Topical formulations, solvents

Little is known on the metabolic fate of l-methylpyrrolidin-2-one (5.60), an industrial solvent also useful as a solubilizing agent and a penetration enhancer in topical formulations. A preliminary investigation of the disposition and metabolism of labeled l-methylpyrrolidin-2-one in the rat showed that the compound is excreted mainly in urine [171]. Three urinary metabolites were detected, the major of which (ca. 15% of the dose) was 4-(methylami-no)but-2-enoic acid (5.61). This unsaturated product may likely have been formed by H20 elimination from a hydroxylated metabolite. 

Betnovate scalp application is an aqueous suspension and contains carbomer, isopropyl alcohol, sodium hydroxide and purified water. Carbomer is a thickening agent and it is used to increase the stability of suspension/emulsion formulations. Isopropyl alcohol is often used in topical formulations. It may be used as a solvent or as a disinfectant (if >70% concentration). Sodium hydroxide would be used to adjust the pH of the formulation, specifically in this case... 

In 11 patients allergic to topical minoxidil lotion, patch tests showed that four were positive to minoxidil itself (11). Propylene and butylene glycol are used as solvents for minoxidil in topical formulations. Nine of the 11 patients appeared to have positive patch tests to propylene glycol and one of the 11 reacted to its alternative butylene glycol. 

Cyclomethicone has been used in cosmetic formulations, at concentrations of 0.1-50%, since the late 1970s and is now the most widely used silicone in the cosmetics industry. Its high volatility, and mild solvent properties, make it ideal for use in topical formulations because its low heat of vaporization means that when applied to skin it has a dry feel. 

In topical formulations, ethylcellulose is used as a thickening agent in creams, lotions, or gels, provided an appropriate solvent is used. " Ethylcellulose has been studied as a stabilizer for emulsions. ... 

In oral solutions, glycerin is used as a solvent, sweetening agent, antimicrobial preservative, and viscosity-increasing agent. It is also used as a plasticizer and in film coat-ings. Glycerin is additionally used in topical formulations such as creams and emulsions. " ... 

Isopropyl alcohol (propan-2-ol) is used in cosmetics and pharmaceutical formulations primarily as a solvent in topical formulations. It is not recommended for oral use owing to its toxicity see Section 14. 

Due to experimental and ethical concerns, development of topical formulations tends to utilise skin ex vivo in vitro) which inherently reduces some of the above noted complexity—regeneration stops, immune responses cease and metabolic activity is usually greatly reduced or lost in these studies. However, it should always be borne in mind that data obtained from excised skin may not translate directly to the in vivo situation. In particular, applying exogenous chemicals, such as solvents in a formulation, can induce immunological, histological and metabolic changes that may not be evident from in vitro studies. 

Table 2. Summary of some typical solvents used in topical formulations.

Propylene glycol is extensively used in numerous topical formulations as illustrated in Table 3, abstracted from the FDA Inactive Ingredient Guide (1996). Over 230 drug products at that time contained the solvent, and at levels up to 99.99% of the formulation. 

Several other solvents are used extensively in topical formulations. Isopropyl myristate (1PM) could be classified as an oily ingredient, which can be grouped within a series of isopropyl fatty acid esters such as isopropyl linoleate and isopropyl palmitate. 1PM has been included in emulsions and gels at around 10%... 

Figure 5. An example of a decision tree for solvent selection in topical formulations. The tree is not exhaustive but illustrates some of the factors to consider when selecting a solvent.

Hydroxyethylcellulose (HEC) (Nalrosol, Hercules) 135-140 °C T — 70S Ctccnposmoi Soluble in hot or cold water Insoluble in organic solvents Viscosity = 2-20,0(X) MPa for 2% aqueous solution. Ophthalmic formulations Topical formulations Thickener Stabiliser Water binder... 

Quick-breaking foams consist of a miscible solvent system such ethanol (qv) [64-17-5] and water, and a surfactant that is soluble in one of the solvents but not in both. These foams are advantageous for topical appHcation of pharmaceuticals because, once the foam hits the affected area, the foam coUapses, deUvering the product to the wound without further injury from mechanical dispersion. This method is especially usehil for treatment of bums. Some personal products such as nail poHsh remover and after-shave lotion have also been formulated as quick-breaking foams. 

Formulators can use the tendency of creams, gels, and other systems to evaporatively concentrate to advantage. Solvents are chosen and blended so that the drug remains soluble in the formed film long after application is made. This can be accomplished by replacing a fraction of the water or other highly volatile solvent found in these systems with solvents of far lower volatility. As previously pointed out, 5-15% propylene glycol is found in many topical corticosteroid creams and lotions just for this reason. 

The second group comprises the mixing of the polymer with non-reactive bromine compounds. This can be done by adding the compound to the melt in the extruder, by topical deposition or coating of the polymer with a suitable formulation containing the compound, as well as by exhaustion of dissolved compounds from a solvent bath f11. Cases are also known in which the bromine compound was encapsulated in the polymer in order to avoid deleterious interaction [61. 

Suspensions are two-phase systems consisting of a finely divided solid dispersed in a liquid, solid, or a gas (Table 6). They are appropriate when the drug to be incorporated is not sufficiently soluble in an ordinary solvent or cosolvent system. They are used orally and topically. Examples of compounded suspensions include pediatric oral liquids where a commercial pediatric dosage form is not available. Commercial tablets and capsules are formulated into a vehicle and can be individually flavored to the patient s preference. 

On the basis of the findings on LiBOB performance in nonaqueous solvents and other advances made to improve the low-temperature performance of lithium ion electrolytes. Jow and co-workers proposed that an electrolyte with a much wider temperature range could be formulated using LiBOB alone or in combination with other salts. The following section (8.4) will be dedicated to this topic. 

The widespread applicability of di-O-methylisosorbide as a medium for chemical reactions or as a solvent for pharmaceutical formulations is well documented. In some cases, an additive synergism of the solvent and the solute was observed. Some typical examples mentioned include that it acts as a solvent for muscle-relaxant drugs, which are otherwise difficultly soluble,226 and is used for topical and other types of pharmaceutical formulations,227,228 transdermal controlled-release films229 and tapes,230 anthelmintic solutions,231 antimycotic emulsions,232 and for the treatment of skin disorders, such as eczema.233... 

Additional naturally occurring lipids may be minor components of oral lipid-based formulations. Terpenes such as peppermint oil (>50% menthol) are fairly hydrophobic but can provide some solvent capacity. Steroids such as cholesterol, while important in topical and in parenteral liposomal products, are not important as oral pharmaceutical adjuvants. Phospholipids (e.g., egg or soybean phosphatidylcholine) an essential component of cell membranes, are considered polar lipids, and have surfactant properties. 

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