Introduction to Pharmaceutical Semisolid Dosage Forms
Pharmaceutical semisolid preparations include ointments, creams, emulsions, pastes and gels. Their common property is the ability to cling to the surface of application for reasonable duration before they are washed or worn off. This adhesion is due to their plastic rheological behaviour, which allows the semisolids to retain their shape and cling as a film until acted upon by an outside force, in which case they deform and flow.
Ointments
Ointments are composed of fluid hydrocarbons meshed in a matrix of higher-melting solid hydrocarbons. Most ointments are based on mineral oil and petrolatum, but there are alternative types also. Polyethylene incorporated into mineral oil yields a plastic matrix, (e.g. Plastibase, manufactured by Squibb). Mixtures of polyethylene glycols can yield products of ointment consistency that are water soluble. Most ointments are prepared by melting the components together. Drugs or other components are added in the fluidized state. If the solids are insoluble and are to be suspended, the system is put through a milling process (a colloid mill, homogenizer or ultrasonic mixer) so that the solids are fully dispersed. Ointments are used as emollients or for drug delivery either to the surface of the skin, or for deeper penetration.
Creams
Creams are semisolid emulsion systems with opaque appearances. Their consistency and rheological character depend on whether the emulsion is water-in-oil (o/w) or oil-in-water (o/w) type and on the nature of the solids in the internal phase. Emulsified creams produce a cooling effect and are less greasy than ointments. They can be used for drug delivery onto or into the skin. For stability, creams require antimicrobial preservatives.
Pastes
Pastes are basically ointments into which a high percentage of insoluble solids have been added. They are valuable as protective barriers on the skin, such as for treating diaper rash or protecting the face and lips from the sun. Pastes are usually prepared by incorporating a solid directly into a congealed system by levigation with a portion of the base to form a paste-like mass. The remainder of the base is added with continued levigation until the solids are uniformly dispersed in the vehicle. They localize drug delivery (e.g. Dithranol in Lassar’s Paste BP).
Gels or Jellies
Gels (jellies) are semisolid systems in which a liquid phase is constrained within a three-dimensional polymeric matrix (consisting of natural or synthetic gums) in which a high degree of physical (or sometimes chemical) cross-linking has been introduced. The polymers used to prepare pharmaceutical gels include the natural gums tragacanth, pectin, carrageen, agar and alginic acid; synthetic and semisynthetic materials such as methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, and the Carbopols, which are synthetic vinyl polymers with ionizable carboxyl groups. Gels are prepared by a fusion process or by procedure necessitated by the gelling characteristics of the gellant.
Ingredients of Semisolid Pharmaceutical Dosage Forms
Water-miscible vehicles
These include water, alcohol and the macrogols (polyethylene glycols). Alcohol is added to water to increase the rate of evaporation and produce a cooling effect. The macrogols are good solvents for a wide range of drugs. But they tend to dry the skin, inactivate some antimicrobials, interact with some plastics and can give poor release of drugs.
Oily vehicles
Mineral oils (paraffins) are the most widely used. Soft paraffin is the main ingredient. Liquid or hard paraffin may be added to thin or thicken them. The paraffins are occlusive and chemically inert, but do not give good skin penetration. Vegetable oils from peanut, castor, olive or coconut may be used as mobile solvent, or as part of an ointment or cream. If thickening is required, a high melting point material such as cetostearyl alcohol may be used. They are occlusive and give good skin penetration, but may go rancid.
Synthetic oils such as silicone oils (Dimethicone BP) are used as water repellents and occlusive because they are hydrophobic. The semi-synthetic isopropylmyristate is similar to vegetable oil in properties and use.
Emulsifying agents
Liquid and semi-solid emulsions, both o/w and w/o, are used externally and require the addition of emulsifying agents. The presence of a surfactant usually increases the skin penetration of any drug. The selection of surfactant depends on the type of emulsion and the charge on the other ingredients (anionic, cationic or non-ionic).
Emulsifiers – w/o
Wool fat is a complex mixture of fatty acid esters of cholesterol and other sterols and alcohols. Wool alcohol and wool fat increase the water holding capacity of greasy bases. Beeswax is also a w/o emulsifier.
Emulsifiers – o/w
These are the emulsifying waxes. There are three emulsifying waxes – Emulsifying Wax BP which consists of 9 parts of cetostearyl alcohol and one part of surface-active agent (sodium lauryl sulphate); Cetrimide Emulsifying Wax BPC which consists of 9 parts of cetostearyl alcohol and one part of surface-active agent (cetrimide); Cetomacrogol Emulsifying Wax BPC which consists of 8 parts of cetostearyl alcohol and two parts of surface-active agent (cetomacrogol 1000). All three are waxy solids that mix with oily materials. Addition of water produces an o/w emulsion – a cream. The creams are easily washed off the skin.
Other emulsifiers
Calcium soaps are formed in situ by mixing a fatty acid with lime water (calcium hydroxide solution). They form w/o emulsions.
Synthetic surface-active agents are also used. Low HLB materials will produce w/o emulsions, while high HLB surfactants give o/w emulsions.
Suspending agents
These materials are used for suspending solids in shake lotions or to produce gels. The main group of materials are the clays e.g. bentonite, attapulgite, montmorrilonite and Veegum (aluminium magnesium silicate). They leave a lubricant layer of powder on the skin. They are unsuitable for use below pH 3.5 and their consistency is affected by alcohol and electrolytes.
Gelling agents are used to produce thickened, semi-solid to very thick bases to immobilise the skin. For aqueous gels, materials include tragacanth, alginates, pectin, gelatin, methylcellulose, carbomer, polyvinyl alcohol and clays. Oils may be thickened using cetostearyl alcohol, hard paraffin, beeswax, wool alcohols and polyvalent soaps such as magnesium stearate. The latter, when heated with oil, produces a clear lipogel.
Other Ingredients of Semisolid Dosage Forms
Wetting agents are required for hydrophobic solids. Tincture of quillaia, alcohol or Manoxol OT (synthetic) may be used.
Humectants are added to reduce the rate of water loss from creams and gels. Examples include glycerol, propylene glycol, PEG 300, and sorbitol syrup. Solids may be added to semi-solid occlusive bases. They provide channels for migration of water from the skin surface e.g. zinc oxide, talc, starch and Aerosil.
Majority of these semisolid preparations are applied to the skin, where they serve as vehicles for topically applied drugs, as emollients or as protective or occlusive dressings. A less portion of topical semisolid is applied to mucous membranes such as rectal tissue, buccal tissue, vaginal mucosa, urethral membrane, external ear lining, nasal mucosa and cornea. The mucous membranes permit more ready access to the systemic circulation, whereas normal skin is relatively impenetrable.
Containers for semi-solid preparations
Semi-solid products are packed in ointment jars with tight-fitting closure, or collapsible tubes. The most common metal tubes used are made of aluminium with an internal lacquered surface. Plastic tubes are also used. The tube sleeve may be made of LDPE with either a LDPE or HDPE head or the entire tube may be made of polypropylene.