Suspensions

Dispersion system consist of (1)- particulate matter (dispersed phase) (2)- continuous medium (dispersion medium)

Classification of dispersed systems (based on particle size)

1 Molecular dispersion

< 1 nm Oxygen molecules, glucose solution

2 Colloidal dispersion

1nm- 0.5 mm Natural polymers

3Coarse dispersion

> 0.5 mmSuspension and

emulsion

Definition of suspension : Pharmaceutical suspensions are uniform dispersions of solid drug particles in a vehicle in which the drug has minimum solubility. Particle size of the drugs may vary from one formulation to the other depending on the physicochemical characteristics of the drug and the rheological properties of the formulation.

A suspension containing particles between 1 nm to 0.5 µm in size is called colloidal suspension. When the particle size is between 1 to 100 µm, the suspension is called coarse suspension. Most of the pharmaceutical suspensions are coarse suspension.

Majority of the marketed suspensions are available as dry powders that must be reconstituted before administration but occasionally some products in the market are ready-to-use. The first products are not very stable once reconstituted; must be used within 7 to 10 days.

Examples of Pharmaceutical Suspensions:

A. Antacid oral suspensions Antibacterial oral suspension B. Dry powders for oral suspension (antibiotic) C. Analgesic oral suspension

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D. Anthelmentic oral suspension E. Anticonvulsant oral suspension F. Antifungal oral suspension

Pharmaceutical applications of suspensions:

1) 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)

2) To over come the instability of certain drug in aqueous solution:a. Insoluble derivative formulated as suspension

An example is oxytetracycline HCL calcium salt (instable) (stable)

b. Reduce the contact time between solid drug particles and dispersion media increase the stability of drug like Ampicillin by making it as reconstituted powder.

c. A drug that degraded in the presence of water suspended in non-aqueous vehicles. Examples are phenoxymethypencillin/ coconut oil and tetracycline HCL/ oil

3) To mask the taste: Examples are paracetamol suspension (more palatable) and chloramphenicol palmitate.

4) Some materials are needed to be present as finely divided forms to increase the surface area. Fore example, Mg carbonate and Mg trisilcate are used to adsorb some toxins

5) Suspension can be used topical applications:An example is calamine lotion Bp after evaporation of dispersing media; the active agent will be left as light deposit

6) Can be used for parentral administration intramuscular (i.m.) to control arte of absorption

7) In vaccines

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Aluminum hydroxide

Absorbed antigen

Aluminum hydroxide

Absorbed antigen

e.g. Diphtheria and Tetanus vaccines

8) X-ray contrast media: an example is oral and rectal administration of propyliodone

9) In aerosol suspension of active agents in mixture of propellants

Qualities of ideal suspension: A well-formulated suspension should have the following properties:

1) The dispersed particles should not settle readily and the settle should redispersed immediately on shacking. Ideally, the particles in a suspension should not sediment at any time during the storage period. Unfortunately, the present technology does not allow us to prepare such a suspension. Since one cannot completely avoid the sedimentation of particles, it is desirable that the particles should settle slowly. The easy redispersion of sedimented particles in a suspension is important for the uniformity of dose.

2) The particle should not form a cake on settling

3) The viscosity should be such that the preparation can be easily poured. A highly viscous suspension would make pouring difficult.

4) It should be chemically and physically stable

5) It should be palatable (orally)

6) It should be free from gritting particles (external use)

FACTORS TO BE CONSIDERED

A- Wetting of the particles:

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Suspending media

Solid particles Hydrophilic can be

dispersed easily

Difficult to disperse and float on the surface due to hydrophobic surface or entrapped air

Suspending media

Solid particles Hydrophilic can be

dispersed easily

Difficult to disperse and float on the surface due to hydrophobic surface or entrapped air

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 removing this air from the surface and to easy penetration of the vehicle into the pores. Alcohol, glycerin, and propylene glycol are frequently used to remove adsorbed air from the surface of particles when aqueous vehicle is used to disperse the solids. When the particles are dispersed in a non-aqueous vehicle, mineral oil is used as wetting agent. Irrespective of the method of preparation, the solid particles must be wetted using any of the suitable wetting agents before the dispersion in the vehicle.

Solid particles that are not easily wetted by aqueous vehicle after the removable of the adsorbed air are referred to as hydrophobic particles. It is necessary to reduce the interfacial tension between the particles and the vehicle by using surface-active agents to improve the wettibility. Sodium lauryl sulfate is one of the most commonly used surface-active agents. Hydrophilic particles are easy to disperse in the aqueous vehicle once the adsorbed air is removed. Hydrophilic particles do not require the use of surface-active agents.

The main function of wetting agents: (1)- to reduce the contact angle between surface of solid particles and wetting liquid via displace the air in the voids (2)- surfactant

Examples of wetting agents are tragcanth mucilage, glycerin, glycols, bentonite and polysorbates.

Excessive amounts of wetting agents can cause foaming or undesirable taste or odor.

Contact angle can be used to measure wettibility, if the angle approximately equal or more than 90 0, particles are floating well out of fluid.

B-Particle size:

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Particle size of any suspension is critical and must be reduced within the range as determined during the preformulation study.

Too large or too small particles should be avoided. Larger particles will settle faster at the bottom of the container and too fine particles will easily form hard cake at the bottom of the container.

The particle size can be reduced by using mortar and pastel but in large-scale preparation different milling and pulverization equipments are used.

Limitation in particle size reduction (after reaching a certain particle size):

1. Expensive and time consuming

2. Movement of small particles due to brownian motion cause particles to aggregate, settle, form hard cake that it is difficult to redispersed

C-Sedimentation:

Sedimentation of particles in a suspension is governed by several factors: particle size, density of the particles, density of the vehicle, and viscosity of the vehicle. The velocity of sedimentation of particles in a suspension can be determined by using the Stoke's law:

Where:

v = velocity of sedimentation d = diameter of the particle g = acceleration of gravity 1 = density of the particle = density of the vehicle = viscosity of the vehicle

According to the Stoke's equation, the velocity of sedimentation of particles in a suspension can be reduced by decreasing the particle

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v =d2 (p1-p2) g

18 v =

d2 (p1-p2) g

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size and also by minimizing the difference between the densities of the particles and the vehicle. Since the density of the particles is constant for a particular substance and cannot be changed, the changing of the density of the vehicle close to the density of the particle would minimize the difference between the densities of the particles and the vehicle. The density of the vehicle of a suspension can be increased by adding the following substances either alone or in combination: polyethylene glycol, polyvinyl pyrolidone, glycerin, sorbitol, and sugar.

The viscosity of the vehicle also affects the velocity of sedimentation. It decreases as the viscosity of the vehicle increases. The viscosity and density of any vehicle are related to each other, so any attempt to change one of these parameters will also change the other one.

D-Electrokinetic Properties

Dispersed solid particles in a suspension may have charge in relation to their surrounding vehicle. These solid particles may become charged through one of two situations.

1. Selective adsorption of a particular ionic species present in the vehicle. This may be due to the addition of some ionic species in a polar solvent. Consider a solid particle in contact with an electrolyte solution. The particle may become positively or negatively charged by selective adsorption of either cations or anions from the solution.

2. Ionization of functional group of the particle. In this situation, the total charge is a function of the pH of the surrounding vehicle.

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------

-

-----

-

- -

--

----

-

-- - -

- -

-

-

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

In the above figure, the particle is positively charged and the anions present in the surrounding vehicle are attracted to the positively charged particle by electric forces that also serve to repel the approach of any cations. The ions that gave the particle its charge, cations in this example, are called potential-determining ions. 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, anions in this example. These ions, oppositely charged to the potential-determining ions, are called counterions or gegenions. These two layers of ions at the interface constitute a double layer of electric charge. The intensity of the electric force decreases with distance from the surface of the particle. Thus, the distribution of ions is uniform at this region and a zone of electrolneutrality is achieved.

E-Nernst and zeta potential-

The difference in electric potential between the actual surface of the particle and the electroneutral region is referred to as Nernst potential. Thus, Nernst potential is controlled by the electrical potential at the surface of the particle due to the potential determining ions. Nernst potential has little effect in the formulation of stable suspension.

The potential difference between the ions in the tightly bound layer and the electroneutral region, referred to as zeta potential (see the figure), has significant effect in the formulation of stable suspension. Zeta potential governs the degree of repulsion between adjacent, similar charged, solid dispersed particles.

If the zeta potential is reduced below a critical value, the force of attraction between particles succeed the force of repulsion, and the particles come together. This phenomenon is referred to as flocculation and the loosely packed particles are called floccule.

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F-Deflocculation and flocculation:

Deflocculation of particles is obtained when the zeta potential is higher than the critical value and the repulsive forces supersede the attractive forces.

The addition of a small amount of electrolyte reduces the zeta potential. When this zeta potential goes below the critical value, the attractive forces supersede the repulsive forces and flocculation occurs.

The following table illustrates the relative properties of flocculated and Non-flocculated suspension

It should be noted that the deflocculated suspensions should be avoided because of the formation of irreversible solid hard cake. Although flocculated suspensions sediment faster and form a clear supernatant, these are easy to redisperse.

The following figure shows the effect of period of standing on flocculated and deflocculated suspension:

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Flocculated Non-flocculated

1. Particles forms loose aggregates and form a network like structure

2. Rate of sedimentation is high 3. Sediment is rapidly formed4. Sediment is loosely packed and

doesn’t form a hard cake5. Sediment is easy to redisperse6. Suspension is not pleasing in

appearance7. The floccules stick to the sides of

the bottle

1. Particles exist as separate entities 2. Rate of sedimentation is slow3. Sediment is slowly formed4. Sediment is very closely packed and a

hard cake is formed5. Sediment is difficult to redisperse6. Suspension is pleasing in appearance7. They don’t stick to the sides of the

bottle

G-Thixotropic suspension-A thixotropic suspension is the one that is viscous during storage but loses consistency and become fluid upon shaking. A well-formulated thixotropic suspension would remain fluid long enough for the easy dispense of a dose but would slowly regain its original viscosity within a short time.

Method of preparation

The preparation of suspension includes three methods: (1) use of controlled flocculation and (2) use of structured vehicle (3)- combination of both of the two pervious methods. The following is the general guidelines to suspension formulation:

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Particles

Addition of wetting agent and dispersion medium

Uniform dispersion of deflocculated particles

A

Incorporation ofstructured vehicle

Deflocculated suspension in structured vehicle

as final product

B C

Addition of flocculating agent

Flocculated suspensionas final product

Addition of flocculating agent

Flocculated suspension

Incorporation ofstructured vehicle

Flocculated suspension in structured vehicle as

final product

A-Structured vehicle

Structured vehicles called also thickening or suspending agents. They are aqueous solutions of natural and synthetic gums. These are used to increase the viscosity of the suspension.

Methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, acacia, gelatin and tragacanth are the most commonly used structured vehicle in the pharmaceutical suspensions. These are non-toxic, pharmacologically inert, and compatible with a wide range of active and inactive ingredients.

These structured vehicles entrapped the particle and reduces the sedimentation of particles. Although, these structured vehicles reduces the sedimentation of particles, not necessarily completely eliminate the particle settling. Thus, the use of deflocculated particles in a structure vehicle may form solid hard cake upon long storage.

The risk of caking may be eliminated by forming flocculated particles in a structured vehicle.

Note that too high viscosity isn’t desirable and 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.

Structured vehicles are pseudoplastic or plastic in their rheological behaviors

In the following table is summary of suspending agents

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Table summary of suspending agent

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B-Controlled flocculation

Controlled flocculation of particles is obtained by adding flocculating agents, which are (1)-electrolytes (2)- surfactants (3)- polymers

Typical Flocculation agents

Most frequently used flocculating agents are electrolytes, which reduce the zeta potential surrounding the solid particles. This leads to decrease in repulsion potential and makes the particle come together to from loosely arrange structure (floccules).

The flocculating power increases with the valency of the ions. As for example, calcium ions are more powerful than sodium ions because the velency of calcium is two whereas sodium has valency of one.

The following figure shows the flocculation of a bismuth subnitrate suspension by means of monobasic potassium phosphate (flocculating agents).

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1-Addition of electrolyte to control flocculation

Both ionic and non-ionic surfactants could be used to control flocculation

Surfactant adsorbed on the surface of solid particle leading to neutralization or reversing the surface charge

Since most of surfactants act as wetting agents and flocculating agents, the amount of surfactant to be added should be calculated based on this fact.

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The particles of bismuth subnitrate are positively charged originally. By addition of electrolyte (phosphate, -ve) the zeta potential fell down near zero. At this neutralization value noted absence of caking. Continuing adding of negatively charged electrolyte resulted in changing the overall zeta potential of particles to negative and formation of cake.

2-Addition of surfactant to control flocculation

Polymers are long-chained, high molecular-weight compounds containing active groups spaced along their length.

These agents promote flocculation through adsorption of part of the chain on the surface of particle and the remaining part project out into the dispersion medium. Formation of bridge between the projected parts leads to formation of floccules (see the following figure)

Hydrophilic polymers also act as protective colloids resulting in coated particles have fewer tendencies to form cake.

Polymers exhibits pseudoplastic flow in solution that promotes the physical stability of suspension

Some polymers like gelatin stabilize the suspension based on the pH and ionic strength of dispersion medium (carry charge)

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3- Addition of polymers to control flocculation

Example of surfactant used as flocculating agents

Formation of bridge between particles

Projection out into dispersion medium

Adsorption on the surface of particles

Solid particle Solid particle

Formation of bridge between particles

Projection out into dispersion medium

Adsorption on the surface of particles

Solid particle Solid particle

An example of polymer is xanthan gum

Positively charged Liposomes (vesicles of phospholipids) adsorbed on negatively charged particles to prevent caking formation.

B- Flocculation in structured vehicles

Sometimes suspending agents can be added to flocculated suspension to retard sedimentation

Examples of these agents are Carboxymethylcellulose (CMC), Carbopol 934, Veegum, and bentonite

It should be noted that physical incompatibility can limit the addition of suspending agent

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Most of hydrophilic colloids are negatively charged

-

Compatible Incompatible

-+

++

++

Addition of electrolyte

_

_

__

__

-+

++

++

---- -

-

---- -

-

Addition of suspending agent

_

_

_

_

_

Positively charged particles

Negatively charged particles

Particle settle rapidly

Most of hydrophilic colloids are negatively charged

--

Compatible Incompatible

-+

++

++--

++

++

+

Addition of electrolyte

__

__

____

____

-+

++

++--

++

++

+

---- -

- --

-- --

-- - -- -

-

---- -

- --

-- --

-- - -- -

-

Addition of suspending agent

__

__

__

__

__

Positively charged particles

Negatively charged particles

Particle settle rapidly

Under this circumstance, the formulator can protect particle by changing sign of particle from negative to positive using protective colloids. This is illustrated by the following figure:

Ready to use suspension is manufactured as you learn in this class Extemporaneous suspension is unordinary preparation that pharmacist

wants to prepare to a water-insoluble drug that exists in tablet or capsule for situations when liquid dosage from is needed. The following steps could be done to prepare extemporaneous suspension:

1. Put the tablet or capsule content in mortar and crush it

2. Add the suspending vehicle slowly with mixing

3. You could add any flavoring agent or coloring agent available

4. Example of ready available suspending agents are Roxanes diluent and Cologel

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Evaluation of suspensions

Ready to use suspension and extemporaneous preparation

Suspensions are evaluated by determining their physical stability. Two useful parameters for the evaluation of suspensions are sedimentation volume and degree of flocculation. The determination of sedimentation volume provides a qualitative means of evaluation. A quantitative knowledge is obtained by determining the degree of flocculation.

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 normally lies between 0 to 1 for any pharmaceutical suspension. 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

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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

When the total volume of both the flocculated and the deflocculated suspensions are same; the degree of flocculation, ß = (Vu)floc/(Vu)defloc .The minimum value of ß is 1; this is the case when the sedimentation volume of the flocculated suspension is equal to the sedimentation volume of deflocculated suspension. ß is more fundamental parameter than F since it relates the volume of flocculated sediment to that in a deflocculated system

Rheological consideration: viscosity of suspension affects and controls the settling of dispersed particle. It, also, affects pouring the product from bottle and spreading qualities in case of lotion. Best viscosity for suspension is to be high during storage to prevent sedimentation and to be low at high shear to ease the administration. Thus, pseudoplastic/ thixotrpic and plastic/ thixotropic suspending agents could be use for this purpose. Combination of two suspending agents can enhance the stability of suspension

Ingredients of suspension:

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7. Active ingredient8. Wetting agent9. Suspending agent10.Flocculated agent11.Protective colloid12.Sweetener

1. Preservative 2. Buffer system3. Color agent4. Flavor agent5. Antifoaming agent6. Preservative

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

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). It should be stored in the refrigerator after opening or reconstitute (freezing should be avoided to prevent aggregation)

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Buffer

Flavor

Colorant

Preservative

Ammonia solutionCitric acidFumaric acidSodium citrate

CherryGrapeMethyl salicylatteOrangePeppermint

D &C Red No. 33FD &C Red No. 3D &C Yellow No. 33

ButylparabenMethylparabenPropylparabenSodium benzoate

Class Agent

Stability of suspension

A-Physical stability:

B-Chemical stability:

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1. Appearance, color, odor and taste2. pH3. Specific gravity4. Sedimentation arte5. Sedimentation volume6. Zeta potential measurement7. Compatibility with container8. Compatibility with cap liner9. Microscopic examination10.Determination crystal size11.Determination uniform drug distribution

1. Degradation of active ingredient2. Viscosity change3. antimicrobial activity:

a. Incompatibility with preservative b. Degradation of preservativec. Adsorption of preservative onto drug particle