Chapter 10 Semi-solid Dosage Forms PDF

Pharmaceutical Technology II Semi- solid dosage forms Chapter 10 Chapter 10| Semi- solid dosage forms Contents : Objectives. 3 Semisolid Dosage Forms 4 Ointments. 10 Preparation of Ointments. 31 Ophthalmic ointments. 51 Pastes 59 Creams 63 Gels 68 Emulgel 74 Chapter 10| Semi- solid dosage forms Obje...

Pharmaceutical Technology II Semi- solid dosage forms Chapter 10 Chapter 10| Semi- solid dosage forms Contents : Objectives. 3 Semisolid Dosage Forms 4 Ointments. 10 Preparation of Ointments. 31 Ophthalmic ointments. 51 Pastes 59 Creams 63 Gels 68 Emulgel 74 Chapter 10| Semi- solid dosage forms Objectives : At the end of this topic, the student will be: Differentiate between the various types of semisolid bases on the basis of physical and chemical properties. List the criteria for the selection of a semisolid base to treat a topical affliction. Describe the methods to incorporate (an) active ingredient(s) into a semisolid base. Explain the difference between an ointment, a cream, and a gel. Compare and contrast an ophthalmic ointment base and a topical ointment base for application to the skin. Chapter 10| Semi- solid dosage forms Semisolid Dosage Forms : Ointments, creams, and gels are semisolid dosage forms intended for topical application. They may be applied to the skin , Placed on the surface of the eye , Or used nasally, vaginally and rectally. Most of these preparations are used for the effects of the therapeutic agents they contain. Chapter 10| Semi- solid dosage forms Systemic drug absorption should always be considered when using topical products if the patient is pregnant or musing, because drugs can enter the fetal blood supply and breast milk and be transferred to the fetus or nursing infant. Recently there is an increase in the number of topical ointments, creams, and gels designed to deliver a drug systemically. This is often accomplished by addition of penetration enhancers to the topical vehicle Chapter 10| Semi- solid dosage forms The rate of drug movement across skin layer depends on : The drug concentration in the vehicle , Physicochemical properties of the drug substance such as solubility, partition coefficient, pKa, and molecular wight The characteristics of the base or vehicle, hydrophilic– lipophilic character and viscosity Conditions of the skin itself “broken, hydrated other features of the skin. Chapter 10| Semi- solid dosage forms Chapter 10| Semi- solid dosage forms Ointments Chapter 10| Semi- solid dosage forms Ointments : Ointments are semisolid preparations intended for external application to the skin or mucous membranes. Ointments may be medicated or Unmedicated. Unmedicated ointments are used for the physical effects they provide as protectants, emollients, or lubricants. Ointment bases, as described, may be used for their physical effects or as vehicles for medicated ointments. Chapter 10| Semi- solid dosage forms Ointment Bases : Ointment bases are generally classified by the United States Pharmacopeia (USP) into four groups : 1. Oleaginous bases 2. Absorption bases 3. Water removable bases 4. Water soluble bases Chapter 10| Semi- solid dosage forms Ideal properties of ointment bases : 1. Stable 11. Non-staining 2. Neutral in reaction 12. Capable of serving as medium for drugs that are water and lipid soluble 3. Non-greasy 4. Not degreasing in action 5. Nonirritating 6. Non-dehydrating 7. Non-hygroscopic 8. Water-removable 9. Compatible with medications 10. Free from objectionable odor 13. Efficient on dry, oily or moist skin 14. Composed of readily available components of known chemical composition 15. Easily compounded by the pharmacist 16. Can melt or softened at body temperature Chapter 10| Semi- solid dosage forms Oleaginous Bases ( Hydrocarbon bases) Oleaginous bases are also termed Hydrocarbon bases. On application to the skin 1. They have an emollient effect 2. Protect against the escape of moisture 3. They are effective as occlusive dressings 4. Can remain on the skin for long periods without drying out , Because of their immiscibility with water, are difficult to wash off. Chapter 10| Semi- solid dosage forms Water and aqueous preparations may be incorporated, but only in small amounts and with some difficulty. When powdered substances are to be incorporated into hydrocarbon bases, liquid petrolatum (mineral oil) may be used as the levigating agent Examples : Petrolatum “Vaseline,” White petrolatum “White Vaseline ” Yellow ointment White ointment. Chapter 10| Semi- solid dosage forms Petrolatum, USP, is a purified mixture of semisolid hydrocarbons obtained from petroleum. It has yellow to light amber color. It is also known as yellow petrolatum and petroleum jelly. A commercial product is Vaseline. Chapter 10| Semi- solid dosage forms White petrolatum, USP, is a purified mixture of semisolid hydrocarbons obtained from petroleum that has been wholly or nearly decolorized. White petrolatum is also known as white petroleum jelly. A commercial product is White Vaseline Chapter 10| Semi- solid dosage forms Yellow ointment, USP, this ointment has the following formula for the preparation of 1,000 g : Yellow wax 50 g Petrolatum 950 g Yellow wax is the purified wax obtained from the honey comb of the bee Chapter 10| Semi- solid dosage forms White Ointment, USP. This ointment differs from yellow ointment by substitution of white wax (bleached and purified yellow wax) and white petrolatum in the formula. White wax 50 g White Petrolatum 950 g Chapter 10| Semi- solid dosage forms 1. Absorption Bases These bases are of two types : A. Those that permit the incorporation of solutions resulting in the formation of w/o emulsion for example, Hydrophilic petrolatum. B. Those that are w/o emulsions that permit the incorporation of an additional quantities of aqueous solutions for example, lanolin They are used as emollients Chapter 10| Semi- solid dosage forms They are not easily removed from the skin by water washing, because the external phase is oleaginous They do not provide the degree of occlusion afforded by the oleaginous bases Examples: Hydrophilic petrolatum, lanolin and modified lanolin. Chapter 10| Semi- solid dosage forms Hydrophilic Petrolatum, USP, has the following formula for the preparation of 1,000 g : Cholesterol 30 g Stearyl alc. 30 g White wax 80 g White petrolatum 860 g Chapter 10| Semi- solid dosage forms Commercial products, Aquaphor and Aquabase variations of hydrophilic petrolatum, have the capacity to absorb up to three times their weight in water and are useful to help incorporate a watersoluble drug, for example, tobramycin sulfate, into an oleaginous ointment base Lanolin, USP Lanolin, USP (anhydrous lanolin), obtained from the wool of sheep, is a purified waxlike substance that has been cleaned, deodorized, and decolorized. It contains not more than 0.25% water. Chapter 10| Semi- solid dosage forms 2. Water-Removable Bases (Water-washable) : They are oil-in- water emulsions (o/w) resembling creams. Because the external phase of the emulsion is aqueous, they are easily washed from skin and are often called water-washable bases. They may be diluted with water or aqueous solutions. They can absorb serous discharges. Chapter 10| Semi- solid dosage forms Hydrophilic Ointment, USP, is an example of this type of base. Hydrophilic Ointment, USP, has the following formula for 1,000 g : Methylparaben 0.25 g Propylparaben 0.15 g lauryl sulfate 10 g propylene glycol 120 g Stearyl alcohol. 250 g White petrolatum 250 g Purified water 370 g Chapter 10| Semi- solid dosage forms Water-Soluble Bases (Greaseless) These bases do not contain oleaginous components. They are completely water washable. Because they soften greatly with the addition of water, large amounts of aqueous solutions are not effectively incorporated into these bases. Example: Polyethylene Glycol Ointment NF Chapter 10| Semi- solid dosage forms The general formula for preparation of 1,000 g of PEG ointment is : PEG 335 400 g PEG 4000 600 g Chapter 10| Semi- solid dosage forms Classification and properties of USP ointment bases : Chapter 10| Semi- solid dosage forms Selection of the appropriate ointment base : Selection of the base to use in the formulation of an ointment depends on careful assessment of a number of factors, including the following : 1. The release rate of the drug substance from the base. 2. Desirability of topical or systemic action. 3. Desirability of occlusion of the moisture from the skin. 4. Stability of the drug in the ointment base. Chapter 10| Semi- solid dosage forms 5. Effect of drug on the consistency of the base. 6. Water wash ability of the base. 7. Characteristics of the surface to which it is applied. For example, an ointment is generally applied to dry, scaly skin; a cream is applied to weeping or oozing surfaces Preparation of Ointments Chapter 10| Semi- solid dosage forms Preparation of Ointments : Depending primarily on the nature of the ingredients, ointments are prepared by two general methods. A. Incorporation B. Fusion Incorporation Method : In this method, the components are mixed until uniform preparation is attained. Chapter 10| Semi- solid dosage forms On small scale, the pharmacist may mix the components using mortar and pestle, or a spatula may be used to rub the ingredients together on an ointment slab (a large glass or porcelain plate or pill tile). If the components of an ointment react with metal (as does iodine), hard rubber or silicone spatulas may be used. The ointment is prepared by thoroughly rubbing and working the components together on the hard surface until the product is smooth and uniform. Chapter 10| Semi- solid dosage forms Incorporation of solids. When preparing an ointments by spatulation, the pharmacist works the ointment with a stainless steel spatula having a long, broad blade and periodically removes the accumulation of ointment on the large spatula with a smaller one. For incorporating a gummy material, such as camphor, pulverization by intervention can be used. The material is dissolved in a solvent and spread out on the pill tile. The solvent is allowed to evaporate, leaving a thin film of the material onto which the other ingredient or ingredients are spread. Chapter 10| Semi- solid dosage forms Incorporation of liquids. Liquid substances or solutions of drugs, are added to an ointment only after due consideration of an ointment base's capacity to accept the volume required. For example, only very small amounts of an aqueous solution may be incorporated into an oleaginous ointment, whereas hydrophilic ointment bases readily accept aqueous solutions. Chapter 10| Semi- solid dosage forms Levigation in ointment preparation : It often is desirable to reduce the particle size of a powder or crystalline material before incorporation into the ointment base so the final product will not be gritty. The reduction in particle size of the powder be done by levigating, or mixing the solid material in a vehicle in which it is insoluble to make a smooth dispersion. “wet grinding.” Chapter 10| Semi- solid dosage forms The levigating agent like mineral oil or glycerin should be physically and chemically compatible with the drug and the base. The levigating agent is used in an equal volume of the solid material. A mortar and pestle are used in levigation. Levigation allows both the reduction in particle size and the dispersion of the substance in the vehicle. Chapter 10| Semi- solid dosage forms Solids soluble in a common solvent that will affect neither the stability of the drug nor the efficacy of the product may first be dissolved in that solvent (e.g., water or alcohol) and the solution added to the ointment base by spatulation or in a mortar and pestle. On large scale, Ointment or roller mills can be used to force coarsely formed ointments through stainless steel or ceramic rollers to produce ointments uniform in composition and smooth in texture Chapter 10| Semi- solid dosage forms Chapter 10| Semi- solid dosage forms Fusion Method : By this method, all or some of the components of an ointment are combined and melted together and cooled with constant stirring until congealed. Other components like heat labile substances and volatile oils are added after cooling the mixture to prevent their decomposition and volatilization respectively. Substances may be added to the congealing mixture as Solutions Or insoluble powders levigated with a portion of the base. Chapter 10| Semi- solid dosage forms On a small scale, fusion may be done by using porcelain dish or glass beaker. On a large scale, it is carried out in large steamjacketed kettles. After congealing, the ointment may be passed through an ointment mill “large scale”, or rubbed with a spatula or in a mortar “small scale” to ensure uniform texture. Chapter 10| Semi- solid dosage forms Medicated ointments containing components like beeswax, stearyl alcohol, high molecular wight PEGs are best prepared by fusion method rather than incorporation method. By fusion method, the materials with the highest melting points are heated to the lowest required temperature to produce a melt, then the additional substances are added with constant stirring during cooling the melt until the melt is congealed. In this way, not all components are subjected to the highest temperature. Chapter 10| Semi- solid dosage forms Compendial requirements for ointments Ointments and other semisolid dosage forms must meet USP tests for : Microbial content Minimum fill Packaging, storage and labeling. Chapter 10| Semi- solid dosage forms Microbial Content : With the exception of ophthalmic preparations, topical applications are not required to be sterile. Topical preparations must meet the acceptable standards for microbial contents Preparations that contain water tend to support microbial growth to a greater extent than water-free preparations. Dermatological products should be examined for the absence of Staphylococcus aureus and Pseudomonas aeruginosa. Chapter 10| Semi- solid dosage forms Other products intended for rectal, vaginal and urethral application should be tested for yeasts and molds. Preparations subjected to microbial growth must contain preservatives. Among the antimicrobial preservatives used to inhibit microbial growth in topical preparations are methylparaben, propylparaben, phenols, benzoic acid, sorbic acid, and quaternary ammonium salts. Chapter 10| Semi- solid dosage forms Microbial limit test is conducted for both raw materials and finished products. The USP states certain products should be routinely tested for microorganisms because of the way they are used. Minimum fill : The USP’s minimum fill test is used to determine the net weight or volume of the content of the filled containers to ensure proper content compared with the labeled amount. Chapter 10| Semi- solid dosage forms Packaging, Storage, and Labeling : Ointments and other semisolid preparations are packaged either in large mouth ointment jars or in metal or plastic tubes. Topical dermatologic products are packaged either in jars or in tubes, whereas ophthalmic, nasal, vaginal and rectal semisolid products are almost always packaged in tubes. Ointment jars are either clear or opaque glass or plastic. Chapter 10| Semi- solid dosage forms The jars and tubes should be compatible and stable with the intended product. Tubes are superior to jars because they are lighter in weight, relatively inexpensive, conveniently used, compatible with most formulative ingredients, and provide greater protection against external contamination and environmental conditions. They are made of aluminum or plastic sometimes equipped with applicator. Chapter 10| Semi- solid dosage forms Chapter 10| Semi- solid dosage forms Semisolid preparations must be stored in well-closed containers to protect against contamination and in a cool place to protect against product separation in heat. When required, light-sensitive preparations are packaged in opaque or lightresistant containers. In addition to the usual labeling requirements for pharmaceutical products, the USP directs the labeling for certain ointments and creams include the type of base used (e.g., water soluble or water insoluble). Ophthalmic ointments Chapter 10| Semi- solid dosage forms Ophthalmic ointments : Ophthalmic ointments differ from conventional ointments in that they must be sterile. In selecting an ointment base for an ophthalmic preparation, it must meet several qualities such as Must not be irritating to the eye Chapter 10| Semi- solid dosage forms Must permit the diffusion of the medicinal substance throughout the secretions bathing the eye Ointment bases used for ophthalmic should have a softening point close to body temperature, both for comfort and for drug release. Mixtures of mineral oil and white petrolatum are commonly used as the base in medicated and non-medicated (lubricating) ophthalmic ointments. Chapter 10| Semi- solid dosage forms Usually, the medicinal agents are added to an ointment base either as a solution or as a finely micronized powder. The ointment is made uniform and smooth by fine milling Chapter 10| Semi- solid dosage forms Residence time In general, ocular ophthalmic drug penetration is limited by : 1. The short residence time on the surface of the eye because of rapid removal by tearing and other natural mechanisms. 2. The small surface area of the cornea for drug absorption , 3. The cornea's natural resistance to drug penetration. Chapter 10| Semi- solid dosage forms Compared with ophthalmic solutions, ophthalmic ointments and gels provide extended residence time on the surface of the eye, increasing the duration of their surface effects and bioavailability for absorption into the ocular tissues. Ophthalmic ointments are cleared from the eye as slowly as 0.5% per minute, compared with solutions, which can lose up to 16% of their volume per minute Chapter 10| Semi- solid dosage forms Sterility and preservation of ophthalmic ointments In addition to the quality standards for ointments, ophthalmic ointments must meet the USP sterility tests and the test for metal particles in ophthalmic ointment Rendering an ophthalmic ointment sterile requires special aseptic techniques and processing. Chapter 10| Semi- solid dosage forms Each drug, along with other components, is rendered sterile separately, aseptically weighed, and incorporated in preparing a final product that meets the sterility requirement. This is done because of difficulty in terminal product sterilization, such as lack of penetration of steam into the ointment base and instability of components owing to high dry heating. Antimicrobial preservatives such as methylparaben and propylparaben combinations, chlorobutanol and benzalkonium chloride are used as needed. The USP test for metal particles is microscopic examination of a heat-melted ophthalmic ointment Pastes Chapter 10| Semi- solid dosage forms Pastes Pastes are semisolid preparations intended for application to the skin. They generally contain a larger proportion of solid material (such as 25%) than ointments and therefore are stiffer. Pastes can be prepared in the same manner as ointments, by direct mixing or the use of heat to soften the base prior to incorporating the solids, which have been comminuted and sieved. Chapter 10| Semi- solid dosage forms However, when a levigating agent is to be used to render the powdered component smooth, a portion of the base is often used rather than a liquid, which would soften the paste. Because of the stiffness of pastes, they remain in place after application and are effectively employed to absorb serous secretions. Because of their stiffness and impenetrability, pastes are not suited for application to hairy parts of the body. Chapter 10| Semi- solid dosage forms Among the few pastes in use today is zinc oxide paste, which is prepared by mixing 25% each of zinc oxide and starch with white petrolatum. The product is very firm and is better able to protect the skin and absorb secretions than is zinc oxide ointment. Creams Chapter 10| Semi- solid dosage forms Creams Pharmaceutical creams are semisolid preparations containing one or more medicinal agents dissolved or dispersed in either a water-in-oil (w/o) emulsion or an oil-in-water (o/w) emulsion intended for external use. Their consistency and rheological properties are based on whether the emulsion is o/w or w/o and on the nature of the solid in the internal phase. Chapter 10| Semi- solid dosage forms Creams are used topically, rectally and vaginally. Creams are preferred by many patients and physicians because they are easier to spread and remove Example : Vanishing creams are oil in water emulsions (o/w) containing large percentage of water, stearic acid and other oleaginous components. They are named so because water is evaporating leaving a thin layer of the stearic acid and other oleaginous components. Chapter 10| Semi- solid dosage forms Preparation of creams Preparation usually involves separating the formula components into two portions: lipid and aqueous. The lipid portion contains all waterinsoluble components and the aqueous portion the water-soluble components. Both phases are heated to a temperature above the melting point of the highest melting component. Chapter 10| Semi- solid dosage forms The phases then are mixed, and the mixture is stirred until the mixture has congealed. Creams usually require the addition of a preservative(s) unless they are compounded immediately prior to use and intended to be consumed in a relatively short period of time Gels Chapter 10| Semi- solid dosage forms Gels :Gels (sometimes called jellies) are semisolid systems consisting of dispersions of small or large molecules in an aqueous liquid vehicle rendered jellylike by the addition of a gelling agented.. Chapter 10| Semi- solid dosage forms Among the gelling agents used are: 1. Synthetic macromolecules, such as carbomer 2. Cellulose derivatives, such CMC (Carboxymethylcellulose), HPMC ( hydroxypropyl methylcellulose) 3. Natural gums, such as tragacanth Gels have good appearance usually translucent or transparent. Medicated gels may be prepared for administration by various routes, including the skin, and to mucous membranes of the eye, the nose, the vagina, and the rectum, giving high rates of release of the medicament and rapid absorption. Chapter 10| Semi- solid dosage forms Gels may thicken on standing, forming a thixotropic , and must be shaken before use to liquefy the gel and enable pouring Gel preparation (Main Procedure) Hydrophilic gelling agent is dispersed in water with continuous stirring (at the appropriate temperature for the gelling agent) Drug is dissolved in a suitable solvent with the preservatives, and other additives. This solution is added to the gelling agent dispersion Chapter 10| Semi- solid dosage forms In addition to the gelling agent and water, gels may be formulated to contain a drug substance, solvents, such as alcohol and/or propylene glycol; antimicrobial preservatives, such as methylparaben propyl paraben; and stabilizers, such as edetate disodium. Chapter 10| Semi- solid dosage forms Examples on gels : Active Ingredient Proprietary Product Gelling Agent Route and Use Metronidazole MetroGel Vaginal Carbomer 934P Vaginal: bacterial vaginosis Clobetasol propionate Temovate Gel Carbomer 934P Dermatologic: antipruritic Cyanocobalamin Nascobal Methylcellulose Nasal: hematologic Diclofenac sodium Voltaren emulgel Systemic effect (transdermal) Emulgel Chapter 10| Semi- solid dosage forms Emulgel Emulgel is an emerging topical drug formulation which is becoming increasingly popular due to its advantages over the conventional topical preparations. The emulgel is a combination of an emulsion and a gel and thus has a dual release control system. Chapter 10| Semi- solid dosage forms Its biggest and most favorable advantage has been the ability to incorporate hydrophobic drugs, thus making it emerge as a more popular choice these days. The emulgel is also greaseless, transparent; it can be easily spread and removed, has a long shelf- life, is thixotropic and is also pleasant looking. Voltaren emulgel contain diclofenac diethyl ammonium is an example on emulgel