Disperse Systems PDF

DISPERSE SYSTEMS SUSPENSIONS  Suspensions may be defined as preparations containing finely divided drug particles (the suspensoid) distributed somewhat uniformly throughout a vehicle in which the drug exhibits a minimum degree of solubility.  Generally, this type of product is a...

DISPERSE SYSTEMS SUSPENSIONS  Suspensions may be defined as preparations containing finely divided drug particles (the suspensoid) distributed somewhat uniformly throughout a vehicle in which the drug exhibits a minimum degree of solubility.  Generally, this type of product is a powder mixture containing the drug and suitable suspending and dispersing agents to be diluted and agitated with a specified quantity of vehicle, most often purified water FEATURES DESIRED IN A PHARMACEUTICAL SUSPENSION In addition to therapeutic efficacy, chemical stability of the components of the f o r m u l a t io n , p e r m a n e n c y o f t h e p r e p a r a t io n , a n d a e s t h e t i c a p p e a l o f t h e preparation—a few other features apply more specifically to the pharmaceutical suspensions: 1. A properly prepared pharmaceutical suspension should settle slowly and should be readily redispersed upon gentle shaking of the container. 2. The particle size of the suspensoid should remain fairly constant throughout long periods of undisturbed standing. 3. The suspension should pour readily and evenly from its container. PHYSICAL FEATURES OF THE DISPERSED PHASE OF A SUSPENSION  Probably the most important single consideration in a discussion of suspensions is the size of the particles. In most good pharmaceutical suspensions, the particle diameter is 1 to 50 μm.  Generally, particle size reduction is accomplished by dry milling prior to incorporation of the dispersed phase into the dispersion medium.  One of the most rapid, convenient, and inexpensive methods of producing fine drug powders of about 10 to 50 μm size is micropulverization.  For still finer particles, under 10 μm, fluid energy grinding, sometimes referred to as jet milling or micronizing, is quite effective. DISPERSION MEDIUM  Oftentimes, as with highly flocculated suspensions, the particles of a suspension settle too rapidly to be consistent with what might be termed a pharmaceutically elegant preparation. The rapid settling hinders accurate measurement of dosage and, from an aesthetic point of view, produces too unsightly a supernatant layer.  In many commercial suspensions, suspending agents are added to the dispersion medium to lend it structure.  Carboxymethylcellulose (CMC), methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, xanthan gum, and bentonite are a few of the agents employed to thicken the dispersion medium and help suspend the suspensoid. PACKAGING AND STORING OF SUSPENSIONS  All suspensions should be packaged in wide-mouth containers having adequate airspace above the liquid to permit thorough mixing by shaking and ease of pouring.  Most suspensions should be stored in tight containers protected from freezing, excessive heat, and light. It is important that suspensions be shaken before each use to ensure a uniform distribution of solid in the vehicle and thereby uniform and proper dosage. EMULSIONS  An emulsion is a dispersion in which the dispersed phase is composed of small globules of a liquid distributed throughout a vehicle in which it is immiscible.  In emulsion terminology, the dispersed phase is the internal phase, and the dispersion medium is the external or continuous phase.  Generally, to prepare a stable emulsion, a third phase, an emulsifying agent, is necessary. Depending on their constituents, the viscosity of emulsions can vary greatly, and pharmaceutical emulsions may be prepared as liquids or semisolids. HLB SYSTEM  A method has been devised whereby emulsifying or surface-active agents may be categorized on the basis of their chemical makeup as to their hydrophilic–lipophilic balance, or HLB.  By this method, each agent is assigned an HLB value or number indicating the substance’s polarity.  Generally, surface-active agents having an assigned HLB value of 3 to 6 are greatly lipophilic and produce w/o emulsions, and agents with HLB values of about 8 to 18 produce o/w emulsions. HLB SYSTEM ACTIVITY AND HLB VALUE OF SURFACTANTS ACTIVITY ASSIGNED HLB Antifoaming 1-3 Emulsifiers (w/o) 3-6 Wetting Agents 7-9 Emulsifiers (o/w) 8-18 Solubilizers 15-20 Detergents 13-16 METHODS OF EMULSION PREPARATION The methods in preparing emulsions are as follows: 1. Continental or Dry Gum Method 2. English or Wet Gum Method 3. Bottle or Forbes Bottle Method 4. Auxiliary Method CONTINENTAL OR DRY GUM METHOD  The continental method is also referred to as the 4:2:1 method because for every 4 parts by volume of oil, 2 parts of water and 1 part of gum are added in preparing the initial or primary emulsion.  In this method, the acacia or other o/w emulsifier is triturated with the oil in a perfectly dry Wedgwood or porcelain mortar until thoroughly mixed.  After the oil and gum have been mixed, the two parts of water are added all at once, and the mixture is triturated immediately, rapidly, and continuously until the primary emulsion is creamy white and produces a crackling sound to the movement of the pestle.  Generally, about 3 minutes of mixing is required to produce a primary emulsion. ENGLISH OR WET GUM METHOD  By this method, the same proportions of oil, water, and gum are used as in the continental or dry gum method, but the order of mixing is different, and the proportion of ingredients may be varied during the preparation of the primary emulsion as is deemed necessary by the operator.  Generally, a mucilage of the gum is prepared by triturating in a mortar granular acacia with twice its weight of water. The oil is then added slowly in portions, and the mixture is triturated to emulsify the oil.  Should the mixture become too thick, additional water may be blended into the mixture before another portion of oil is added. After all of the oil has been added, the mixture is thoroughly mixed for several minutes to ensure uniformity. BOTTLE OR FORBES BOTTLE METHOD  The bottle method is useful for the extemporaneous preparation of emulsions from volatile oils or oleaginous substances of low viscosities.  Powdered acacia is placed in a dry bottle, two parts of oil are added, and the mixture is thoroughly shaken in the capped container. A volume of water approximately equal to that of the oil is then added in portions and the mixture thoroughly shaken after each addition.  This method is not suited for viscous oils because they cannot be thoroughly agitated in the bottle when mixed with the emulsifying agent. When the intended dispersed phase is a mixture of fixed oil and volatile oil, the dry gum method is generally employed. AUXILIARY METHODS  An emulsion prepared by either the wet gum or the dry gum method 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 orifice that reduces the globules of the internal phase to about 5 μm and sometimes less.  The hand homogenizer is less efficient in reducing the particle size of very thick emulsions, and it should not be employed for emulsions containing a high proportion of solid matter because of possible damage to the valve. STABILITY OF EMULSIONS Generally speaking, an emulsion is considered to be physically unstable if: a) the internal or dispersed phase upon standing tends to form aggregates of globules, b) large globules or aggregates of globules rise to the top or fall to the bottom of the emulsion to form a concentrated layer of the internal phase, and c) if all or part of the liquid of the internal phase separates and forms a distinct layer on the top or bottom of the emulsion as a result of the coalescing of the globules of the internal phase. GELS AND MAGMAS  Gels are defined as semisolid systems consisting of dispersions made up of either small inorganic particles or large organic molecules enclosing and interpenetrated by a liquid.  Gels in which the macromolecules are distributed so that no apparent boundaries exist between them and the liquids are called single-phase gels.  When the gel mass consists of floccules of small, distinct particles, the gel is classified as a two-phase system and frequently called a magma or a milk.  Gels and magmas are considered colloidal dispersions because they contain particles of colloidal dimension. TERMINOLOGY RELATED TO GELS 1. Imbibition is the taking up of a certain amount of liquid without a measurable increase in volume. 2. Swelling is the taking up of a liquid by a gel with an increase in volume. 3. Syneresis occurs when the interaction between particles of the dispersed phase becomes so great that on standing, the dispersing medium is squeezed out in droplets and the gel shrinks. 4. Thixotropy is a reversible gel–sol formation with no change in volume or temperature 5. A xerogel is formed when the liquid is removed from a gel and only the framework remains. Examples include gelatin sheets, tragacanth ribbons, and acacia tears.  CLASSIFICATION AND TYPES OF GELS CLASS DESCRIPTION EXAMPLES Inorganic Usually two-phase systems Aluminum Hydroxide Gel Bentonite Magma Organic Usually single-phase systems Carbopol Tragacanth Hydrogels Organic Hydrogels Pectin paste, tragacanth jelly Natural and synthetic gums Methylcellulose, sodium CMC, Pluronic Inorganic Hydrogels Bentonite gel, Veegum, silica Hydrogums Hydrocarbon Type Petrolatum, mineral oil/polyethylene gel Animal, vegetable fats Lard, cocoa butter Soap base greases Aluminum stearate w/ heavy mineral oil gel Hydrophilic organogels Carbowax bases (PEG ointment) Polar Non-ionic AEROSOLS  Pharmaceutical aerosols are pressurized dosage forms that, upon actuation, emit a fine dispersion of liquid and/or solid materials containing one or more active ingredients in a gaseous medium.  Pharmaceutical aerosols are similar to other dosage forms because they require the same types of considerations with respect to formulation, product stability, and therapeutic efficacy.  However, they differ from most other dosage forms in their dependence upon the function of the container, its valve assembly, and an added component—the propellant—for the physical delivery of the medication in proper form. AEROSOLS  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.  Upon activation of the valve assembly of the aerosol, the pressure exerted by the propellant forces the contents of the package out through the opening of the valve.  Aerosol products may be designed to expel their contents as a fine mist; a coarse, wet, or dry spray; a steady stream; or a stable or a fast-breaking foam.  The physical form selected for a given aerosol is based on intended use. ADVANTAGES OF AEROSOL 1. A portion of medication may be easily withdrawn from the package without contamination or exposure to the remaining material. 2. By virtue of its hermetic character, the aerosol container protects medicinal agents adversely affected by atmospheric oxygen and moisture. Being opaque, the usual aerosol container also protects drugs adversely affected by light. This protection persists during the use and the shelf life of the product. 3. Topical medication may be applied in a uniform thin layer to the skin without anything else touching the affected area. This method of application may reduce the irritation that sometimes accompanies mechanical (fingertip) application of topical preparations. The rapid volatilization of the propellant also provides a cooling, refreshing effect. ADVANTAGES OF AEROSOL 4. By proper formulation and valve control, the physical form and the particle size of the emitted product may be controlled, which may contribute to the efficacy of a drug, as with the fine controlled mist of an inhalant aerosol. Through the use of metered valves, dosage may be controlled. 5. Aerosol application is a clean process, requiring little or no washup by the user. THE AEROSOL PRINCIPLE  An aerosol formulation consists of two component parts: the product concentrate and the propellant.  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.  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.  In certain aerosol systems, compressed gases—carbon dioxide, nitrogen, and nitrous oxide—are employed as the propellant. AEROSOL CONTAINER  Various materials have been used in the manufacture of aerosol containers, including a) glass, uncoated or plastic coated; b) metal, including tin-plated steel, aluminum, and stainless steel; and c) plastics.  The selection of the container for an aerosol product is based on its adaptability to production methods, compatibility with formulation components, ability to sustain the pressure intended for the product, the interest in design and aesthetic appeal on the part of the manufacturer, and cost.  Tin-plated steel containers are the most widely used metal containers for aerosols VALVE ASSEMBLY The usual aerosol valve assembly is composed of the following parts: 1. Actuator: the button the user presses to activate the valve assembly for emission of the product. The actuator permits easy opening and closing of the valve. It is through the orifice in the actuator that the product is discharged. 2. Stem: supports the actuator and delivers the formulation in the proper form to the chamber of the actuator. 3. Gasket: placed snugly with the stem and prevents leakage of the formulation when the valve is closed. 4. Spring: holds the gasket in place and is the mechanism by which the actuator retracts when pressure is released, returning the valve to the closed position VALVE ASSEMBLY 5. Mounting cup: attached to the aerosol can or container and holds the valve in place. Because the underside of the mounting cup is exposed to the formulation, it must receive the same consideration as the inner part of the container with respect to meeting criteria of compatibility. 6. Housing: Directly below the mounting cup, the housing links 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. Dip tube: extends from the housing down into the product; brings the formulation from the container to the valve. The viscosity of the product and its intended delivery rate dictate to a large extent the inner dimensions of the dip tube and housing for a particular product. FOAMS  A foam is an emulsion dosage form containing dispersed gas bubbles. When dispensed, it has a fluffy, semisolid consistency.  Medicated foams are emulsions containing a dispersed phase of gas bubbles in a liquid continuous phase containing the active pharmaceutical ingredient.  They are packaged in pressurized containers or special dispensing devices and are intended for application to the skin or mucous membranes.  Medicated foams have a fluffy, semisolid consistency and can be formulated to break to a liquid quickly or to remain as foam to ensure prolonged contact. Medicated foams intended to treat severely injured skin or open wounds must be sterile. PREPARATION OF FOAMS  A foam may contain one or more active pharmaceutical ingredients, surfactants, aqueous or nonaqueous liquids, and propellants. If the propellant is in the internal, or discontinuous, phase, a stable foam is discharged.  If the propellant is in the external, or continuous, phase, a spray or a quick-breaking foam is discharged. Quick-breaking foams formulated with alcohol create a cooling sensation when applied to the skin and may have disinfectant properties.  Foams containing flammable components should be appropriately labeled. Labeling indicates that a foam drug product must be shaken well to ensure uniformity prior to dispensing.  The instructions for use must clearly note special precautions that are necessary to preserve sterility. In the absence of a metering valve, the delivered volume may be variable.