The taste of the medication has a significant impact on the ability of patients to follow their treatment regiment when taking oral pharmaceutical suspension. This is especially true for children, the elderly and those with sensitivity to tastes. Many active pharmaceutical ingredients (APIs) have a naturally occurring bitter or unpleasant taste that can negatively affect the medicine taking ability of patients.
To address this issue, sweetening agents have been included in oral suspension in order to mask the lack of palatability associated with certain APIs. However, there is more to selecting a sweetening agent than simply picking one that is good tasting. There are a number of factors that need to be considered, such as chemical compatibility with the formulation, chemical stability, sweetness intensity, calories per gram and whether or not the particular sweetening agent is approved for use by regulatory agencies.
This article presents the types of sweetening agents available for use in oral pharmaceutical suspensions and provide an overview of their respective properties, benefits and considerations useful in formulation development.
1) To mask unpalatable tastes of active pharmaceutical ingredients.
2) To improve the ability of pediatric and geriatric patients to take the drug.
3) To provide a better overall sensory experience through a better flavor combination and improved mouthfeel (i.e., how it feels in your mouth).
A good sweetener is selected to fit in well with the other flavoring and taste-masking agents in order to provide the best-tasting product possible.
Natural Sweeteners: Sucrose, Sorbitol, Mannitol, Xylitol and Honey are natural sweeteners. Varying levels of sweetness 1-2 times sweeter than sugar. These have high or moderate levels of caloric value.
Artificial Sweeteners: Saccharin, Aspartame, Acesulfame K, Sucralose and Stevia are artificial sweeteners. Varying levels of sweetness 30-600 times sweeter than sugar. These have very low or no levels of caloric value.
Key considerations when choosing a sweetener include:
Here are some examples of sweetener combinations that work together in a synergistic way.
- Aspartame and Acesulfame K together provide an increased level of sweetness and minimize the aftertaste associated with aspartame.
- Sucralose and Sorbitol combined balance the level of sweetness against the mouth feel.
- Saccharin and Mannitol combined are often used in low-calorie children's medication suspensions.
By using these combinations of sweeteners, formulators can recreate the flavor of sugar while using lower amounts of individual sweeteners compared to using these saperately.
1. pH-sensitivity: Aspartame is susceptible to degradation under acidic conditions.
2. Temperature: Sucrose and sorbitol solutions can caramelize when exposed to heat.
3. Microbial Susceptibility: Natural sugars are capable of promoting the growth of microbes so require to add preservatives.
4. Reactivity: Reducing sugars such as glucose may react with drugs those contain amine group through the maillard reaction process.
Therefore, formulation compatibility must be established prior to commencing a product’s development so that manufacturers do not experience any unforeseen degradation or discoloration.
Examples of ADIs for the sweeteners included within this document which come from regulatory agencies include:
Saccharin - 5 mg/kg body weight/day
Aspartame - 40 mg/kg (EU) or 50 mg/kg (US)
Sucralose - 15 mg/kg
Steviol equivalents (stevia) - 4 mg/kg
Implementation of ICH Q8 guidelines (on pharmaceutical development) guarantee the sweeteners comply with the FDA's Inactive Ingredient Database (IID), therefore they can be classified as acceptable pharmaceuticals.
Oral pharmaceutical suspensions must contain sweeteners because they play an important role in taste masking, enhance patient compliance and overall product acceptability.
It is important to understand such factors as sweetness intensity, stability, compatibility and permissible limits while choosing a sweetener of combination of sweeteners. Factors contributing to the increasing popularity of new natural and low-calorie sweeteners such as Stevia and Sucralose in today’s market are the efficient, safe and tasteful properties of these new products.
A scientifically based methodology for selecting sweetening agents has a direct impact on product quality, as well as the establishment of patient trust — both of which can lead to effective and long-lasting therapeutic results.
To address this issue, sweetening agents have been included in oral suspension in order to mask the lack of palatability associated with certain APIs. However, there is more to selecting a sweetening agent than simply picking one that is good tasting. There are a number of factors that need to be considered, such as chemical compatibility with the formulation, chemical stability, sweetness intensity, calories per gram and whether or not the particular sweetening agent is approved for use by regulatory agencies.
Role of Sweetening Agents in Oral Suspensions
Sweetening agents play an important role in improving the taste of oral dosage forms. This ensures that the medicine is effective and that the sweetening agent do not alter the stability or efficacy. There are three major functions of sweeteners in oral solutions.1) To mask unpalatable tastes of active pharmaceutical ingredients.
2) To improve the ability of pediatric and geriatric patients to take the drug.
3) To provide a better overall sensory experience through a better flavor combination and improved mouthfeel (i.e., how it feels in your mouth).
A good sweetener is selected to fit in well with the other flavoring and taste-masking agents in order to provide the best-tasting product possible.
Classification of Sweetening Agents
There are two main groups of sweetening agents used in pharmaceuticals 1) natural sweeteners and 2) artificial sweeteners. Both groups of sweeteners have different properties and regulatory requirements for usage.Natural Sweeteners: Sucrose, Sorbitol, Mannitol, Xylitol and Honey are natural sweeteners. Varying levels of sweetness 1-2 times sweeter than sugar. These have high or moderate levels of caloric value.
Artificial Sweeteners: Saccharin, Aspartame, Acesulfame K, Sucralose and Stevia are artificial sweeteners. Varying levels of sweetness 30-600 times sweeter than sugar. These have very low or no levels of caloric value.
1. Natural Sweetening Agents
Natural sweeteners are considered a good choice for use in many formulations because they are well-known by patients as well as being generally recognized as safe (GRAS). However, natural sweetening agents may add additional calories and can support the bacterial growth of microbes in an aqueous suspension.A. Sucrose
The sweetener that is most commonly found in very similar levels to glucose and fructose is sucrose. It offers a pleasant taste, good solubility and will increase the thickness of products containing sucrose. Because of this it can typically be found as a sweetener in over the counter medications with many different formulations, including medications for children such as a sweetener in many of the formulations including antacids and antibiotics. As sucrose will promote growth of bacteria, it is not recommended for use by persons with diabetes or those who are on sugar restricted diets.B. Sorbitol
Sorbitol is made by reducing glucose and is mostly supplied as a 70% aqueous solution. It has a mild sweet taste, will produce a smooth mouth feel and has been shown to be non-cariogenic (does not promote tooth decay). Because of this sorbitol is commonly used in sugar free products and it can also be used as a humectant (moisture retaining property). Excessive amounts of sorbitol can produce osmotic (water retaining) diarrhea as well as potentially cause irritations.C. Mannitol
Mannitol is produced by hydrogenation of fructose or glucose. Mannitol produces a cooling sensation when consumed and does not attract moisture (hygroscopic) to it. Mannitol is used in diabetic and chewable dosage forms and in powders or powders that are to be mixed with liquids. Mannitol has poor solubility in water and is not used as a component in liquid suspensions.D. Xylitol
It is a sugar alcohol that has the same sweetness as sucrose, has been shown not to promote dental caries, is suitable for Diabetics, and has a cooling effect when consumed. Xylitol is mostly used in the production of pediatric oral suspension and chewing sweets. High price of xylitol makes it impractical to be used in pharmaceutical products and when consumed in large quantities xylitol can create gastrointestinal discomfort.E. Honey and Glucose Syrups
Glucose syrup and honey both occur naturally in nature and contains fructose and glucose along with some traces of minerals. Both products have a pleasant flavor which gives them good mouthfeel and smooth texture. Both products have many uses in herbal products and traditional suspensions. These should not be used as primary ingredients in any pharmaceutical formulations because of variability of the composition and chances of bacterial and fungal contamination.2. Artificial (Synthetic) Sweetening Agents
Those high-intensity synthetic compounds that are sweet at a low concentration and contribute very little or no calories are called artificial sweeteners. The artificial sweetener is very good at sweetening sugar-free or low-calorie food. There are various artificial sweetening agents. They are given below.A. Saccharin or Sodium Saccharin
These are generally used as artificial sweeteners that can be as much as 300-500x sweeter than sugar (sucrose). Despite its great sweetness potential, saccharin is also a very stable sweetening agent to high temperatures and pH changes. Because of its non-cariogenic nature saccharin is often added to drugs such as antacids and sugar free suspension. When it is used in large amounts, it leaves behind a slight metallic or bitter taste that some people find unpleasant.B. Aspartame
It can be considered the purest type of artificial sweetener. It is about 200x sweeter than sucrose and having the sugar-like flavor of any type of sweetener in the market. Aspartame is also very stable as a dry powder and can easily be reconstituted into liquid and chewable dosage forms. However, it becomes unstable in heat and acid conditions, as well as being ineffective (due to its broken down nature) to some individuals with the genetic disorder known as phenylketonuria (PKU).C. Acesulfame Potassium
It is another sweetening agent that has the capacity to be up to 200x sweeter than sugar. Similar to each of the other compounds above (saccharin, aspartame), acesulfame potassium is able to be used at relatively high temperatures, and at a broad range of pH levels. Typically, though most prefer to utilize sweetness along with either saccharin or aspartame to create a flavor profile that suits them, the excessive use of acesulfame potassium can result in a bitter/off tasting flavor when used alone.D. Sucralose
Sucralose is approximately 600 times sweeter than sucrose and stable when exposed to wide range of heat, light and pH. It does not leave any aftertaste like traditional sugar substitutes and it makes it popular for manufacturing of sugar free and low calorie syrups. The price for sucralose is generally higher than other traditional artificial sweeteners.E. Stevia (Steviol glycosides)
It is 200-300 times sweeter than sucrose and is obtained from a plant with no calories; it also maintains stability over an extensive pH range and temperature range. Stevia’s use in natural or herbal medicinals is increasing. At very high levels of concentration, stevia can produce a slight licorice flavor aftertaste.Factors Influencing the Selection of Sweeteners
When selecting a sweetening agent or any formulation, an equal weighting must be given to taste, functional properties of sweetener and any applicable regulatory guidelines.Key considerations when choosing a sweetener include:
1. Interaction between Sweetening Agent and other Ingredients
Certain sweeteners can react with drug molecules and can alter the drug's stability and its bioavailability. (For example, reducing sugars may react with an amine).2. Sweetener Stability
The sweetening agent must be stable throughout the entire shelf life of the finished product and at product storage temperature and pH value.3. Total Caloric Content
When formulating products for consumers who have diabetes or who are on a calorie-restricted diet, non-nutritive sweeteners like sucralose, aspartame are preferred to sugar-containing sweeteners.4.Taste Considerations
The intensity of sweetness, the rate of onset and the aftertaste have all been shown to influence a product's overall acceptability. It is often preferable to blend sweeteners to produce a desirable overall flavor profile.5. Regulatory Considerations
Only the sweeteners that have been sanctioned for use in pharmaceutical products by an appropriate regulatory agency such as the FDA, EMA or WHO should be used in any formulation.6. Physical (Solubility and Characteristics)
The solubility of a sweetener has a major impact on the level of sweetness and the consistency of suspensions in liquid formulations. As such, sweeteners that dissolve in water should be the preferred choice for liquid dosage forms.Combining Sweeteners for Synergistic Effect
Combinations of different sweeteners are generally used in formulations to enhance taste and eliminate any unwanted aftertastes that may occur after using just one type of sweetener.Here are some examples of sweetener combinations that work together in a synergistic way.
- Aspartame and Acesulfame K together provide an increased level of sweetness and minimize the aftertaste associated with aspartame.
- Sucralose and Sorbitol combined balance the level of sweetness against the mouth feel.
- Saccharin and Mannitol combined are often used in low-calorie children's medication suspensions.
By using these combinations of sweeteners, formulators can recreate the flavor of sugar while using lower amounts of individual sweeteners compared to using these saperately.
Stability and Compatibility Considerations
The chemical stability of sweeteners and their lack of influence on the potency of the drug should be maintained. Other considerations:1. pH-sensitivity: Aspartame is susceptible to degradation under acidic conditions.
2. Temperature: Sucrose and sorbitol solutions can caramelize when exposed to heat.
3. Microbial Susceptibility: Natural sugars are capable of promoting the growth of microbes so require to add preservatives.
4. Reactivity: Reducing sugars such as glucose may react with drugs those contain amine group through the maillard reaction process.
Therefore, formulation compatibility must be established prior to commencing a product’s development so that manufacturers do not experience any unforeseen degradation or discoloration.
Regulatory Guidelines and Safety
Regulatory agencies such as the European Food Safety Authority (EFSA) and the United States Food & Drug Administration (FDA) have established acceptable daily intake (ADI) limits for various artificial sweetening agents for safety of patients from harm.Examples of ADIs for the sweeteners included within this document which come from regulatory agencies include:
Saccharin - 5 mg/kg body weight/day
Aspartame - 40 mg/kg (EU) or 50 mg/kg (US)
Sucralose - 15 mg/kg
Steviol equivalents (stevia) - 4 mg/kg
Implementation of ICH Q8 guidelines (on pharmaceutical development) guarantee the sweeteners comply with the FDA's Inactive Ingredient Database (IID), therefore they can be classified as acceptable pharmaceuticals.
Oral pharmaceutical suspensions must contain sweeteners because they play an important role in taste masking, enhance patient compliance and overall product acceptability.
It is important to understand such factors as sweetness intensity, stability, compatibility and permissible limits while choosing a sweetener of combination of sweeteners. Factors contributing to the increasing popularity of new natural and low-calorie sweeteners such as Stevia and Sucralose in today’s market are the efficient, safe and tasteful properties of these new products.
A scientifically based methodology for selecting sweetening agents has a direct impact on product quality, as well as the establishment of patient trust — both of which can lead to effective and long-lasting therapeutic results.
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