CHAPTER 14: DISPERSE SYSTEM Suspension 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. 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) In general sense, Suspension may include: 1. Gels 2. Lotions 3. Magmas & Milk 4. Mixtures GeLoMaMi 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 & should be re-dispersed completely and evenly with a minimum amount of agitation Characteristics of Suspension Should not be too viscous to pour freely from the mouth of the bottle Should have an agreeable odor, color and taste & must not decomposed or support mold growth during storage Must have therapeutic efficacy 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 Suspension 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 doses Safety 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 Features Desired in a Pharmaceutical Suspensions 1. A properly prepared suspension should settle slowly & 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 & evenly from its container - 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. 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.

Sustained-Release Suspension In liquid preparations (suspensions) of the coated particles, the drug remains adsorbed onto resin, but slowly released by the ionexchange 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 EXTEMPORANEOUS COMPOUNDING 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 Difficulty of pharmacist: lack of ready information on stability of a drug in liquid vehicle 1 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 International Journal of Pharmaceutical Compounding journal wherein hundreds of compounded liquid formulations, based upon documented stability data are available *others: unpublished data compiled by manufacturers and practitioners are also available for pharmacist to use Typically: 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 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 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 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 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 All suspensions should be packaged in containers having: 1. Adequate airspace above the liquid to permit adequate shaking. 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 Preparation methylparaben & 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 Examples of Oral Suspensions by Category Antacids Alumina, Magnesia and Simethicone Mylanta liquid Magaldrate Oral Suspension - Riopan Oral Suspension Magnesia and Alumina Oral Maalox Suspension Aluminum Hydroxide and Magnesium Carbonate - Gaviscon liquid Anthelminitics Pyrantel Pamoate Antiminth Oral Suspension Thiabenzadole Oral Suspension - Mintezol Oral Suspension Antibacterial Chloramphenicol (Antibiotics) Palmitate Chloromycetin Palmitate Oral Suspen. Ertythromycin Estolate - Ilosone Oral Suspension Antibacterial (non- Methenamine antibiotic Anti- Mandelate infectives) Mandelamine Suspension/Forte Sulfamethoxazole and Trimethoprim Bactrim, Septra Susp. Sulfamethoxazole -

Gantanol Suspension Sulfisoxazole Acetyl Oral SuspensionGantrisin Syrup/Pedia Anticonvulsants Pimidone Oral Suspension Mysoline Suspension Antidiarrheal Bismuth Subsalicylate - PeptoBismol liquid Antiflatulent Simethicone Oral Suspension Mylicone Drop Antifungals Nystatin Oral Suspension - Nystatin Oral Susp Griseofulvin Oral Suspension -Grifulvin Oral Susp Antihypertensive Methyldopa Oral Suspension - Aldomet Oral Suspension Antipsychotics, Hydroxyzine Pamoate Sedatives, Oral Suspension Antiemetic Vistaril Oral Suspension Thioridazine Oral Suspension - MellarilS Oral Suspension Diuretic Chlorothiazide Oral Suspension - Diuril Oral Suspension Nonsteroidal Anti- Indomethacin Oral inflammatory 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

Assert more immediate action, but do not require time to disintegrate intended to counteract the effects of gastric hyperacidity pleasantly flavored to enhance their palatability and patient appeal employed by persons, such as peptic ulcer patients, who must reduce the level of acidity in the stomach widely employed and sold OTC to patients w/ acid indigestion, heartburn, and sour stomach act within the gastrointestinal tract to counter act the acid and/or soothe the

irritated or inflamed linings of the GI tract Example: - Sodium Bicarbonate - neutralizes acid effectively yet produce Na overload and systemic alkalosis, a hazard on patients on Na restricted diets - Aluminum hydroxide less effective and more slow, excessive use may lead to constipation and phosphate depletion with consequent mucle weakness, bone resotption and hypercalciuria - Aluminum phosphate - Dihydroxyaluminum aminoacetate - Calcium carbonate can neutralizes acid effectively, carries the potential to induce hypercalcemia and stimulation of gastric secretion and acid production (acid rebound) - Calcium phosphate - Magaldrate - Magnesium carbonate - Magnesium oxide - Magnesium hydroxide neutralizes acid effectively, converted to MgCl, w/c is water soluble and is partially absorbed Selection of antacid Heartburn/ gastric distress- single dose of Na bicarbonate/ MgOH Acute peptic ulcer/ duodenal ulcer (therapeutic regimen includes frequent administration of anatacid) Na bicarbonate provides too much Na and MgOH induces diarrhea combination of MgOH and Al hydroxide is frequently used 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 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 Examples: - Antibiotics ( Chloramphenicol palmitate, Erythromycin derivatives, and tetracycline and its derivatives) - Sulfonamides (Sulfamethoxazole, sulfisoxazole acetyl) - other chemotherapeutic agents(methanamine mandelate & 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 Crohns disease, distal ulcerative colitis, proctosigmoiditis, and proctitis. - 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. The dry products contain 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 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 Antibiotics for Oral Suspension (Reconstitution) Amoxicillin for Oral Suspension FOR ORAL AMOXIL SUSPENSION Ampicillin for Oral Suspension FOR ORAL OMNIPEN SUSPENSION Bacampicillin for Oral FOR ORAL Suspension SUSPENSION SPECTROBID Cefaclor for Oral Suspension FOR ORAL CECLOR SUSPENSION Cefixime for Oral Suspension FOR ORAL SUPRAX POWDER SUSPENSION Cephadrine for Oral FOR ORAL Suspension SUSPENSION KEFLEX Dicloxacillin Sodium for Oral FOR ORAL Suspension (PATHOCIL) SUSPENSION Doxycycline for Oral FOR ORAL Suspension SUSPENSION VIBRAMYCIN MONOHYDRATE Erythromycin Ethylsuccinate FOR ORAL for Oral Suspension SUSPENSION E.E.S. GRANULES Penicillin V for Oral Suspension Other examples (Combination) 1. Erythromycin ethylsuccinate/ acetylsulfisoxazole granules - treatment for acute middle ear infection - Hemophilus influenza 2. Probenecid/ampicillin for reconstitution treatment for uncomplicated infections (urethral, endocervical or rectal) Neisseria gonorrhoeae Cholestyramine (Questran, Par) used in the management of hyperlipidemia 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, intestine, and colon

stomach,

small

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, & W/O emulsion with an oleaginous or oil miscible liquid The aqueous phase may contain watersoluble 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. Purpose of Emulsification 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 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 - 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 & 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. 2. 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. 3. Plastic or Internal 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. 4. 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 1. Natural emulsifying agent - 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 is too fluid - Carbohydrates: acacia, tragacanth, agar, chondrus, pectin - Proteins: gelatin, egg yolk, casein 2. High Molecular Weight alcohols - 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. - E.g. stearyl alcohol, cetyl alcohol, glyceryl monostearate 3. Finely 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 including: Bentonite, Magnesium hydroxide, Aluminum hydroxide 4. Synthetic - (wetting agents), which may be: a. Anionic: triethanolamine oleate and sodium lauryl sulfate b. Cationic: benzalkonium chloride c. Nonionic: 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 shelflife 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 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 Ex.: 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 6.1

glycol

monolaurate

Examples 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 HLB 1. Antifoaming 1 to 3 2. Emulsifiers (W/O) 3 to 6 3. Wetting agents 7 to 9 4. Emulsifiers (O/W) 8 to 18 5. Solubilizers 15 to 20 6. Detergents 13 to 15

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 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 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. 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. 2. English or wet gum method 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: 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 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. 4. Auxiliary method An emulsion by either the wet gum or 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 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 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

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 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. 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 Example of Microemulsion 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

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

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 forconcentrated layer of the internal phase.

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. 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. Acacia 2. Bentonite 3. Carbocymethylcellulose sodium 4. Colloidal silicon dioxide 5. Gelatin 6. Hydroxyethylcellulose 7. Hydroxypropryl methylcellulose 8. Polyvinyl alcohol 9. Propylene carbonate 10. Alginic acid - obtained from seaweed, prepared products is tasteless, odorless, yellowishwhite 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 11. Carbomer - 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) - Ex.: Carbomers 910,934,934P,940 and 1342 12. Cetostearyl Alcohol 13. Ethylcellulose 14. Guar gum 15. Hydroxypropryl cellulose 16. Magnesium aluminum silicate 17. Methylcellulose 18. Povidone 19. Sodium alginate

20. 21. 22. 23.

Sodium starch glycolate Starch TragacanthX Xanthan gum

Other examples: 1. 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 2. CMC sodium - soluble in water at all temperature 3. Colloidal silicone dioxide - can be used with other ingredients of similar refractive index to prepare transparent gels 4. Gelatin - dispersed in hot water and cooled to form gels 5. 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 6. Plastibase (Jelene) - mixture of 5% low molecular weight polyethylene and 95% mineral oil 7. 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 8. 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 9. 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. 10. Povidone - about 10% in concentrations to prepare gels - also increase solubility of poorly soluble drugs 11. Sodium alginate - 10 % to produce gels

- aqueous preparations are most stable at pH 4 to 10; below pH 3, alginic acid is precipitated 12. 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 13. 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 Preparations 1. By Hydration Ex.: Hydration of Magnesium oxide MgO + 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 solutions 2NaOH + MgSO4 Mg(OH)2 + Na2SO4 (direct hydration) Examples of Magmas and Bentonite Magma NF Sodium Fluoride & USP Phosphoric Acid gel Fluocinonide Gel USP Tretinoin Gel Erythromycin and Benzoyl peroxide Gel Clindamycin Topical Gel Hydroquinone Gel Salicylic acid gel Desoximethasone gel Alumnium phosphate gel (Amphogel) Alumnium hydroxide gel Dihydroxyalumninum Aminoacetate Magma Milk of Magnesia (Magnesia Magma) USP USP USP USP Gels suspending agent dental care prophylactic Anti-inflammatory corticosteroid USP treatment for acne

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. Ex.: room disinfectants, room deodorizers, and space insecticides. Aerosols intended to carry the active ingredient to a surface are termed Surface sprays or surface coatings. Ex: 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. 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

Hyperpigmented skin Keratolytic Anti-inflammatory and anti-pruritic agent Antacid Antacid Antacid Antacid; laxative

Examples of Propellants 1. Carbon dioxide 2. Nitrogen 3. Nitrous oxide 4. 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. container 3. 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 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 coated 2. Metal, including tinplated steel, aluminum, and stainless steel 3. Plastics The selection of containers for an aerosol product is based on 1. Its adaptability to production methods 2. Compatibility with formulation components 3. Ability to sustain the pressure intended for the product 4. The interest in design and aesthetic appeal on the part of the manufacturer 5. 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) Ex.: Allupent. Each metered dose is delivered through the mouthpiece upon actuation of the aerosol units 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 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 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 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

1. The actuator is the button which the user presses to activate the valve assembly for the emission of the product. 2. The stem supports the actuator and delivers the formulation in the proper form to the chamber of the actuat 3. The gasket, placed snugly with the stem, serves to prevent leakage of the formulation when the valve is in closed position 4. 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 5. The mounting cup, which is attached to the aerosol can or container, serves to hold the valve in place. 6. 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. 7. 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. Leaks 2. Weakness in the valve assembly or container 3. Proper function s of the valve 4. 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 spray 6. For accuracy and reproducibility of dosage when using metered valves 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 hydrochloride Vaginal and Rectal Aerosols Aerosols foams are commercially available containing estrogenic substances and contraceptives agents. Ex.: ProctoFoam

- contains pramoxine hydrochloride - use to relieve inflammatory anorectal disorder Examples of Inhalation Aerosols Albuterol Proventil Beta-adrenergic Inhalation inhalation aerosol Beclomethaso Beclovent Adrenocortical ne inhalation beconace steroid Dipropionate Cromolyn Intal inhaler Antiasthmatic, Sodium antiallergy Ipratropium Atrovent Anticholinergic bromide Isoetharine Bronkomete Sympathomimetic Mesylate r - brochial asthma Metaproteren Alupent Sympathomimetic ol sulfate Salmeterol Serevent Beta-adrenergic Xinafoate agonist Terbutaline Brethaire Beta-adrenergic sulfate agonist Triamcinolone Azmacort Corticosteroids for acetonide 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 Oxymetazole nasal Spray/ drops decongestant/a drenergic Beconase AQ Bechlomethasone synthetic Nasal Spray diproprionate corticosteroid Diapid Nasal Lopressin antidiuretic; Spray prevention of diabetes Nasalcrom Cromolyn allergic rhinitis Spray Ocean Mist Isotonic sodium restore chloride moisture/reliev e dry Privine HCl Naphazoline HCl nasal Solution adrenergic/dec ongestant Syntocinon Tetrahydrozoline adrenergic/dec Spray HCl ongestant NeoOxymetazoline nasal Synephrine HCl adrenergic/dec ongestant Nasalide Flunisolide perennial/seaso Nasal nal rhinitis Solution

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, Acute otitis Benzocaine media Cerumenex Triethanolamin Cerumenolyti drops e c agent Chloromyce Chloramphenic Anti-infective tin ol Cortisporin Polymyxin B antibacterial solution sulfate, neomycin sulfate Debrox Carbamide Ear wax drops Peroxide remova Pediotic Polymyxin B - Antibacterial sulfate neomycin sulfate Metreton Prednisolone Antiinflammat sodium ory phosphate Otobiotic Polymyxin B Antibacterial solution Sulfate, hydrocortisone Vosol Acetic acid Antibacterial/ solution 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

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 pain 2. 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. 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. Ex.: 1. Isoetharine inhalation - bronchial asthma 2. Isoproterenol Inhalation - bronchial asthma 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. 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 Ex.: Calamine lotion 2. Chemical Reaction Ex.: White lotion Types Of Lotion According To Use 1. Medical Lotions a. Antiseptic and germicidal b. As cooling and mildly anesthetic for skin irritations Ex.:Benzyl 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 g Zinc Oxide g Glycerin mL Bentonite Magma mL Calcium Hydroxide solution q.s.

80 80 20 250

to make 1000 mL Uses: relieves itching and pain of sunburn, insect bites 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-HydrinPromotes 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 - Antiinflammatory 5. Calamine Lotion -Topical protectant 6. Clotrimazole - Lotrimin - dermal infections tinea pedis, tinea cruris, and tinea corporus 7. indane - Kwell Lotion - Pediculicide; scabicide (twice a week) 8. Hydrocortisone - Hytone - Adrenocortical steroid and anti-inflammatory 9. Permethrin Rinse - Nix Crme 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 BPC Calamine Wool fat 50 g 10 g

Oleic acid 5 mL Arachic oil 500 mL Ca(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.