CHAPTER 14

DISPERSE SYSTEMS
Reporters: #25 LEE, Sharmaine C. #26 LOTERTE, Edwin A. #27 LUMBAO, Jicah A. #28 MONSALUD, Miguel M.

DISPERSE SYSTEMS
Preparations in disperse systems are referred to as the Dispersed Phase; the vehicle used is the Dispersing Phase or Dispersion Medium. Together, they produce a Dispersed System. The dispersed phase are usually solid materials that are insoluble in the dispersion medium.

AEROSOL

The dispersed phase may be small air bubbles throughout a solution or an emulsion.

EMULSIONS
Emulsification - this results in the dispersion of liquid drug as fine droplets throughout the dispersing phase. The dispersed phase is a liquid that is neither soluble nor miscible with the liquid of the dispersing phase.

COARSE DISPERSIONS
These are dispersions containing coarse particles usually 10 to 50 m. Examples are suspensions and emulsions. Because of greater size have a greater tendency to separate from the dispersion medium than do the particles in a fine dispersion.

COARSE DISPERSIONS
Most solids in dispersion tend to settle to the bottom of the container because of their greater density than the dispersion medium. (However, most emulsified liquids for oral use are oils, which generally have less density than the aqueous medium in which they are dispersed, so they tend to rise toward the top of the preparation.)

FINE DISPERSIONS
Dispersions containing particles of smaller sizes about 0.5 to 10m. Magmas and gels

COLLOIDAL DISPERSIONS
Particles are in the colloidal range. Note: Complete and uniform redistribution of the dispersed phase is essential to the accurate administration of uniform doses. For a properly prepared dispersion, this should be accomplished by moderate agitation of the container.

SOMETHING INTERESTING:

SUSPENSIONS

May be defined as preparations containing finely divided drug particles (suspenoid) distributed somewhat uniformly throughout a vehicle in which the drug exhibits a minimum degree of solubility.

SUSPENSIONS
Ready-to-use forms are already distributed through a liquid vehicle with or without stabilizers and other additives. Powder Mixtures are another type where in the powder contains the drug and suitable dispersing agents to be diluted and agitated with a vehicle but usually purified water.

SUSPENSIONS
(ANTIBIOTIC drugs are usually powder mixtures because they are unstable at extended periods.) For Oral Suspension is given to these powder mixtures in the USP. Oral Suspension- Prepared suspensions not requiring reconstitution at the time of dispensing.

REASONS FOR SUSPENSIONS

Chemical Stability ( unstable in solution but stable when suspended) Flexibility ( Liquid form over Solid Form for infants, children and the elderly) o Disadvantage: Disagreeable taste of certain drugs. Ex. Erythromycin estolate which becomes Erythromycin estolate Oral Suspension, USP

REASONS FOR SUSPENSIONS

Oral Suspensions are aqueous preparations with the vehicle flavoured and sweetened to suit the anticipated taste preferences of the intended patient.

FEATURES DESIRED IN A PHARMACEUTICAL SUSPENSION Therapeutic efficacy Chemical Stability of components Permanency of the preparation Esthetic appeal of the preparation (desirable qualities in the preparation) Suspension pored completely from its container.

SEDIMENTATION RATE OF THE PARTICLES OF A SUSPENSION

Stokes equation was derived for an ideal situation in which uniform, perfectly spherical particles in a very dilute suspension settle without producing turbulence, without colliding with other particles of the suspenoid, and without chemical or physical attraction or affinity for the dispersion medium.

SEDIMENTATION RATE OF THE PARTICLES OF A SUSPENSION

Does not apply precisely the usual pharmaceutical suspension but gives basic concepts that are important to suspension of the particles and possible adjustments that can be made to decrease the rate of sedimentation.

SEDIMENTATION RATE OF THE PARTICLES OF A SUSPENSION Velocity of fall of a suspended particle must be greater than for larger particles than it is for smaller particles, all other factors remaining constant. Reducing the particle size of the dispersed phase produces a slower rate of descent of particles.

SEDIMENTATION RATE OF THE PARTICLES OF A SUSPENSION

The greater the rate of descent provided the density of the vehicle is not altered. (The density of the particles is generally greater than that of the vehicle, a desirable feature.) The rate of sedimentation may be appreciably reduced by increasing the viscosity of the dispersion medium, and within limits of practicality, this may be done. (Too high viscosity is not desirable; it pours with difficulty and is equally difficult to redisperse the suspenoid.)

SEDIMENTATION RATE OF THE PARTICLES OF A SUSPENSION Viscosity Characteristics of a suspension may be altered not only by the vehicle used, but the solid content. Solid particles viscosity

SEDIMENTATION RATE OF THE PARTICLES OF A SUSPENSION Brookfield Viscometer- the viscosity of a pharmaceutical preparation may be determined through the use of a viscometer such as this. it measures viscosity by the force required to rotate a spindle in the fluid being tested.

SEDIMENTATION RATE OF THE PARTICLES OF A SUSPENSION Adjustments are concerned mainly with: Particle Size Uniformity of Particle Size Separation of the Particles

PHYSICAL FEATURES OF THE DISPERSED PHASE OF A SUSPENSION Particle Size- the most important single consideration in a discussion of suspensions is this. (Diameter of 1 to 50 m) Dry Milling- Particle Size Reduction is accomplished by this prior to incorporation of the dispersed phase into the dispersion medium.

PHYSICAL FEATURES OF THE DISPERSED PHASE OF A SUSPENSION

Micropulverization- One of the most rapid, convenient and inexpensive methods of producing fine drug powders of about 10 to 50m size. Micropulverizers- these are high-speed attrition or impact mills that are efficient in reducing powders to the size acceptable for most oral and topical suspensions.

PHYSICAL FEATURES OF THE DISPERSED PHASE OF A SUSPENSION

Fluid Energy Grinding (Jet Milling/Micronizing) For still finer particles, under 10m is quite effective. By this process, the shearing action of high-velocity compressed airstreams on the particles in a confined space produces the desired ultrafine or micronized particles. Particles to be micronized are swept into violent turbulence by sonic and supersonic velocities of the airstreams. With high velocities, they collide with each other resulting in fragmentation. (Usually employed for parenteral and ophthalmic suspensions.)

PHYSICAL FEATURES OF THE DISPERSED PHASE OF A SUSPENSION Spray Drying- particles of extremely small dimensions may also be produced by this Spray Dryer- this is a cone-shaped apparatus into which a solution of a drug is sprayed and rapidly dried by a current of warm, dry air circulating in the cone.

PHYSICAL FEATURES OF THE DISPERSED PHASE OF A SUSPENSION One must AVOID reducing the particle size too much, because fine particles have a tendency to form a compact cake upon settling to the bottom of the container. Symmetrical barrel-shaped particles of calcium Carbonate produced more stable suspensions than did asymmetrical needle shaped particles of the same agent.

PHYSICAL FEATURES OF THE DISPERSED PHASE OF A SUSPENSION Floc or floccule- a common method of preventing rigid cohesion of small particles of a suspension is intentional formation of a less rigid or loose aggregation of particles. The flocs settle to form a higher sediment volume than unflocculated particles, the loose structure of which permits the aggregates to break-up easily and distribute readily with a small amount of agitation.

PHYSICAL FEATURES OF THE DISPERSED PHASE OF A SUSPENSION

Oral suspensions of a drug, clays such as bentonite magma are commonly employed as the flocculating agent. The structure of Bentonite Magma and of other clays used for this purpose also assists the suspension by helping to support the floc once formed.

PHYSICAL FEATURES OF THE DISPERSED PHASE OF A SUSPENSION

Parenteral suspension, when clay are unsuitable as agents, as in parenteral suspensions, frequently a floc of the dispersed phase can be produced by an alteration in the pH of the preparation (generally to the region of minimum drug solubility)

PHYSICAL FEATURES OF THE DISPERSED PHASE OF A SUSPENSION

Electrolytes can also act as flocculating agents, apparently by reducing the electrical barrier between the particles of the suspenoid and forming a bridge so as to link them together.

PHYSICAL FEATURES OF THE DISPERSED PHASE OF A SUSPENSION

Nonionic and ionic surface-active agents (surfactants) can also induce flocculation of particles in suspension and increase the sedimentation volume.

DISPERSION MEDIUM

When highly flocculated suspensions settle too rapidly, they produce an unsightly supernatant layer.

DISPERSION MEDIUM

In many commercial suspensions, many suspending agents are added to the dispersion medium to lend it structure. Carboxymethylcellulose (CMC), Methylcellulose, microcrystalline cellulose, polivinylpyrrolidone, xanthan gum and bentonite are among a few of the agents used to thicken the dispersion medium.

DISPERSION MEDIUM

When polymeric substances and hydrophilic colloids are used as suspending agents, appropriate tests must be performed to show that the agent does not interfere with availability of the drug. These materials can bind certain medicinal agents, rendering them unavailable or only slowly available for therapeutic function.

DISPERSION MEDIUM
Support of the suspenoid by the dispersion medium may depend on several factors: the density of the suspenoid, whether it is flocculated, and the amount of material requiring support. Frequently, the usual adult oral suspension is designed to supply the dose of a particular drug in a convenient measure of 5mL or 1 teaspoonful.

DISPERSION MEDIUM
Pediatric suspensions are formulated to deliver the appropriate dose of drug by administering a dose-calibrated number of drops or with the use of a teaspoon. Many of the suspensions of the antibiotic drugs intended for pediatric use are prepared in a highly flavoured, sweetened, coloured base, they are frequently referred to by manufacturers and also popularly as syrups, even though in fact they are known as suspensions.

PREPARATION OF SUSPENSIONS
Other drugs are not penetrated easily by the vehicle and have a tendency to clump together or to float on the vehicle. In the latter case, the powder must first be wetted to make it more penetrable by the dispersion medium.

PREPARATION OF SUSPENSIONS
Alcohol, glycerine, propylene glycol, and other hygroscopic liquids are employed as wetting agents when aqueous vehicles are to be used as dispersion phases. They function by displacing the air in the crevices of the particles, and allowing penetration of dispersion medium into the powder.

PREPARATION OF SUSPENSIONS
Colloid mill- In large scale preparations, wetting agents are mixed with the particles by an apparatus such as this. On a small scale in the pharmacy, they are mixed with a mortar and a pestle. Whenever appropriate, suitable preservatives should be included in the formulation of suspensions to preserve against bacterial and mold contamination.

PREPARATIONS OF SUSPENSIONS

An example would be for the suspensoid Antacid Aluminum Hydroxide, the preservatives used are methylparaben and propylparaben. Sorbitol and syrup serve as the sweetening and viscosity agent.

Procedure: The parabens are dissolved in heated mixture of sorbitol solution, glycerine, syrup and a portion of the water. The mixture is rested to cool while adding Aluminum Hydroxide with stirring.

PROCEDURE
Flavor is added and purified water to volume. The suspension is homogenized by the use of a hand homogenizer, homomixer or a colloid mill.

PROCEDURE
An industrial-size mixer is used to prepare dispersions of various types, including suspensions and emulsions. A large storage tank with a liquid filling unit in the process of filling large-mouth suspension bottles is also used in final packaging.

SUSTAINED-RELEASE SUSPENSIONS

The formulation of liquid oral suspensions having sustained-release has had only limited success because of the difficulty of maintaining the stability of sustained-release particles in liquid disperse systems.

SUSTAINED-RELEASE SUSPENSIONS

Product development research has centered on the same types of technologies used in preparing sustained release tablets and capsules (coated beads, drug-impregnated wax matrix, microencapsulation, ion exchange resins).

SUSTAINED-RELEASE SUSPENSIONS
Pennkinetic system- the use of combination of ion exchange resins and particle coating has resulted in product success via this so called system. In the Pennkinetic System, ionic drugs are complexed with ion exchange resins and the drug-resin complex particles coated with ethylcellulose.

SUSTAINED-RELEASE SUSPENSIONS

In liquid formulations (suspensions), the drug remains absorbed onto the resin but is slowly released by the ion exchange process in the GIT. An example of this would be hydrocodone polistirex (Tussionex Pennkinetic Extended-release suspension, Medeva)

EXTEMPORANEOUS COMPOUNDING

PROBLEMS
Not all medicines are available in a convenient, easy to take liquid dosage form Special considerations are needed for infants and elderly and other who cannot take solid dosage forms lack of ready information on stability of a drug in liquid vehicle

Leucovorin Calcium most stable in milk or antacid and is unstable in acidic solutions when compounded from crushed tablets or the injectable form

Leucovorin Calcium most stable in milk or antacid and is unstable in acidic solutions when compounded from crushed tablets or the injectable form

Drugs with extemporaneous formulations in literature Prednisone oral suspension

Ketoconazole suspension

Formula for preparation of an oral liquid form in the package insert

Rifadin

 journal wherein hundreds of compounded liquid formulations, based upon documented stability data are available

TYPICAL COMPOUNDING

contents of capsule are emptied into a mortar/ tablets crushed in a mortar w/ a pestle
selected vehicle is slowly added to and mixed with the powder mixture to create a paste and then diluted to the desired volume

NEONATE

should not include preservatives, colorings, flavorings or alcohol because of the potential for each of these to cause either acute or long term adverse effects
flavoring agent is not required

NEONATE

alcohol can alter liver functions, cause gastric irritation and effect neurologic depression (e.g. Aromatic Elixir NF)
preservatives have been implicated in adverse effects in preterm infants

NEONATE

propylene glycol has also been implicated in problems such as seizures and stupor in some preterm infants

benzyl alcohol should be omitted from neonate because this cause gasping syndrome characterized by a deterioration of multiple organ systems and eventually death

NEONATE

formulations should be kept simple and not compounded to supply more than a few days of medicine

ELDERLY

some medications depresses the central nervous system (metronidazole)

some medications causes the patient to get violently ill (antabuse)

WAYS TO MINIMIZE STABILITY PROBLEMS

it should be placed in an air-tight, lightresistant container by the pharmacist

should be stored in the refrigerator by the patient

WAYS TO MINIMIZE STABILITY PROBLEMS

since it is a suspension, the patient should be instructed to shake well prior to use
watch for any color change/ consistency change that might indicate a stability problem

PACKAGING AND STORAGE OF SUSPENSIONS

Adequate airspace above the liquid to permit adequate shaking.

Should be provided in wide mouth containers to permit the prompt and ease of removal of the suspension.

PACKAGING AND STORAGE OF SUSPENSIONS

Store in tight containers protected from freezing, excessive heat and light.
Suspensions should be shaken before use.

EXAMPLES OF ORAL SUSPENSIONS BY CATEGORY (PAGE 390-391)

Antacids

Anthelmintics

Magaldrate Oral Suspension

Pyrantel Pamoate

EXAMPLES OF ORAL SUSPENSIONS BY CATEGORY (PAGE 390-391)

Antibacterial (Antibiotics)

Antibacterial (nonantibiotic Antiinfectives)

Chloramphenicol Palmitate

Sulfamethoxazole + trimethorpin

EXAMPLES OF ORAL SUSPENSIONS BY CATEGORY (PAGE 390-391)

Antiflatulent

Antidiarrheal

Simethicone

Bismuth subsalicylate

EXAMPLES OF ORAL SUSPENSIONS BY CATEGORY (PAGE 390-391)

Antifungals

Antiprotozoal

Nystatin

Atovaquone

EXAMPLES OF ORAL SUSPENSIONS BY CATEGORY (PAGE 390-391)

Antipsychotics, Sedatives, Antiemetics

Diuretic

Chlorothiazide

Hydroxyzine Pamoate

EXAMPLES OF ORAL SUSPENSIONS BY CATEGORY (PAGE 390-391)

Nonsteroidal Antiinflammatory

Psychotropic

Indomethacin

Paroxetine HCl

ANTACID ORAL SUSPENSION

Are intended to counteract the effects of gastric hyperacidity and such are employed by persons, as peptic ulcer patients, who must reduce the level of acidity in the stomach. Also referred to as acid indigestion, heartburn, and sour stomach

ANTACID ORAL SUSPENSION

Sodium Bicarbonate - neutralizes acid effectively yet produce sodium overload and systemic alkalosis, a hazard on patients on sodium restricted diets

ANTACID ORAL SUSPENSION

Aluminum hydroxide less effective and more slow, excessive use may lead to constipation and phosphate depletion with consequent mucle weakness, bone resumption and hypercalciuria

Calcium carbonate can neutralizes acid effectively, carries the potential to induce hypercalcemia and stimulation of gastric secretion and acid production (acid reb

ANTACID ORAL SUSPENSION

Calcium carbonate can neutralizes acid effectively, carries the potential to induce hypercalcemia and stimulation of gastric secretion and acid production (acid rebound)

ANTACID ORAL SUSPENSION

Magnesium hydroxide neutralizes acid effectively, converted to MgCl, w/c is water soluble and is partially absorbed

ANTACID ORAL SUSPENSION

Calcium phosphate Magaldrate Magnesium carbonate Magnesium oxide Aluminum phosphate Dihydroxyaluminum aminoacetate

Selection of antacid Heartburn/ gastric distress- single dose of Na bicarbonate/ MgOH

Acute peptic ulcer/ duodenal ulcer (therapeutic regimen includes frequent administration of anatacid)

ENDOSCOPIC STUDIES

shows that very little antacid remains in the fasting stomach 1 hour after administration
frequent food snacks prolong the time an antacid remains in the stomach and can prolong its action

ANTIBACTERIAL ORAL SUSPENSION

The antibacterial oral suspensions include preparations of antibiotic substances Many are unstable when maintained in solution for an appreciable length of time and therefore, from a stability standpoint

ANTIBACTERIAL ORAL SUSPENSION

Provide a convenient way to administer dosages to infants and children and to adult patients who prefer liquid preparations

Dispersing phase is aqueous and usually colored, sweetened and flavored to render the liquid more appealing and palatable

ANTIBACTERIAL ORAL SUSPENSION

Antibiotics ( Chloramphenicol palmitate, Erythromycin derivatives, and tetracycline and its derivatives)

ANTIBACTERIAL ORAL SUSPENSION

Sulfonamides (Sulfamethoxazole, sulfisoxazole acetyl)

ANTIBACTERIAL ORAL SUSPENSION

other chemotherapeutic agents(methanamine mandelate & nitrofurantoin)

ANTIBACTERIAL ORAL SUSPENSION

combination of these (sulfamethoxazole trimethoprim)

OTIC SUSPENSION

Polymyxin B sulfate

Neomycin sulfate

Hydrocortisone - pH 3.0 to 3.5

OTIC SUSPENSION

Cortisporin Otic Suspension - pH 4.8 to 5.1

PediOtic - pH of 4.1

RECTAL SUSPENSIONS

Barium sulfate for Suspension, USP may be employed orally or rectally for the diagnostic visualization of the GIT.

RECTAL SUSPENSIONS

Mesalamine (5-aminosalicylic acid) - for treatment of Crohns disease, distal ulcerative colitis, proctosigmoiditis, and proctitis.

RECTAL SUSPENSIONS

Colocort hydrocortisone rectal suspension indicated as adjunctive therapy in the treatment of ulcerative colitis and is packaged in a convenient disposable single dose enema designed for self-administration

DRY POWDERS FOR ORAL SUSPENSION

Preparations consist of dry powder mixtures or granules, which are intended to be suspended in water or some other vehicle prior to administration.

DRY POWDERS FOR ORAL SUSPENSION

1. Antibiotic 2. Colorant (FD and C dyes) 3. Flavorants 4. Sweeteners - sucrose or sodium saccharin 5. Stabilizing agents - citric acid and sodium citrate 6. Suspending agents - guar gum, xanthan gum, methylcellulose 7. Preserving agents - methylparaben, sodium benzoate

ANTIBIOTICS FOR ORAL SUSPENSION (RECONSTITUTION) (PAGE 393)

Amoxicillin for Oral Suspension AMOXIL Ampicillin for Oral Suspension OMNIPEN Bacampicillin for Oral Suspension SPECTROBID Cefaclor for Oral Suspension CECLOR

ANTIBIOTICS FOR ORAL SUSPENSION (RECONSTITUTION) (PAGE 393)

Cefixime for Oral Suspension SUPRAX POWDER Cephadrine for Oral Suspension KEFLEX Dicloxacillin Sodium for Oral Suspension (PATHOCIL) Doxycycline for Oral Suspension VIBRAMYCIN MONOHYDRATE

ANTIBIOTICS FOR ORAL SUSPENSION (RECONSTITUTION) (PAGE 393)

Erythromycin Ethylsuccinate for Oral Suspension E.E.S. GRANULES Penicillin V for Oral Suspension

COMBINATION

Erythromycin ethylsuccinate/ acetylsulfisoxazole granules - treatment for acute middle ear infection - Hemophilus influenza

COMBINATION

Probenecid/ampicillin for reconstitution treatment for uncomplicated infections (urethral, endocervical or rectal) - Neisseria gonorrhoeae

OFFICIAL FOR RECONSTITUTION

Cholestyramine (Questran, Par) used in the management of hyperlipidemia

OFFICIAL FOR RECONSTITUTION

Barium Sulfate used orally or rectally as a radiopaque contrast medium to visualize the gastrointestinal tract as an aid to diagnosis fine, nongritty, odorless and tasteless white powder used to diagnose conditions of hypopharynx, esophagus, stomach, small intestine, and colon

EMULSIONS

The word emulsion, came from emulgio, meaning to milk out. 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.

EMULSIONS TERMINOLOGY

The dispersed phase is referred to as the Internal phase The dispersion medium as the External or Continuous phase Emulsions having an oleaginous internal phase and aqueous external phase are referred to as oil-in-water (o/w) emulsions

EMULSIONS TERMINOLOGY

Emulsions having an aqueous internal phase and an oleaginous external phase are termed water-in- oil (w/o) emulsions.

Unless a third component - the emulsifying agent - is present the dispersion is unstable, and the globules undergo coalescence to form two separate layers of water and oil

EMULSIONS TERMINOLOGY

Because the external phase of an emulsion is continuous, an O/W emulsion may be diluted with water or an aqueous preparation, & W/O emulsion with an oleaginous or oil miscible liquid The aqueous phase may contain watersoluble drugs, preservatives, coloring and flavoring agents

EMULSIONS TERMINOLOGY

The oil phase frequently consists of fixed oil or volatile and drugs that exist as oil, such as oil-soluble vitamins and antiseptic

It is necessary to add antioxidant to prevent autoxidation of the oil and rancidity/and or destruction of any vitamin present.

PURPOSE OF EMULSIFICATION
Pharmaceutically a. The pharmacist can prepare relatively stable and homogenous mixture of 2 immiscible liquids

b. Emulsification can permit the administration of liquid drug in the form of minute globules rather than in bulk

PURPOSE OF EMULSIFICATION
Therapeutically a. Beneficial to the rate and degree of absorption of the drug after administration by any of the usual route

b. O/W emulsions may also be useful as vehicle to develop the bioavailability of poorly absorbed drugs

PURPOSE OF EMULSIFICATION
c. For orally administered emulsion the O/W type permits the palatable administration of an otherwise distasteful oil by dispersing it in a sweetened, flavored vehicle. d. The reduced particle size of the oil globules may render the oil more digestible and more readily absorbed and therefore more effective

PURPOSE OF EMULSIFICATION

e. Emulsion to be applied externally can be made such that the medicinal agent that are irritating to the skin surface may be incorporated in the internal phase than in the external phase since the latter is in direct contact with the skin

PURPOSE OF EMULSIFICATION

f. On the unbroken skin, a W/O emulsion can usually be applied more evenly since the skin is covered with a thin film sebum, and this surface is more readily wetted by oil than by water. On the other hand, if it is easily removed from the skin, O/W is preferred.

THEORIES OF EMULSIFICATION
Sphere shape of a drop Internal forces tends to promote association of molecules to resist distortion Coalesce tendency to join of two or more drops when they come in contact with one another Liquids surface tension Interfacial tension - force

THEORIES OF EMULSIFICATION
1. Surface Tension Theory A property of liquids in which the exposed surface tends to contract to the smallest possible In a spherical drop of liquid there are internal forces that tend to promote the association of the molecule of the substance to resist the distortion of the drop into a less spherical form use of substances as emulsifiers & stabilizers Results in the lowering of the interfacial tension of the 2 immiscible liquids, reducing the repellant force between the liquids and diminishing each liquids attraction for its own molecules. These tension lowering substances are referred to as surface active (surfactants) or wetting agents.

METHODS OF PREPARATION
1.

Continental or Dry gum method The method is also referred to as the 4:2:1 method because for every 4 parts (volumes) of oil, 2 parts of water and 1 part of gum are added in preparing the initial or primary emulsion. For instance, if 40 mL of oil are to be emulsified, 20 mL of water and 10 g of gum would be employed, with additional water or other formulation ingredients being added afterward to the primary emulsion

PREPARATION OF CONTINENTAL OR DRY GUM METHOD

a. The acacia or other O/W emulsifier is triturated with the oil in a perfectly dry Wedgewood or porcelain mortar until thoroughly mixed. b. 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, rapidly, and continuously until the primary emulsion that forms is creamy white and produces a crackling sound to the movement of the pestle c. Generally, about 3 minutes of mixing are required to produce such a primary emulsion

PREPARATION OF CONTINENTAL OR DRY GUM METHOD

d. Other liquid formulative ingredients that are soluble in or miscible with the external phase may then be added to the primary emulsion with mixing. e. Solid substances such as preservatives, stabilizers, colorants, and any flavoring material are usually dissolved in a suitable volume of water and added as a solution to the primary emulsion NOTE: A mortar with a rough rather than smooth inner surface must be used to ensure proper grinding action and the reduction of the globule size during the preparation of the emulsion. A glass mortar has too smooth a surface to produce the proper size reduction of the internal phase.

Methods of Preparation
2. English or wet gum method

The same proportions of oil, water, and gum are used as in the dry method, but the order of mixing is different, and the proportion of ingredients may be varied during the preparation of the primary emulsion as is deemed necessary by the operator.

Methods of Preparation
3. Bottle or Forbes bottle method (G+O+W) For the extemporaneous preparation of emulsions from volatile oils or oleaginous substances of low viscosities, the bottle method is used. (2:2:1)

PREPARATION OF BOTTLE OR FORBES BOTTLE METHOD (G+O+W)

a. The powdered acacia is placed in a dry bottle b. Two parts of oil is then added, and the mixture is thoroughly shaken in the capped container. c. A volume of water approximately equal to the oil is then added in portions d. The mixture being thoroughly shaken after each addition

PREPARATION OF BOTTLE OR FORBES BOTTLE METHOD (G+O+W)

e. When all of the water has been added, the primary emulsion thus formed may be diluted to the proper volume with water or other an aqueous solution of other formulative agents NOTE: This method is not suited for viscous oils, because they cannot thoroughly agitated in the bottle.

Methods of Preparation
4. Auxiliary Methods An emulsion by either the wet gum or dry gum methods can generally be increased in quality by passing it through a hand homogenizer. In this apparatus, the pumping action of the handle forces the emulsion through a very small orifices which reduces the globules of the internal phase to about 5 um and sometime less

Methods of Preparation
5. In SITU soap method

Two types of soap developed by this method are Calcium soaps and Soft soaps. Calcium soaps

water

- in - oil emulsions which contain certain vegetable oil (e.g. Oleic acid) in combination with lime water ( Syn: Calcium Hydroxide Solution USP) and prepared by mixing equal volumes of the oil and lime water

Methods of Preparation
Example: Calamine Liniment (itchy, dry skin, sunburn) Calamine Zinc Oxide . 80.0 g Olive oil Calcium Hydroxide Soln aa q.s ad 1000.0 mL

Methods of Preparation
6. Microemulsions Thermodynamically stable, optically transparent, isotropic mixtures of a biphasic oil-water system stabilized with surfactants. The diameter of droplets in a microemulsion may be in the range of 100 A (10 microns) to 1000 A whereas in a microemulsion the droplets may be 5000 angstroms in diameter. Both O/W and W/O microemulsions may be formed spontaneously by agitating the oil and water phases with carefully selected surfactant.

Methods of Preparation
Advantages: a. More rapid and efficient oral absorption of drugs than through solid dosage forms b. Enhance transdermal drug delivery through increased drug diffusion into the skin c. The technique potential application of microemulsion in the development of artificial red blood cells and in the argeting of cytotoxic drugs to cancer cells

Methods of Preparation
Example of Microemulsion 1. Turpentine Oil Emulsion Rectified Turpentine oil 150 mL Acacia powder 50 g Purified water, q.s to make 1000 mL 2. Liquid Petrolatum Emulsion - Mineral oil Emulsion; Liquid Paraffin Mineral oil 500 mL Acacia .. 125 g Syrup 100 mL Vanilla .. 40 mg Alcohol . 60 mL Purified water, q.s to make 1000 mL 3. Cod liver Oil Emulsion - laxative with empty stomach Cod liver oil .. 500 mL Acacia . 125 g Syrup .. 100 mL Methyl salicylate .. 4 mL Purified water, q.s to make 1000 mL

Emulsion Stability
A stable emulsion is characterized by the following: 1. Absence of flocculation and creaming 2. Absence of coalescence of globules & separation of the layers 3. Absence of deterioration due to microorganisms 4. Maintenance of elegance with respect to appearance, odor, color and consistency

Emulsion Stability
Emulsion is considered physically unstable if: 1. The internal or dispersed phase upon standing tends to form aggregates of globules. 2. Large globules or aggregates of globules rise to the top or fall to the bottom of the emulsion to forconcentrated layer of the internal phase. 3. If all or part of the liquid of the internal phase becomes unemulsified and forms a distinct layer on the top or bottom of the emulsion as result of the coalescing of the globules of the internal phase

TERMINOLOGY
1. Flocculation - is the joining together of globules to form large clumps or floccules which rise or settle in the emulsion more rapidly than do the individual particles 2. Creaming - is the rising (upward creaming) or settling (downward creaming) of globules or floccules to form a concentrated layer at the surface or to the bottom of the emulsion 3. Coalescence & breaking - unlike creaming, the coalescence of globules and the subsequent breaking of an emulsion are irreversible processes. In creaming, the globules are still surrounded by a protective coating or sheath of emulsifying agent and may redispersed simply by agitating the product.

TERMINOLOGY
4. Detoriation by Microorganism - Molds, yeast and bacteria may bring about decomposition and contamination of the emulsion. Preservatives should be more fungistatics than bacteriostatic 5. Miscellaneous Physical & Chemical Change - Light and rancidity affect the color and the odor of oils and may destroy their vitamin content. Freezing and thawing and high temperature result in the coarseness and breaking of an emulsion. 6. Imbibition - is taking up of a certain amount of liquid without a measurable increase by a gel with an increase volume

TERMINOLOGY
7. Swelling - is the taking up of a liquid by a gel with an increase in volume. Only those liquid that solvate a gel can cause swelling. The swelling of protein gels is influenced by pH and the presence of electrolytes 8. Syneresis - is when the interaction between particles of the dispersed phase becomes so great than on standing, the dispersing medium is squeezed out in droplets and the gel shrinks. Syneresis is a form of instability in aqueous and nonaqueous gels

TERMINOLOGY
9. Thixotrophy - is a reversible gel-sol formation with no change in volume or temperature-a type of nonNewtonian flow. 10. Xerogel - is formed when the liquid is removed from a gel and only the framewok remains. Examples: gelatin sheet, tragacanth ribbons and acacia tears

CLASSIFICATION AND TYPES OF GELS

Two general classification:

1. Inorganic hydrogels - are usually two phase systems such as Aluminum Hydroxide Gel and Bentonite Magma 2. Organic Gels - are usually single phase systems and may include such as gelling agents as Carbomer and Tragacanth and those that contain an organic liquid, such Plastibase.

CLASSIFICATION AND TYPES OF GELS

Second classification Scheme 1. Hydrogels - include ingredients that are dispersible as colloidals or soluble in water and include organic hydrogels, natural and sythetic gums and inorganic hydrogels Ex.: silica, bentonite, tragacanth, pectin, sodium alginate, methylcellulose, sodium carboxymethylcellulose and alumina 2. Organogels - include the hydrocarbons, animal and vegetable fats, soap base greases and the hydrophilic organogels. Ex.: Hydrocarbon - Jelene, or Plastibase

PREPARATION OF MAGMAS AND GELS

1. By freshly precipitating the disperse phase 2. By direct hydration in water

EXAMPLES OF GELLING AGENTS

1. 2. 3. 4. 5. Acacia Bentonite Carbocymethylcellulose sodium Colloidal silicon dioxide Gelatin silicate 6. Hydroxyethylcellulose 7. Hydroxypropryl methylcellulose 8. Maltodextrin 9. Polyvinyl alcohol 10. Propylene carbonate 11. Alginic acid 12. Carbomer 13. Cetostearyl Alcohol 14. Ethylcellulose 15. Guar gum 16. Hydroxypropryl cellulose 17. Magnesium aluminum

18. Methylcellulose 19. Povidone 20. Sodium alginate 21. Sodium starch glycolate 22. Starch 23. Tragacanth 24. Xanthan gum

EXAMPLES OF GELLING AGENTS

1)Alginic acid- obtained from seaweed, prepared products is tasteless, odorless, yellowish-white colored fibrous powder -used as thickening agent in concentrations of 1 to 5% -swells in water to about 200 to 300 times its own weight without dissolving 2)Carbomer (Carbopol)- resins with high molecular weight allylpentaerythritol-cross-linked acrylic acid-based polymers modified with C10 to C30alkyl acrylates -fluffy white powders with large bulk density (0.5 and 1% aqueous dispersion) Example: Carbomers 910,934,934P,940 and 1342

EXAMPLES OF GELLING AGENTS

3) Carboxymethylcellulose - concentrations of 4 to 6% of medium viscosity can be used to produce gel; glycerin may be added to prevent drying; incompatible with alcohol 4) CMC sodium- soluble in water at all temperature 5) Colloidal silicone dioxide- can be used with other ingredients of similar refractive index to prepare transparent gels 6) Gelatin- dispersed in hot water and cooled to form gels 7) Magnesium aluminum silicate (Veegum)- concentrations of about 105 forms a firm thixotropic gel -material is inert and has few incompatibilities but is less used above pH 3.5

EXAMPLES OF GELLING AGENTS

8) Methylcellulose- long-chain substituted cellulose that can be used to form gels in concentration up to 5% - dispersed with high shear in about 1/3 of water 9) Plastibase (Jelene)- mixture of 5% low molecular weight polyethylene and 95% mineral oil 10) Poloxamer (Pluronic)- concentrations ranging from 15 to 50% to form gel -poloxamers 124 (L-44 grade), 188 (F-68 grade), 237 (F-87 grade), 338 (F-108 grade) and 407 (F-127 grade) types are freely soluble in water F = refers to flake form L = refers to liquid form

EXAMPLES OF GELLING AGENTS

11) Polyvinyl alcohol (PVA)- used at concentrations of about 2.5% in the preparartion of various jellies that dry rapidly when applied to the skin -borax is a good agent that will gel PVA solutions -for best result, dispersed PVA in cold water, followed by hot water. It is less soluble in cold. 12) Povidone - about 10% in concentrations to prepare gels -also increase solubility of poorly soluble drugs 13) Sodium alginate- 10 % to produce gels -aqueous preparations are most stable at pH 4 to 10; below pH 3, alginic acid is precipitated 14) Tragacanth gum-used to prepare gels that are most stable at pH 4 to 8 -must be preserved with 0.1% benzoic acid or .17% methylparaben and 0.03% propyl paraben

Sample Products

ANTIINFLAMMATORY, ANTIPRURITIC, AND ANTIALLERGIC

Thickener

GEL FORMULATION CONSIDERATIONS

polymer solutions tend to be cast as gels because the solute consists of long, flexible chain of molecules Inorganic salts will compete with the water in a gel and cause gelatin at lower concentrations Aqueous polymer solutions, especially of cellulose derivatives are stored for approximately 48hours after dissolution to promote full hydration and maximum viscosity and clarity.

EXAMPLES OF MAGMAS AND GELS

Bentonite Magma NF suspending agent

Sodium Fluoride and Phosphoric Acid Gel

Fluocinonide Gel Tretinoin Gel Erythromycin and Benzoyl peroxide Gel

USP
USP USP

dental care prophylactic

Anti-inflammatory corticosteroid treatment for acne

Clindamycin Topical Gel

Hydroquinone Gel Salicylic acid Gel Desoximethasone Gel Aluminum Phosphate Gel (Amphogel) Aluminum hydroxide Gel Dihydroxyaluminum Aminoacetate Magma Milk of Magnesia (Magnesia Magma) USP USP USP USP Hyperpigmented skin keratolytic anti-inflammatory and antipruritic agent antacid antacid antacid Antacid; laxative