Formulation Development and Evaluation of Water Dispersible Tablet for Pediatrics

Water dispersible tablets (WDTs) are an innovative and patient-friendly dosage form specifically designed to disintegrate rapidly in water or saliva, creating a smooth dispersion that is easy to swallow. These tablets are particularly advantageous for pediatric, geriatric, and dysphagic patients who often struggle with swallowing conventional solid dosage forms like tablets and capsules [1].

Figure 1: Water dispersible tablets

Pediatric patients present unique challenges in drug administration due to their developmental differences, difficulty in swallowing pills, and heightened sensitivity to the taste of medications. Given these challenges, there is a need for age-appropriate formulations that are easy to administer, well-tolerated, and ensure accurate dosing. Water dispersible tablets cater to these needs by offering a convenient, palatable, and flexible drug delivery option [2,3].

Key Features of Water Dispersible Tablets:

1. Ease of Administration: WDTs can be dispersed in a small amount of water, forming a uniform mixture that is easy for children to swallow. This method of administration is particularly beneficial for young children who have not yet developed the ability to swallow solid tablets.
2. Improved Patient Compliance: The pleasant taste and ease of administration enhance patient adherence, especially in children who are often averse to taking bitter or large pills.
3. Dose Flexibility: WDTs allow caregivers to adjust the dosage easily by dispersing the tablet in water, making it suitable for varying doses based on the child’s age and weight.
4. Enhanced Stability: Compared to liquid formulations, WDTs offer better stability and a longer shelf life, reducing the risk of microbial contamination and degradation [4,5].

Need for Pediatric-Friendly Formulations

Pediatric patients often face difficulties with conventional dosage forms like tablets and capsules due to their inability to swallow whole pills. Therefore, there is a pressing need for age-appropriate, palatable, and easy-to-administer formulations. WDTs are a promising solution designed to disintegrate rapidly in water, forming a palatable dispersion that can be easily swallowed. They combine the advantages of solid dosage forms, such as stability and accurate dosing, with the ease of liquid formulations [6].

Children, especially those under the age of 5, face significant challenges when taking medications in solid form. Traditional dosage forms such as capsules and uncoated tablets are often unsuitable due to the risk of choking and difficulty swallowing. Liquid formulations, while easier to administer, may have limitations such as poor stability, unpleasant taste, and complex dosing requirements. Water dispersible tablets provide a middle ground, combining the stability of solid dosage forms with the ease of administration of liquid forms, making them an ideal solution for pediatric patients [7-9].

Formulation Considerations for Water Dispersible Tablets

The development of an effective WDT requires careful selection of excipients and consideration of the properties of the active pharmaceutical ingredient (API). The key components of the formulation include:

Active Pharmaceutical Ingredient (API)

• Selection Criteria: The API must be compatible with the chosen excipients and stable under the intended storage conditions. Additionally, its solubility and taste profile are important factors to consider, especially for pediatric patients who may be sensitive to bitterness.
• Dose Range: The amount of API incorporated in the tablet must be within a range that ensures therapeutic efficacy while maintaining the tablet's disintegration and palatability properties [10].

Candidates for Water Dispersible Tablets

Water dispersible tablets are particularly suited for drugs that exhibit specific physicochemical and pharmacokinetic properties. Firstly, the drug should have good solubility in both water and saliva to ensure rapid disintegration and dissolution in the oral cavity, facilitating swift onset of action. The drug's ionization profile is also important; at the oral cavity pH (approximately 6.8), the compound should be partially nonionized. This nonionized form is more lipophilic, enabling better diffusion and absorption across the mucosal membranes. Additionally, the drug should have the capability to diffuse and partition effectively into the upper gastrointestinal tract (GIT) epithelium, enhancing systemic absorption upon swallowing the dissolved drug. For rapid absorption through the oral mucosa, the compound should possess good permeability characteristics, allowing it to penetrate the mucosal tissue efficiently. Lastly, drugs with a short half-life that require frequent dosing are excellent candidates for disintegrating formulations. The rapid onset provided by these formulations can reduce the dosing frequency and enhance patient compliance, especially in pediatric and geriatric populations where swallowing conventional tablets may be challenging [11-13].

Excipients

Excipients play a crucial role in the formulation of WDTs. The primary excipients used include [14-18]:

• Superdisintegrants: These are essential for rapid tablet disintegration. Common examples include:
  • Crospovidone: Known for its high water-wicking capacity and rapid disintegration.
  • Sodium Starch Glycolate: Provides efficient and rapid swelling, promoting quick dispersion.
  • Croscarmellose Sodium: A highly effective disintegrant that enhances the rate of tablet breakup.
• Binders: Help in the cohesion of powder particles, ensuring tablet integrity during handling. Examples include:
  • Microcrystalline Cellulose: Provides good binding properties and aids in rapid disintegration.
  • Lactose: Acts as both a binder and a filler, improving tablet consistency.
• Sweeteners and Flavoring Agents: Essential for masking the taste of the API and enhancing the palatability of the tablet, particularly in pediatric patients. Examples include:
  • Aspartame: Provides a sweet taste without the need for sugar, beneficial for diabetic patients.
  • Sucralose and Saccharin: Non-nutritive sweeteners that enhance taste without contributing to calorie intake.
  • Fruit Flavors: Improve taste acceptability, especially in children.
• Fillers (Diluents): Increase the bulk of the tablet to achieve the desired size and weight. Common fillers include:
  • Mannitol: Provides a pleasant mouthfeel and a cooling sensation upon dissolution.
  • Dicalcium Phosphate: Enhances the flow properties of the powder blend.

Taste Masking Agents

Given the sensitivity of pediatric patients to bitter tastes, taste masking is an essential consideration. Techniques used include:

• Coating the API: Using polymers like Eudragit to create a barrier that prevents the immediate release of the bitter API.
• Microencapsulation: Encases the API in a tasteless matrix, improving the overall taste profile of the tablet [19,20].

Manufacturing Methods for Water Dispersible Tablets

Direct Compression

In the Direct Compression method, the process begins with the selection of excipients like superdisintegrants (e.g., Crospovidone), fillers (e.g., microcrystalline cellulose), and lubricants (e.g., magnesium stearate). These are sifted through a fine mesh to ensure uniform particle size. The active pharmaceutical ingredient (API) and excipients are then blended using a mixer to form a homogeneous powder blend. After blending, a lubricant is added and mixed gently to prevent capping or lamination during compression. The final blend is fed into a tablet press machine to produce tablets. The resulting tablets are then evaluated for weight uniformity, hardness, friability, disintegration time, and dissolution to ensure they meet quality standards [21].

• Advantages: It is a simple, cost-effective, and fast process. It requires fewer steps and minimal equipment, making it suitable for APIs that are stable and have good flow properties.
• Process: The powder blend of the API and excipients is directly compressed into tablets using a tablet press.
• Limitations: Direct compression may not be suitable for APIs with poor flow properties or those that require extensive taste masking [21,22].

Wet Granulation

For Wet Granulation, the process starts with sifting the API, fillers, and disintegrants. A binder solution is prepared by dissolving a binder (like PVP K30) in a solvent such as water or ethanol. This binder solution is added to the powder blend while mixing to form a wet mass. The wet mass is then passed through a sieve to form granules, which are dried in a tray dryer or fluidized bed dryer. Once dried, the granules are milled to achieve uniform size and mixed with additional disintegrants and lubricants. The final blend is compressed into tablets, which are then subjected to quality control tests including hardness, friability, and disintegration time to ensure they disperse quickly in water [23].

• Advantages: Improves the flow properties of the powder blend and ensures uniformity of the final product.
• Process: The API and excipients are mixed with a granulating fluid to form wet granules, which are then dried and compressed into tablets.
• Limitations: The process is more complex and time-consuming than direct compression. It may also affect the stability of moisture-sensitive APIs [23,24].

Freeze-Drying (Lyophilization)

The Freeze-Drying (Lyophilization) method involves preparing a solution of the API, matrix formers (such as mannitol or sucrose), and disintegrants in water. This solution is then dispensed into pre-formed blister cavities or molds. The filled trays are quickly frozen at a temperature below -40°C to solidify the mixture. The frozen solution undergoes primary drying in a freeze-dryer, where a vacuum is applied to sublimate the water directly from ice to vapor, leaving behind a porous structure. This is followed by secondary drying at a slightly higher temperature to remove any remaining moisture. The resulting porous tablets are highly friable and are sealed immediately in moisture-resistant packaging. The tablets produced via freeze-drying disintegrate rapidly in water or saliva due to their porous structure. Finally, all the tablets from each method are evaluated for key quality attributes such as disintegration time, dissolution profile, and stability to ensure they meet the desired specifications for water-dispersible tablets [21,25].

• Advantages: Produces tablets with rapid disintegration and dissolution rates, ideal for patients requiring fast-acting formulations.
• Process: The API and excipients are dissolved in a solvent, frozen, and then dried under reduced pressure to remove the solvent, forming a porous tablet.
• Limitations: Freeze-drying is an expensive and time-intensive process, typically reserved for highly sensitive or specialty products [25].

Table 1: Comparison of Methods

Evaluation Parameters for Water Dispersible Tablets

Physical characterization of water-dispersible tablets is an essential aspect of their quality evaluation, focusing on various properties that affect the tablet's performance, stability, and patient acceptability [26].

1. Appearance and Organoleptic Properties

The initial physical characterization involves a visual inspection to assess the appearance of the tablets. This includes evaluating the color, shape, size, surface texture, and any visible defects like chipping, cracking, or uneven coating. Organoleptic properties, such as taste, odor, and mouthfeel, are also assessed, as these factors are crucial for patient compliance, particularly in pediatric and geriatric populations who may be sensitive to unpleasant tastes or textures [26].

2. Weight Uniformity

Weight uniformity is a critical parameter that ensures consistent dosing of the active pharmaceutical ingredient (API). This test involves weighing individual tablets from a batch and comparing their weights. Uniform weight indicates uniform distribution of the API and excipients, which is vital for maintaining the efficacy and safety of the dosage form. According to pharmacopeial standards, the weight of each tablet should fall within a specified range, typically ±7.5% for tablets weighing 130–324 mg [26,27].

3. Tablet Dimensions (Thickness and Diameter)

The thickness and diameter of the tablets are measured using vernier calipers or micrometers. These physical dimensions are important for ensuring uniform size, which affects packaging and handling. Consistency in thickness and diameter also contributes to uniform weight and dosage, while deviations may indicate issues during compression, such as variations in the force applied or inconsistent filling of the die cavity [28].

4. Hardness

Hardness is a measure of the tablet's mechanical strength, determining its ability to withstand physical stresses during packaging, handling, and transportation. The test is performed using a hardness tester, which applies force until the tablet breaks. For water-dispersible tablets, a balance between hardness and rapid disintegration is required, with typical hardness values ranging from 2 to 4 kg/cm² [28,29].

5. Friability

Friability assesses the tablet's resistance to abrasion and crumbling. This is determined using a friabilator, where a sample of pre-weighed tablets is rotated at a specified speed and then reweighed. The percentage weight loss is calculated, and a friability value of less than 1% is generally considered acceptable. Low friability indicates good mechanical strength and durability of the tablets [29].

6. Porosity and Density

The porosity of a tablet affects its disintegration and dissolution rates, making it a crucial parameter for water-dispersible tablets. Porosity can be evaluated using techniques such as mercury intrusion porosimetry. Density measurements, including bulk density and tapped density, are also performed to understand the packing properties of the powder blend before compression. The Carr's Index and Hausner ratio, derived from density measurements, provide insights into the flowability and compressibility of the powder blend [27,29].

7. Moisture Content

Moisture content is an important factor influencing the stability and disintegration of the tablet. Excess moisture can lead to degradation of the API, affecting the tablet's shelf life, while insufficient moisture may reduce the tablet's disintegration ability. The moisture content is determined using techniques like loss on drying (LOD) or Karl Fischer titration. Controlling moisture content is especially crucial for water-dispersible tablets to ensure rapid disintegration upon contact with water [29].

8. Wetting Time and Water Absorption Ratio

The wetting time measures how quickly a tablet becomes completely wet when placed on the surface of a liquid. It is a key parameter for assessing the disintegration performance of water-dispersible tablets. The water absorption ratio is calculated based on the increase in tablet weight after being exposed to water. These tests are indicators of how well the tablet will disperse in water or saliva, which is essential for patient compliance and rapid onset of action [26].

Challenges in Developing Water Dispersible Tablets

• Taste Masking: Achieving effective taste masking without compromising the tablet's disintegration time is a significant challenge, particularly for bitter APIs.
• High Dose Formulation: For APIs with high dose requirements, achieving rapid disintegration and maintaining a small tablet size can be difficult.
• Stability Issues: Moisture sensitivity can affect the stability of WDTs, requiring careful selection of packaging materials and storage conditions [30].

Table 2: Studies on the Formulation Development and Evaluation of WDTs