guar gum, pectin, gelatin, wool fat, egg yolk, bentonite, Veegum, Methylcellulose etc.

III- Wetting Agents…… 19:28

IV - Compounds Controlling Stability and Sedimentation

• Suspensions have least physical stability amongst all dosage forms

due to sedimentation and cake formation.

• As per the STOKES LAW sedimentation can be minimized by

increasing viscosity of suspensions.

• When viscosity of the dispersion medium increases, the terminal

settling velocity decreases thus the dispersed phase settle at a slower

rate and they remain dispersed for longer time yielding higher

stability to the suspension.

• On the other hand as the viscosity of the suspension increases, it’s pour ability decreases and inconvenience to the patients for dosing

increases.

• Therefore viscosity of suspension should be maintained within

optimum range to yield stable (slow sedimentation) and easily

pourable suspensions.

Suspending agents / viscosity modifier / Thickener –A

19:28

• Should have a high viscosity at negligible shear, i.e., during storage.

• Should have a low viscosity at high shearing rate, i.e., it should be

free flowing during agitation, pouring, and spreading.

Pseudo-plastic substances such as: Tragacanth, sodium alginate, and

sodium carboxymethyl cellulose show these desirable qualities.

A suspending agent which is thixotropic as well as pseudo-plastic are

useful since it forms a gel on standing and becomes fluid when

disturbed.

Apart from above, suspending agents should also be inert, non-toxic

and compatible with other excipients used in suspensions.

They should be readily dissolved or dispersed in water without need

of special technique.

They should not influence the absorption or dissolution rate of the

drugs.

The Ideal Suspending Agent 19:28

Natural gums (acacia, tragacanth, Xanthan gum ),

Sugars (glucose, fructose)

Cellulose derivatives (sodium CMC, methyl cellulose, MCC),

Alginates & Gelatin

Clays (bentonite, veegum),

Carbomers,

Colloidal silicon dioxide (Aerosil)

Co-solvents Some solvents which themselves have high viscosity are used as co-

solvents to enhance the viscosity of dispersion medium: For example

glycerol, propylene glycol, sorbitol.

Glycerin viscosity is too high to pour easily and to spread on the skin.

It shows the undesirable property of stickiness.

It is too hygroscopic to use in undiluted form.

Suspending Agents….. 19:28

IV - Flocculating Agents • Suspending agents gives too high viscosity which is not desirable

and as it causes difficulty in pouring and administration. Also, it

may affect drug absorption since they adsorb on the surface of

particle and suppress the dissolution rate.

• Although, these structured vehicles reduces the sedimentation of

particles, not necessarily completely eliminate the particle settling.

• Thus, the use of deflocculated particles in a structured vehicle may

form solid hard cake upon long storage.

• The basic concern in developing a suitable suspension is to

adequately control the

• Rate of settling and

• Ease of re-dispersion,

• Prevention of caking the particles as a dense mass.

• The risk of caking may be eliminated by forming flocculated

particles in a structured vehicle which will be easily redispersible.

19:28

IV - Flocculating Agents

• Flocculating agents are added to enhance particle “re-dispersability.

• Flocculation is the formation of light, fluffy groups of particles held

together by weak Van der Waal's forces.

• In contrast to deflocculated particles, flocculated suspensions can

always be re-suspended with gentle agitation.

• The best approach is to achieve a controlled flocculation of the

particles, where they appear as floccules or like tufts of wool with a

loose fibrous structure.

• Controlled flocculation of particles is obtained by adding

flocculating agents, which are (1)-electrolytes (2)-

surfactants (3)- polymers

cake floccules

19:28

• Dispersed solid particles in a suspension may have charge in relation to

their surrounding vehicle, because of-

• Selective adsorption of a particular ionic species present in the

vehicle.

• Ionization of functional group of the particle.

• The ions that gave the particle its charge, are called POTENTIAL-

DETERMINING IONS that serve to repel the particles.

• Immediately adjacent to the surface of the particle is a layer of tightly

bound solvent molecules, together with some ions oppositely charged to

the potential-determining ions, called COUNTER IONS or

GEGENIONS.

• Electrolytes acts as flocculating agents by reducing the

electrical barrier between the particles, thus, decrease the

zeta potential, this leads to decrease in repulsion potential

and makes the particle come together to form loosely

arranged structure (floccules).

IV - Flocculating Agents: Electrolytes 19:28

------

-

---

--

-

- -

--

--

-

-

-

-

- - -

- -

-

-

a-

a

b-

b

c-

c

d-

d

Tightly

bound

layer

Diffusion

layer

Electro-neutral

region

Surface

Counterion Shear plan

------------

--

------

----

--

-- --

----

----

--

--

--

--

-- -- --

-- --

--

--

a-

a

b-

b

c-

c

d-

d

Tightly

bound

layer

Diffusion

layer

Electro-neutral

region

Surface

Counterion Shear plan

Zeta potential is the potential difference between the ions in

the tightly bound layer and the electroneutral region.

Zeta potential governs the degree of repulsion between

adjacent, similar charged, solid dispersed particles.

IV - Flocculating Agents: Electrolytes.. 19:28

Caking diagram, showing the flocculation of suspension by means of the electrolyte

IV - Flocculating Agents: Electrolytes 19:28

If we disperse particles of bismuth subnitrate in water, we find that, they, possess a large positive charge, or zeta potential.

Because of the strong forces of repulsion between adjacent particles, the system is deflocculated.

The addition of monobasic potassium phosphate to the suspended bismuth subnitrate particles causes the positive zeta potential to decrease due to the adsorption of the negatively charged phosphate anion.

With the continued addition of the electrolyte, the zeta potential falls to zero and then increases in a negative direction.

The flocculating power increases with the valency of the ions.

Calcium ions are more powerful than sodium ions because the valency of calcium is two whereas sodium has valency of one.

IV - Flocculating Agents: Electrolytes.. 19:28

• Both ionic and non ionic surfactants could be used to

control flocculation, e.g. Tween 80, Sodium lauryl sulfate.

• The concentration of surfactants necessary to achieve

flocculation is critical since these compounds may also act as

wetting agents to achieve dispersion.

• Optimum concentrations of surfactants bring down the surface

free energy by reducing the surface tension between liquid

medium and solid particles.

• The particles possessing less surface free energy are attracted

towards each other by van der-waals forces and forms loose

agglomerates.

IV - Flocculating Agents: Surfactants 19:28

Polymers like Starch, alginates, cellulose derivatives, carbomers,

tragacanth are long chain, high molecular weight compounds containing

active groups spaced along their length.

These agents act as flocculating agents because part of the chain is

adsorbed on the particle surface with the remaining parts projecting out

in the dispersion medium.

Bridging between these portions leads to the formation of floccules.

Polymers exhibit pseudo-plastic flow in solution promoting the physical

stability of suspension.

Floculating agent

Floccules Solid particles

IV - Flocculating Agents: Polymers 19:28

Flocculated and deflocculated suspensions 19:28

Supernatant

Redispersibility

Sediment

Rheology Viscosity

Suspension

Boundary

Velocity of sedimentation

Sedimented particle

Deflocculated Flocculated

Forms a network like structure

fast fall together

a distinct boundary between sediment and supernatant

clear

Separate individual particles

slow fall according to size

no distinct boundary between sediment and supernatant

turbid

High Low

plastic & pseudoplastic Dilatent

Loosely packed and doesn’t form a cake

Difficult Easy

Closely packed and form a hard cake

Not pleasing in appearance Pleasing in appearance

19:28

Typical buffering agents, flavors, colorants, and preservative used in

suspensions:

Buffer

Flavor

Colorant

Preservative

Ammonia solution

Citric acid

Fumaric acid

Sodium citrate

Cherry

Grape

Methyl salicylatte

Orange

Peppermint

D &C Red No. 33

FD &C Red No. 3

D &C Yellow No. 33

Butylparaben

Methylparaben

Propylparaben

Sodium benzoate

Class Agent

Other Additives 19:28

•The flow of the acceptable suspension will be either

pseudoplastic or plastic & it is desirable that thixotropy be

associated with these two types of flow.

•Thixotropy is defined as the isothermal slow reversible

conversion of gel to sol.

•Thixotropic substances on applying shear stress convert to

sol(fluid) and on standing they slowly turn to gel(semisolid).

•At rest the solution is sufficient viscous to prevent

sedimentation and thus aggregation or caking of the

particles.

•When agitation is applied the viscosity is reduced and

provide good flow characteristic from the mouth of bottle.

Rheological properties of pharmaceutical suspensions

19:28

The rheological properties of suspensions are affected by

The degree of flocculation that occurs in a given suspension.

The presence of floccules tends to reduce the amount of free

continuous medium; since much of it is entrapped within the

floccules. The viscosity of a flocculated suspension is therefore

usually higher than that of a similar suspension in which the

particles are deflocculated.

Flocculated suspensions exhibit plastic or pseudo-plastic

behavior.

i.e. the viscosity of flocculated suspensions is relatively high

when the applied shearing stress is low, but decreases as the

applied stress increases.

If plastic behavior is exhibited then the system behaves like a

solid up to particular shearing stress (yield value), and no flow

occurs in the system until the value is exceeded.

Rheological Characteristics of suspensions 19:28

Rheological properties of flocculated suspensions

Shear Stress

Rate

of

Sh

ear

fB (yield value)

Shear Stress

Rate

of

Sh

ear

Shear Stress

Rate

of

Sh

ear

fB (yield value)fB (yield value)

Plastic Flow

Shear Stress

Rat

e o

f S

hea

r

Shear Stress

Rat

e o

f S

hea

r Pseudoplastic Flow

The yield value is because the van der Waals forces between adjacent particles, which must be broken first before flow can occur.

The more flocculated the suspension the higher will be the yield value.

19:28

Deflocculated suspensions exhibit dilatant behavior.

i.e. the viscosity of deflocculated suspensions is low at low

shearing stresses and increases as the applied stress increases.

Rheological Characteristics of deflocculated suspensions

Shear Stress

Rate

of S

hear

Shear Stress

Rate

of S

hear

DilatantFlow

19:28

Preparation of a suspension

Overview

• Wetting and Dispersion of the Active Ingredient.

• Stabilization of Dispersed Solid.

• Preparation of the Vehicle /structured vehicle.

• Addition and Dispersion of Active Ingredient in

Vehicle.

• Addition of Remaining Ingredients and Final Mixing

19:28

Preparation of a suspension Step 1. Wetting and dispersion of the Active Ingredient.

• Dry mill the powders to achieve target particle size and

particle size range.

• Powder should be added to a low viscosity portion of the

product, preferably plain water. This allows for most

efficient mixing and homogenization.

• Wetting agent is added to the water to aid in wetting and

displacement of air.

• Drug powder may be treated with a water miscible material

such as glycerin to aid in wetting.

Step 2. Stabilization of the Dispersed Solid

• Electrical (Controlled flocculation). Addition of electrolytes

to produce charges around each particle and allow for

electrical repulsion to prohibit particle interactions.

19:28

Preparation of a suspension

Step 3. Preparation of the Vehicle

• Polymers such as sodium carboxymethylcellulose and gums

such as xanthan gum and tragacanth will form lumps if

added to water improperly.

• It is often practical to disperse them in a water miscible

liquid in which they are insoluble.

• A common technique is to make a paste of the material in

glycerin, then carefully add this paste to water.

• It is also usual to allow this mixture to stand for up to 24

hours to ensure complete hydration of the polymer.

Step 4. Addition and Dispersions in Vehicle

• The dispersion of the active ingredient is added to the

vehicle with low intensity mixing.

• The mixture is then homogenized to ensure uniform

dispersion of the ingredients.

• Step 5. Addition of Remaining Ingredients and Final Mixing.

19:28

Preparation of a suspension: Summary 19:28

• Based On General Classes

• Oral suspension

• Externally applied suspension

• Parenteral suspension

• Based On Size Of Solid Particles

• Colloidal suspension (< 1 micron)

• Coarse suspension (>1 micron)

• Nano suspension (10 ng)

• Based On Proportion Of Solid Particles

• Dilute suspension (2 to10%w/v solid)

• Concentrated suspension (50%w/v solid)

• Based On Electro-kinetic Nature Of Solid Particles

• Flocculated suspension

• Deflocculated suspension

Classification of Suspension 19:28

Evaluation of Suspensions

Suspensions are evaluated by determining their physical

stability.

Two useful parameters for the evaluation of suspensions are

Sedimentation volume "F" & Degree of flocculation “B”

1. Sedimentation volume: (F), sedimentation volume of a

suspension is expressed by the ratio of the equilibrium

volume of the sediment, Vu, to the total volume, Vo of the

suspension. F = Vu/Vo

The value of F provides a qualitative knowledge about the

physical stability of the suspension.

F= 1 No sedimentation, no clear supernatant

F =0.5 50% of the total volume is occupied by sediment

F > 1 Sediment volume is greater than the original volume due to formation of floccules which are fluffy and loose

19:28

Evaluation of Suspensions: Sedimentation volume 19:28

2. Degree of flocculation: (ß), degree of flocculation is the ratio of the sedimentation volume of the flocculated suspension, F, to the sedimentation volume of the deflocculated suspension, F

ß = F / F (Vu/Vo) flocculated

ß = --------------------

(Vu/Vo) deflocculated

ß is a quantitative & more fundamental parameter than F as it relates the volume of flocculated sediment to that in a deflocculated system

3-Re-disperseability: This is determined by the number of upside down inversions of the suspension contained in a measure.

The smaller the number, the easier would be the re-dispersability of the sediment.

A number greater than 15 inversions indicated caking.

Evaluation of Suspensions: Degree of flocculation 19:28

Stability of suspensions

Physical Stability •Appearance, color, odor & taste

•Specific gravity

•Sedimentation rate

•Sedimentation volume

•Zeta potential measurement

•Compatibility with container

•Compatibility with cap liner

•Microscopic examination

•Determination of crystal size.

•Determination of uniform drug

distribution

Chemical Stability pH change Viscosity change.

Degradation of active ingredient Antimicrobial activity:

1.Incompatibility with preservative

2.Degradation of preservative

3.Adsorption of preservative onto

drug particle

19:28

Packaging and Storage of Suspensions: 1) Should be packaged in wide mouth containers having adequate air space above the liquid.

2) Should be stored in tight containers protected from:

freezing, excessive heat & light. 3) Label: "Shake Before Use" to ensure uniform distribution

of solid particles and thereby uniform and proper dosage. 4) Stored in room temperature if it is dry powder (25 0C).

Note: It should be stored in the refrigerator after opening or

freezing should be avoided to prevent reconstitute (

)aggregation

Stability of suspensions.. 19:28

THANK YOU FOR ATTENTION

GOOD LUCK ..

19:28