Semisolid Dosage Forms: Ointments, Creams, and Gels

• Semisolid dosage forms like ointments, creams, and gels are for topical application
• These forms can be applied to the skin, eye surface, or used nasally, vaginally, or rectally
• Medicated preparations provide therapeutic effects from their active agents
• Unmedicated preparations serve as protectants or lubricants

Topical vs. Transdermal

• Topical drugs deliver medication into the skin to treat skin disorders, targeting the skin itself
• Transdermal products deliver drugs through the skin for systemic effects, where the skin is not the target organ

Factors Affecting Drug Movement

• Drug concentration in the vehicle
• Physicochemical properties like solubility, partition coefficient, pKa, and molecular weight
• Vehicle characteristics like hydrophilic-lipophilic balance and viscosity
• Skin condition, including hydration and any breaks in the surface

Ointments

• Semisolid preparations for external use on skin or mucous membranes
• Unmedicated ointments act as protectants, emollients, or lubricants
• Ointment bases can be used for their physical effects or as vehicles for medicated ointments

Ointment Base Classifications

• Oleaginous bases (hydrocarbon bases)
• Absorption bases
• Water-removable bases
• Water-soluble bases

Ideal Properties of Ointment Bases

• Stable, neutral, non-greasy, and non-dehydrating
• Non-irritating, non-hygroscopic, and water-removable
• Compatible with medications and free from objectionable odors
• Non-staining and effective on various skin types (dry, oily, moist)
• Composed of readily available components with known chemical composition
• Easily compounded and able to soften or melt at body temperature

Oleaginous Bases (Hydrocarbon Bases)

• Emollient effect and protect against moisture escape
• Effective as occlusive dressings
• Can remain on the skin for extended periods without drying
• Difficult to wash off due to immiscibility with water
• Can only incorporate small amounts of water and aqueous preparations with difficulty
• Liquid petrolatum (mineral oil) may be used as a levigating agent when incorporating powdered substances
• Examples: Petrolatum (Vaseline), white petrolatum, yellow ointment, white ointment

Petrolatum USP

• Purified mixture of semisolid hydrocarbons from petroleum
• Yellow to light amber color
• Also known as yellow petrolatum or petroleum jelly
• Commercial product: Vaseline

White Petrolatum USP

• Purified mixture of semisolid hydrocarbons from petroleum, wholly or nearly decolorized
• Also known as white petroleum jelly
• Commercial product: White Vaseline

Yellow Ointment USP

• Formula per 1,000 g: 50 g yellow wax, 950 g petrolatum
• Yellow wax is purified wax from honeycombs

White Ointment USP

• Differs from yellow ointment by using white wax (bleached and purified yellow wax) and white petrolatum
• Formula: 50 g white wax, 950 g white petrolatum

Absorption Bases

• Two types: those that form w/o emulsions when incorporating solutions and those that are w/o emulsions allowing additional aqueous solution incorporation
• Act as emollients
• Not easily removed by water washing due to the oleaginous external phase
• Do not provide the same level of occlusion as oleaginous bases
• Examples: Hydrophilic petrolatum, lanolin, and modified lanolin

Hydrophilic Petrolatum USP

• Formula per 1,000 g: 30 g cholesterol, 30 g stearyl alcohol, 80 g white wax, 860 g white petrolatum
• Commercial products like Aquaphor and Aquabase can absorb up to three times their weight in water
• Helpful for incorporating water-soluble drugs into oleaginous bases

Lanolin USP

• Anhydrous lanolin obtained from sheep's wool
• Purified waxlike substance that is cleaned, deodorized, and decolorized
• Contains no more than 0.25% water

Water-Removable Bases (Water-Washable)

• Oil-in-water (o/w) emulsions resembling creams
• Easily washed from the skin due to the aqueous external phase
• Can be diluted with water or aqueous solutions
• Can absorb serous discharges easily
• Example: Hydrophilic Ointment USP

Hydrophilic Ointment USP

• Formula per 1,000 g: 0.25 g methylparaben, 0.15 g propylparaben, 10 g sodium lauryl sulfate, 120 g propylene glycol, 250 g stearyl alcohol, 250 g white petrolatum, 370 g purified water

Water-Soluble Bases (Greaseless)

• Do not contain oleaginous components
• Completely water washable
• Not suitable for incorporating large amounts of aqueous solutions due to softening
• Example: Polyethylene Glycol Ointment NF

Polyethylene Glycol Ointment NF

• General formula per 1,000 g: 400 g PEG 3350, 600 g PEG 4000

Selection of Ointment Base Considerations

• Drug release rate from the base
• Desirability of topical or systemic action
• Desirability of skin moisture occlusion
• Drug stability in the ointment base
• Effect of the drug on the base's consistency
• Water washability of the base
• Characteristics of the application surface
• Ointments are generally for dry, scaly skin, while creams are for weeping or oozing surfaces

Preparation of Ointments

• Incorporation
• Fusion

Incorporation Method

• Mixing components until a uniform preparation is achieved
• On a small scale, mortar and pestle or spatula and ointment slab are used
• Hard rubber or silicone spatulas should be used if components react with metal (e.g., iodine)
• Thoroughly rubbing and working components together on a hard surface until smooth and uniform

Incorporation of Solids

• Pulverization by intervention can be used for gummy materials like camphor, dissolving in a solvent and evaporating to create a thin film

Incorporation of Liquids

• Consider the ointment base's capacity to accept the required volume
• Hydrophilic ointment bases readily accept aqueous solutions
• Incorporate small amount of aqueous solution into oleaginous ointments

Levigation

• Reduce the particle size of powders or crystalline materials before incorporation to avoid grittiness
• Mix the solid material with a vehicle in which it is insoluble to make a smooth dispersion
• Levigating agent (e.g., mineral oil or glycerin) should be compatible with the drug and base
• Use levigating agent in an equal volume to the solid material
• Use mortar and pestle for levigation
• Solids soluble in a common solvent may be dissolved first and then added to the ointment base

Large Scale Preparation

• Ointment or roller mills force coarsely formed ointments through stainless steel or ceramic rollers for uniform composition and smooth texture

Fusion Method

• Combine and melt all or some components together, then cool with constant stirring until congealed
• Add heat-labile substances and volatile oils after cooling to prevent decomposition and volatilization
• Substances may be added as solutions or insoluble powders levigated with a portion of the base
• Carried out in a porcelain dish or glass beaker on a small scale and in large steam-jacketed kettles on a large scale
• After congealing, pass the ointment through an ointment mill or rub with a spatula or in a mortar to ensure uniform texture
• Best for medicated ointments containing beeswax, stearyl alcohol, or high molecular weight PEGs

Considerations by Fusion Method

• Heat materials with the highest melting points to the lowest required temperature to produce a melt
• Add additional substances with constant stirring during cooling until the melt is congealed

Compendial Requirements for Ointments

• Must meet USP tests for microbial content, minimum fill, packaging, storage, and labeling

Microbial Content

• Topical applications are not required to be sterile, except for ophthalmic preparations
• Preparations containing water are more susceptible to microbial growth
• Dermatological products should be examined for the absence of Staphylococcus aureus and Pseudomonas aeruginosa
• Products for rectal, vaginal, and urethral application should be tested for yeasts and molds
• Preparations susceptible to microbial growth must contain preservatives
• Microbial limit test should be conducted for both raw materials and finished products

Examples of Antimicrobial Preservatives

• Methylparaben, propylparaben, phenols, benzoic acid, sorbic acid, and quaternary ammonium salts

Minimum Fill

• The USP's minimum fill test is performed to determine the net weight or volume of the content of filled containers

Packaging

• Ointments and other semisolid preparations are packaged in large-mouth ointment jars or in metal or plastic tubes
• Topical dermatologic products are packaged in jars or tubes, while ophthalmic, nasal, vaginal, and rectal semisolid products are almost always packaged in tubes
• 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

Storage

• 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
• Light-sensitive preparations are packaged in opaque or light-resistant containers

Labeling

• The USP directs the labeling for certain ointments and creams to include the type of base used (e.g., water-soluble or water-insoluble)

Ophthalmic Ointments

• Must be sterile
• Must not be irritating to the eye
• Must permit the diffusion of the medicinal substance throughout the secretions bathing the eye
• Should have a softening point close to body temperature for comfort and drug release
• Mixtures of mineral oil and white petrolatum are commonly used as the base
• Medicinal agents are added as a solution or finely micronized powder

Residence Time

• Ocular ophthalmic drug penetration is generally limited by short residence time due to tearing
• Small surface area of the cornea for drug absorption
• The cornea's natural resistance to drug penetration

Benefits of Ophthalmic Ointments and Gels

• Compared with ophthalmic solutions, ophthalmic ointments and gels provide extended residence time on the surface of the eye
• Ophthalmic ointments are cleared from the eye as slowly as 0.5% per minute

Sterility

• 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
• Antimicrobial preservatives are used as needed

Pastes

• Semisolid preparations intended for application to the skin
• Contain a larger proportion of solid material (such as 25%) than ointments and therefore are stiffer
• Prepared by direct mixing or using heat to soften the base prior to incorporating the solids
• Because of the stiffness of pastes, they remain in place after application and are effectively employed to absorb serous secretions
• Not suited for application to hairy parts of the body
• Example: zinc oxide paste

Creams

• 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
• Used topically, rectally, and vaginally
• Easier to spread and remove
• Example: Vanishing creams

Preparation of Creams

• Separating the formula components into lipid and aqueous portions
• Lipid portion contains all water-insoluble 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
• The phases then are mixed, and the mixture is stirred until the mixture has congealed

Gels

• Semisolid systems consisting of dispersions of small or large molecules in an aqueous liquid vehicle rendered jellylike by the addition of a gelling agent
• Gelling agents: synthetic macromolecules, cellulose derivatives, and natural gums
• Translucent or transparent
• May thicken on standing (thixotropic) and must be shaken before use to liquefy

Gel Preparation

• Hydrophilic gelling agent is dispersed in water with continuous stirring
• Drug is dissolved in a suitable solvent with the preservatives and other additives
• This solution is added to the gelling agent dispersion
• Formulated to contain a drug substance, solvents, antimicrobial preservatives, and stabilizers

Mechanism of Gelation

• The areas where adjacent polymer chains interact are referred to as junction zones
• Hydrophilic (physical) gels are held together by weaker intermolecular bonds such as hydrogen bonds

Examples of Gels

• Metronidazole vaginal gel, clobetasol propionate gel, cyanocobalamin nasal gel, and diclofenac sodium emulgel

Emulgel

• A combination of an emulsion and a gel and thus has a dual release control system
• 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.
• Example: Voltaren emulgel contain diclofenac diethyl ammonium