DISPERSE SYSTEMS - Pharmaceutical Information, … · DISPERSE SYSTEMS The term ... Each phase can...

DISPERSE SYSTEMS

Vishal mogalNIPER

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DISPERSE SYSTEMS

The term "Disperse System" refers to a system in which one substance (The Dispersed Phase) is distributed, in discrete units, throughout a second substance (the continuous Phase or vehicle).

Each phase can exist in solid, liquid, or gaseous state .

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pharmaceutical suspensions

Suspension

Suspensions are heterogenous system consisting of 2 phases.

The continuous phase is generally liquid or semisolid & dispersed or internal phase is particulate matter i.eessentially insoluble, but dispersed throughout the continious phase.

Colloidal suspension 1 nm to 1 µm Coarse suspension 1 to 100 µm

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Advantages

Suspension can improve chemical stability of certain drug. E.g. Procaine penicillin G

Drug in suspension exhibits higher rate of bioavailability than other dosage forms. bioavailability is in following order,

Solution > Suspension > Capsule > Compressed Tablet > Coated tablet

Duration and onset of action can be controlled.E.g.Protamine Zinc-Insulin suspension

Suspension can mask the unpleasant/ bitter taste of drug. E.g. Chloramphenicol

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Disadvantages

Physical stability, sedimentation and compaction can causes problems.

It is bulky sufficient care must be taken during handling and transport.

It is difficult to formulate. Uniform and accurate dose can not be achieved

unless suspension are packed in unit dosage form.

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Routes of Administration

Oral Ocular Otic Rectal Parenteral Topical

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Properties of an Ideal Suspension

Resuspend easily upon shaking Physically and chemically stable during its shelf life Sterile (parenteral, ocular) Gets into syringe (parenteral, ocular) Uniform dispersion Palatable Pleasing odor and color No grittiness Easy to pour yet not watery No cap-lock Temperature insensitive

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Examples of Pharmaceutical Suspensions:

1. Antacid oral suspensions 2. Antibacterial oral suspension 3. Dry powders for oral suspension (antibiotic) 4. Analgesic oral suspension 5. Anthelmentic oral suspension 6. Anticonvulsant oral suspension 7. Antifungal oral suspension

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Suspension formation

1. Precipitation method• Organic solvent precipitation-• Precipitation effected by changing pH of medium-

protamine zinc insuline

• Double decomposition: preparation of “White Lotion”, that is forming zinc polysulphide by mixing zinc sulfate and sulfurated potash solutions

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2. Dispersion method Vehicle must be formulated so that the solid phase

is easily wetted and dispersed The use of surfactant is desirable to ensure uniform

wetting of hydrophabic solids

Formulation

1.Components of Suspending system:a. wetting agent b. Dispersants or deflocculating agentc. Flocculating agentd. Thickeners

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2. components of suspending vehicle or external phase:a. Bufferb. osmotic agentc. coloring agent, flavors & fragranced. preservativese. liquid vehicles

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Technology

Four basic types of size reduction equipmentI. Micropulverization: It is one of the most rapid, convenient, and inexpensive

methods of producing fine drug powders. The milling equipment includes hammer mills,

micropulverizers, universal mills, end-runner mills, and ball mills.

Micropulverizers are high speed attrition or impact mills especially adapted for fine grinding.

The main disadvantage of micropulverization is the large distribution of particle sizes produced, normally in the range of 10–50 µm or higher.

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(A) crushers and shredder (B) hammer mills

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(C) colloid mills (D) fluid energy mills

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2. fluid energy grinding:

jet milling or microsizing < 10 µ, so used for parentrals. shearing action of high velocity streams of

compressed air on particles in a confined space. disadvantage : high electrostatic charge built up on

the surfaces of the milled powder, which makes powder classification and collection exceedingly difficult.

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3. Controlled Crystallization

A solvent that dissolves a solid very readily at room temperature may serve as a crystallizing medium when mixed with another miscible solvent in which the compound is only sparingly soluble

A solution that is nearly saturated at a temperature about 10C below the boiling point of the solvent combination is prepared in a temperature ranging between 60 and 150C.

Rapid introduction of another cold miscible solvent in which the drug is only sparingly soluble, formation of minute crystalline particles (nucleates) proceeds without appreciable crystal growth, and uniform microcrystals of the drug are thus obtained.

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4. Spray drying

Particles of microcrystalline size can also be obtained by spray-drying procedures, resulting in a porous, free-flowing, easily wetted, essentially monodispersedpowder.

With proper control of process variables, spherical particles are obtained that may be coated with agents to aid suspension and promote stability.

However, the process is not normally considered for the preparation of ultrafine powders.

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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

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Problems- Caking/Crystal growth

Attributed to one or more of the following mechanisms: ‘‘Oswalt ripening’’ or the growth of large particles at the expense of

smaller ones, because of a difference in solubility rates of different size particles.

Crystal growth due to temperature fluctuations on storage is of minor importance, unless suspensions are subjected to temperature variations of 20C or more.

A polymorphic form may change to another more stable crystalline form; changes in crystal habit may be related to the degree of solvation or hydration.

Crystal growth may also arise when the more energetic amorphous or glassy forms of a drug exhibit significantly higher initial solubility in water than the corresponding crystalline forms.

Size reduction by crushing and grinding can produce particles whose different surfaces exhibit high and low solubility rates. This effect can be related to differences in the free surface energy introduced during comminution (grinding).

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Crystal growth and changes in particle size distribution can generally be controlled by employing one or several of the following procedures and techniques.


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1. Selection of particles with a narrow range of particle sizes, such as microcrystals between 1 and 10 µm.

2. Selection of a stable crystalline drug form that usually exhibits lower solubility in water. The crystalline form that is physically most stable usually has the highest melting point.

3. High-energy milling should not be used during particle size reduction. Microcrystals are best formed by controlled precipitation techniques or shock cooling.

4. A water-dispersible surfactant wetting agent dissipates the free surface energy of particles by reducing the interfacial tension between the solid and the suspending vehicle.

5. A protective colloid, such as gelatin, gum, or a cellulosic derivative, is used to form a film barrier around the particles, inhibiting dissolution and subsequent crystal growth.


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6. The viscosity of the suspending vehicle is increased to retard particle dissolution and subsequent crystal growth.

7. Temperature extremes during product storage (freeze–thaw conditioning) must not occur.

8. Supersaturation favors the formation of needlelike crystals and should be avoided.

9. Rapid or shock cooling and high agitation favor the formation of thin, small crystals and should be avoided. Slow crystallization by evaporation yields compact crystals.

10. Experimentation with different crystallizing solvents is recommended to change crystal size and shape.

11. Impurities and foreign substances during crystallization affect the reproducibility and aggregation potential of many drug particle systems.

12. Constant crystallizing conditions are essential. Batch-to-batch variation in crystal size and shape is often associated with poor control of processing and crystallization procedures.

Evaluation

Sedimentation volume Degree of flocculation Ease of dispersibiility Rheological measurement & viscosity Zeta potential measurement Particle size Density measurement Preservative efficacy testing Stability pH measurement

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Sedimentation volume-F = Vsed/Vtot

The value of F normally lies between 0 to 1 for any pharmaceutical suspension.

The value of F indicates physical stability of the suspension.

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The suspension shall form loose networks of flocks that settle rapidly, do not form cakes and are easy to resuspend.

Settling and aggregation may result in formation of cakes (suspension) that is difficult to resuspend or phase separation (emulsion).

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Nernst potential

The difference in electric potential between the actual surface of the particle and the electroneutralregion is referred to as Nernst potential.

Zeta potential Potential difference between the ions in the tightly

bound layer and the electroneutral region, referred to as zeta potential.

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Flocculation

When this zeta potential goes below the critical value, the attractive forces supersede the repulsive forces and flocculation occurs.

These loosely packed particles or floccs settle faster than the defflocculated particles because of their larger sizes.

But unlike deffloculated particles this sediment of floccs does not form solid cake.

This sediment of floccs is easy to redisperse by agitation

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Degree of flocculation-ß = Ffloc/Fdefloc

(Vsed/Vtot)floc

=-------------------(Vsed/Vtot)defloc

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When the total volume of both the flocculated and the deflocculated suspensions are same, the degree of flocculation,

ß = (Vsed)floc/(Vsed)defloc

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References


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The encyclopedia of pharmaceutical technology, vol. 1, 3rd edition, p.g. 3597.

The theory and practice of industrial pharmacy, Leon lachman,p.g 479-500.

FACTORS TO BE CONSIDERED

Sedimentation. Particle size. Nernst and zeta potential. Deflocculation and flocculation. Electrokinetic Properties. Density of the vehicle. Viscosity of the vehicle.

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