Development of Solid Dispersion System for Improving Solubility and Bioavailability of Poorly Soluble Drug

Fenofibrate is an antihyperlipidemic medication classified as a fibrate. It aids in diminishing high plasma levels of triglycerides and LDL. It is generally a more effective medicine compared to other fibrates. Fenofibrate is classified as a BCS Class II medication, which results in its limited bioavailability.[1]The improvement of oral bioavailability for poorly water-soluble drugs frequently results in inadequate bioavailability due to low and inconsistent absorption levels. Drugs that experience dissolution rate limitations in gastrointestinal absorption exhibit enhanced solubility and bioavailability through a reduction in particle size. [2]

Nevertheless, medications frequently induce the aggregation and agglomeration of particles, resulting in inadequate wettability. Solid dispersions of poorly water-soluble medicines with water-soluble carriers have mitigated these issues and improved solubility. The advancement of solid dispersions as a feasible technique to improve the bioavailability of weakly water-soluble pharmaceuticals has surpassed the constraints of earlier methods, including salt creation, solubilization via co-solvents, particle size reduction, and solvent evaporation techniques. Research indicated that medications in solid dispersion may not necessarily have to be in a micronized form. A portion of the drug may molecularly disperse within the matrix, resulting in a solid dispersion.[3]

Upon exposure of the solid dispersion to aqueous media, the carrier dissolves, resulting in the release of the drug as fine colloidal particles. Solid dispersions in water-soluble carriers have garnered significant attention for enhancing the dissolution rate and potentially the bioavailability of various hydrophobic drugs. Fenofibrate requires enhancement of its oral bioavailability, solubility, and dissolution rate. The approach has been employed to enhance the solubility, dissolution rate, and bioavailability of poorly water-soluble pharmaceuticals, including solid dispersions. solvent evaporation technique.[4] This method enhances the solubility, dissolution rate, and bioavailability of poorly soluble Fenofibrate medication. It is a direct, industrially advantageous technique.

The objective of the present research project was to formulate Fenofibrate tablets utilizing a solvent evaporation method to enhance solubility and dissolution rate.

Solid dispersion

Solid dispersion facilitates the fragmentation of the drug into exceedingly fine particles, thereby augmenting its surface area and enhancing its dissolution rate, as articulated by the Noyes-Whitney equation. While diminishing particle size to the nanoscale can enhance dissolution rates, it cannot augment the drug's solubility beyond its inherent threshold in intestinal fluids. To address this issue, solid dispersion is an efficacious method for improving the solubility and bioavailability of poorly water-soluble pharmaceuticals. It can elevate the drug concentration at the absorption site and potentially induce a transient supersaturated state, thereby enhancing bioavailability. Solid dispersion continues to be a prominent research focus due to its versatility and applicability across various dosage forms, particularly tablets, which are the most prevalent method for oral drug delivery.[5]

DRUG PROFILE

Fenofibrate is an antihyperlipidemic drug chemically known as Isopropyl 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropionate, with a molecular formula of C??H??ClO? and molecular weight of 360.83 g/mol. It acts by activating PPAR-α receptors, which enhance lipid metabolism and reduce triglyceride levels in the body. Fenofibrate belongs to BCS Class II drugs, characterized by low solubility and high permeability. It appears as a white to off-white crystalline powder with a melting point of 79–82 °C. The drug is practically insoluble in water but soluble in various organic solvents. The λmax of Fenofibrate in methanol is approximately 286 nm. Due to its poor aqueous solubility, it was selected as a model drug for the development of a solid dispersion system to improve solubility and bioavailability.[6]

MATERIALS AND METHOD

MATERIALS

Fenofibrate was obtained from Shree Chem Products. Polyethylene glycol (PEG 6000), methanol, and potassium dihydrogen phosphate were procured from Loba Chemie Pvt. Ltd.. Polyvinylpyrrolidone (PVP K30) was supplied by HiMedia Laboratories Pvt. Ltd., while Hydroxypropyl methylcellulose (HPMC) was obtained from Colorcon Asia Pvt. Ltd.. Poloxamer 188 was purchased from BASF Chemicals India Pvt. Ltd.. Ethanol and sodium hydroxide were obtained from Merck Specialities Pvt. Ltd., and chloroform was procured from S.D. Fine Chemicals Ltd.. Distilled water used in the study was supplied by the in-house laboratory. All chemicals and reagents used were of analytical or laboratory grade.

METHOD OF PREPARATION (SOLVENT EVAPORATION METHOD)

Solid dispersions of Fenofibrate were prepared using the solvent evaporation method. Accurately weighed quantities of Fenofibrate, PEG 6000, and PVP K30 were taken according to the formulation composition. The drug and polymers were dissolved in a sufficient quantity of ethanol with continuous stirring to obtain a clear and uniform solution. The resulting solution was subjected to solvent evaporation at controlled temperature until complete removal of ethanol and formation of a dry solid mass. The dried mass was further pulverized using mortar and pestle and passed through a suitable sieve to obtain uniform particle size. The prepared solid dispersions were stored in airtight containers for further evaluation studies.[7]

PREFORMULATION STUDIES[21-25]

Preformulation studies of Fenofibrate were carried out to evaluate its physicochemical properties for the development of a solid dispersion system intended to improve solubility and bioavailability.

Solubility Profile of Fenofibrate

The solubility study was performed to determine the intrinsic solubility of Fenofibrate in different solvents and buffer media. Excess amount of Fenofibrate was added separately to distilled water, ethanol, pH 1.2 buffer, and pH 6.8 buffer. The mixtures were kept in a water bath shaker at 37°C for 24 hours to attain equilibrium. After shaking, the solutions were filtered to remove undissolved drug particles. The concentration of dissolved drug was analyzed using UV-Visible spectrophotometry or HPLC method. The study helped in understanding the solubility behavior of Fenofibrate under gastric and intestinal conditions.[8]

Partition Coefficient Study (Log P)

The partition coefficient study was carried out to determine the lipophilic nature of Fenofibrate. Equal volumes of octanol and water (1:1 v/v) were taken, and Fenofibrate was added to the mixture. The system was shaken thoroughly until equilibrium was achieved. After phase separation, the concentration of drug in both octanol and aqueous phases was determined. The partition coefficient (Log P) was calculated as the logarithm of the ratio of drug concentration in octanol phase to aqueous phase, indicating the hydrophilic or lipophilic characteristics of the drug.[9]

Melting Point Determination

The melting point of Fenofibrate was determined using the capillary method. A small quantity of the drug was weighed and dried in a desiccator to remove moisture. The sample was triturated gently to obtain a fine powder. The powdered drug was filled into a sealed capillary tube to a height of approximately 2–3 mm. The capillary tube was placed in a melting point apparatus near the temperature probe. The temperature was gradually increased at a heating rate of 1–2°C per minute. The temperature at which the drug started melting and the temperature at which complete melting occurred were recorded. The experiment was performed in triplicate, and the average melting point was calculated.[10]

UV Spectroscopy

Determination of λmax

Accurately weighed 10 mg of Fenofibrate was transferred into a 100 mL volumetric flask. The drug was dissolved in a small quantity of methanol, and the volume was made up to 100 mL with methanol to obtain a stock solution of 100 µg/mL. From this stock solution, a suitable dilution of 10 µg/mL was prepared. The solution was scanned in the wavelength range of 200–400 nm using a UV-Visible spectrophotometer with methanol as blank. The wavelength showing maximum absorbance (λmax) was found to be 286 nm.[11]

Calibration Curve Preparation

A standard stock solution of Fenofibrate (100 µg/mL) was prepared by dissolving 10 mg of drug in 100 mL of methanol. From this stock solution, aliquots were withdrawn and diluted with methanol to prepare concentrations of 5, 10, 15, 20, 25, and 30 µg/mL. The absorbance of each solution was measured at 286 nm using methanol as blank. All measurements were carried out in triplicate, and the average absorbance values were recorded. A calibration curve was plotted by taking concentration on the X-axis and absorbance on the Y-axis. The regression equation and correlation coefficient (R²) were calculated.[12]

Fourier Transform Infrared Spectroscopy (FTIR) Study

FTIR study was performed to evaluate the compatibility between Fenofibrate and excipients used in the formulation. Approximately 2 mg of pure drug and excipients were weighed individually. Physical mixtures of drug and excipients were prepared in a 1:1 ratio. Each sample was mixed with 100 mg of dry potassium bromide (KBr) and finely triturated using a mortar and pestle. The mixture was compressed into pellets using a hydraulic press under pressure of 6–8 tons for 2–3 minutes. The prepared KBr pellets were placed in the FTIR sample holder, and spectra were recorded over the range of 4000–400 cm?¹ at a resolution of 4 cm?¹ with 32 scans per sample.[13]

Differential Scanning Calorimetry (DSC)

Differential Scanning Calorimetry (DSC) analysis was carried out to study the thermal behavior of Fenofibrate, excipients, physical mixtures, and solid dispersion formulations. Approximately 3–5 mg of pure drug, excipients, and prepared solid dispersion samples were accurately weighed and placed into clean aluminum DSC pans. The pans were sealed using a crimping tool to prevent sample loss. An empty sealed aluminum pan was used as reference. The DSC instrument was calibrated using indium standard. The samples were analyzed under a nitrogen atmosphere maintained at a flow rate of 20–40 mL/min to provide inert conditions during analysis.[14]

Table: Evaluation Parameters and Methods for Solid Dispersion of Fenofibrate

Table: Composition of Solid Dispersion Formulations of Fenofibrate by Solvent Evaporation Method

RESULT AND DISCUSSION

Solubility Profile of Fenofibrate

The solubility of Fenofibrate was evaluated in different solvents and buffer systems to study its solubility behavior under various physiological conditions. The observations obtained are presented in Table

Table : Solubility of Fenofibrate in Different Media

The solubility study of Fenofibrate was carried out in different solvents and buffer media. The drug was found to be practically insoluble in distilled water, slightly soluble in pH 1.2 and pH 6.8 buffer, and freely soluble in ethanol. These results confirmed the poor aqueous solubility and lipophilic nature of Fenofibrate, supporting the use of solid dispersion technique to enhance its solubility and bioavailability.

Partition Coefficient Study of Fenofibrate

The partition coefficient study of Fenofibrate using n-octanol and water showed a Log P value of 5.18 ± 0.12. The high Log P value indicates the highly lipophilic nature of the drug, which contributes to poor aqueous solubility and supports the need for solid dispersion technique to improve solubility and bioavailability.

Melting Point Determination of Fenofibrate

The melting point of Fenofibrate was determined by capillary method and found to be 80.2°C ± 1.1°C. The sharp and consistent melting range indicated the purity of the drug and matched reported literature values.

UV Spectrophotometric Analysis and Calibration Curve

The UV spectrum of Fenofibrate in methanol showed maximum absorbance (λmax) at 286 nm. A calibration curve was prepared in the concentration range of 5–30 µg/mL, and absorbance was measured at 286 nm. The results showed a linear increase in absorbance with concentration, confirming Beer-Lambert’s law.

Table : Calibration Data of Fenofibrate

Fig.: Calibration Curve

The correlation coefficient (R²) was found to be 0.999, indicating excellent linear relationship between concentration and absorbance. Regression equation:y=0.056x+0.001y = 0.056x + 0.001y=0.056x+0.001

Fourier Transform Infrared Spectroscopy (FTIR) Study

FTIR analysis was performed to identify characteristic functional groups and possible drug- excipient interactions.

Fig : Fenofibrate FTIR

FTIR analysis of Fenofibrate showed characteristic peaks at approximately 1725 cm?¹ for ester C=O stretching, 1600 cm?¹ for aromatic C=C stretching, 1200–1300 cm?¹ for C–O stretching, and 2850–2950 cm?¹ for C–H stretching. All major characteristic peaks of the drug were retained without significant shifting. No new peaks or disappearance of peaks were observed in drug–excipient mixtures, indicating the absence of chemical interaction and good compatibility of Fenofibrate with selected excipients.

Differential Scanning Calorimetry (DSC)

DSC thermograms were recorded to study thermal behavior and crystallinity.

Fig.: Fenofibrate DSC thermograms

DSC analysis of pure Fenofibrate showed a sharp endothermic peak at 207°C, confirming its crystalline nature. The physical mixture showed a similar but slightly broadened peak, indicating minor interaction with excipients. In the solid dispersion formulation, reduction or disappearance of the peak was observed, suggesting conversion of the drug from crystalline to amorphous form, which contributes to enhanced solubility and dissolution.

Physical Appearance

The physical appearance of solid dispersion batches (SD1–SD9) of Fenofibrate was evaluated for color, texture, lumpiness, and homogeneity. Most formulations showed white to off-white color with smooth or fine powder texture, indicating uniform drug distribution and absence of degradation. Batch SD2 showed the best physical appearance with white color, fine texture, no lumpiness, and excellent homogeneity. Slight aggregation was observed in SD3 due to possible residual moisture during preparation.

Powder Flow Properties

The powder flow properties were evaluated using bulk density, tapped density, Carr’s index, and angle of repose. All batches showed acceptable flow properties with Carr’s index ranging from 11.1% to 18.2% and angle of repose between 25° and 30°. Batch SD2 exhibited the best flow behavior with lowest Carr’s index (11.1%) and angle of repose (25°), indicating excellent compressibility and flowability suitable for further formulation processing.

Drug Content

Drug content analysis showed that all solid dispersion batches contained drug within acceptable pharmaceutical limits. The observed drug content ranged from 97.8% to 98.6%, indicating uniform drug incorporation and minimal drug loss during preparation. Batch SD1 showed the highest drug content (98.6%), followed by SD4 and SD3, confirming efficient entrapment of drug within the carrier system.

In-Vitro Dissolution Studies

In-vitro dissolution studies of Fenofibrate solid dispersions were carried out in pH 1.2 and pH 6.8 media using USP Type II apparatus. All formulations showed improved drug release compared to pure drug. Drug release ranged from 68–78% in pH 1.2 and 82–90% in pH 6.8 buffer. Batch SD4 exhibited maximum drug release in both media, indicating enhanced solubility and dissolution due to reduced crystallinity, improved wettability, and molecular dispersion of drug in hydrophilic carriers.

Dissolution Profile

The dissolution profile study demonstrated gradual and enhanced release of Fenofibrate from all solid dispersion batches over 120 minutes. Batch SD4 showed the highest dissolution performance, while SD3 exhibited comparatively lower release due to slight particle aggregation. Overall, the solid dispersion system significantly improved the dissolution behavior of Fenofibrate, confirming the effectiveness of the formulation approach.

Table : Physical Characteristics of Solid Dispersion Batches of Fenofibrate

Table :Powder Flow Properties

Table : Drug Content

Table : In-Vitro Dissolution Studies

Table : Dissolution Profile Table

Table: Stability study