Development and Optimization of Polyethylene Glycol-Based Solid Dispersion of Pitavastatin Incorporated into Fast Dissolving Oral Films for Enhanced Dissolution and Oral Drug Delivery

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, accounting for nearly one-third of all global deaths. Hypercholesterolemia and dyslipidemia are among the most significant modifiable risk factors responsible for the development of atherosclerosis, coronary artery disease, ischemic stroke, and peripheral vascular disorders. Effective lipid-lowering therapy has therefore become an essential component of cardiovascular disease prevention. Among currently available lipid-lowering agents, statins have demonstrated remarkable clinical success owing to their ability to inhibit hepatic cholesterol biosynthesis by competitively blocking the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Besides reducing low-density lipoprotein cholesterol (LDL-C), statins also exhibit pleiotropic effects including anti-inflammatory activity, endothelial protection, plaque stabilization, and improvement of vascular function (Ansel et al., 2019; Aulton & Taylor, 2022).

Pitavastatin calcium is a synthetic lipophilic statin that has attracted considerable attention because of its potent lipid-lowering efficacy, favorable safety profile, and reduced potential for cytochrome P450-mediated drug interactions compared with several earlier statins (Kawabata et al., 2011). It effectively lowers total cholesterol, triglycerides, and LDL cholesterol while simultaneously increasing high-density lipoprotein cholesterol (HDL-C). Consequently, Pitavastatin is widely prescribed for primary hypercholesterolemia, mixed dyslipidemia, and prevention of cardiovascular complications in high-risk patients (Mikrani et al., 2024).

Despite its pharmacological advantages, Pitavastatin exhibits poor aqueous solubility and is classified as a Biopharmaceutical Classification System (BCS) Class II drug (Kawabata et al., 2011). Drugs belonging to this class possess high membrane permeability but low aqueous solubility, making dissolution the rate-limiting step for gastrointestinal absorption. The crystalline nature of Pitavastatin contributes significantly to its slow dissolution, leading to incomplete drug absorption, variability in oral bioavailability, delayed onset of action, and inconsistent therapeutic outcomes. Therefore, improving the dissolution behavior of Pitavastatin remains an important pharmaceutical challenge (Dasari et al., 2016).

Various formulation strategies have been explored to overcome the limitations associated with poorly soluble drugs, including micronization, nanosuspensions, cyclodextrin complexation, lipid-based formulations, self-emulsifying drug delivery systems, co-crystals, amorphous solid dispersions, and polymeric nanoparticles. Among these approaches, solid dispersion technology has emerged as one of the most successful and commercially viable techniques because of its simplicity, scalability, cost-effectiveness, and remarkable ability to enhance dissolution (Vasconcelos et al., 2007; Vo et al., 2013). In solid dispersions, drug molecules are molecularly dispersed or finely distributed within a hydrophilic polymeric matrix, leading to significant reduction in particle size, improved wettability, increased surface area, enhanced porosity, and partial or complete conversion of crystalline drug into an amorphous state. These physicochemical changes collectively improve the dissolution rate and may subsequently enhance oral bioavailability (Van den Mooter, 2012).

Hydrophilic polyethylene glycols (PEGs) are among the most widely investigated carriers for preparing solid dispersions because of their excellent aqueous solubility, biocompatibility, low toxicity, thermal stability, and regulatory acceptance (Zhang et al., 2018). PEGs improve wettability of hydrophobic drug particles, facilitate rapid dissolution of the polymer matrix, reduce drug crystallinity, and promote molecular dispersion of the active pharmaceutical ingredient. Owing to these favorable characteristics, PEG-based solid dispersions have been successfully employed to improve the dissolution of numerous poorly water-soluble therapeutic agents (Singh & Van den Mooter, 2016).

Although enhancement of dissolution is essential, conventional solid dosage forms such as tablets and capsules may still present challenges for pediatric, geriatric, and dysphagic patients who have trouble swallowing. Fast dissolving oral films (FDOFs) have therefore emerged as an attractive alternative oral drug delivery platform (Dixit & Puthli, 2009; Khan et al., 2015). These thin polymeric films rapidly hydrate upon contact with saliva, disintegrate within seconds, and release the incorporated drug without the need for water. Fast dissolving films provide several clinical advantages, including ease of administration, improved patient compliance, accurate dosing, portability, reduced choking risk, rapid onset of action, and enhanced convenience during emergency conditions or in patients with swallowing disorders (Sharma et al., 2015; Yadav et al., 2021).

The combination of solid dispersion technology with fast dissolving oral films offers a synergistic strategy for improving both the physicochemical performance and patient acceptability of poorly water-soluble drugs. Incorporation of an optimized amorphous solid dispersion into a rapidly dissolving polymeric film can simultaneously enhance dissolution, improve wettability, accelerate drug release, and simplify administration (Ahmed et al., 2023; Sangeetha et al., 2024).

2. MATERIALS AND METHODS

2.1 Materials

Pitavastatin calcium was obtained as a gift sample from a reputed pharmaceutical manufacturer. Polyethylene glycol (PEG 4000, PEG 6000 and PEG 20000) was employed as hydrophilic carriers for preparation of solid dispersions. Hydroxypropyl methylcellulose (HPMC E5), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP K30), glycerol, propylene glycol, Tween 80, citric acid, sodium saccharin, and peppermint flavour were used during formulation of fast dissolving oral films. Methanol, ethanol, chloroform and all analytical-grade reagents were procured from certified chemical suppliers and used without further purification. Double-distilled water was used throughout the investigation.

2.2 Experimental Design

The study was carried out in two successive stages. Initially, Pitavastatin-polyethylene glycol solid dispersions were prepared using different polymer concentrations and preparation techniques to improve aqueous solubility and dissolution characteristics. The optimized solid dispersion was subsequently incorporated into a fast dissolving oral film using the solvent casting technique. All formulations were evaluated for physicochemical properties, drug content, mechanical characteristics and dissolution performance to identify the optimized formulation.

2.3 Preparation of Pitavastatin Solid Dispersion

Solid dispersions of Pitavastatin were prepared using polyethylene glycol as a hydrophilic carrier at different drug-to-polymer ratios. The carrier was accurately weighed and processed according to the selected preparation technique. Pitavastatin was incorporated gradually with continuous mixing to ensure homogeneous distribution throughout the polymer matrix.

The prepared dispersions were cooled to room temperature, pulverized gently using a mortar and pestle, passed through a suitable sieve and stored in airtight containers until further characterization.

Nine formulations (F1–F9) were prepared by varying the polymer composition and processing conditions to optimize drug loading, dissolution behaviour and physicochemical properties (Dasari et al., 2016; Mikrani et al., 2024).

2.4 Characterization of Solid Dispersion

2.4.1 Physical appearance

Prepared solid dispersions were visually examined for colour, homogeneity, flow behaviour and absence of aggregation.

2.4.2 Percentage yield

Percentage yield was determined to evaluate production efficiency using the following equation:

Percentage Yield =Practical Yield-Theoretical Yield\100 (Aulton & Taylor, 2022).

2.4.3 Drug content

Solid dispersion equivalent to a predetermined quantity of Pitavastatin was dissolved in methanol, filtered and analysed spectrophotometrically at 268 nm after suitable dilution. Drug content was calculated using the calibration curve (Indian Pharmacopoeia Commission, 2022).

2.4.4 Saturated solubility

Excess solid dispersion was added to distilled water and phosphate buffer (pH 6.8) and shaken for 24 h at 25 ± 2°C. The samples were filtered, diluted appropriately and analysed spectrophotometrically (Kawabata et al., 2011).

2.4.5 In vitro dissolution study

Dissolution studies of pure Pitavastatin and solid dispersions were carried out using USP Dissolution Apparatus II containing phosphate buffer (pH 6.8) maintained at 37 ± 0.5°C. Samples were withdrawn at predetermined intervals, filtered and analysed at 268 nm. Equal volumes of fresh dissolution medium were replaced after each withdrawal to maintain sink conditions (United States Pharmacopeia, 2024).

2.5 Selection of Optimized Solid Dispersion

The optimized formulation was selected based on percentage yield, drug content, saturated solubility, dissolution efficiency and overall physicochemical performance. The selected formulation was further utilized for fabrication of fast dissolving oral films.

2.6 Preparation of Fast Dissolving Oral Films

Fast dissolving oral films were prepared by the solvent casting method. The required quantity of film-forming polymer was dispersed in distilled water with continuous stirring until a clear and homogeneous solution was obtained. Plasticizer, sweetener, flavouring agent and other excipients were added sequentially with constant mixing.

The optimized Pitavastatin solid dispersion was dispersed uniformly into the polymeric solution to ensure homogeneous drug distribution. Air bubbles were removed by sonication before casting the solution onto a clean glass mould. The cast films were dried at room temperature under controlled conditions until complete solvent evaporation. The dried films were carefully peeled, cut into uniform dimensions and stored in aluminium foil until further evaluation.

Twelve formulations (F5G1–F5G12) were prepared by varying polymer and plasticizer concentrations to optimize film characteristics (Patel et al., 2010; Khan et al., 2015; Ahmed et al., 2023).

2.8 Evaluation of Fast Dissolving Oral Films

2.8.1 Physical appearance and film-forming capacity

Films were visually examined for transparency, smoothness, flexibility, stickiness, brittleness and ease of peeling.

2.8.2 Surface pH

Film samples (2 × 2 cm²) were placed in Petri dishes containing distilled water. After complete hydration, the pH electrode was brought into contact with the film surface and the pH was recorded.

2.8.3 Drug content

Film equivalent to the required quantity of Pitavastatin was dissolved in water, centrifuged and analysed spectrophotometrically at 268 nm following appropriate dilution (Indian Pharmacopoeia Commission, 2022).

2.8.4 Weight variation

Individual films (2 × 2 cm²) were weighed using a calibrated digital analytical balance, and the mean weight was calculated (United States Pharmacopeia, 2024).

2.8.5 Thickness

Film thickness was measured at different positions using a digital screw gauge, and the average value was reported.

2.8.6 Folding endurance

Mechanical strength was evaluated by repeatedly folding the film at the same position until visible cracking or breakage occurred. The number of folds required to break the film was recorded as the folding endurance (United States Pharmacopeia, 2024).

2.8.7 In vitro disintegration time

Film disintegration was determined using the USP disintegration apparatus containing distilled water maintained at 37 ± 0.5°C. The time required for complete disintegration of the film was recorded (United States Pharmacopeia, 2024).

2.8.8 In vitro dissolution study

Dissolution behaviour of the optimized films was evaluated using USP Dissolution Apparatus I containing 900 mL simulated salivary fluid (pH 6.8) maintained at 37 ± 0.5°C with a paddle speed of 50 rpm. Samples were withdrawn at predetermined intervals, filtered and analysed spectrophotometrically at 268 nm. Fresh dissolution medium was added after each withdrawal to maintain constant volume (United States Pharmacopeia, 2024).

3. RESULTS AND DISCUSSION

1. 1. Preformulation studies

These investigations are a necessary part of the development process for a stable, reliable dosage form. By using a variety of analytical techniques, including melting point, solubility, melting spectroscopy, and UV/IR spectroscopy, the acquired drug sample was identified.

1. 1. 1. Organoleptic properties

Organoleptic properties of drug Pitavastatin was found to be as per literature. The Organoleptic properties of Pitavastatin were found to the given in table 7.1.

Table 1: Organoleptic properties of Pitavastatin

3.1.2 Melting point

Table 2: Data of Pitavastatin Melting Point

1. 1. 3. Determination of absorption maxima by UV spectroscopy in 0.1N HCl

The result of UV spectrum of Pitavastatin in 0.1N HCl is shown in Figure 1.

Figure 1: UV spectrum of Pitavastatin in 0.1N HCl

Figure 2: FTIR spectrum of Pitavastatin

4.2 In Vitro Disintegration Study

Rapid disintegration is one of the most important quality attributes of fast dissolving oral films because it governs the onset of drug release and ultimately influences therapeutic efficacy. The disintegration time of formulations F5G1–F5G12 was evaluated using the USP disintegration apparatus in distilled water maintained at 37 ± 0.5°C. The results are presented in Table 2.

The prepared films exhibited disintegration times ranging from. The differences among formulations were primarily attributed to variations in polymer concentration and plasticizer content. Films containing an optimum polymer-to-plasticizer ratio disintegrated rapidly due to efficient hydration and swelling of the polymeric matrix. Conversely, formulations containing higher polymer concentrations exhibited relatively longer disintegration times because of increased matrix density and slower penetration of dissolution medium.

Among the prepared formulations, F5G5 demonstrated one of the shortest disintegration times, indicating rapid hydration and excellent film integrity. The optimized formulation satisfied the pharmacopeial requirement for fast dissolving oral films and is therefore expected to provide rapid drug availability in the oral cavity.

The rapid disintegration observed for the optimized formulation can be attributed to the combined effect of the hydrophilic polymer matrix, optimized plasticizer concentration, and incorporation of the PEG-based solid dispersion, which enhanced water uptake and accelerated film erosion.

In Vitro Dissolution Study

The dissolution profile of Pitavastatin from the prepared fast dissolving oral films was evaluated in phosphate buffer (pH 6.8) to investigate the influence of formulation variables on drug release. The cumulative percentage drug release profiles are presented in Table 5.

Table 5 Comparison of disintegration time and in  vitro drug release of Pitavastatin fast dissolving oral film formulations (F5G1–F5G12).

4.4 Optimization of Fast Dissolving Oral Film

Selection of the optimized oral film was based on comprehensive evaluation of physicochemical properties, mechanical characteristics, disintegration behaviour, and dissolution performance.

Although several formulations demonstrated satisfactory film quality, F5G5 exhibited the most desirable balance between rapid disintegration and maximum drug release. The formulation also showed acceptable surface pH, satisfactory drug content, uniform thickness, and adequate mechanical properties.

The superior performance of F5G5 can be attributed to the optimized polymer composition, appropriate plasticizer concentration, and incorporation of the PEG-based solid dispersion. The presence of the hydrophilic carrier significantly improved drug wettability and facilitated rapid dissolution immediately after film hydration.

The optimization results confirm that careful selection of formulation variables is essential for developing oral films possessing both satisfactory mechanical integrity and rapid drug release characteristics.

4.5 Correlation Between Solid Dispersion and Oral Film Performance

The present investigation successfully integrated two formulation approaches to overcome the poor aqueous solubility of Pitavastatin. Initially, preparation of PEG-based solid dispersions reduced drug crystallinity and increased saturated solubility, resulting in enhanced dissolution. Subsequent incorporation of the optimized solid dispersion into fast dissolving oral films further accelerated drug release through rapid film hydration and disintegration.

The complementary findings obtained from physicochemical evaluation, solid-state characterization, and dissolution studies demonstrate that the developed formulation strategy effectively improved the pharmaceutical performance of Pitavastatin. The optimized formulation exhibited excellent physicochemical characteristics, rapid disintegration, and almost complete drug release within a few minutes, indicating its potential as an efficient immediate-release oral dosage form.

Overall, the results suggest that PEG-mediated solid dispersion combined with solvent-cast fast dissolving oral film technology represents a promising platform for improving the dissolution behaviour and potential oral bioavailability of poorly water-soluble drugs such as Pitavastatin.

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