c 14 Suspension

Chapter 14

DISPERSE SYSTEM

Suspensions

Is a two-phase system consisting of a finely divided solid dispersed in a liquid vehicle. The finely divided particles are also referred to as ‘Suspensoids” .

In these preparations, the substance distributed is referred to as dispersed phase and the vehicle is termed the dispersing phase or dispersion medium. Together, they produce a dispersed system.

Suspensions

Dispersions containing coarse particles, usually 10 to 50 um in size, are referred to as coarse dispersion.Dispersions containing particles of

smaller size are termed fine dispersions (0.5 to 10 um)

Suspensions

In general sense, Suspension may include:

1. Gels

2. Lotions

3. Magmas and Milk

4. Mixtures

Suspensions

Characteristics of Oral Suspension

Particles should be small uniform sizes that do not settle rapidly

The particles that do settle to the bottom of the container should not pack in to a hard cake and should be re-dispersed

completely and evenly with a minimum amount of agitation

Should not be too viscous to pour freely from the mouth of the bottleShould have an agreeable odor,

color and taste and must not decomposed or support mold growth during storage

Must have therapeutic efficacy

Characteristic of Suspensions


Suspensions for injections must contain particles size such that they can pass freely through the syringe needle called “syringeability”.

Ophthalmic suspension should be formulated such that the particles do not exceed 10 microns. Below this size, the patient experiences no pain when instilled into the eyes.


For Topical use, fine particles are desired to avoid grittiness when applied to the skin. The smaller the size, the greater the covering and protective power of the preparation


Reasons for Suspensions

Certain drugs are chemically unstable when in solution but stable when suspended.

Suspension insures chemical stability while permitting liquid therapy.

Many patients prefer liquid form than solid forms for swallowing.

Convenience in administration of usually large dosesSafety and convenience of liquid doses for infants and children.Disagreeable taste of certain drugs

when given in solution is negligible when the drug is administered as undissolved particles of a suspension, e.g chloramphenicol

Reasons for Suspensions

1. A properly prepared suspension should settle slowly and should be readily redispersed upon gentle shaking of the container.

2. The characteristics of the suspension should be such that the particles

size of the suspensoid remains fairly constant throughout long periods of undisturbed standing.

3. The suspension should pour readily and evenly from its container

Features Desired in a Features Desired in a Pharmaceutical SuspensionsPharmaceutical Suspensions

Good pharmaceutical suspensions, the particle diameter is between 1 to 50.

Particle size reduction is generally accomplished by dry-milling prior to the incorporation of the dispersed phase into the dispersion medium.

One of the methods of producing fine drug powders of about 10 to 50 um size is micropulverization.

For still finer particles, under 10 um, the process of fluid energy grinding, sometimes referred to as jet-milling or micronizing.

Physical Features of the Dispersed Physical Features of the Dispersed Phase of a SuspensionPhase of a Suspension

Dispersion Medium

Suspending agents are added to the dispersion medium to lend its structure to assist in the suspension of the dispersed phase

Examples: Carboxymethylcelulose Methylcellulose Microcrystalline cellulose Polyvinyl pyrolidone, Xanthan gum Bentonite

The amount of the suspending agent must not be such to render the suspension too

viscous to agitate (to distribute the suspensoid) or to pour.

The study of the flow characteristics is termed rheology

Dispersion Medium

Sustained-Release Suspension

In liquid preparations (suspensions) of the coated particles, the drug remains adsorbed onto resin, but slowly released by the ion-exchange process when taken into gastrointestinal tract. The use of a combination of ion-exchange resins complex and particle coating is called Pennkinetic system.

Examples: Hydrocodone polistirex =Tussionex

Pennkinetic Extended-Release Suspension

Packaging and Storage of Suspensions

All suspensions should be packaged in containers having:

1. Adequate airspace above the liquid to permit adequate shaking.

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

suspension. 3. Store in tight containers protected from freezing,

excessive heat and light.

4. Suspensions should be shaken before use.

Example of Preparation

Aluminum Hydroxide Compressed Gel 326.8 g Sorbitol Solution 282.0 mL Syrup 93.0 mL

Glycerin 25.0 m Methylparaben 0.9 g Propylparaben 0.3 g Flavor q.s Purified water, to make

1000.0 mL

USE: ANTACID

methylparaben and propylparaben - preservatives; syrup and sorbitol - viscosity and sweetness. In the preparation, the parabens are dissolved

in a heated mixture of the sorbitol solution, glycerin, syrup and a portion of the water. The mixture then cooled and the aluminum hydroxide added with stirring. The flavor is added and sufficient purified water to

volume. The suspension is then homogenized, using hand homogenizer, homomixer, or colloid mill

Preparation…

Examples of Oral Suspensions by Category

Antacids Alumina, Magnesia and Simethicone - Mylanta liquidMagaldrate Oral Suspension - Riopan Oral SuspensionMagnesia and Alumina Oral - Maalox Suspension Aluminum Hydroxide and Magnesium Carbonate - Gaviscon

liquid

Anthelminitics Pyrantel Pamoate - Antiminth Oral SuspensionThiabenzadole Oral Suspension - Mintezol Oral Suspension

Antibacterial (Antibiotics)

Chloramphenicol Palmitate - Chloromycetin Palmitae Oral Suspen.

Ertythromycin Estolate - Ilosone Oral Suspension

Antibacterial (non-antibiotic Anti-infectives)

Methenamine Mandelate - Mandelamine Suspension/ForteSulfamethoxazole and Trimethoprim - Bactrim, Septra

SuspensionSulfamethoxazole - Gantanol Suspension Sulfisoxazole Acetyl Oral Suspension- Gantrisin Syrup/Pedia

Anticonvulsants Pimidone Oral Suspension - Mysoline Suspension

Antidiarrheal Bismuth Subsalicylate - Pepto-Bismol liquid

Examples of Oral Suspensions by Category

Antiflatulent Simethicone Oral Suspension - Mylicone Drop

Antifungals Nystatin Oral Suspension - Nystatin Oral Suspension

Griseofulvin Oral Suspension -Grifulvin Oral Suspension

Antihypertensive Methyldopa Oral Suspension - Aldomet Oral Suspension

Antipsychotics, Sedatives, Antiemetic Hydroxyzine Pamoate Oral Suspension - Vistaril Oral Suspension

Thioridazine Oral Suspension - Mellaril-S Oral Suspension

Diuretic Chlorothiazide Oral Suspension - Diuril Oral Suspension

Nonsteroidal Anti-inflammatory Indomethacin Oral Suspension - Indocin Oral Suspension

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”

Examples:

Sodium Bicarbonate,Aluminum hydroxide,

Aluminum phosphate, Dihydroxyaluminum aminoacetate, Calcium carbonate, Calcium phosphate,Magaldrate, Magnesium carbonate, Magnesium oxide and Magnesium hydroxide.

Antacid Oral Suspension

Antibacterial Oral Suspension

The antibacterial oral suspensions include preparations of antibiotic substances

Examples: Antibiotics ( Chloramphenicol palmitate,

Erythromycin derivatives, and tetracycline and its derivatives),

Sulfonamides (Sulfamethoxazole, sulfisoxazole acetyl),

other chemotherapeutic agents( methanamine mandelate and nitrofurantoin),

combination of these ( sulfamethoxazole - trimethoprim)

Otic Suspension

Examples: Polymixin B sulfate, Neomycin sulfate, Hydrocortisone - pH 3.0 to 3.5; Cortisporin Otic Suspension - pH 4.8 to 5.1; PediOtic - pH of 4.1

Note: Pharmacist must be aware that there may be subtle differences in the formulation of some otic suspensions that could be potentially bothersome to the patient

Rectal Suspensions

Examples: Barium sulfate for Suspension, USP may

be employed orally or rectally for the diagnostic visualization of the GIT.

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

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.

The dry products contain 1. Antibiotic2. Colorant (FD and C dyes)3. Flavorants4. Sweeteners - sucrose or sodium saccharin5. Stabilizing agents - citric acid and sodium citrate6. Suspending agents - guar gum, xanthan gum,

methylcellulose7. Preserving agents - methylparaben, sodium benzoate

NOTE: When called on to “RECONSTITUTE” and dispense, the pharmacist loosens the powder at the bottom of the container by lightly tapping it against a hard surface, and then adds label designated amount of purified water, usually in portions, and shakes well until all of the powder has been suspended.

Examples of Antibiotic Drugs for Oral Suspension (Reconstitute)

Amoxicillin for Oral Suspension AMOXIL

FOR ORAL SUSPENSION

Ampicillin for Oral Suspension OMNIPEN

FOR ORAL SUSPENSION

Bacampicillin for Oral Suspension

SPECTROBID

FOR ORAL SUSPENSION

Cefaclor for Oral Suspension

CECLOR

FOR ORAL SUSPENSION

Cefixime for Oral Suspension

SUPRAX POWDER

FOR ORAL SUSPENSION

Examples of Antibiotic Drugs for Oral Suspension (Reconstitute)

Cephadrine for Oral Suspension

KEFLEX

FOR ORAL SUSPENSION

Dicloxacillin Sodium for Oral Suspension (PATHOCIL)

FOR ORAL SUSPENSION

Doxycycline for Oral Suspension

VIBRAMYCIN MONOHYDRATE

FOR ORAL SUSPENSION

Erythromycin Ethylsuccinate for Oral Suspension

E.E.S. GRANULES

FOR ORAL SUSPENSION

Penicillin V for Oral Suspension

Other Examples (Combination)

1. Erythromycin ethylsuccinate/acetylsulfisoxazole granules

- treatment for acute middle ear infection - Hemophilus influenzae

2. Probenecid/ampicillin for reconstitution

- treatment for uncomplicated infections (urethral, endocervical or rectal) - Neisseria gonorrhoeae

Sample Products

TERGECEF GRANULES FOR SUSPENSION

CEFIXIME

BIOGESIC SUSPENSION

PARACETAMOL

SOLMUX FORTE SUSPENSION

CARBOCISTEINE

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.

Emulsion 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 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 Because the external phase of an emulsion is continuous, an O/W emulsion may be diluted with water or an aqueous preparation, and W/O emulsion with an oleaginous or oil miscible liquid



The aqueous phase may contain water-soluble drugs, preservatives, coloring and flavoring agents

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.

1. 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 EmulsificationPurpose of Emulsification

2. 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

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

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

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

1. Surface Tension Theory

2. Oriented-Wedge Theory

3. Plastic or Internal Film Theory

4. Viscosity Theory

Surface Tension Theory

Surface tension

A property of liquids in which the exposed surface tends to contract to the smallest possible are. 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.

The use of substances as emulsifiers and 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.

Surface Tension Theory

Oriented-wedge Theory

Assumes monomolecular layers of emulsifying agent curved around a droplet of the internal phase of the emulsion.

It is based on the presumption that certain emulsifying agents orient themselves about and within a liquid in a manner reflective of their solubility in that particular liquid.

An emulsifying agent having a greater hydrophilic character than hydrophobic character will promote an O/w emulsion and a W/O emulsion results through use of more hydrophobic than hydrophilic emulsifiers.

Plastic or Interfacial-Film Theory

Places the emulsifying agent at the interface between the oil and water, surrounding the droplets of the internal phase as a thin layer of film adsorbed on the surface of the drops.

The film prevents the contact and the coalescence of the dispersed phase, the tougher and more pliable the film, the greater the stability of the emulsion.

Viscosity Theory

States that the viscosity of an emulsion aids emulsification by the mechanical hindrance to coalescence of the globules although it is not the cause of emulsification.

Emulsifying Agents

NaturalEmulsifying

Agents

These materials form hydrophilic colloids when added to water and generally produced O/W emulsions. Acacia is most frequently use. Tragacanth and Agar - thickening agents in Acacia emulsified products.

These substances produce O/W emulsions. The disadvantage of gelatin is that the emulsion prepared from it are too fluid.

Carbohydrates: acacia, tragacanth agar, chondrus, pectin

Proteins gelatin, egg yolk, casein

HighMolecularWeightalcohols

These materials employed primarily as thickening and stabilizing agents for O/W emulsions such as lotion and ointments

Cholesterol may also be employed in externally used emulsion and promote W/O emulsions.

stearyl alcohol, cetyl alcohol, glyceryl

monostearate

Emulsifying AgentsFinely Divided Solids

These materials generally form O/W emulsions when the insoluble material is added to the aqueous phase if there is greater volume of the aqueous phase than of the oleaginous phase

Colloidal clays includingBentonite, Magnesium hydroxideAluminum hydroxide

Synthetic (wetting agents), which may be Anionic, Cationic, Nonionic

Anionic: triethanolamine oleate and sodium lauryl sulfateCationic: benzalkonium chlorideNonionic: sorbitan esters (span); polyethylene glycol 400 monostearate; polyoxyethylene sorbitan esters (Tweens)

Qualities Required for Emulsifiers

Must be compatible with other ingredients in the formula

Must not interfere with the stability and efficacy of the therapeutic agent

Must be stable to microorganisms Must be non-toxic Must possess little or no odor, taste or color Must promote emulsification and maintain stability

of the emulsion for intended shelf-life

The HLB or Hydrophilic- Lipophile Balance

Each emulsifying agents has a hydrophilic portion (water-loving) and a lipophilic portion (oil-loving) with one or other being more or less predominant and influencing

A method indicative of the substances polarity devised and lead to the assigning of an HLB value for each agent. The usual range is between 1 to 20.

Materials that are highly polar or hydrophilic have assigned higher numbers than materials that are less polar and were lipophilic.

The HLB System or Hydrophilic-Lipophile Balance

Surfactants having an assigned HLB value from 3 to 6 are greatly lipophilic and produce W/O emulsions and those HLB values of from about 8 to 18 produce O/W emulsions.

In selecting an Emulsifier for an emulsion, choose one having the same or nearly the same HLB value as the oleaginous phase

Example: Mineral oil has assigned HLB of 4 if a W/O emulsion is desired and a value of 10.5 if O/W emulsion is prepared

Therefore, use surfactant SPAN 80 (Sorbitan monoleate) with HLB 4.3 for W/O emulsion and methylcellulose with HLB of 10.5 for O/W.

Examples of HLB Values for Selected Emulsifiers

Ethylene glycol distearate 1.5 Sorbitan tristearate (Span 65) 2.1 Propylene glycol monostearate 3.4 Triton X-15 3.6 Sorbitan monooleate (Span 80) 4.3 Sorbitan monostearate (Span 60) 4.7 Diethylene glycol monolaurate 6.1Examples of HLB Values for Selected Emulsifiers Sorbitan monopalmitate (Span 40) 6.7 Sucrose dioleate 7.1 Acacia 8.0


Amercol L-101 8.0 Polyoxyethylene lauryl ether (Brij 30) 9.7 Gelatin 9.8 Triton X-45 10.4 Methylcellulose 10.5 Polyoxyethylene monostearate (Myrj 45) 11.1 Triethanolamine oleate 12.0 Tragacanth 13.2 Triton X-100 13.5 Polyoxyethylene sorbitan monostearate (Tween 60) 14.9 Polyoxyethylene sorbitan monooleate (Tween 80) 15.0


PSM (Tween 20) 16.7 Pluronic F 68 17.0 Sodium oleate 18.0 Potassium oleate 20.0 Sodium lauryl sulfate 40.0

Activity and HLB Value of Surfactants

Activity Assigned HLB1. Antifoaming 1 to 32. Emulsifiers (W/O) 3 to 63. Wetting agents 7 to 94. Emulsifiers (O/W) 8 to 185. Solubilizers 15 to 206. Detergents 13 to 15

Methods of Preparation

1. Continental or Dry gum method

2. English or wet gum method

3. Bottle or Forbes bottle method

4. Auxiliary method

5. In SITU soap method

6. Microemulsions

Continental or Dry gum method ( G + O + W )

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

1. The acacia or other O/W emulsifier is triturated with the oil in a perfectly dry Wedgewood or porcelain mortar until thoroughly mixed.

2. 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

3. Generally, about 3 minutes of mixing are required to produce such a primary emulsion.

4. Other liquid formulative ingredients that are soluble in or miscible with the external phase may then be added to the primary emulsion with mixing.

5. 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.

Preparation of Continental or Dry Gum Method

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:1. The powdered acacia is placed in a dry bottle2. Two parts of oil is then added, and the mixture is

thoroughly shaken in the capped container.3. A volume of water approximately equal to the oil is then

added in portions4. The mixture being thoroughly shaken after each addition5. 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.

Bottle or Forbes Bottle Method (G+O+W)

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

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

Example: Calamine Liniment (itchy, dry skin, sunburn)

Calamine………………………Zinc Oxide ……………………. 80.0 gOlive oil …………………………Calcium Hydroxide Sol’n aa q.s ad

1000.0 mL

In SITU Soap Method

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.

Advantages:More rapid and efficient oral absorption of drugs than through solid dosage formsEnhance transdermal drug delivery through increased drug diffusion into the skinThe technique potential application of microemulsion in the development of artificial red blood cells and in the argeting of cytotoxic drugs to cancer cells

Microemulsions

Examples of Emulsions

1. Turpentine Oil Emulsion Rectified Turpentine oil 150 mL Acacia powder 50 g Purified water, q.s to make 1000 mL2. Liquid Petrolatum Emulsion - Mineral oil Emulsion; Liquid Paraffin

Mineral oil………………………………… 500 mLAcacia …………………………………….. 125 gSyrup ……………………………………… 100 mLVanilla …………………………………….. 40 mgAlcohol ……………………………………. 60 mLPurified water, q.s to make 1000 mL

3. Cod liver Oil Emulsion - laxative with empty stomachCod liver oil …………………………….. 500 mLAcacia ……………………………………. 125 gSyrup …………………………………….. 100 mLMethyl salicylate ……………………….. 4 mLPurified water, q.s to make 1000 mL

Emulsion Stability

A stable emulsion is characterized by the following:

1. Absence of flocculation and creaming2. Absence of coalescence of globules and

separation of the layers3. Absence of deterioration due to

microorganisms4. Maintenance of elegance with respect to

appearance, odor, color and consistency

Emulsion is considered physically unstable if:The internal or dispersed phase upon standing tends to form aggregates of globules.

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

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

Emulsion Stability

Terminology

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

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

Coalescence and 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.

Deterioration by Microorganism

Molds, yeast and bacteria may bring about decomposition and contamination of the emulsion. Preservatives should be more fungistatics than bacteriostatic

Miscellaneous Physical and 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.

Terminology Related To Gels

Imbibition is taking up of a certain amount of liquid without a measurable increase by a gel with an increase volume.

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 thepresence of electrolytes.

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

Thixotrophy is a reversible gel-sol formation with no change in volume or temperature-a type of non-Newtonian flow.

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 Scheme1. Hydrogels

include ingredients that are dispersible as colloidals or soluble in water and include organic hydrogels, natural and sythetic gums and inorganic hydrogels

Examples: 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.

Examples: 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. Acacia 11. Alginic acid2. Bentonite 12. Carbomer3. Carbocymethylcellulose sodium 13. Cetostearyl Alcohol4. Colloidal silicon dioxide14. Ethylcellulose5. Gelatin 15. Guar gum6. Hydroxyethylcellulose 16. Hydroxypropryl cellulose7. Hydroxypropryl methylcellulose 17. Magnesium aluminum silicate8. Maltodextrin 18. Methylcellulose9. Polyvinyl alcohol 19. Povidone10. Propylene carbonate 20. Sodium alginate21. Sodium starch glycolate 22. Starch23. Tragacanth 24. Xanthan gum


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


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

Examples of Gelling Agents7. 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

8. Plastibase (Jelene)

mixture of 5% low molecular weight polyethylene and 95% mineral oil

9. 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


10. 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.

11. Povidone

about 10% in concentrations to prepare gels

also increase solubility of poorly soluble drugs


12. Sodium alginate

10 % to produce gels

aqueous preparations are most stable at pH 4 to 10; below pH 3, alginic acid is precipitated

13. 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

14. Methylcellulose

5% to form gels; dispersed with high shear in about 1/3 of water

MAGMAS and MILK

Are aqueous suspensions of insoluble, inorganic drugs and differ from gels mainly in that the suspended particles are larger. When prepared, they are thick and viscous, so need of a suspending agent.

Preparations1. By Hydration –

Example: Hydration of Magnesium oxideMgO + H2O Mg(OH)2

2. Chemical Reaction Milk of Bismuth is made by reacting Bismuth

subnitrate with Nitric acid and Ammonium carbonate with Ammonium solution and then mixing the resulting two solutions2NaOH + MgSO4 Mg(OH)2 + Na2SO4 (direct hydration)

MAGMAS and MILK

Examples of Magmas and Gels

Bentonite Magma NF suspending agent

Sodium Fluoride and Phosphoric Acid Gel

USP dental care prophylactic

Fluocinonide Gel USP Anti-inflammatory corticosteroid

Tretinoin Gel USP treatment for acne

Erythromycin and Benzoyl peroxide Gel

Clindamycin Topical Gel

Hydroquinone Gel Hyperpigmented skin

Salicylic acid Gel keratolytic

Desoximethasone Gel anti-inflammatory and antipruritic agent

Aluminum Phosphate Gel (Amphogel) USP antacid

Aluminum hydroxide Gel USP antacid

Dihydroxyaluminum Aminoacetate Magma

USP antacid

Milk of Magnesia (Magnesia Magma) USP Antacid; laxative

Sample Product

ALAXAN GEL

METHYL SALICYLATE + MENTHOL

AEROSOLS

Are pressured dosage forms containing one or more active ingredients which upon actuation emit a fine dispersion of liquid and/or solid materials in gaseous medium

The term Pressurized package is commonly used when referring to the aerosol container or completed product. Pressure is applied to the aerosol system through the use of one or more liquefied or gaseous propellants.

Aerosols used to provide an airborne mist are termed space sprays. Examples: room disinfectants, room deodorizers, and space insecticides.

Aerosols intended to carry the active ingredient to a surface are termed Surface sprays or surface coatings.

Examples: dermatologic aerosols, pharmaceutical aerosols, as personal deodorant sprays, cosmetic hair lacquers and sprays, perfumes and cologne sprays, shaving lathers, toothpaste, surface pesticide sprays, paint sprays and others.

AEROSOLS

Advantages of the Aerosol Dosage Forms

1. A portion of medication may be easily withdrawn from the package without contamination or exposure to the remaining material.

2. Hermetic character, the aerosol container protects medicinal agents from atmospheric oxygen, moisture and even from light.

3. Topical medication may be applied in a uniform, thin layer to the skin, without touching the affected area thus, reducing irritation.

4. By proper formulation and valve control, the physical form and the particles size of the emitted product may be controlled which may contribute to the efficacy of a drug. Example: the fine controlled mist of an inhalant aerosol. Through the use of metered valves, dosage may be controlled.

5. Aerosol application is “clean” process, requiring little or no “wash-up” by the user.

The Aerosol Principle

As aerosol formulation consists of 2 components:

1. The product concentrate is the active ingredient of the aerosol combined

with the required adjuncts, such as antioxidants, surface-active agents, and solvents, to prepare a stable and efficacious product.

2. The propellant when the propellant is a liquefied gas or a

mixture of liquefied gases, it frequently serves the dual role of propellant and solvent or vehicle for the product concentrate

Examples of Propellants1. Carbon dioxide2. Nitrogen3. Nitrous oxide4. Fluorinated Hydrocarbons:

Trichloromonofluoromethane; Dichlorodifluoromethane;

Dichlorotetrafluoroethane; Chlorpentafluoroethane;

Monochlorodifluoroethane; Octafluorocyclobutane

Aerosol Container and Valve Assembly

The effectiveness of the aerosol depends on:1. proper combination of formulation, 2. container3. valve assembly.

The formulation must not chemically interact with the container or valve components to avoid unstability of the formulation.

The container and the valve must be capable of withstanding the pressure required by the product

It must be corrosive resistant Valve must contribute to the form of the product to be

emitted.

AEROSOL SYSTEMS

SPACE AEROSOLS usually operate at pressures between 30 to 40 psig (pounds per square inch gauge) at 700F and may contain as much as 85% propellant

SURFACE AEROLSOLS commonly contain 30 to 70% propellant with pressures between 25 to 55 psig at 700F

FOAM AEROSOLS usually operate between 35 and 55 psig at 700F and may contain only 6 to 10% propellant

AEROSOL SYSTEMS

TWO PHASE SYSTEM = comprised (1) the liquid phase – propellant and product concentrate (2) the vapor phase

THREE PHASE SYSTEM = comprised (1) layer of water immiscible liquid propellant, (2) layer of highly aqueous product concentrate, and (3) vapor pressure

COMPRESSED GAS SYSTEM = compressed rather liquefied, gases may be used to pressure aerosols. The pressure of the compressed gas contained in the headspace of the aerosol container forces the product concentrate up the dip tube and out of the valve

Examples: Nitrogen; carbon dioxide; nitrous oxide

Containers

1. Glass, uncoated or plastic coated2. Metal, including tinplated steel, aluminum, and

stainless steel3. Plastics The selection of containers for an aerosol product is

based on1. Its adaptability to production methods2. Compatibility with formulation components3. Ability to sustain the pressure intended for the product4. The interest in design and aesthetic appeal on the

part of the manufacturer, and5. Cost

VALVE ASSEMBLY

The function of the valve assembly is to permit the expulsion of the contents of the can in the desired form, at the desired rate, and, in the case of metered valve, in the proper amount or dose.

The materials used in the manufacture of valves must be inert and approved by BFAD.

Among the materials used in making valve parts are plastic, rubber, aluminum, and stainless steel.

Metered Dose Inhalers (MDIs)Metered Dose Inhalers (MDIs)

Example: Allupent. Each metered dose is delivered through the mouthpiece upon actuation of the aerosol unit’s valve

Nitrolingual spray - permits a patient to spray droplets onto or under the tongue for acute relief of an attack, or prophylaxis, of angina pectoris due to coronary artery disease. The product contains 200 doses of nitroglycerin in a propellant mixture of dichlorofluoromethane and dichlorotetrafluoroethane

Filling OperationsFilling Operations

Fluorinated hydrocarbon gases may be liquefied by cooling below their boiling points or by compressing the gas at room temperature. These 2 features are utilized in the filling of aerosol containers with propellant.

Cold FillingCold Filling

Both the product concentrate and the propellant must be cooled to temperatures of -300 to -40 0F. This temperature is necessary to liquefy the propellant gas. The cooling system may be a mixture of dry ice and acetone.

Pressure FillingPressure Filling

The product concentrate is quantitatively placed in the aerosol container, the valve assembly is inserted and crimped into place, and liquefied gas, under pressure, is metered into the valve stem from a pressure burette.

Parts of Aerosol Valve

Actuator The actuator is the button which the user presses to activate the valve assembly for the emission of the product.

Stem The stem supports the actuator and delivers the formulation in the proper form to the chamber of the actuat

Gasket The gasket, placed snugly with the stem, serves to prevent leakage of the formulation when the valve is in closed position

Spring The spring holds the gasket in place and also is the mechanism by which the actuator retracts when pressure is released, thereby returning the valve to the closed position

Mounting cup

The mounting cup, which is attached to the aerosol can or container, serves to hold the valve in place.

Housing The housing, located directly below the mounting cup, serves as the link between the dip tube and the stem and actuator. With the stem, its orifice helps to determine the delivery rate and the form in which the product is emitted.

Dip tube The dip tube, which extends from the housing down into the product, serves to bring the formulation from the container to the valve.

Testing the Filled Containers

Container is tested under various environmental conditions

1. Leaks2. Weakness in the valve assembly or container3. Proper function s of the valve4. The valve discharge rate - determine by discharging a

portion of the contents of a previously weighed aerosol during a given period of time, and calculating, by the difference in weight, the grams of contents discharged per unit of time.

5. Particle size distribution of the spray5. For accuracy and reproducibility of dosage when

using metered valves

Aerosols

Topical Aerosols Aerosols packages for topical use on the skin which include:

Antiinfectives: Povidone - iodine, Tolnaftate and Thimerosal

Adrenocortical steroids: Betamethasone and Triamcinolone

Acetonide

Local anesthetic: Dibucaine hydrochlorideVaginal and Rectal Aerosols• Aerosols foams are commercially available containing estrogenic substances and contraceptives agents.

Example: ProctoFoam - contains pramoxine hydrochloride - use to relieve inflammatory anorectal disorder

Examples of Inhalation Aerosols

Albuterol Inhalation Proventil Inhalation Aerosol

Beta-adrenergic

Beclomethasone Dipropionate

Beclovent Inhaltion Adrenocortical Beconace steroid

Cromolyn Sodium Intal Inhaler Atiasthmatic, Antiallergic

Ipratropium Bromide Atrovent Anticholinergic

Isoetharine Mesylate Bronkometer Sympathomimetic - brochial asthma

Metaproterenol Sulfate Alupent Sympathomimetic

Salmeterol Xinafoate Serevent Beta-adrenergic agonist

Terbutaline Sulfate Brethaire Beta-adrenergic agonist

Triamcinolone Acetonide Azmacort Corticosteroids for asthma

NASAL PREPARATIONS

aqueous preparations, rendered isotonic to nasal fluids (approximately equivalent to 0.9% sodium chloride) buffered to maintain drug stability while approximating the normal pH range of the nasal fluids (pH 5.5 to 6.5), and stabilized and preserved as required.

Examples of Some Commercial Nasal Preparations

Afrin Nasal Spray/ drops Oxymetazole nasal decongestant/adrenergic

Beconase AQ Nasal Spray Bechlomethasone diproprionate

synthetic corticosteroid

Diapid Nasal Spray Lopressin antidiuretic; prevention of diabetes

Nasalcrom Spray Cromolyn - allergic rhinitis

Ocean Mist Isotonic sodium chloride restore moisture/relieve dry

Privine HCl Solution Naphazoline HCl nasal adrenergic/decongestant

Syntocinon Spray Tetrahydrozoline HCl adrenergic/decongestant

Neo-Synephrine Oxymetazoline HCl nasal adrenergic/decongestant

Nasalide Nasal Solution Flunisolide perennial/seasonal rhinitis

OTIC SOLUTIONS

sometimes referred to as ear or aural preparations.

Preparations frequently used in the ear, with suspensions or ointments also finding some application.

Usually placed in the ear canal by drops or small amounts for the removal of excessive cerumen (ear wax), or treatment of ear infections, inflammation, or pain.

Examples of Some Commercial Otic Preparations

AMERICAINE Benzocaine local anesthetic

AURALGAN Antipyrine, Benzocaine Acute otitis media

CERUMENEX DROPS Triethanolamine Cerumenolytic agent

CHLOROMYCETIN Chloramphenicol Anti-infective

CORTISPORIN SOLUTION Polymyxin B sulfate, neomycin sulfate

antibacterial

DEBROX DROPS Carbamide Peroxide Ear wax remova

PEDIOTIC Polymyxin B sulfate neomycin sulfate

- Antibacterial

METRETON Prednisolone sodium phosphate

Antiinflammatory

OTOBIOTIC SOLUTION Polymyxin B Sulfate, hydrocortisone

Antibacterial

VOSOL SOLUTION Acetic acid Antibacterial/Antifungal

MUCILAGES

The official mucilages are thick, viscid, adhesive liquids, produced by dispersing gum in water or by extracting with water mucilagenous principle from vegetable substances.

Mucilages are used primarily to aid in suspending insoluble substances in liquids due to their (1) colloidal character and (2) viscosity which prevents the immediate sedimentation

Example of Mucilage

Method: Place acacia in wide mouth graduated bottle with capacity not exceeding 1000 mL. Wash the drug with cold water, drain and add sufficient quantity of purified water in which benzoic acid has been dissolved to make 1000 mL, Stopper and lay the bottle, rotate occasionally, and when acacia has been dissolved, strain the mucilage

Uses: Demulcent, suspending agent, excipient in making pills and troches,and as emulsifying agent for cod liver oil

Preparation: Acacia Mucilage NFSynonym: Mucilago Acaciae; Mucilage of Gum ArabicFormula : Acacia, in small fragments 350 g

Benzoic acid 2 gPurified water, q.s to make 1000 mL

Example of Mucilage

Preparation: Tragacanth Mucilage NFSynonym: Mucilago Tragacanthae

Formula : Tragacanth 6.0 g Benzoic acid 0.2 g Glycerin 18.0 g

Purified water, q.s to make 100 g

Method : Mix 75 mL of purified water with glycerin in a tared vessel, heat to boiling, discontinue application of heat, add Tragacanth and the Benzoic acid and macerate during 24 hours, stirring occasionally. Add sufficient quantity of purified water to make the mucilage 100 g, stir actively until uniform consistency and strain through muslin cloth

Uses: excipient for pills or troches, suspending agent for insoluble substances for internal mixtures and as protective agent

INHALANTS

Are drugs or combinations of drugs that by virtue of their high vapor pressure can be carried by an air current into the nasal passage where they exert their effect.

The device in which they are administered is termed an inhaler.

Examples:1. Amyl Nitrite Inhalant - treatment of anginal pain2. Propylhexedrine Inhalant - nasal decongestant

INHALATIONS

Inhalations are drugs or solutions of drugs administered by the nasal or oral respiratory route.

A widely used instrument capable of producing fine particles for inhalation therapy is the NEBULIZERS.

When volatile medication is added to the water in the chamber, the medication is volatilizes and also inhaled by the patient, HUMIDIFIERS will be used.

INHALATIONS

The common household VAPORIZER, produces a fine mist of steam that may be used to humidify a room will be used also.

ULTRASONIC HUMIDIFIERS are also available.

Examples:1. Isoetharine inhalation - bronchial asthma2. Isoproterenol Inhalation - bronchial asthma

Sample Products

LIBRENTIN INHALER

SALBUTAMOL

LOTIONS

Also called “WASHES” or meaning “LOTIO” or “LAVARE” to wash. Lotions are liquid suspension or dispersion intended for external application to the skin, frequently containing suspended particles or emulsified liquid droplets.

Depending therefore, whether they are solid-liquid or liquid-liquid dispersions, some lotions can also classified as suspension or emulsion.

Characteristics: Since the finely powdered substances

are insoluble in the dispersion medium, the use of suspending agents and dispersion agent is made.If the substance is immiscible, an emusifying agent is used. Most commonly, the vehicles of lotions are aqueous.

LOTIONS

Characteristics Of GOOD Lotion

Dries quickly and provides a protective film that will not rub off easily. It should not run off the surface of the skin.

The particles settle or rise only slowly and solid do not form a hard cake at the bottom of the vessel.

The lotion should pour freely from the bottle and apply evenly over the affected area.

Should have an acceptable color and odor. Must remain physically and chemically stable Free from contamination during storage

Methods Of Preparation

1. Trituration

Example: Calamine lotion

2. Chemical Reaction

Example: White lotion

Types Of Lotion According To Use

1. Medical LotionsA. Antiseptic and germicidalB. As cooling and mildly anesthetic for skin irritations

ExamplesBenzyl Benzoate Lotion

Benzyl Benzoate 250 mL; Triethanolamine 5 g; Oleic acid 20 g; water 750 mL - emulsion type lotion

Use: for scabies Calamine Lotion, USP

liquefied phenol 10 mL; Calamine lotion 990 mL to make 1000 mL

Uses: anesthetic and antiseptic

Lotio Alba; Lotio Sulfurata Uses: for acne and antiseptic since it has sulfur

Example: Calamine Lotion

Calamine 80 g Zinc Oxide 80 gGlycerin 20 mL Bentonite Magma 250 mL Calcium Hydroxide solution q.s.

to make 1000 mL

Uses: relieves itching and pain of sunburn, insect bites

MEDICATED LOTION


2. Cosmetics Lotions - are applied to hair, scalp, face and hands. They are common as sunscreen preparation. Contain glycerin, perfume and preservatives.Examples Of Medicated Lotions

1. Ammonium Lactate - Lac-Hydrin- Promotes hydration, removal of excess keratin dry skin, hyperkeratolytic conditions

2. Benzoyl Peroxide - Sulfoxyl Lotion - antibacterial (Propionibacterium acnes)

3. Betamethasone Diproprionate - Diprolene - Anti-inflammatory

4. Betamethasone Valerate- Betatrex - Anti-inflammatory5. Calamine Lotion -Topical protectant6. Clotrimazole - Lotrimin - dermal infections tinea pedis, tinea

cruris, and tinea corporus


7. Lindane - Kwell Lotion - Pediculicide; scabicide (twice a week)

8. Hydrocortisone - Hytone - Adrenocortical steroid and anti-inflammatory

9. Permethrin Rinse - Nix Crème Rinse - a synthetic pyrethroid which is active against lice, i.e. pediculosis

10. Selenium Sulfide - Selsun and Selsun Blue - Anti-fungal, antiseborrheic. Used principally in the treatment of dandruff and seborrheic dermatitis

11. Urea Lotion - Ureacin 10 Lotion - Promotes hydration and removal of excess keratin dry skin and hyperkeratotic conditions.

Calamine Liniment/Lotion. Oily BPCCalamine 50 gWool fat 10 gOleic acid 5 mLArachic oil 500 mLCa(OH)2 solution to make 1000 mL

Triturate the calamine with the wool fat, the arachis oil and oleic acid, previously melted together. Transfer to a suitable container, add the Ca(OH)2 solution and shake vigorously.

c 14 Suspension

Documents

add sufficient

forbes bottle

mounting cup

oleaginous

external phase

internal phase

emulsifying

oral suspension