The Pharmaceutics and Compounding Laboratory
Aesthetic Considerations of
Oral Liquid Dosage Forms

Palatability

"The worse the taste of the medication, the better the cure" was once the prevailing attitude. Today, changes in patient attitude and the development of numerous flavoring agents has reversed that opinion. Patients now expect and demand liquid medications that are pleasantly, or at least tolerably, flavored. This is especially true with children and older adults for whom solutions are most often prescribed.

The human tongue contains over 9000 taste buds which distinguish salty, bitter, sour, and sweet tastes. Drugs in solution directly and immediately contact and stimulate these taste buds. Thus, the flavoring of oral solutions is a major concern in the pharmaceutical industry.

Palatability is influenced by a combination of sensory perceptions including taste and smell, and to a lesser extent texture, appearance, and temperature of the products. We can improve product palatability by optimizing these factors.

There is often a correlation between the chemical structure of a compound and its taste. Low molecular weight salts tend to taste salty where higher molecular weight salts tend toward bitterness. Nitrogen containing compounds, such as the alkaloids, tend to be quite bitter. Organic compounds containing hydroxyl groups tend to become increasingly sweet as the number of OH groups increase. Organic esters, alcohols, and aldehydes are known for their pleasant taste and cool sensation produced by their volatility.

Discovering the flavoring agent best suited to masking an unpleasant taste is often a very empirical matter. Experience and experimentation have produced some general guidelines regarding the type of flavor best suited to mask a given taste. Such recommendations are listed in Table 1.

Table 1
Taste Masking Flavor
Salty cinnamon, raspberry, orange, maple, butterscotch, glycyrrhiza (licorice) syrup
Sweet fruit, berry, vanilla, acacia syrup
Bitter cocoa, chocolate-mint, wild cherry, walnut, glycyrrhiza (licorice), eriodictyon, raspberry syrup
Sour fruit, citrus, cherry syrup

Many flavoring agents are available or may be compounded in the pharmacy. The student is referred to the chapter on Pharmaceutical Necessities in Remington's for a more thorough discussion of the numerous syrups, aromatic waters, essences, and elixirs used as flavoring vehicles. Major flavoring companies, such as Fritzshe Brother, Inc. in New York City, are excellent sources of flavoring agents and recommendations for their use.

Although altering taste perception by masking unpleasant tastes with a flavoring agent is the major factor in producing palatable products, other factors contribute as well. Aroma (odor) is a strong determinant of taste perception. The preparation is of little therapeutic value if the patient can't get it beyond his nose. (Remember your mom holding your nose to get your medication in you; she really wasn't trying to torture you!) The scent of any oral solution should be pleasant and should correlate with the flavor. Product temperature also influences taste perception. Refrigerating liquid products generally reduces unpleasant taste.

Product texture also plays a role in taste perception and patient acceptance. Gritty or chalky preparations are poorly received by most patients (as attested to by the millions of dollars spent by antacid manufacturers to promote their new, creamier, nonchalky... products). Solutions, by definition, should be homogenous and thus contain no undissolved solids. Remember that if you are preparing an oral solution from prefabricated solids you will most likely need to filter out insoluble tablet excipients (e.g. bulk fillers, glidants, lubricants, etc. used in the tableting process) once sufficient solvent/diluent has been added to dissolve the active ingredients.

The age of the patient and the frequency of dosing will further influence patient taste preferences. Children generally prefer sweet, fruity, and candy-like tastes while adults prefer less sweet, tart-fruity flavors. Flavoring agents are generally unnecessary and not recommended for infants under 3-6 months of age. Older adults may prefer mint or even wine flavored vehicles. Liquids which require frequent administration, such as antacids, may rapidly become tiresome with a sweet fruity taste. Instead, such products are usually formulated in mint or tart citrus flavors.

Now consider the role of coloring agents in determining patient acceptability. Clear, water-like solutions may be poorly accepted on the basis of perceived inertness or lack of potency. Dark colors, often associated with poisons, such as dark purple, navy, black and brown, may also be rejected. More pleasant, fruity colors are generally preferred and should be coordinated with flavors and scents (e.g., yellow-lemon, red cherry). Occasionally, manufacturers will resort to "visual distraction" as a means of enhancing palatability. For example, a particularly bitter drug might be formulated in a blue, peach flavored, mint-scented vehicle. While the brain tries to reconcile the contradictions of a minty blue peach, the bitter substance has been swallowed. This approach is probably useless with small children who have not yet developed an expectation of color/aroma/taste correlation.

Some attention should also be given to choice of coloring agents. Once considered inert and benign, closer scrutiny has shown many agents to be unsafe or to cause produce instabilities. The Federal Food and Drug Administration regulates the certification of food and drug dyes through the Federal Food, Drug, and Cosmetic Act of 1938 as amended in 1960.

Dyes are classified as:

  • F, D, and C dyes (may be used in foods, drugs, or cosmetics)
  • D and C dyes (may be used in drugs and cosmetics), or
  • External D and C dyes (may be used only in drugs and cosmetics for external use)

The certification status of dyes is constantly changing and may be difficult to keep up with. From a practical standpoint, the pharmacist may consider those food colorings currently marketed in grocery stores to be safe and appropriate to use. These come in the form of red, blue, yellow, or green aqueous solutions and are ideally suited to coloring aqueous solutions. Blends may be used to produce nearly any color.

One dye is of particular interest today. FD&C yellow #5 (tartrazine) is a salicylate-type compound found to produce sometimes severe allergic reactions. As many as 100,000 people in the U.S. are thought to be sensitive to tartrazine. Additionally, tartrazine exacerbates a condition in children known as Minimal Brain Dysfunction (MBD) children and patients with known salicylate sensitivity. Tartrazine has been removed from most products.

In choosing a colorant, physiochemical reactions with other formulation ingredients must be considered. Many dyes are salts of sulfonic acids and may be incompatible with large cationic compounds like the alkaloids. The pharmacist should consider how pH changes or light exposure will alter the color or stability of the product. He/she must, also, consider the solubility of the dye. An oil soluble dye would not produce an "elegant" aqueous solution.

Finally, when formulating an oral liquid product (or a topical one for that matter), you should consider product texture. Viscosity seems to play an important role in patient acceptance. The characteristic viscosity of syrups appears to have a positive effect on patient acceptance, whereas less viscous solutions may be perceived as "watered down" and more viscous solutions as unpleasant (slimy, gooey...). When formulating solutions, you should always remember to filter out any undissolved solids (e.g., excipients from component tablets, or excess solute from saturated solutions). When formulating suspensions (more next semester), you should also attempt to adjust particle size so that the product is non-chalky or non-gritty and viscosity so that the product is fluid enough to flow while being viscous enough to maintain particle dispersion.