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SEMISOLID DOSAGE FORMS. DEPARTMENT OF PHARMACEUTICS CHALAPATHI INSTITUTE OF PHARMACEUTICAL SCIENCES. semisolids.
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SEMISOLID DOSAGE FORMS DEPARTMENT OF PHARMACEUTICS CHALAPATHI INSTITUTE OF PHARMACEUTICAL SCIENCES
semisolids Pharmaceutical semisolid preparations may be defined as topical products intended for application on the skin or accessible mucous membranes to provide localized and sometimes systemic effects at the site of application. They are often composed of two phases (oil and water), one of which is a continuous (external) phase and the other a dispersed (internal) phase. The active ingredient is often dissolved in one or both phases, thus creating a three-phase system. The physical properties of the dosage form depend on various factors, including the size of the dispersed particles, the interfacial tension between the phases, the partition coefficient of the active ingredient between the phases, and the product rheology.
These factors combine to determine the release characteristics of the drug as well as other characteristics such as viscosity. • Most of the semisolid preparations are applied to the skin for topical relief of dermatologic conditions, whereas a lesser portion of these preparations are applied to mucous membranes such as rectal and buccal tissue, vaginal mucosa, urethral Membrane,external ear lining, nasal mucosa, and cornea. • Semisolids are characterized by a three dimensional structure that is sufficient to impart solid-like character to the undisturbed system but that is easily broken down and realigned under an applied force.
In broad terms, semisolid preparations may be classified as ointments, creams, pastes, and gels. • Ointments are composed mostly of fluid hydrocarbons meshed in a matrix of higher melting solid hydrocarbons. • Common examples of ointment bases include mineral oil, petrolatum, and polyethylene glycol. • Creams are semisolid emulsion systems with an opaque appearance. 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.
Pastes are basically ointments into which a high percentage of insoluble solids has been added. Powders such as zinc oxide, titanium dioxide, starch, and kaolin are incorporated in high concentrations into a preferably lipophilic greasy vehicle to form a paste like mass. • Gels are semisolid systems in which a liquid phase is constrained within a three-dimensional polymeric matrix in which a high degree of physical cross-linking has been introduced. • Though the nature of the underlying structures differ remarkably across all the different semisolid systems, they all share the property that their structures are easily broken down, rearranged, and reformed.
Formulation aspects • In general, ointment bases may be classified into four general groups: Hydrocarbon, Absorption, water-removable, and water soluble bases. • Hydrocarbon Bases also known as oleaginous bases, the hydrocarbon bases are essentially water-free, incorporating aqueous preparations only in small amounts and with considerable difficulty. • Hydrocarbon vehicles have several advantages, such as stability and emolliency; however, they suffer from one major disadvantage— greasiness which may stain clothing and is usually difficult to remove • The primary features of this type of base include its emollient effect, retention on the skin for prolonged periods, prevention of escape of moisture from the skin to the atmosphere, and difficulty in washing off. • They act as occlusive dressings, thus increasing skin hydration by reducing the rate of loss of surface water.
Also, they do not dry out or change noticeably on aging. Hydrocarbon-based semisolids comprise fluid hydrocarbons C16 to C30 straight chain and branched, entrapped in a fine crystalline matrix of yet higher- molecular-weight solid hydrocarbons. Common examples of these bases include: Petrolatum, USP—a mixture of semisolid hydrocarbons obtained from petroleum. It is an unctuous mass, varying in color from yellowish to light amber. It melts at temperatures between 38 and 608C and may be used alone or in combination with other agents as an ointment base. White petrolatum, USP—a petrolatum that has been decolorized, either partially or wholly. It is used for the same purpose as petrolatum but is more esthetically acceptable to a patient than petrolatum because of its lighter color.
Yellow ointment, USP—the purified wax obtained from the honeycomb of the bee. It contains 5% yellow wax and 95% petrolatum in the formulation. Mineral oil—a mixture of liquid hydrocarbons obtained from petroleum. These are useful as levigating agents to wet and incorporate solid substances (e.g., salicylic acid, zinc oxide) into the preparation of ointments that consist of oleaginous bases as their vehicle. There are two types of mineral oils listed in the U.S. Pharmacopeia / National Formulary (USP/NF). Mineral oil USP is also called heavy mineral oil with a specific gravity between 0.845 and 0.905. Light mineral oil, NF has a specific gravity between 0.818 and 0.880
Absorption Bases- Absorption bases, as such, are hydrophilic, anhydrous materials (w/o emulsions) or hydrous bases (w/o emulsions that have the ability to absorb additional water). Addition of lanolin, lanolin isolates, cholesterol, lanosterol, or acetylated sterols renders the hydrocarbon base hydrophilic. Such hydrophilic mixtures have been known as absorption bases These bases are useful as emollients, although they do not provide the degree of occlusion as oleaginous bases. They are also used pharmaceutically to incorporate aqueous solutions of drugs (e.g., sodium sulfacetamide solution) into oleaginous bases. A typical example of an anhydrous absorption base is hydrophilic petrolatum, USP
Commercially available absorption bases include Aquaphor and Polysorb. A new group of w/o emulsifiers based on the linkage of polymethoxysiloxane chains with alkyl side chains and polyol groups known as organosilicone polymers, have the capability of producing w/o emulsions with a high water content. Although the polymethylsiloxane chains possess both hydrophilic and lipophilic properties, the alkyl side chains supply the necessary lipophilic and polyol groups to provide the hydrophilic characteristics of the emulsifier. • Other examples of w/o emulsifiers include cetyl dimethicone copolymer , polyethylene glycol-20- com glycerides , and a series of caprylic–capryl stearates .
Water-Removable Bases(Water-Washable Creams) -These are the most commonly used o/w emulsion bases that are capable of being washed from skin or clothing with water. They may contain water-soluble and insoluble components. From a therapeutic viewpoint, they have the ability to absorb serous discharges in dermatologic conditions. The water-removable bases form a semipermeable film on the site of application after the evaporation of water. A typical water-removable emulsion base is hydrophilic ointment, USP and vanishing cream.
The Cosmetic, Toiletry and Fragrance Association’s International Cosmetic Ingredient Dictionary provides an exhaustive listing of the variety of emulsion base components, particularly the oil phase components. • Over 6000 ingredients, cross-referenced to more than 25,000 trade names and synonyms, are presented. • These include emulsifiers, coemulsifiers, surfactants, and stabilizers. • The McCutcheons Detergents and Emulsifiers also lists thousands of emulsifiers and surfactants. Water-Soluble Bases - These bases contain only water-soluble components. • Water-soluble bases are also referred to as greaseless because of a lack of oleaginous materials. Incorporation of aqueous solutions is difficult because they soften greatly with the addition of water. • They are better used for nonaqueous or solid substances. Polyethylene glycols (PEG) make up the majority of components of the watersoluble base.
Gelling agents - commonly used are synthetic macromolecules (e.g., carbomer 934), cellulose derivatives (e.g., carboxymethylcellulose and hydroxypropylmethylcellulose), and natural gums (e.g., tragacanth). • Carbomers in particular are high-molecular-weight water-soluble polymers of acrylic acid cross-linked with allyl ethers of sucrose and/or pentaerythritol. • The NF contains monographs for six such polymers: carbomers 910, 934, 934P, 940, 941, and 1342. They are used as gelling agents at concentrations of 0.5–2.0% in water. Carbomer 940 yields the highest viscosity: between 40,000 and 60,000 CP as a 0.5% aqueous dispersion. • Depending on their polymeric composition, different viscosities result. Gels may be classified as two-phase or single-phase systems. A two-phase gel system consists of floccules of small distinct particles rather than large molecules, thus called a two-phase system often referred to as a magma.
Preservatives The USP addresses this subject inits monograph Microbiological Attributes of Non- SterilePharmaceutical Products. An ideal preservative system should have attributes such as effectiveness at lowconcentrations against a host of microorganisms, solubility, nontoxicity, nonsensitizing, compatibility with other components, absence of odor, stability, and inexpensive. In addition, they must have the appropriate oil/water partition coefficient and be effective at the pH level of the products. Several sources of contamination include water, raw materials, and poor sanitation conditions during manufacture, storage, and use. As such, preparations that contain water tend to support microbial growth to a greater extent than do preparations that are water-free.
Preservatives Antimicrobial preservatives such as methylparaben (0.05%) and propylparaben (0.01%) and its combinations phenylmercuric acetate (0.0008%), chlorobutanol (0.5%), and benzalkonium chloride (0.008%) are used. In the case of emulsion manufacture, the process of heating between 70 and 80.8oC usually kills most of the microorganisms.
MANUFACTURING METHODSOintments There are two primary methods of manufacturing ointment dosage forms: Incorporation Fusion. On a small scale, as in a pharmacy, small quantities of ointments may be prepared using a mortar and pestle or an ointment slab (porcelain or glass) and spatula. The finely divided drug material is dispersed into an appropriate vehicle by mixing the components or rubbing the ingredients together to form an ointment.
When incorporating solids by the method of spatulation the ointment base is placed on one side of the slab, and the finely divided drug powder components are placed on the other side. • A small portion of the powder is mixed with a small portion of the base and worked in together to form a uniform mass. The procedure is repeated with the remaining base and powdered materials until all of the components are uniformly combined and blended. • A broad blade spatula, made of metal or hard plastic, may be used. Hard plastic spatulas are used when a component (e.g., phenol) of the mixture sometimes reacts with the metal.
Incorporation (industrial scale) • Mechanical mixers are used to prepare ointments in large quantities, especially in the Pharmaceutical industry. • Stainless steel kettle mixers may be used to manufacture hydrocarbon and water-soluble base ointments • The stainless steel kettle is jacketed for heating and cooling and is equipped with a mixing device. The kettle configuration is especially well-suited for the melting and mixing of oils and waxes and for complete bottomemptying. • Depending on the formulation to be processed, the mixer may be either a propeller or an anchor–agitator design. If the formulation is primarily liquid, a propellermixer is more suitable. • If the formulation consists of solid waxes, lanolin, petrolatum, and similar components, a kettle with a removable agitator is suitable.
Planetary mixers may also be used for largescale preparations of the ointments. Here, the finely divided powdered materials are added slowly or sifted into the vehicle (ointment base) previously placed inside the rotating mixer. On achieving a uniform consistency, the ointment preparation may be processed through the roller mill to ensure complete dispersion and reduce the size of aggregates that may have formed during processing. The roller mills force the coarsely formed ointments through stainless steel rollers to produce ointments that are uniform in composition and smooth in texture.
Double planetary mixer showing mixing patterns at different stirring speeds
Fusion Process The process of fusion uses heat to melt all or some of the components of the ointment; the mixture is then allowed to cool with constant stirring until congealed. Additional components of the ointment preparation that were not subject to the initial melting process are added to the congealing mixture as it is being cooled and stirred. Heatlabile substances are added to the preparation after careful observation that the temperature of the mixture is sufficiently low so as not to cause decomposition or volatilization of the components.
All the other components may be added with constant stirring and cooling of the melt until the mixture is congealed. • Alternatively, the component with the lowest melting point may be added first. With increasing temperature, the remaining materials may be added to melt the entire mixture and then the process of cooling and congealing. Some common examples of components that are subjected to the fusion process include beeswax, paraffin, stearyl alcohol, and high-molecular-weight polyethylene glycols (PEG). The order of addition of components in the process of fusion plays a role in the manufacture of ointments.
Emulsion Products • Emulsions are prepared by means of a two-phase heat system. • In the first phase, the oil phase ingredients are combined in a jacketed tank and heated between 70 and 75.8oC to melt or liquefy all the ingredients to a uniform state. • In a separate tank, the second phase, aqueous phase ingredients are heated together to slightly above 75.8oC. • The aqueous phase is then slowly added to the oil phase through constant agitation. • The mixture is cooled slowly with continuing agitation as the emulsion is formed. The medicinal ingredients may be added when the emulsion is in the cooling stage. For capacities of 200 gallons or less, a single high-turbulence agitator may be used in most cases.
High-turbulence mixers (turboemulsifiers) of varying capacities.
For larger batches of up to 1000 gallons, a large-scale multiagitator mixer may be used that involves a mixer–emulsifier (for high degree of shear), a high-speed disperser (to disperse solids into viscous liquids), and an anchor–agitator (to provide maximum movement of product under low shear conditions in the mix vessel).
Large-scale manufacturing unit (Tri-mix Turboshear) with counter-rotating mixing bars.
To improve the stability of the oil phase, colloid mills may be used to disperse the oil phase further once the emulsion is formed. A homogenizer may be used to reduce the size of the oil globules by exerting a smearing action in which the emulsion is forced through a small orifice under high pressure. • The advantage of the homogenizer over the colloid mill is that it does not incorporate air into the emulsion. The throughput of the homogenizer is 10–100 times lower than that of the • colloid mill.
Another in-line method of emulsification is the ultrasonic process, which uses a sonolator This process uses a very high-intensity mixing device that mechanically generates ultrasonic acoustic energy to produce emulsions and dispersions. Liquid to be processed is pumped through a special orifice, forming a flat, high-pressure stream. This jet impinges on the edge of a flat blade enclosed in a tube, causing it to vibrate at ultrasonic frequencies. Cavitation produces violent local pressure changes that act on the liquid, causing instantaneous and intense dispersion of any immiscible liquids or insoluble particles.
Schematic representation of colloid mill and microphotographs showing emulsion globule size before and after milling.
The packaging of semisolid products, usually in jars and tubes, represents the best and worst conditions for microbial contamination. When using jars, the risk of contamination is higher time fingers touch the product. • semisolid products in jars require a highly effective, long-acting preservative system to remain active throughout the life of the product. • With tubes, the risk of microbial contamination is significantly reduced because they expose only a very small area each time a cap is removed. • Tubes also provide control of dose by an amount expressed with minimum exposure to the environment or human contact. Therefore, because products packaged in tubes are less likely to become contaminated, the use of preservative is also reduced.
All drug product containers and closures must be approved by stability testing of the product in the final container in which it is marketed. The stability test includes testing filled containers at room temperature (e.g., 700F) as well as under accelerated conditions (e.g., 105 and 1200F). Opaque jars are used to protect light-sensitive products and are available as porcelain white or dark green or amber in color. Plastic containers used for emulsion systems must be thoroughly evaluated for physical and chemical changes in the emulsion as well as for physical changes in the container.
Stability testing is a routine procedure performed on drug substances and products. It is involved at various stages of product development. In early stages, accelerated stability testing (at relatively high temperatures and/or humidities) can be used to determine the types of degradation products that may be found after long-term storage. Testing under more gentle conditions (those recommended for long-term shelf storage) and slightly elevated temperatures can be used to determine product shelf life and expiration dates.
According to the FDA draft guidelines to the industry ,semisolid preparations should be evaluated for appearance, clarity, color, homogeneity, odor, pH, consistency, viscosity, particle size distribution (when feasible), assay, degradation products, preservative and antioxidant content (if present), microbial limits/sterility, and weight loss (when appropriate). • Additionally, samples from production lots of approved products are retained for stability testing in case of product failure in the field. • Ointments, pastes, gels, and creams in large containers including tubes should be assayed by sampling at the surface, top, middle, and bottom of the container. In addition, tubes should be sampled near the crimp.
Stability Stations and Sampling Periods: Three 24-h freeze–thaw cycles are used: 1, 2, and 3 months at 500C; 1, 3, 6, and 12 months at 400C; and 1, 6, 12, 18, 24, and 36 months at 250C (room temperature). At the end of each period, the sample is evaluated for chemical and physical properties as applicable (as noted earlier). The sample should also be examined to evaluate product–package compatibility. Microscopic examination of the sample can provide a very useful evaluation of changes in particle size and crystal structure.
Tests for evaluating the compatibility of the product with the container include weight loss and moisture loss (if applicable). Reduction in the concentration of critical ingredients would indicate loss owing to binding with the container material or permeation through the container walls. The container should also be examined to evaluate interaction of the product with the container surface.
