Taste Masking and Solubility Enhancement Strategies for Mefenamic Acid and Paracetamol in Oral Dispersible Drug Delivery Systems: A Comprehensive Review

Oral drug delivery remains the most preferred route of administration due to its simplicity, non-invasiveness, patient acceptance, and economic advantages. Solid oral dosage forms such as tablets and capsules dominate the pharmaceutical market; however, their effectiveness is often compromised by poor palatability and inadequate dissolution characteristics of active pharmaceutical ingredients (APIs). These challenges are particularly evident in paediatric and geriatric populations, where dysphagia, heightened taste sensitivity, and poor adherence are common clinical concerns.

Paracetamol is extensively used for the management of pain and fever and is generally regarded as safe at therapeutic doses. Nevertheless, its distinctly bitter taste significantly affects acceptability, especially in paediatric formulations. Mefenamic acid, a non-steroidal anti-inflammatory drug (NSAID), is categorized as a Biopharmaceutics Classification System (BCS) Class II drug, exhibiting low aqueous solubility and high permeability. The low solubility of mefenamic acid results in dissolution-limited absorption, delayed onset of action, and variable bioavailability. Furthermore, its bitter taste further complicates formulation development.

Oral dispersible dosage forms such as orally dispersible tablets (ODTs), dispersible tablets, and granules for oral suspension have emerged as patient-centric alternatives to conventional tablets. These systems are designed to disintegrate rapidly in the mouth or upon dispersion in water, facilitating ease of administration without the need for swallowing intact tablets. However, the rapid disintegration of these dosage forms leads to immediate drug exposure to taste buds, intensifying bitterness and necessitating robust taste masking strategies. Therefore, the simultaneous application of taste masking and solubility enhancement techniques is crucial for the successful development of such formulations [1,2].

2. Taste Perception: Anatomy and Physiology

Taste perception is a complex physiological process involving the interaction of dissolved chemical substances with taste receptors located in taste buds on the tongue. Taste buds are onion-shaped structures embedded in the papillae of the tongue and consist of approximately 50–100 specialized taste receptor cells. These receptors are capable of detecting five primary taste modalities: sweet, salty, sour, bitter, and umami.

Bitter taste perception is primarily mediated through G-protein-coupled receptors (T2R family). When bitter drug molecules dissolve in saliva, they penetrate taste pores and bind to these receptors, triggering intracellular signaling pathways that generate neural impulses. These signals are transmitted to the brain via cranial nerves, where they are interpreted as bitterness. Bitterness is often associated with toxicity from an evolutionary perspective, which explains the strong aversive response elicited by bitter compounds [3].

Several physicochemical properties of drugs influence bitterness perception, including dose, solubility, ionization state, particle size, and surface area. Highly soluble drugs dissolve rapidly in saliva, increasing receptor interaction, while small particle sizes enhance surface contact with taste buds. In oral dispersible dosage forms, these factors are amplified due to rapid wetting and disintegration [4].

3. Rationale for Taste Masking in Paediatric and Geriatric Formulations

Taste masking is a critical quality attribute in the development of paediatric and geriatric pharmaceutical products. Poor palatability is a major cause of medication refusal, incomplete dosing, and non-compliance, which can compromise therapeutic outcomes. In paediatric patients, unpleasant taste often leads to spitting, vomiting, or refusal of medication, while geriatric patients may experience aversion due to altered taste perception and xerostomia.

For drugs such as paracetamol and mefenamic acid, bitterness poses a significant barrier to acceptance. Therefore, taste masking is not merely a formulation preference but a clinical necessity. Taste masking strategies aim either to suppress bitterness perception using sensory modifiers such as sweeteners and flavours or to physically prevent drug–taste receptor interaction by modifying drug release in the oral cavity [5].

4. Conventional Taste Masking Strategies

4.1 Sweeteners

Sweeteners are the most commonly employed taste masking agents due to their simplicity and cost-effectiveness. Sweeteners such as sucrose, sucralose, aspartame, and saccharin stimulate sweet taste receptors, thereby counteracting bitterness. Sucralose is particularly advantageous due to its high sweetness intensity, stability, and non-cariogenic nature.

In formulations containing paracetamol and mefenamic acid, sweeteners have been used in combination with flavours to improve palatability. Studies on taste-masked granules for oral suspension demonstrated that increasing concentrations of sucralose and maltodextrin significantly reduced bitterness, with optimized formulations showing high acceptability scores [6,7].

4.2 Flavours

Flavours play a supportive role in taste masking by providing a pleasant sensory experience and masking residual bitterness. Citrus flavours such as orange and lemon are commonly used in analgesic formulations. The selection of flavour must consider drug compatibility, patient preference, and cultural acceptance.

4.3 Granulation Technique

Granulation is an effective physical taste masking approach that reduces the surface area of drug particles exposed to taste buds. Wet granulation increases particle size and entraps the drug within excipient matrices, thereby minimizing direct contact with taste receptors. Taste-masked granules for oral suspension containing paracetamol and mefenamic acid prepared by wet granulation exhibited excellent flow properties, uniform drug distribution, rapid dissolution, and improved palatability [7,8].

5. Polymer-Based Taste Masking

5.1 pH-Dependent Polymer Coating

Polymer coating involves coating drug particles or granules with polymers that are insoluble at salivary pH but soluble in gastric conditions. Eudragit EPO, a cationic polymer soluble below pH 5, has been widely used for taste masking. Paracetamol particles coated with Eudragit EPO demonstrated effective taste masking while maintaining rapid drug release in gastric media [9].

5.2 Advantages and Limitations

Polymer coating provides robust taste masking and is suitable for highly bitter drugs. However, it requires specialized equipment and precise process control. Inadequate coating may lead to dose dumping or incomplete taste masking.

6. Solubility Enhancement Strategies for Mefenamic Acid

Mefenamic acid exhibits poor aqueous solubility (approximately 0.2 mg/mL), resulting in dissolution-limited absorption. Various solubility enhancement strategies have been explored, including particle size reduction, use of surfactants, solid dispersions, and incorporation of superdisintegrants.

6.1 Solid Dispersions

Solid dispersion technology improves solubility by converting crystalline drugs into amorphous forms and enhancing wettability. Solid dispersions of mefenamic acid prepared using solvent evaporation and hot-melt extrusion showed significantly enhanced dissolution compared to pure drug [10].

6.2 Hot-Melt Extrusion (HME)

Hot-melt extrusion is a solvent-free, scalable technique used to prepare solid dispersions. Mefenamic acid extrudates prepared with Eudragit® RL-PO achieved up to 88% drug release within 30 minutes, compared to only 27% release from pure drug. Thermal and spectroscopic analyses confirmed amorphization and absence of chemical interaction [10].

7. Orodispersible Tablets of Paracetamol and Mefenamic Acid

Orodispersible tablets are designed to disintegrate rapidly in the oral cavity, providing ease of administration and rapid onset of action. Direct compression is the most commonly used method for ODT preparation due to its simplicity and cost-effectiveness.

Paracetamol ODTs formulated using superdisintegrants such as crospovidone and croscarmellose sodium exhibited disintegration times below 40 seconds and nearly complete drug release within 10 minutes. Taste masking using polymer coating further enhanced acceptability [9,11].

Mefenamic acid ODTs prepared using optimized concentrations of superdisintegrants demonstrated rapid disintegration (approximately 14 seconds) and complete drug release within 15 minutes, indicating improved dissolution performance [12].

8. Integrated Taste Masking and Solubility Enhancement Approaches

Modern formulation strategies increasingly focus on integrating taste masking and solubility enhancement within a single dosage form. Examples include polymer-coated solid dispersions incorporated into ODTs and taste-masked granules formulated as dispersible tablets. Such integrated approaches ensure minimal drug release in the oral cavity while maintaining rapid dissolution in gastrointestinal conditions, thereby improving both palatability and bioavailability [10–12].

9. Evaluation of Taste-Masked Oral Dispersible Systems

Comprehensive evaluation of taste-masked formulations includes preformulation studies, drug–excipient compatibility studies (FTIR, DSC, XRD), flow property assessment, tablet hardness, friability, disintegration time, dissolution studies, and stability testing as per ICH guidelines.

Taste evaluation is commonly performed using human taste panels, visual analogue scales, and acceptability scoring systems. Recent studies have also employed swirl-and-spit methods and electronic tongue systems to assess bitterness objectively [13].

10. Stability and Regulatory Considerations

Stability studies conducted under accelerated conditions (40°C ± 2°C / 75% RH ± 5%) have demonstrated the physical and chemical stability of taste-masked paracetamol and mefenamic acid formulations. Regulatory agencies emphasize patient-centric drug product design, particularly for paediatric formulations, requiring justification of excipient safety and palatability [14].

11. Future Perspectives

Emerging technologies such as three-dimensional printing, multifunctional polymers, and advanced sensory evaluation tools offer promising avenues for the development of palatable and bioavailable oral dispersible dosage forms. Further research is required to establish standardized taste evaluation methodologies and to develop cost-effective integrated formulation strategies suitable for large-scale manufacturing.

CONCLUSION

Taste masking and solubility enhancement are critical for the successful formulation of oral dispersible dosage forms containing paracetamol and mefenamic acid. Conventional approaches such as sweeteners, flavours, granulation, and polymer coating, along with advanced techniques like solid dispersions and hot-melt extrusion, have demonstrated significant potential. Integrated formulation strategies provide a comprehensive solution to improve palatability, dissolution, bioavailability, and patient compliance.

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