FORMULATION: Sweeteners and Flavors

"It TastesLikeMedicine"

There are Ways to Make Drugs Taste Better

Whenever a method of drug administration requires the patient to taste the drug, palatability becomes a critical factor in patient compliance, prescribing practices, the perceived quality of the drug product, and its overall commercial success. Sweeteners and flavors are essential ingredients in masking unpleasant tastes and providing the appealing tastes that make a drug product palatable. But how does a formulator assess palatability and select the best combination of sweeteners and flavors from the wide array available?

This article discusses the relative advantages and disadvantages of the existing options in the context of the broad range of formulation challenges. It also borrows a page from food scientists to explain how blending components can achieve better flavor targets in pharmaceutical formulation. A proven sensory method of assessing palatability will also be presented.

Taste and Flavor vs. Palatability and Compliance

Our sense of taste and flavor perception is fascinating and complex. Stimuli affect our sensory systems on different levels involving the basic tastes (salty, sour, sweet, and bitter), the sense of smell, and the sense of touch and mouthfeel (astringency, oiliness, etc.). The National Pharmaceutical Council estimates that noncompliance results in $8.5 billion in unnecessary medical spending annually. Drug palatability plays a major role in patient compliance, especially among children for whom drug products are typically chosen on the basis of texture, taste and ease of use. Retrospective studies indicate that negative palatability has a negative influence on pediatric compliance and pleasing taste improves compliance. Palatability is also an important factor in a product's perceived quality and in its ability to stand out from the competition.

The Art of Creating Palatability

Attaining palatability by masking undesirable tastes and imparting a pleasant flavor with its associated elements, such as mouthfeel and absence of "off-notes," all within the context of a bioavailable stable dosage form, presents a formulation challenge unlike any other. Food science has long recognized that palatability is not straightforward. Every added ingredient interacts with the rest of the ingredients, creating new flavors that identify the mix even when each or one of the substances can still be identified individually. Blending components to balance flavors and using objective sensory methods to evaluate flavor greatly increase the chance of achieving a flavor target. Sensory analysis methods are used to identify the taste challenge that results from the active ingredient and the functional excipients (buffers, preservatives, etc.). They are also used to guide the formulator toward the defined flavor target in the excipient selection process. In addition to palatability aspects, flavoring excipients are chosen on the basis of requirements related to the dosage form (liquid, chewable tablet, etc.); physical, chemical and microbiological attributes; compatibilities; and processing conditions. Other considerations include restrictions on use in pediatric products, dental health, cost, and, of course, regulatory status. The primary taste-masking excipients used in pharmaceutical formulation are sweeteners, flavoring agents and flavor potentiators.

Sweeteners; Definition and Classes

In pharmaceutical formulation, sweeteners are widely used for several functional reasons (e.g., diluents in tablets), in addition to their essential role in taste masking. They can be classified as nutritive sweeteners; polyols and hydrogenated starch hydrolysates; and high-intensity sweeteners. They differ in their organoleptic and functional properties, and no single sweetener works for every situation. Thus, using a blend of sweeteners often helps improve the outcome, overcomes the limitations of certain sweeteners and reduces the ingestion level of one specific sweetener.

Nutritive Sweeteners

Nutritive sweeteners are simple carbohydrates generally present in food. Sucrose, a disaccharide of glucose and fructose, is the most commonly used sweetener. Its taste is considered the standard of sweetness and, as a result, its sweetness intensity represents 100. Nutritive sweeteners are the major ingredients in invert sugar, honey, molasses, and high-fructose corn syrup. Commonly used sweeteners of this category are presented in Table 1.

Table 1: Nutritive Sweeteners and Polyols (Sugar Alcohols)

Polyols (Sugar Alcohols) and Hydrogenated Starch Hydrolysates

Polyols are the hydrogenated derivatives of a corresponding sugar (e.g., mannitol from mannose). Compared to their parent sugars, polyols are lower in calories, less reactive, do not promote dental cavities, and have greater stability and longer shelf life. They have endothermic heats of solution resulting in different degrees of cooling sensation in the mouth. Polyols are used in combination with other sweeteners to provide bulk, improve texture and mouth-feel, and reduce the tendency of sucrose to crystallize and cause cap-locking. Table 1 presents the available polyols, including their properties and uses.

In pharmaceutical formulation, the identifying flavors are often chosen on the basis of market studies, age of user, mode of use, product characteristics, composition and other product-specific requirements.

High-Intensity Sweeteners

High-intensity sweeteners are artificial sweeteners with very low caloric content and high sweetness intensity. They are used in small concentrations in many dosage forms (e.g., chewable tablets, powder for suspension, etc.) to replace or reduce the amount of sugars needed in a formulation. Major drawbacks of this category of sweeteners include their artificial sweet taste and possible off-notes, in addition to regulatory concerns. Examples of high-intensity sweeteners are described in Table 2.

Table 2: High Intensity Sweeteners

Definitions and Classes

Without flavor, coffee would not be coffee and orange juice and apple juice would be nearly indistinguishable. Flavors determine identity. In pharmaceutical formulation, the identifying flavors are often chosen on the basis of market studies, age of user, mode of use, product characteristics, composition and other product-specific requirements. As in food formulation, flavors may be added to act as a noticeable identifying flavor, to potentiate one flavor element or to complement or depress others. Flavoring agents should act in synergy with the other ingredients in the system. Several functional factors should also be considered in choosing the correct flavor, including the required concentration, pH, processing temperature, compatibility with components, storage conditions, and shelf life.

Flavors fall into three classes: Natural, artificial, and natural and artificial (NandA) flavors.

Natural Flavors

Natural flavors are the oldest class of flavors to be used in food and pharmaceutical formulations. However, they are being replaced by synthetic flavors and their use alone in pharmaceutical formulations is very limited due to several disadvantages, including unpredictable quality due to the natural origin, instability, cost, and availability.

Artificial Flavors

Artificial flavors are created by identifying the composition of a certain natural flavor and synthetically recreating that experience. They are chemically superior (i.e., more stable and pure) to their natural counterparts. However, natural flavors are complex and difficult to precisely reproduce. For example, no available artificial vanilla can exactly mimic the flavor of vanilla beans.

Natural and Artificial (NandA) Flavors

Natural and artificial (NandA) flavors are combinations of synthetic and natural flavors. Their purpose is to closely match the natural flavor experience using better performing and consistent quality chemicals and minimizing the use of natural components. Another advantage of this class of flavors is the wide variety available and the potential to create new flavor experiences beyond traditional flavors (e.g., bubble gum, cheesecake). Most flavor blends are proprietary to their makers and since any minor change can have a large influence on flavor, flavors sold under the same name (e.g., strawberry) often differ from one supplier to another.

Flavors can be added to different oral dosage forms as powders or in solution. Flavor suppliers usually provide recommended concentration ranges of their flavor blends and their regulatory status in a specific application. The concentration of the flavor should be defined on the basis of the flavor challenge and on sensory data (e.g., blend, fullness, and after-taste) collected from an objective sensory analysis method.

Acidulants and Flavor Potentiators

Acidulants and flavor potentiators are commonly added to food products in small levels to enhance certain flavors. They act in a complex manner that is not always predictable.

Acidulants are added to fortify flavors. The most common acidulants are organic acids such as citric, malic, fumaric, and tartaric acid. They are mostly used in lozenges and oral liquids to improve the overall flavor quality. Flavor potentiators include salts (e.g., NaCl), amino acids, and amino acid derivatives (e.g., mono-sodium glutamate or MSG). Salt, for example, is known to enhance the bland flavor of vanilla. MSG is commonly used in food as a flavor enhancer. Its taste is associated with what is arguably the fifth basic taste "Umami."

Assessing Palatability

For centuries, food scientists have used sensory analysis techniques to develop better products. These techniques belong to one of two categories: affective, including preference and liking evaluations; and analytical, including discriminative and descriptive techniques.

Examples of descriptive techniques include the "Flavor Profile method" and "Profile Attributes Analysis." Both methods use trained panelists who apply their ability to recognize, describe and compare aromas and flavors to measure the palatability aspects of a sample in a descriptive and numerically reproducible manner.

Flavor Profile Method

In the flavor profile method, a product flavor profile is created and refined with repeated panel sessions. Aroma and flavor are assessed in terms of the following factors:

• Amplitude - overall impression of the aroma and flavor, integrating balance and body

• Perceptible aroma

• Flavor

• Taste character notes

• - Intensity of each character note

• - Order of appearance of each character note - larger differences in the time of appearance of notes are more apparent in unblended flavors

• Aftertaste - flavor residue after the product has been completely swallowed

Sensory analysis provides an objective way to identify the taste challenge, benchmark a product against its competitors and identify a reasonable flavor target to lead the formulator.

Profile Attributes Analysis

Profile attributes analysis (PAA) is an extension of the Flavor Profile method for which the expert panel rates the intensity of each attribute. The attributes are a set of characteristics properly defined to provide a complete description of the sensory quality of a sample. (13) PAA data can be efficiently handled, summarized and is amenable to statistical analysis. Sensory analysis provides an objective way to identify the taste challenge, benchmark a product against its competitors and identify a reasonable flavor target to lead the formulator. It is also useful in quality control to monitor stability in terms of organoleptic properties and detect any quality change that may arise from processing changes.

The value of palatability in compliance and the value of compliance in treatment outcome are unquestionable. Consumer expectations are high and their preference is increasingly influential in the selection of drug products. These trends underscore the need to create sensory-appealing (i.e., palatable) drug products, especially for pediatric markets. But palatability is not a straightforward science. Choosing the right taste masking and flavoring systems can be facilitated when drug formulators integrate sensory-directed approaches that have evolved from common food science practices.�