Pediatric-Oriented Formulation Strategies for Sodium Valproate: Advances in Water-Dispersible Tablet Design, Evaluation, and Clinical Relevance

Pediatric drug administration presents several challenges owing to immature swallowing reflexes, increased sensitivity to taste, and the requirement for accurate and flexible dosing. Conventional solid dosage forms such as tablets and capsules are often inappropriate for children, resulting in poor patient compliance and variable therapeutic outcomes. To overcome these limitations, advanced oral drug delivery systems have been developed with the aim of improving ease of administration, patient adherence, and overall therapeutic effectiveness. Among these systems, water-dispersible tablets (WDTs) have gained considerable attention due to their ability to rapidly disintegrate in a small volume of water, forming a uniform and easily swallowable dispersion suitable for pediatric use. Water-dispersible tablets offer the combined advantages of solid and liquid dosage forms by maintaining dose accuracy and stability while providing improved palatability and convenience similar to liquid preparations. These characteristics make WDTs particularly suitable for pediatric therapy. Sodium valproate, a broad-spectrum antiepileptic agent used in the management of absence seizures, generalized tonic–clonic seizures, and complex partial seizures, poses formulation challenges such as bitter taste, limited aqueous solubility, and the need for precise dosing. Although liquid formulations improve palatability, they are often associated with drawbacks including poor stability, bulky packaging, and dosing inaccuracies. Therefore, the development of a stable, palatable, and easy-to-administer water-dispersible tablet of sodium valproate represents a promising alternative to conventional dosage forms.The performance of water-dispersible tablets is highly dependent on the judicious selection of excipients to ensure rapid disintegration, adequate mechanical strength, and formulation stability. Hydroxypropyl methylcellulose (HPMC K30M) functions as a binder and film-forming agent, contributing to tablet integrity and uniform dispersion. Carbopol 940, a cross-linked polyacrylic acid polymer, promotes rapid swelling and disintegration while aiding suspension stability. Polyvinylpyrrolidone (PVP K30) enhances binding efficiency and solubility, thereby improving drug distribution and bioavailability. Microcrystalline cellulose (MCC) acts as both a filler and superdisintegrant, imparting excellent flow characteristics and facilitating rapid tablet breakup. Magnesium stearate and talc are incorporated as a lubricant and glidant, respectively, to improve compressibility and prevent manufacturing-related defects. To effectively mask the intense bitterness of sodium valproate, citric acid is included as a flavoring and effervescent agent. It enhances palatability and facilitates rapid tablet dispersion through mild effervescence, thereby improving patient acceptability. Thus, the rational combination of selected excipients plays a crucial role in developing a stable, palatable, and rapidly dispersing formulation. The present study focuses on the formulation and evaluation of sodium valproate water-dispersible tablets optimized for pediatric use, with emphasis on critical quality attributes such as disintegration time, mechanical strength, content uniformity, and in-vitro drug release, ultimately aiming to enhance compliance and ensure consistent therapeutic outcomes in pediatric epileptic patients.

MATERIALS AND METHODS

MATERIALS

Sodium Valproate was obtained from Glenmark Pvt. Ltd, Mumbai, India. All excipients used in the formulation were of pharmaceutical grade and procured from S. D. Lab Chem, Mumbai.

METHODS

Pre-formulation Evaluation

Drug Characterization: A small quantity of Sodium Valproate was placed on butter paper and examined under good lighting for colour. Its odour was assessed directly, while appearance and texture were evaluated visually and by touch¹¹.

Determination of Melting Point: The melting point of Sodium Valproate was determined by the open capillary method. A small amount of the drug was packed into a sealed capillary tube, placed in a melting point apparatus, and the temperature range from initial melting to complete liquefaction was recorded as the melting point, indicating drug purity¹².

Solubility Study: An excess amount of Sodium Valproate was added to various solvents methanol, 0.1 N HCl, and phosphate buffer (pH 7.4) and shaken for 24 hours at room temperature to attain equilibrium. The mixtures were then filtered, and the supernatants analyzed using a UV–Visible double beam spectrophotometer to determine equilibrium solubility¹³.

Determination of pH: The pH of a saturated Sodium Valproate solution in methanol was measured using a calibrated digital pH meter to assess its ionization and stability in different environments¹¹.

Calibration Curve by UV Spectroscopy: A standard calibration curve of Sodium Valproate was prepared in methanol and 0.1 N HCl. A 100 μg/mL stock solution was serially diluted to obtain concentrations of 10–35 μg/mL. Absorbance was measured at 214 nm using a UV–Visible spectrophotometer, with respective solvents as blanks. Absorbance values were plotted against concentration to construct a Beer–Lambert calibration curve for quantitative analysis in drug release studies¹?.

Determination of IR Spectrum: Drug identity and purity were confirmed by Fourier Transform Infrared (FTIR) Spectroscopy. The sample was mixed with dry KBr, compressed into a disc, and scanned from 4000– 450 cm?¹ using an FTIR spectrophotometer (Jasco- 4100, Japan). The resulting spectrum was compared with the reference spectrum of Sodium Valproate to confirm characteristic peaks¹?.

Thermal Analysis by Differential Scanning Calorimetry (DSC): Thermal behavior was analyzed using DSC. About 5 mg of the drug was sealed in an aluminum pan and heated from 30°C to 250°C at 10°C/min under a nitrogen flow. An empty sealed pan served as reference. The thermogram was evaluated for melting endotherm and enthalpic changes to determine thermal stability and purity¹?.

Compatibility Studies

1. IR Spectral Compatibility: Drug–excipient compatibility was studied by FTIR spectroscopy. Physical mixtures of Sodium Valproate and each excipient (1:1 ratio) were analyzed using the KBr pellet method and scanned from 450–4000 cm?¹ (AFFINITY Mirracal 10, Shimadzu, Japan). The spectra were compared with that of the pure drug to identify any peak shifts or disappearance indicating interactions.

2. DSC Compatibility Study: Differential scanning calorimetry was also used to assess compatibility. Physical mixtures (≈ 5 mg) were heated from 25°C to 220°C at 10°C/min under nitrogen (20 mL/min) using a DSC system (Star SW 12.10). Thermograms were examined for melting point variations or new peaks suggesting possible interactions¹?.

Evaluation of Powder Blends

Bulk Density: A pre-weighed quantity of the powder blend was carefully transferred into a 100 mL graduated measuring cylinder without compacting. The initial volume occupied by the powder was recorded as the bulk volume 18. Bulk density was calculated using the following formula:

Bulk density = Mass of the powder / Bulk volume

Tapped Density: The same sample was then subjected to 100 mechanical tappings using a tapped density apparatus. The volume after tapping was recorded as the tapped volume. Tapped density was calculated using the formula:

Tapped density (g/cm³) = Weight of the powder / Tapped volume

Angle of Repose: The angle of repose was determined using the fixed funnel method. The funnel was positioned vertically and the powder blend was allowed to flow through it onto a flat surface, forming a conical pile. The height (h) of the cone and the radius (r) of its base were measured. The angle of repose (θ) was then calculated using the formula:

tan θ = h /r

Carr’s Index: Carr’s compressibility index was calculated to evaluate the flowability and compressibility of the blend using the formula:

% Carr’s index = Tapped density - Bulk density /Tapped density ? 100

Hausner’s Ratio: Hausner’s ratio was calculated to further assess powder flow characteristics using the following equation 19-21:

Hausner’s ratio = Tapped density / Bulk density ? 100

Formulation of Sodium Valproate Water- Dispersible Tablet

Sodium Valproate tablets were prepared by the direct compression method using a rotary tablet compression machine. The formulations (Table 1) contained varying concentrations of Hydroxypropyl Methylcellulose K30 (HPMC K30) and Carbopol 940 to study their effects on matrix formation and drug release. Microcrystalline Cellulose (MCC) served as a matrix-forming agent, aiding controlled erosion upon contact with dissolution medium, while Polyvinylpyrrolidone K30 (PVP K30) acted as a binder to enhance mechanical strength. All ingredients were sieved through an 80# mesh to ensure uniform particle size and homogeneity. Citric acid was incorporated as a flavoring and disintegrating agent to promote rapid tablet dispersion. Finally, magnesium stearate and talc were added as lubricant and glidant, respectively²². The final blend was compressed into 300 mg tablets for each formulation (F1–F8), as shown in Table 1.

Table 1: Formulation of Sodium Valproate Water-Dispersible Tablet

Post-formulation Evaluation

Thickness and Diameter: Three tablets from each formulation were randomly selected and their thickness and diameter were measured using a digital vernier calliper. Individual readings were recorded and the mean values were calculated to assess dimensional uniformity²³.

Hardness: Tablet hardness was determined using a Monsanto hardness tester. Three tablets from each batch were tested, and the force required to break each tablet was recorded. The average hardness was expressed in kg/cm²²?.

Percentage Friability: Friability was evaluated using a Roche friabilator. Twenty pre-weighed tablets were rotated at 25 rpm for 4 minutes, then dedusted and reweighed. The percentage friability was calculated using the formula:

% Friability = (Initial Weight−Final / Weight Initial Weight) × 100

Weight Variation: The weight variation test was performed as per Indian Pharmacopoeia (IP, 2007) guidelines. Twenty tablets from each batch were individually weighed using a digital balance. The mean weight was calculated, and no more than two tablets were allowed to deviate by ±5% from the average.

In-Vitro Dissolution Studies: Dissolution testing was carried out using a USP Type II (paddle) apparatus in 900 mL of medium maintained at 37 ± 0.5°C and stirred at 50 rpm. 0.1 N HCl (pH 1.2) was used for the first 6 hours, followed by phosphate buffer (pH 6.8). At specified intervals, 5 mL samples were withdrawn and replaced with fresh medium to maintain sink conditions. Samples were filtered and analyzed at 214 nm using a UV–Visible spectrophotometer to determine drug release.

Stability Study: The optimized formulation was subjected to accelerated stability testing at 40 ± 2°C and 75 ± 5% RH for one month. Tablets were packed in butter paper, sealed in aluminum foil, and stored in a stability chamber. After the study period, samples were evaluated for physical appearance, drug content, and in-vitro release²²-²?.

RESULT AND DISCUSSION

Pre-formulation Evaluation

Drug Characterization: The preliminary organoleptic properties of Sodium Valproate were evaluated to confirm its physical characteristics. A small quantity of the drug was placed on butter paper and examined under well-illuminated conditions, where it was observed to be round shape white in color. The sample was then smelled directly to assess its odor and it was found to be odorless. Additionally, a pinch of the drug was taken between the fingers to examine its texture and form; it appeared as a fine powder.

Determination of Melting Point: The melting point of Sodium Valproate was determined to assess the purity and identity of the drug substance. The standard melting point of Sodium Valproate is reported as 219 °C, while the experimentally observed melting point was found to be 217 °C. The slight deviation of 2 °C falls within the acceptable range, suggesting that the sample was of high purity and free from significant impurities.

Solubility Study: Sodium Valproate showed the highest solubility in 0.1N HCl (4.0 g/ml), followed by ethanol (1.5 g/ml) and methanol (1.2 g/ml). The greater solubility in acidic medium indicates favourable dissolution in gastric conditions, supporting its suitability for oral formulations.

Determination of pH: The pH of Sodium Valproate in 0.1N HCl was found to be 4.0, indicating a slightly acidic environment. This pH is suitable for maintaining drug solubility and stability in gastric conditions, supporting its effectiveness in oral dosage forms.

Ultraviolet Absorbance Spectroscopy: The ultraviolet absorbance spectroscopy analysis of Sodium Valproate in methanol revealed a maximum absorbance (λmax) at 214 nm. This λmax indicates the wavelength at which Sodium Valproate exhibits peak absorbance in the UV region, corresponding to its optimal electronic transition. The strong absorbance at this wavelength suggests the presence of specific chromophoric groups within the drug molecule that interact efficiently with UV light, making 214 nm a suitable analytical wavelength for its quantitative estimation using UV spectrophotometry.

Figure 1: λmax of Sodium valproate

Calibration curve of Sodium valproate: The standard calibration curve for Sodium Valproate in methanol was constructed by plotting absorbance values against known concentrations ranging from 0 35 μg/ml. The obtained data showed a linear relationship with a slope of 0.0334, an intercept of 0.0613, and a coefficient of correlation (r²) of 0.9903, indicating excellent linearity between concentration and absorbance. The λmax was determined at 214 nm, confirming the optimal wavelength for analysis.

Figure 2: Calibration curve of Sodium valproate Compatibility Studies

IR Spectral Compatibility

The FTIR spectrum of Sodium Valproate was analyzed to identify the functional groups present in the molecule by comparing the observed absorption peaks with standard frequency ranges. The characteristic peaks were observed at 3368.99 cm?¹ corresponding to aromatic C–H and N–H stretching, confirming the presence of amine and aromatic functionalities. The strong peaks at 1646.68 cm?¹ and 1676.14 cm?¹ were attributed to C=O–N–H stretching, indicative of amide linkages. Peaks at 1459.43 cm?¹ and 1430.97 cm?¹ corresponded to C–H stretching, while 1363.66 cm?¹ and 1315.64 cm?¹ were assigned to the CH? group. Additionally, the peaks at 1279.46 cm?¹ and 1242.59 cm?¹ represented ether (-O-) linkages, and the absorption at 837.70 cm?¹ was attributed to C–Cl stretching. These findings confirm the presence of all expected functional groups in Sodium Valproate, validating its structural integrity and purity for formulation development.

Figure 3: IR spectrum of Sodium Valproate

Figure 4: IR spectrum of Sodium Valproate and mixture

Differential Scanning Calorimetry:

The Differential Scanning Calorimetry (DSC) thermogram of Sodium Valproate shows a distinct endothermic peak corresponding to its melting point, indicating its crystalline nature and thermal behavior. The onset temperature was recorded at 284.45 °C, with a peak temperature of 288.49 °C and an end set temperature of 295.55 °C. The extrapolated peak temperature was noted at 289.27 °C, and the peak width measured 2.80 °C, signifying a sharp melting transition characteristic of a pure compound. The enthalpy change associated with the melting was 0.93 J g?¹, and the peak height was 0.14 mW. The area distribution under the curve showed 39.83% on the left side and 60.17% on the right side, with the total (partial) area being 100%. These DSC findings confirm the purity and stability of Sodium Valproate, with no additional thermal events suggesting degradation or polymorphic transitions before melting. This thermal profile supports its suitability for formulation development, as the compound remains stable up to its melting range.