User:Moataz abdo

pharmacy Module 3

SUSPENSIONS & EMULSIONS

SUSPENSIONS

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 µ m in size is called colloidal suspension. When the particle size is between 1 to 100 µ m, the suspension is called coarse suspension. Most of the pharmaceutical suspensions are coarse suspension. Some of the commercially available suspensions are listed in Table. Majority of the available suspensions in the market are ready-to-use but occasionally some products are available as dry powders which must be reconstituted before administration. The later products are not very stable once reconstituted; must be used within 7 to 10 days. The packaging of these products contain the easy to follow reconstitution procedure.

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 FACTORS TO BE CONSIDERED

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 equation:

v = [2 r2 (D-d) g]/ 9h

Where:

v = velocity of sedimentation r = radius of the particle g = acceleration of gravity D = density of the particle d = density of the vehicle h = visocsity 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 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 can not 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 velocity of sedimentation is also affected by the viscosity of the vehicle. 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.

Particle size-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 in a community pharmacy by using mortar and pastel but in large scale preparation different milling and pulverization equipments are used.

Density of 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.

Viscosity of the vehicle- The viscosity of a suspension is increased by adding the following substances either alone or in combination: methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, acacia, tragacanth, and bentonite. These substances are called suspending agents. Majority of the pharmaceutical suspensions available in the market contain suspending agents to minimize the particle sedimentation during storage.

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. The first situation is by 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. The second situation is by ionization of functional group of the particle. In this situation, the total charge is a function of the pH of the surrounding vehicle. Irrespective of the situation let consider a particle, which is positively charged. 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.

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. Whereas, the potential difference between the ions in the tightly bound layer and the electroneutral region, referred to as zeta potential (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 (which depends on the particular system being used) the force of attraction between particles supersede the force of repulsion, and the particles come together. This phenomenon is referred to as flocculation and the loosely packed particles are called floccule.

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. These deflocculated particles when sediment form a close packed arrangement with the smaller particles filling the voids between the larger ones. These close packed deflocculeted sediment eventually form a solid hard cake, which is not easy to redisperse. 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. These loosely packed particles or floccs settle faster than the defflocculated particles because of their larger sizes. But unlike deflloculated particles this sediment of floccs does not form solid cake. This sediment of floccs is easy to redisperse by minute agitation. The smaller particles sediment slower than the larger particles in a deflloculated suspension. Thus, deflloculted suspensions always have some very fine dispersed particles even when the larger particles form a solid hard cake at the bottom of the container. In other words, there is no clear supernatant liquid at the top of the suspension. In case of flocculated suspension, the flocs tend to settle together and form a clear supernatant liquid at the top. The deflloculated 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 sedimentation of floculated suspensions can be minimized by adding appropriate suspending agents to increase the viscosity of the surrounding vehicle.

Thixotropic suspension-A thixotropic suspension is the one which 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.

DESIRABLE PROPERTIES

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 formulation should allow the easy redispersion of sedimented particles in a suspension for the uniformity of dose. Thus, a flocculated suspension is desirable than a deflocculated suspension. It is also desirable that a suspension should not be too viscous to reduce the sedimentation rate. A highly viscous suspension would make pouring difficult. A well-formulated suspension should pour readily and evenly. With the advancement of the physical pharmacy, it is now possible to prepare a suspension which shows slow sedimentation rate; at the same time it is possible to pour a dose from the container easily and uniformly.

METHOD OF PREPARATION

The preparation of suspension include two methods: (1) use of controlled flocculation and (2) use of structured vehicle. The suspensions are generally prepared by using any of these two methods alone or combination of both methods.

Wetting of dispersed particles-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. 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. Aqueous vehicles are used for oral suspension of drugs. When the particles are dispersed in a nonaqueous 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.

Hydrophilic and hydrophobic particles-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.

Controlled flocculation-Controlled flocculation of particles is obtained by adding flocculating agents, which reduces the zeta potential surrounding the solid particles. Most frequently used flocculating agents are electrolytes. 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. Other substances which initiate flocculation are combination of ionic and nonionic surface active agents and lyophilic polymers. These polymers form a bridge between particles and initiate flocculation.

Structured vehicle-Structured vehicles are the 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, 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 vehicle 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.

EVALUATION OF SUSPENSIONS

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.

Sedimentation volume-Sedimentation volume, F, of a suspension is expressed by the ratio of the equilibrium volume of the sediment, Vsed, to the total volume, Vtot of the suspension. Thus,

F = Vsed/Vtot (X)

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. Figure X describes three different suspensions; (a) deflocculated (b) flocculated (c) flocculated in a structured vehicle. In this example, the deflocculated suspension has the minimum equilibrium sediment volume, 5 ml; whereas the equilibrium sediment volume of the flocculated suspension is 50 ml. In case of the flocculated suspension in a structured vehicle, the equilibrium sediment volume is same as the total volume of the suspension. The total volume of each of these suspensions is 100 ml. Thus, the values of F are 0.05, 0.5, and 1, respectively. Since, a desired suspension should have less sedimentation; the suspension with flocculated particles in the structured vehicle would be most desirable.

Degree of flocculation-Degree of flocculation, ß, is the ratio of the sedimentation volume of the flocculated suspension, Ffloc, to the sedimentation volume of the deflocculated suspension, Fdefloc. Thus,

ß = Ffloc/Fdefloc

(Vsed/Vtot)floc =--- (Vsed/Vtot)defloc When the total volume of both the flocculated and the deflocculated suspensions are same, as for example, 100 ml in the Figure; the degree of flocculation, ß = (Vsed)floc/(Vsed)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.

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.

EMULSIONS

An emulsion is a dispersion in which the dispersed phase is composed of small globules of a liquid distributed throughout a vehicle in which it is immiscible.

Microemulsion: Droplets size range 0.01 to 0.1 m m

Macroemulsion: Droplets size range approximately 5 m m.

General Types of Pharmaceutical Emulsions:

1) Lotions 2) Liniments 3) Creams 4) Ointments 5) Vitamin drops Emulsion Type and Means of Detection:

1) Dilution Test:

- o/w emulsion can be diluted with water. - w/o emulsion can be diluted with oil. 2) Conductivity Test:

Continuous phase water > Continuous phase oil.

3) Dye-Solubility Test:

- Water soluble dye will dissolve in the aqueous phase. - oil soluble dye will dissolve in the oil phase. Theories of Emulsification:

1) Surface Tension Theory:

- lowering of interfacial tension.

2) Oriented-Wedge Theory:

- mono molecular layers of emulsifying agents are curved around a droplet of the internal phase of the emulsion.

3) Interfacial film theory:

- A film of emulsifying agent prevents the contact and coalescing of the dispersed phase.

Emulsifying Agents:

1) Carbohydrate Materials:

Acacia, Tragacanth, Agar, Pectin. o/w emulsion.

2) Protein Substances:

Gelatin, Egg yolk, Caesin o/w emulsion.

3) High Molecular Weight Alcohols:

Stearyl Alcohol, Cetyl Alcohol, Glyceryl Mono stearate---o/w emulsion. cholesterol--- w/o emulsion 4) Wetting Agents:

Anionic, Cationic, Nonionic

o/w emulsion

w/o emulsion

5) Finely divided solids:

Bentonite, Magnesium Hydroxide, Aluminum Hydroxide o/w emulsion.

Phase Inversion:

The relative volume of internal and external phases of an emulsion is important.

(increase) internal concentration (increase) viscosity up to a certain point.

Viscosity will decrease after that point.

At this point the emulsion has undergone inversion i.e. it has changed from an o/w to a w/o, or vice versa. In practice, emulsions may be prepared without inversion with as much as about 75% of the vol. of the product being internal phase.

Methods of Preparation of Emulsions:

1) Continental or Dry Gum Method:

"4:2:1" Method

4 parts (volumes) of oil [Ansel. 7th ed. page 369]

2 parts of water

1 part of gum

Acacia or other o/w emulsifier is triturated with oil in a perfectly dry Wedgwood or porcelain mortar until thoroughly mixed. Glass mortar has too smooth a surface to produce the proper size reduction of the internal phase (Do not use glass mortar). After the oil and gum have been mixed, the two parts of water are then added all at once and the mixture is triturated immediately.

2) English or wet Gum Method:

Same proportion of oil, water and gum are used as in the continental or dry gum method but the order of mixing is different. Mucilage of the gum is prepared by triturating acacia (or other emulsifier) with water. The oil is then added slowly in portions, and the mixture is triturated to emulsify the oil. Should the mixture become too thick during the process, additional water may be blended into the mixture before another successive portion of oil is added.

3) Bottle or Forbes Bottle Method:

Useful for-

Extemporaneous preparation of emulsion from volatile oils or oleaginous substance of low viscosity.

put powdered acacia in a dry bottle

Add 2 parts of oil

Thoroughly shake the mixture in the capped bottle. A volume of water approximately equal to the oil is then added in portions, the mixture being thoroughly shaken after each addition.

This method is not suitable for viscous oils (i.e. high viscosity oil).

Stability of Emulsion:

An emulsion is considered to be physically unstable if :

a) The internal phase tends to form aggregates of globules.

b) Large globules or aggregates of globules rise to the top or fall to the bottom of the emulsion to form a concentrated layer of the internal phase.

c) If all or part of the liquid of the internal phase becomes "unemulsified on the top or bottom of the emulsion.

Separation of the internal phase from the external phase is called BREAKING of the emulsion. This is irreversible.

-Protect emulsions against the extremes of cold and heat.

-Emulsions may be adversely affected by microbial contamination.

Gels and Magmas:

Gels are defined as semisolid systems consisting of dispersions made up of either small inorganic particles or large organic molecules enclosing or interpenetrated by a liquid. Magmas or Milks are gels consisted of floccules of small distinct particles. Gels and Magmas are considered colloids because they contain particles within the range of colloidal dispersions.

Examples of Magmas & Gels:

Bentonite Magma, NF:

Preparation of 5% bentonite, a native, colloidal hydrated aluminum silicate, in purified water.

Aluminum Hydroxide Gel, USP:

This is an aqueous suspension of a gelatinous precipitate composed of insoluble aluminum hydroxide and hydrated aluminum oxide, equivalent to about 4% of aluminum oxide.

Milk of Magnesia, USP:

This is a preparation containing between 7 and 8.5% of Magnesium hydroxide.

Back to Top PHCT 4050 Lecture Slides