Taste Masking Techniques in the Pharmaceutical Industry

Abstract

Taste is a crucial factor that determines the palatability of oral dosage form and patient compliance. It also gives a unique identity to a product and thereby provides a competitive advantage to a company, especially in the case of over-the-counter products. There are several taste masking techniques available, which either involve modification of bitter active pharmaceutical ingredient itself or the formulation. This article reviews the concept of perception of taste, various taste masking techniques available, selection of appropriate taste masking technique, and evaluation tests for taste masking.

Introduction

Bitter taste perception is supposed to have evolved as a mechanism that averts possible toxins ingestion. But many compounds such as flavanoids and isoflavones which have a bitter taste are known to elicit beneficial response [1]. Approaches such as phylogenetic-like tree construction, quantitative nuclear magnetic resonance, and ligand identification have been used to recognize the bitter loci in molecules [2-4]. However, structural modification of these loci can alter their pharmacological response. Thus, the most suitable alternative is to mask the taste of these bitter loci.

The oral route is considered the most convenient and easy route of drug delivery. Yet, patient noncompliance, termed “intelligent noncompliance,” due to feeling better, bad taste, etc., which is reasoned out by the patient but may not necessarily be wise, is one of the key causes of failure of oral dosage regimen [5]. Pediatric and geriatric populations are most sensitive to the bad taste of medicaments. Also, currently there is a rising trend to formulate drugs in the form of orally disintegrating dosage forms due to their easy ingestion and absorption process [6]. Thus, in these cases a good taste is indispensable to patient compliance. Moreover, high palatability gives a competitive advantage, especially in the case of over-the-counter products. In this review, we will discuss how taste is perceived, what techniques are available for taste masking, selection of appropriate taste masking technique, and evaluation tests for the same.

Perception of taste

Taste is a sensory response to chemical stimulation of taste receptors by tastants [7]. There are five basic tastes that have been identified: salty, sweet, sour, bitter, and umami [8]. Of these, bitter taste perception is considered the most complex modality [9].

Earlier theory of taste perception was based on taste map, wherein distinct areas of the tongue were shown to respond to certain stimuli [10]. However, according to the latest theory, all taste buds respond to all stimuli [11]. Taste buds are onion-shaped structures comprising 50 to 100 taste receptor cells [12]. The tastants interact with surface proteins (as in the case of sweet and bitter taste) known as taste receptors or with pore-like proteins (as in the case of sour and salty taste) called ion channels. These interactions lead to electrical changes within the taste cells that trigger them to send chemical signals that transform into neurotransmission to the brain [13,14]. The brain then perceives the signal as bitter, salty, sweet, sour, or umami.

Taste masking techniques

An appropriate taste masking technique can affect both product quality and process effectiveness. Following are various taste masking techniques that can be used to taste mask bitter Active Pharmaceutical Ingredient (API):

1. Sweetener, flavorant, and other excipient addition. This is one of the simplest techniques used in taste masking. Excipients such as sweeteners and flavorants can be added to taste mask bitter API. Sweeteners, being highly water soluble, dissolve in saliva and coat the taste buds, thereby retarding the interaction of bitter API with taste buds. Flavorants enhance the formulation and give it a distinct taste. They are to be added in addition to primary taste masking agent. Certain cooling flavorants like menthol numb the taste buds and retard bitter taste perception [15]. Additionally, other excipients such as bitterness inhibitors can also be added.
2. Complexation. In complexation, the drug molecule fits into the cavity of a complexing agent, i.e., the host molecule, forming a stable complex. Complexation decreases the amount of drug particles, which are exposed to taste buds, thereby reducing the perception of bitter taste [16].
3. Coating. Coating is one of the best methods of taste masking. It can involve coating of a tablet containing bitter API or coating of the bitter API particles themselves. Ideally, the polymers selected in coating should be such that they prevent API release in oral cavity and allow its release in the absorption window of the API [17].
4. Matrix entrapment. Matrix entrapment involves trapping of drug into bulky matrix and thereby retarding its contact with taste buds. The matrix may contain polymeric, resinous, gelling, or lipoidal materials [13].
5. Prodrug formation. Prodrugs are molecules that are initially inactive but, upon biotransformation, are converted to active forms. Prodrug formation leads to physicochemical modification of bitter loci and thereby inhibits/retards their interaction with taste receptors [18].
6. Salt formation. Salt formation usually retards the solubility of API in saliva and thereby retards its taste perception [19].
   Examples of various taste masking techniques are illustrated in Table 1
7. Miscellaneous. Other techniques such as granulating with polymeric material, adding effervescent excipients, and rheological modification of liquid preparations can be used for masking the taste of bitter API [40].
8. Recent developments in the field of taste masking. Stimuli responsive drug delivery systems incorporating pH sensitive, ion sensitive polymers have been developed for masking bitter API taste [41]. Lycopodium-derived microcapsules have been used to taste mask ibuprofen [42]. Techniques like nano hydridizing and wet spherical agglomeration have also been used for taste masking [43,44].

Table 1. Examples of various Taste Masking Techniques

Selection of Taste Masking Technique

Appropriate selection of a taste masking technique is a must for developing a palatable and economical formulation. Figure 1 illustrates drug properties that are to be considered while selecting a taste masking technique. For instance, a drug that is extremely bitter cannot be taste masked with sweeteners or flavorants alone, and intermediary techniques like coating or matrix entrapment should be used. An ionic drug can be taste masked with ion exchange resins. A lipophilic drug can be taste masked by entrapping it into a lipoidal matrix. Figure 2 illustrates various economical aspects to be considered when selecting a taste masking technique. Although variations are possible, in general simple techniques are more economical as compared to intermediary ones.

Figure 1. Drug properties that are to be considered while selecting a taste masking technique. (Based on drug properties, one should adopt the directed techniques. if those fail then the subsequent [gray arrow] techniques should be adopted.)

Figure 2. Economical aspects of various techniques.

Taste Evaluation Tests

Taste is a very subjective perception. In vivo tests such as human panel testing and frog taste nerve responses can be used to evaluate taste of formulations. In human panel testing, large groups of healthy volunteers are asked to take bitter drug and then the taste masked formulation. They are then asked to comparatively rate the formulation on various organoleptic properties [45,46]. In frog taste nerve responses, glossopharyngeal nerve of bull frogs is connected to AC amplifier and responses to bitter drug and formulation are taken. The peak height obtained is used to assess taste masking [47]. In vitro methods such as spectrophotometry involve mixing of formulation to 10ml distilled water and then analyzing API concentration. If API concentration is below the threshold, sufficient taste masking is considered to be achieved.

The spectrophotometry method is not an absolute taste evaluation test [19]. Another in vitro test involves usage of electronic (e) tongue to evaluate taste. The e-tongue emulates the three levels of biological taste recognition: the receptor level (taste buds in humans, probe membranes in the e-tongue), the circuit level (neural transmission in humans, transducer in the e-tongue), and the perceptual level (cognition in the thalamus in humans, computer and statistical analysis in the e-tongue). In e-tongue the formulation or API is evaluated against standard (e.g., quinine hydrochloride) and the software generates taste patterns that form the basis of evaluation [20,48–50].

Conclusion

Various techniques discussed herein can help overcome bitter taste of API as well as largely improve the product preference among patients. It will also enhance the quality of the treatment provided to patients, especially children and older patients. Also, various techniques could be combined to develop palatable and cost-effective formulation.

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Author Biographies

Urvi Gala is a graduate student pursuing a Master’s degree in Pharmaceutical Sciences at Creighton University, Omaha, NE. She received her Bachelor’s degree in Pharmacy from Institute of Chemical Technology, Mumbai, India. She has worked as a research associate at Rubicon Research Pvt. Ltd., Mumbai, India, and has also interned at Pfizer, Mumbai, India.

Dr. Harsh Chauhan is an Assistant Professor at Creighton University, Omaha, NE. Dr. Chauhan received his Ph.D. in Pharmaceutics from MCPHS, Boston, MA. His research emphasis is on amorphous systems and solid lipid nanoparticles. He worked as visiting scientist at Vertex Pharmaceuticals and his professional affiliations include AAPS, ACS, and AACP.