5.2.1 Gelling agents
The in-house gelling agents used in the extemporaneous manufacture of gels are Carbopol® polymers and co-polymers. The generic (i.e., non-proprietary) name adopted by USP-NF for various Carbopol® polymers is carbomer. Carbopol® polymers are synthetic high molecular weight polymers of acrylic acid cross-linked with either allylsucrose or allylethers of
pentaerythritol whereas Carbopol® co-polymers are synthetic high molecular weight
polymers of acrylic acid with small amounts of long chain alkyl acrylate co-monomers cross- linked with allylpentaerythritol. All these polymers have the same acrylic acid backbone (227, 229). These polymers contain between 56.0 - 68.0% of carboxylic acid (COOH) groups, calculated on the dry basis (238). They are fluffy, white, mildly acidic flocculated powders averaging 2 to 7 microns in diameter. Each primary particle can be viewed as a network structure of linear polymer chains interconnected by cross-links. These linear polymers are soluble in a polar solvent, such as water. Carbopol® polymers, along with Pemulen® polymeric emulsifiers are all cross-linked. They swell in water up to 1000 times their original volume (and ten times their original diameter) to form a gel when exposed to a pH environment between 4.0 - 6.0. Since the pKa of these polymers is 6.0 ± 0.5, the
carboxylate groups on the polymer backbone ionize, resulting in repulsion between the negative charges, which adds to the swelling of the polymer. Cross-linked polymers do not dissolve in water. The glass transition temperature of Carbopol® polymer is 105°C in powder form. However, the glass transition temperature drops dramatically as the polymer comes into contact with water. The polymer chains starts gyrating and the radius of gyration becomes larger. Macroscopically, this phenomenon manifests itself as swelling (228).
Carbopol® polymers and co-polymers are used mainly in liquid or semisolid pharmaceutical formulations as suspending or viscosity increasing agents. Formulations include creams, gels and ointments. Carbopol® polymers are also employed as emulsifying agents in the
preparation of o/w emulsions for external use and are also employed in cosmetics (238).
In the dry state, a carbomer molecule is tightly coiled, but when dispersed in water the molecule begins to hydrate and partially uncoil, exposing free acidic moieties. To attain maximum thickening effect the carbomer molecule must be fully uncoiled and this can be
achieved by one of two mechanisms. The most common method is to convert the acidic molecule to a salt, by the addition of an appropriate neutralizing agent. For formulations containing aqueous or polar solvents, carbomer gellation can be induced by the addition of simple inorganic bases such as sodium or potassium hydroxide. Less polar or non-polar solvent systems can be neutralised with amines such as triethanolamine or diethanolamine.
Neutralization ionises the carbomer molecule, generating negative charges along the polymer backbone, and the resultant electrostatic repulsion creates an extended three-dimensional structure. It is important to add a sufficient quantity of the neutralising agent to commence gellation. Insufficient or excess amounts of the neutralising agent will result in viscosity or thixotropic changes (93). The use of a strong base such as sodium hydroxide is not
recommended since there is a greater risk of overshooting the desired pH range thus causing loss of the gel integral network.
A number of different Carbopol® polymer grades are commercially available which vary in molecular weight, degree of cross-linking and polymer structure and therefore they may not have identical properties with respect to their use for specific pharmaceutical purposes, e.g., as controlled-release agents, bioadhesives, topical gels, thickening agents and emulsifying agents. Carbopol® polymers should not be interchanged unless performance equivalency has been ascertained (227). Four different types of Carbopol® polymers namely 974 PNF, 980 NF, 981 NF and Ultrez™ 10 NF with one co-polymer namely Pemulen® polymeric
emulsifier, Pemulen® TR1 NF, were used in this laboratory.
Carbopol® 974 PNF polymer was introduced specifically for use in oral and mucoadhesive contact applications such as controlled release tablets, oral suspensions and bioadhesives. In addition Carbopol® 974 PNF provides thickening, suspending and emulsification properties to high viscosity systems for topical applications (227).
Carbopol® 980 NF polymer forms clear hydroalcoholic gels. This polymer is the key to obtaining clear gels. Carbopol® 980 NF polymer is also the most efficient thickener of all the Carbopol® polymers and has extremely slow flow properties suitable for spray-on
polymer performs better than most of the other Carbopol® polymers. Carbopol® 981 NF polymer produces higher viscosities than Carbopol® 980 NF at concentrations below 0.1% in water systems and at concentrations below 1.5% in solvent systems (227).
Carbopol® Ultrez™ 10 NF polymer is a new member of the Carbopol® family. It is a dispersable polymer that offers a wide range of performance properties and can be used in a variety of personal care applications (231). The unique dispersion performance of Carbopol® Ultrez™ 10 NF polymer allows it to wet quickly, yet hydrate slowly. This property helps minimise lumping, which can be troublesome when turbulent mixing is not available during dispersion (227).
Pemulen® TR1 NF is a versatile primary polymeric emulsifier which can emulsify up to 30%
oil by weight, within a pH range of 4.0 - 5.5 and up to 20% oil over the pH range of 3.0 - 11.0. ‘Primary’ indicates that it is an emulsion former, not an emulsion stabiliser, as many of the Carbopol® polymers are. Pemulen® TR1 NF can enable formulation of permanent
emulsions, even at elevated temperatures without the use of irritating surfactants. In addition, the hydrophobic phase of emulsions formed with Pemulen® polymeric emulsifiers do not re- wet in the presence of water as traditional surfactants-based emulsions do. Instead,
emulsions based on Pemulen® polymers deposit an occlusive layer on the skin delivering the topical medication in the form of low irritancy lotions and creams with elegant skin feel.
Pemulen® TR1 NF can also be used for high clarity topical gels with hydrophobic or highly ionic components (227). While Pemulen® TR1 NF thickens the water, Carbopol® polymers should be used with Pemulen® TR1 NF to provide greater thickening properties where higher viscosity emulsions are required. Pemulen® polymeric emulsifiers can actually form o/w emulsions. The lipophilic portion adsorbs at the oil-water interface and the hydrophilic portion swells in the water forming a gel network around oil droplets to provide exceptional emulsion stability to a broad range of oils (230). Pemulen® polymeric emulsifiers have been designed to act both as primary emulsifiers and viscosity increasing agents (126).
It is worth noting that other grades of Carbopol® polymers and co-polymers that can be used in the preparation of topical formulations, namely 934 NF, 934 PNF, 940 NF, 941 NF, 971 PNF, 71G NF, 1342 NF and Pemulen® TR2 NF, are available but were not used in this study.
5.2.2 Triethanolamine
Triethanolamine, also chemically known as triethylolamine, trihydroxytriethylamine or tris(hydroxyethyl)amine is widely used in topical pharmaceutical formulations primarily in the formation of emulsions. It is a clear, colourless to pale yellow-coloured viscous liquid having a slight ammoniacal odour. In this study triethanolamine is used as a weak
neutralizing agent to commence the gelling process by converting the free acidic hydrogens into amine salts. Triethanolamine may turn brown on exposure to air and light and thus should be stored in an airtight container, protected from light, in a cool, dry, place (256).
5.2.3 Propylene glycol
Propylene glycol, chemically known as 1,2-propanediol, is widely used as a solvent extractant and preservative in a variety of parenteral and non-parenteral pharmaceutical formulations. It is a clear, colourless, viscous, practically odourless liquid with a sweet acrid taste resembling glycerine. Propylene glycol can also be used as an antimicrobial
preservative, disinfectant, humectant, plasticizer and water-miscible co-solvent. Propylene glycol is chemically stable when mixed with ethanol 95% v/v or water. Propylene glycol is hygroscopic and should be stored in an airtight container, protected from light, in a cool, dry, place (257). For the purposes of this research propylene glycol was mainly employed as a water-miscible co-solvent to aid in the dissolution of ketoprofen during the manufacture and as a chemical penetration enhancer.
5.2.4 Ethanol
Ethanol is a colourless, clear, volatile, flammable liquid (277) and employed in the
manufacture of topical formulation primarily as a solvent. However, although alcohols are useful to increase solubility of non-polar drugs, their use as co-solvents with hydrophilic polymers is often limited.
5.2.5 Transcutol® HP
Transcutol® HP is highly purified diethylene glycol monoethyl ether. It is a hydroscopic liquid that is freely miscible with both polar and non-polar solvents (53). Transcutol® HP has
Transcutol® HP can be incorporated into all types of topical emulsions (creams and lotions), solutions, gels and ointments. Transcutol® HP has been recognised as a potential transdermal permeation enhancer due to its non-toxicity, biocompatibility with skin and excellent
solubilizing properties (53). Recent studies (51) have shown that Transcutol® HP
significantly increases the percutaneous penetration of various active substances particularly if used in combination with suitable co-solvents. In this study, propylene glycol and ethanol were selected for a possible synergistic enhancer effect on account of their satisfactory solvent power for ketoprofen.
Table 5.2 Common excipients employed and their sources
Excipients Manufacturer Active principal ingredient
Ketoprofen Sigma-Aldrich (Atlasville, SOUTH AFRICA) Carbopol® polymers
Carbopol® 974 PNF Noveon Inc. (Cleveland, USA) Carbopol® 980 NF Noveon Inc. (Cleveland, USA) Carbopol® 981 NF Noveon Inc. (Cleveland, USA) Carbopol® Ultrez™ 10 NF Noveon Inc. (Cleveland, USA) Carbopol® co-polymer
Pemulen® TR1 NF Noveon Inc. (Cleveland, USA) Neutralizing agent
Triethanolamine Aspen Pharmacare (Port Elizabeth, SOUTH AFRICA) Co-solvent/solubilizing agent
Ethanol MERCK (Wadeville, SOUTH AFRICA) Transcutol® HP Gattefossé (Saint-Priest, FRANCE) Propylene glycol MERCK (Wadeville, SOUTH AFRICA)