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Flavor

Flavoring agents in pharmaceutical formulations

Flavoring agents in pharmaceutical preparations such as oral syrup, oral suspension, elixirs, emulsion, lozenges, chewable tablets, effervescent tablets, dispersible tablets, ODT are used to impart not only flavors but also impart a pleasant taste. They are used to improve patient compliance or palatability of pharmaceutical dosage forms. Generally, flavoring agents (pharma grade) are available in two forms a) powder b) liquid form. The word flavor refers to a mixed sensation of taste, smell, touch, sight, and sound, all of which combine to get an unrestricted number of gradations in the perception of a chemical substance. The 4 primary tastes a) saline, b) sour, c) bitter, and d) sweet appear to result partly from psychological action and partly from physicochemical. [1]

Definition of Flavoring Agent

According to USP, a flavoring agent is a single chemical entity or a blend of chemicals of synthetic or natural origin that can produce a taste or aroma (i.e. fragrance) when consumed orally or smelled.[2] Flavoring agents are one of the excipients in some pharmaceutical formulations. Also, flavoring agents are known as Flavorings or Flavorants. Remember that flavor is American English spelling and flavour is British English spelling.

How to use flavoring agents

Solid powder flavoring agents are added in the blending stage of dry granulation or after wet granulation during tablet manufacturing. Flavoring oils and liquid synthetic flavors are coated to get dry flavors powder. While during only wet granulation, liquid flavoring agents or flavor oil are added. More frequently liquid flavoring agents are used in a pharmaceutical liquid dosage form and topical pharmaceutical dosage form such as cold cream. Flavoring agents may be used individually or in a combination of two or more flavoring agents in a different ratio. Approximate 0.5% to 0.75% liquid flavoring agents or flavor oil is used without interfering with tablet characters.[3]

Classification of Flavoring Agents

On the basis of sources

A. Natural flavoring agent

Natural flavoring agents are either a single type or blend of flavoring agents obtained by a physical process such as roasting, heating, or chemical processes such as extraction, distillation, or enzymatic, or microbiological processes from plant parts or animal origin. They may exist as an essential oil, oleoresin, spirits sometimes known as essences (alcoholic or hydroalcoholic solutions of volatile substances) or extractive, distillate, protein hydrolysate, or any product of roasting, heating, or enzymolysis. Examples of natural flavoring agents, complex volatile oil (anise oil), aldehyde (vanillin), ginger oil, peppermint oil, and lemongrass oil.

B. Artificial or synthetic flavoring agents

Artificial flavoring agents are chemical compounds synthesized by chemicals processes that may be organoleptically and chemical structurally indistinguishable to a naturally present flavoring agent. For example, Methyl salicylate (Wintergreen flavor) is obtained from a chemical reaction of salicylic acid and methanol in the presence of H+ ions from H2SO4 and heat.

C. Natural and Artificial flavoring agents

These are a blend of one or more natural flavoring agents and artificial flavoring agents to enhance flavor balance and intensity. For example, a blend of esters, aldehydes, ketones, and lactones with natural essential oils.

On the basis of physical form

A. Solid flavoring agents

These are natural or/and artificial flavoring agents which are available in solid form. For example, mango flavor powder, chocolate flavor powder, and pineapple flavor powder etc.

B. Liquid flavoring agents

These are natural or/and artificial flavoring agents which are available in liquid form. For example, essential oils such as peppermint oil, orange oil, methyl salicylate, and lemon oil etc. You may also read, Tablet Binder : Types and Examples with concentrationflavoring agents, solid and liquid

List of flavoring agents in pharmaceutical formulations [1, 3, 4, 5, 6]

Name of Flavoring agents Chemical Name and Use Concentration
1. Vanillin Vanillin is an organic compound named (4-hydroxy-3-methoxybenzaldehyde). As a pharmaceutical excipient, vanillin is used in tablets such as caffeine tablets and polythiazide tablets, solutions (0.01–0.02% w/v), syrups, and powders.
2. Ethyl Vanillin 0.01% in oral syrups, It has a flavor and odor approximately three times as intense as vanillin.
3. Menthol (USP), Racementhol (BP) Menthol is broadly used in pharmaceutical preparations especially for antacid tablets, suspension, and expectorant tablets. It is capable to exert a cooling or refreshing sensation and used in topical preparations. 0.02–0.05% for inhalation, 0.003% for oral suspension, 0.005–0.015% for oral syrup, 0.2–0.4% for Tablets , 0.05–10.0% for Topical formulations , 0.4% for Toothpaste , 0.1–2.0% for Mouthwash, 0.3% for Oral spray.
4. Apple Manzanate (Ethyl 2-methylpentanoate)
5. Banana Isoamyl Acetate  also known as Isopentyl Acetate
6. Coconut flavor γ-Octalactone
7. Cinnamon Cinnamaldehyde
8. Grape Methyl Anthranilate
9. caraway Carvone & Limonene
10. Pear Ethyl Decadienoate
11. Fruity Ethyl Propionate
12. Truffle 2,4-Dithiapentane
13. Wintergreen Methyl Salicylate
14. Cherry Allyl Benzoate
15. Pineapple Allyl Hexanoate or Allyl Caproate
16. Anise Anethole, Anisaldehyde
17. Lemon 3,7-Dimethyl-2,6-Octadienal
18. Orange d-Limonene, Ethyl Butyrate
19. Peppermint In peppermint flavor, not less than 5% of menthyl Acetate and less than 50% of total menthol must contain.
20. Mango [4] It is a combination of the following chemical flavor: 3-hydroxy-4,5- dimethyl-2(5H)-furanone, ethyl-2-methybutanoate, (E,Z)-2,6-nonadienal, 1-(E,Z)-undecatriene, γ-octalactone with Cultivar compounds as flavor modifiers such as ethyl butanoate for (fruity mango).
21. Spearmint or Mint Ketone 1-Carvone, Limonene, Cineole are responsible to impart this flavor.
22. Ginger Gingerol, d-Camphene And ß- Phellandrene
23. Caramel 3,5-Dimethyl-1,2-Cyclopentadione
24. Lavender Linalyl Acetate
25. Clove Eugenol
26. Rose Geraniol and l-Citronellol
27. Peach Aldehyde C-14 Peach, or Gamma-Undecanolactone,
28. Raspberry Raspberry Ketone (4-(4-Hydroxyphenyl)butan-2-one)
29. Strawberry Ethyl Methylphenylglycidate
30. Chocolate Flavor Cocoa, Cocoa liquor (the essence of the cocoa bean)
31. Cardamon Limonene, Cineol
32. Wild cherry Prunasin is the main ingredient to impart wild cherry flavor.
33. Methionine For oral pharmaceutical formulations as a flavoring agent.
34. Maltol It imparts caramel-like odor and taste but in dilute solution, it imparts a sweet, strawberry-like, or pineapple-like flavor and odor.
35. Ethyl Maltol Its flavor and odor are 4–6 times as intense as maltol. Ethyl maltol at concentrations of about 0.004% w/v is used in oral syrups. It provides a caramel-like odor and taste but in a dilute solution, it provides a sweet, fruitlike flavor and odor.
36. Denatonium Benzoate It has been used as a flavoring agent in placebo tablets, in a topical formulation, and in an anti-nailbiting preparation.
37. Ethyl Acetate In pharmaceutical preparations, ethyl acetate is used as a solvent and a flavoring agent. It is also used in artificial fruit essence. It has Ether-like, sweet, flavor-like nail polish remover.
38. Ethyl Lactate Sweet, ethereal, fruity, butterscotch buttery smell. Acceptable daily intake for lactic acid is 12.5 mg/kg body weight.
39. Monosodium Glutamate Flavor enhancer and use for iron-containing liquids preparations to reduce the metallic taste. It has salty-smelling odors.
40. Citric Acid Monohydrate As a flavor enhancer for its tart flavor and acidic taste.
41. Dibutyl Sebacate Used as a synthetic flavor and flavor adjuvant, up to 5 ppm is used in ice cream and nonalcoholic beverages.
42. Adipic Acid Also, known as hexanedioic acid used to give tart flavor.
43. Capric acid As a flavoring agent in pharmaceutical preparations for providing a citrus-like flavor.
44. Malic Acid It imparts a slight apple flavor and is used to mask bitter tastes and provide tartness [5]
45. Fumaric Acid Primarily used in a liquid pharmaceutical dosage form as an acidulant and flavoring agent.
46. Sodium Metabisulfite Above approximately 550 ppm at concentrations, it imparts a noticeable flavor to preparations.
47. Thymol/Thyme oil Mainly used in cosmetics to impart a sharp, almost minty flavor.

Selection of flavoring agents

The selection of appropriate flavoring agents for a drug product depends on the nature of active pharmaceutical ingredients to improve palatability by changing the unpleasant taste and odor of drug products. A person is more sensitive to odor than to taste. So, flavorant are selected on the basis of the taste and odor of flavoring agents and the drug to be formulated. To mask the unpleasant and high intense odor of API, you should use flavoring agents with high intensity. You may also read: Sweetening agents for Pharmaceutical Preparations

Table-1: Selection of flavoring agents on the basis of taste of flavoring agents (Never use any bitter taste flavoring agent to mask a bitter taste drug)

Flavoring agents Taste of Flavoring agents
Wild Cheery, Mint, Walnut, Chocolate, Anise Bitter taste (Flavoring agents that contain free bases such as alkaloids and amides for example amphetamines give a bitter taste. Polyhydroxy compounds with a molecular weight greater than 300, aliphatic thio-compounds, halogenated substances, and High molecular weight salts may have a bitter taste.)
Peach, Wintergreen, Butterscotch, Apricot, Maple Salty taste (due to the presence of anions and cations for example KBr, NH4Cl, and sodium salicylate).
Licorice, Raspberry, Citrus flavor, Sour taste (Caused by hydrogen ions, and Sour taste is proportional to the hydrogen ion concentration)
Vanilla, Fruit, and Berry flavor Sweet taste (due to polyhydroxy compounds, polyhalogenated aliphatic compounds, and alfa-amino acids).

Table-1: Selection of flavorings on the basis of taste of drug to be formulated

Types of Drugs Preferred flavoring Agents 
Antacid, H2 receptor blockers Peppermint, Mint, Anise
Antibiotics Cherry, Maple, Fruit-Cinnamon, Pineapple, Orange, Banana-Vanilla, Strawberry, Raspberry, Vanilla, Butterscotch
Antihistamines Apricot, Grape, Cinnamon, Cherry, Honey, Raspberry, Wild Cherry,  Peach-Orange,
Analgesic Cherry, Raspberry
Vitamin C Orange, Lemon Flavor
Multi-vitamin Mango, Fruity Flavor
Barbiturates Banana-Pineapple, Cinnamon-Peppermint, Orange, Peach-Orange, Strawberry, Banana-Vanilla,
Expectorants Anise, Apricot, Clove, Custard-Mint-Strawberry, Cherry, Strawberry-Lemon, Fennel, Coriander, Pineapple, Orange-Lemon.
Anathematic Mango, Chocolate, Vanilla
Electrolyte-solutions geriatrics Cherry, Mango, Lemon, Raspberry, Wild Cherry, Mixed Fruit, Wild Strawberry Flavor, Grape

Functions of flavorant

  • To provide a pleasant odor and taste of drug products (medicine).
  • To increase the palatability of a pharmaceutical preparation.
  • Psychologically increase the quality of drug without improving particular therapeutic effects.

Flavoring agent vs Fragrance

Flavoring agents are single or blend of chemical compounds that are consumed orally and appreciated by both smell and taste while fragrances are single or blend of chemical compounds only for external use and appreciated only by smell.

Generally, flavoring agents are vital excipients for chewable tablets, oral disintegrating tablets, dispersible tablets, oral solutions, and oral suspensions to mask the unpleasant smell as well as taste and to make the product more palatable, thus increasing patient compliance. On the other hand, fragrances are used in an external pharmaceutical dosage form such as cream, ointment, and cosmetics preparations.

Flavoring agents in a pharmaceutical preparations are non-toxic and safe for oral administration. On the other hand, fragrances are toxic for oral or parenteral administration.

Read also,

In conclusion, remember that men are less sensitive to odors than women. There is a precise link between chemical structure and taste but no precise link between chemical structure and odor.

References 

  1. Remington, Joseph P, and Paul Beringer. Remington: The Science and Practice of Pharmacy. 21st edition. Philadelphia: Lippincott Williams & Wilkins; 2005.
  2. The United States pharmacopeia The National formulary. Rockville, Md.: United States Pharmacopeial Convention, Inc. (USP 21 – NF 16).
  3. Lachman, Lieberman, H.A. and Kanig, J.L., The Theory and Practice of Industrial Pharmacy, Lea and Febiger, New York, 15th edition; 2013.
  4. WIPO (PCT). Mango flavor compositions, patent no.: WO2014130649A1; 2014.
  5. Allen LV. Featured excipient: flavor enhancing agents. Int J Pharm Compound 2003; 7(1): 48–50.
  6. Rowe, R. C., Sheskey, P. J., Owen, S. C., & American Pharmacists Association. Handbook of pharmaceutical excipients. London: Pharmaceutical Press; 2006.

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