Development and Characterization of Solid Dispersion System for Solubility Enhancement of Fenofibrate

Fenofibrate is an anti-hyperlipidemic drug that belongs to fibrate class. It helps to reduce elevated plasma concentration of triglycerides and LDL. Generally, it is more effective drug as compare to other fibrates. Fenofibrate is included in BCS Class II drugs resulting it shows low bioavailability.¹⁴ The enhancements of oral bioavailability of poorly water-soluble drugs often show poor bioavailability because of low and erratic levels of absorption. Drugs that undergo dissolution rate limited, in gastrointestinal absorption and it shows improved dissolution and bioavailability by reduction in particle size. However, drugs often lead to aggregation and agglomeration of particles, which results in poor wettability^14-5. Solid dispersions of poorly water-soluble drugs with water-soluble carriers have been reduced the incidence of these problems and enhanced dissolution. The development of solid dispersions as a practically viable method to enhance bioavailability of poorly water-soluble drugs overcame the limitations of previous approaches such as salt formation, solubilisation by co solvents, and particle size reduction, solvent evaporation method. Studies revealed that drugs in solid dispersion need not necessarily exist in the micronized state⁵. A fraction of the drug might molecularly disperse in the matrix, thereby forming a solid dispersion. When the solid dispersion is exposed to aqueous media, the carrier dissolves and the drug releases as fine colloidal particles. Solid dispersions in water-soluble carriers have attracted considerable interest as a means of improving the dissolution rate, and hence possibly bioavailability, of a range of hydrophobic drugs. Fenofibrate needs to improve its oral bioavailability, solubility, and dissolution rate¹³. The method have been used to increase the solubility, dissolution rate, and bioavailability of poor water soluble medicines, including solid dispersion. solvent evaporation method. This method used to improving the solubility, dissolution rate, and bioavailability of poorly soluble Fenofibrate medicine. It is a straightforward, industrially useful method¹⁴. The goal of the current research project was to create Fenofibrate tablets with a solvent evaporation method approach to increase solubility and dissolution rate¹².

Solid Dispersion:

Solid dispersion helps break the drug into very fine particles, increasing its surface area and improving its dissolution rate, as described by the Noyes-Whitney equation. Although reducing particle size to the nano level can speed up dissolution, it cannot increase the drug’s solubility beyond its natural limit in intestinal fluids. To overcome this, solid dispersion is an effective technique for enhancing the solubility and absorption of poorly water-soluble drugs. It can increase the drug concentration at the site of absorption and even create a temporary supersaturated state, which boosts bioavailability. Solid dispersion remains a popular area of research because it is versatile and suitable for different dosage forms, especially tablets are most commonly used form for oral drug delivery.¹⁴

MATERIALS:

Fenofibrate API from Balaji Drug Limited, Mumbai, other laboratory chemicals such as chloroform, Ethanol, Acetone, and Excipients PVP-K30, HPMC E15, Microcrystalline cellulose, Croscarmellose Sodium, Aerosil, Sodium lauryl sulphate, Magnesium stearate are available at Institute.

Preformulation studies

An investigation of physical and chemical properties of a drug substance alone is defined as “Pre?formulation.”

OBJECTIVE

It generates useful information to the formulator that is useful in developing stable and bio available dosage forms.

These are

1. Organoleptic properties
2. Solubility studies.

Organoleptic properties

Colour, Odour, taste, appearance of the drug play an important role in the identification of sample of above all properties should be recorded in descriptive terminology¹⁶.

Solubility studies

The solubility of Fenofibrate was tested in ethanol, methanol, and water. About 10 mg of the drug was added to 5 mL of each solvent in separate test tubes. After vigorous shaking, the mixtures were visually observed. Fenofibrate showed complete solubility in ethanol and methanol. It remained practically insoluble in water, with undissolved particles visible.

Determination of melting point

Melting point of Fenofibrate was determined by capillary method. Observed values compared with reported value. This method involves placing the sample in a capillary tube and running an experiment that will heat the sample until it reaches melting point. The melting point can then be recorded.

UV Visible Spectroscopy

In order to create a standard stock solution of 100 µg/ml, 10 mg of precisely weighed Fenofibrate was dissolved in 100 ml of ethanol in a 100 ml volumetric flask. The volume was then increased to 100 ml with ethanol. 2.5 milliliters of the standard stock solution were pipetted into a 10-milliliter volumetric flask. Water was added to get the volume up to 10 ml. Between 200 and 400 nm, the resultant solution, which contained 10 µg/ml, was scanned.

FTIR (Fourier Transform Infra-Red Spectroscopy)

Infrared spectroscopy was used to detect chemical interactions between Fenofibrate and excipients during storage. The IR spectra of pure drug and physical mixtures were compared for any changes. Samples from the stability chamber were analyzed by mixing drug and excipients with KBr in a 1:1 ratio. Pellets were prepared and scanned in the 4000–400 cm?¹ range using an FTIR spectrophotometer. Variations in spectra indicated possible interactions.

Differential Scanning Calorimetry (DSC)

The differential scanning calorimetric technique was used to do a thermal examination of Fenofibrate with all excipients. An device called the Shimadzu DSC-60plus was used to evaluate the samples. All excipients and a sample equal to around 10 mg of fenofibrate were heated in open aluminium pan at a rate of 100 C/min. conducted over a temperature range of 30 to 3200C to a nitrogen flow of 2-bar pressure. Drug melting point to be examined and checked.

Preparation of Fenofibrate tablet by solvent evaporation method

The Formulation of Fenofibrate tablet by solvent evaporation method, the first step is to choose a suitable solvent that can easily dissolve both the drug and the polymer. Ethanol is selected for this process because it is volatile and effectively dissolves both Fenofibrate and the chosen hydrophilic polymers, such as PVP K30, HPMC E15. In the next step, accurately weighed quantity of Fenofibrate and PVP K30, HPMC E15 are added to a sufficient quantity of ethanol. The mixture is stirred continuously until both the drug and polymer completely dissolve, forming a clear and homogeneous solution. Once the solution is ready, the ethanol is gradually evaporated by gentle heating using a water bath at around 40–50°C. As the solvent evaporates, it leaves behind a solid dispersion of Fenofibrate within the polymer matrix. To ensure complete removal of any residual solvent, the solid mass is further dried in a vacuum oven or desiccator. After drying, the solid residue is collected and pulverized into a fine powder using a mortar and pestle. The powder is then passed through a 60# sieve to achieve uniform particle size and mix the all excipients for tablet compression.

Experimental Design

The current Formulation optimization study were performed using Design Expert® Software (Design Expert trial version 12; Stat-Ease). Box Behnken design was applied for the development of the formulation of Fenofibrate tablet by considering 3 factors and 3 levels (high, low). PVP K30, HPMC, and MCC considered as independent factors and drug release and compressibility index is dependent variables. Because to found best optimization batch in research. The level of all autonomous factors to be chosen based on preliminary trials.

Table 1: Composition of independent variables and their levels for the preparation of Fenofibrate tablet.

Table 2: 3³ full factorial design for formulation designed using Stat-Ease Design Expert® soft-ware (Version 12)

Evaluation of Fenofibrate Tablet

Prepared solid dispersions were evaluated for the following parameters:

1. Percentage yield
2. Drug content
3. In vitro dissolution studies

Percentage yield

Percentage yield was calculated to know about efficiency of any method and thus its help in selection of appropriate method of production. The final weights of the prepared solid dispersions were taken, and percentage yield was calculated by using the given formula.

%yield =    Practical yieldTherotical yield  x 100

Drug content

Solid dispersions equivalent to 20 mg of fenofibrate were weighed accurately and dissolved in 100 ml of ethanol. The solution was filtered, diluted suitably, and drug content was analyzed at λmax 290 nm against blank by UV spectrometer.

% Drug content = Observed value Actual value  x 100

In vitro dissolution studies                                       

The dissolution study was conducted using a USP Type II (paddle) dissolution apparatus (USP 30 and NF 25, 2007), equipped with a six-station setup. The temperature of the dissolution medium was maintained at 37 ± 0.5?°C using a circulating water bath. For the study, 900 mL of buffer pH 6.8 SLS was used as the dissolution medium. Prior to initiating the test, the medium was preheated to 37?°C and transferred into each vessel. The paddle rotation speed was set at 50 rpm, and the system was allowed to equilibrate for 15 minutes. After stabilization, the paddles were briefly stopped, and each vessel received a solid dispersion tablet equivalent to 145 mg of Fenofibrate. The paddles were immediately restarted at 50 rpm. Samples of 10 mL were withdrawn at predetermined time intervals: 5, 10, 15, 20, 30, 45 minutes. After each withdrawal, the same volume of fresh buffer Solution (37?°C) was added to maintain sink conditions and constant volume. The collected samples were filtered, diluted as necessary, and  Analyzed using a UV spectrophotometer at 290 nm (λmax of Fenofibrate). The drug concentration in each sample was determined from a standard calibration curve prepared using the USP reference standard of Fenofibrate.

Pre-compression characterization of blend

The Fenofibrate blend was evaluated for its pre-compression parameters to assess flow properties and compressibility. The angle of repose was measured to determine flow behavior, while bulk and tapped densities was calculated to understand powder packing. Using these values, Carr’s index and Hausner’s ratio were derived to evaluate flowability and cohesiveness. Compressibility testing was also performed to assess the blend's ability to form tablets. These parameters ensured suitability of the blend for further tablet formulation.

Evaluation of tablets

After the preparation of tablets, the tablet was evaluated for various post-compression parameters to ensure quality and uniformity. Weight variation was checked to confirm dose uniformity, while thickness and hardness were measured to assess physical strength and dimensional consistency. Friability testing was conducted to evaluate the tablet's ability to resist mechanical stress during handling. Disintegration time was recorded to ensure proper breakdown of the tablet in the body. These evaluations are crucial for the overall performance and stability of the final formulation.

Stability Study

Stability testing evaluates how a drug’s quality changes over time under environmental factors like temperature, humidity, and light. It ensures the product maintains its chemical, physical, and biopharmaceutical properties within specified limits during its shelf life under recommended storage conditions.

RESULTS AND DISCUSSION:

Solubility Studies:

Solubility studies were done in different buffers to select the dissolution medium for the dissolution studies of the solid dispersions as shown in table 3

Table 3: Solubility Studies

Organoleptic Properties

The procured sample of Fenofibrate was studied for organoleptic characters such as color, odor, and appearance.

Table 4: Organoleptic Properties of Fenofibrate

Discussion:

All the tests for Fenofibrate comply with I.P. 2014, confirming that the drug meets the pharmacopeial standards for identity and purity.

Melting Point

The melting point was determined by the capillary fusion method.

Table 5: Melting Point of Fenofibrate

Discussion:

The melting point of Fenofibrate was found to be 79-82 °C, which aligns with the Indian Pharmacopoeia (I.P.) standard range of 78-82 °C, confirming its purity and crystalline form.

UV VISIBLE SPECTROSCOPY

The λ max of Fenofibrate was determined by preparing a standard solution in ethanol. A 10?mg sample of Fenofibrate was dissolved in ethanol and diluted to 100?mL to obtain a 100?µg/mL stock solution. From this, 2.5?mL was further diluted to 10?mL to obtain a 10?µg/mL solution, which was scanned in the UV range of 200–400?nm. The maximum absorbance (λ max) for Fenofibrate in ethanol was found to be at 290?nm.  

Calibration Curve of Fenofibrate in Ethanol

The calibration curve of fenofibrate was prepared in ethanol. Absorbance was measured at 290nm using a UV-visible spectrophotometer.

Table 6: Concentration vs. Absorbance

Drug – Excipients Chemical Compatibility study

(FTIR) Fourier Transform Infrared Spectroscopy

Figure 4: FTIR spectra of Fenofibrate Drug

Discussion                                                                

Figure 4: FTIR spectra of Fenofibrate The FTIR spectrum of Fenofibrate confirms its identity by displaying characteristic functional group absorptions. A strong peak at 1721.84 cm?¹ corresponds to C=O (ester) stretching funvtional group, verifying the ester linkage. The 1646.43 cm?¹ band indicates C=C aromatic stretching. Methyl bending is seen at 1380.11 cm?¹. and 1091.16 cm?¹. Alkyl C–H bending is noted at 1025.27 cm?¹. These bands confirm Fenofibrate as a real, structurally intact drug.

Figure 6: FTIR spectra of Fenofibrate+HPMC

(DSC) Differential Scanning Calorimetry

Table 7: Thermogram of Fenofibrate

Discussion

The Differential Scanning Calorimetry (DSC) thermogram of Fenofibrate was recorded to determine its thermal behavior.The onset of melting was observed at 81.64°C, indicating the beginning of the phase transition. The sharp endothermic peak appeared at 81.11°C, corresponding to the melting point of the drug. The end set temperature was recorded at 85.83°C, marking the completion of the melting process. These results confirm the purity and crystalline nature of Fenofibrate, as indicated by the sharp, well-defined melting endotherm

Table 8: DSC spectra of fenofibrate with All Excipients

Discussion

DSC curve of fenofibrate solid dispersion, indicating the transformation of crystalline fenofibrate (in pure drug) to amorphous fenofibrate. This could be attributed more uniform distribution of the drug in crust of polymer

Percentage Practical Yield:

Percentage practical yield was calculated to know about percent yield or efficiency of any method and help in the selection of the appropriate method of production.

Table 9: Percent practical yield / drug content

Figure 9: Percent practical yield / drug content

Evaluation of Tablet

Table 10: Pre-Compression Evaluation of Formulation Powder

Table 11: Post-Compression Evaluation of Tablets

Physical Drug Content

Table 12:  Percent Drug Content of Formulations

Full and reduced model assessment for the dependent variables:

The range of responses Y? and Y? were 64.55–98.74 and 10.83–25.21, respectively. All the responses were fitted to various models using Design Expert software. It was observed that the best fitted models were quadratic. The values of R², Predicted R², Adjusted R², Std. Dev. and C.V. % are given in the following table, along with the regression equation generated for each response.

A) Full model for R1 (% drug release)

Drug Release = +68.95 + 3.04 × A + 3.28 × B – 0.4100 × C – 0.1975 × A × B + 0.9500 × A × C + 0.4000 × B × C + 22.57 × A² + 2.32 × B² – 0.3746 × C

Discussion:

The independent variables A (PVPK30) and B (HPMC E15), (MCC) showed a positive effect on drug release. Increasing the levels of these excipients resulted in an increase in the percentage of drug release. The quadratic term A² (PVPK30) had a very strong positive effect, suggesting that increasing PVPK30 levels within the experimental range considerably enhanced drug release, though with potential for non-linearity at higher levels.

• A (PVPK30)
• B (HPMC E15).
• C (Microcrystalline cellulose)

 has a positive effect, as shown in Fig. 11 and 12

Figure 11                                                               

Figure 12

B) Full Model for R 2 (Compressibility Index %)

The compressibility index was modeled using the following equation:

Compressibility Index = +17.75 – 0.8088 × A – 1.42 × B + 0.7325 × C + 2.25 × A × B – 0.0350 × A × C + 0.5950 × B × C – 4.41 × A² – 0.1929 × B² – 0.2604 × C²

DISCUSSION:

PVP K30 (A): Exhibited a negative effect on compressibility index. Increasing the concentration of PVPK30 reduced the compressibility index value, indicating an improvement in flow and compressibility characteristics. HPMC E15 (B): showed a positive effect on compressibility index. MCC (C): Demonstrated a positive effect on compressibility index. Increasing the concentration of MCC led to higher compressibility index. shown in Fig. 13 and 14

Figure 14

In-Vitro Percent Drug Release

The drug release study was conducted in phosphate buffer pH 6.8 and compared with pure Fenofibrate. Key findings: SD6 batch (F8) showed maximum drug content (98.94%) and optimal cumulative drug release within 45 minutes. Drug release increased with higher quantities of PVP K30, HPMC E15 enhancing solubility and dissolution rate of Fenofibrate.

Tables 13:  In-Vitro Percent Drug Release of Fenofibrate in Buffer pH 6.8 (F1-F4)

Tables 14:  In-Vitro Percent Drug Release of Fenofibrate in Buffer pH 6.8 (F5-F8)

Tables 15:  In-Vitro Percent Drug Release of Fenofibrate in Buffer pH 6.8 (F1-F12)

Figure 11: In vitro drug release (F1 to F4)

Discussion

The drug release study was conducted in phosphate buffer pH 6.8 and compared with pure Fenofibrate. Key findings: SD6 batch (F8) showed maximum drug content (98.94%) and optimal cumulative drug release within 45 minutes. Drug release increased with higher quantities of PVP K30, HPMC E15 enhancing solubility and dissolution rate of Fenofibrate

Stability study of optimized formulation

Table 16:  Stability study of optimized formulation