INTRODUCTION:

Solubility is one of the key physicochemical properties of drug compounds in predicting drug absorption in the gastrointestinal tract. Drugs with low water solubility often require higher doses to achieve therapeutic concentrations after oral administration. In general, drugs that are weak acids or weak bases tend to have poor water solubility^1,2.

Liquisolid is a technique used to enhance the rate of drug dissolution. It offers the advantage of simple manufacturing with relatively low production costs and can increase the bioavailability of BCS (Biopharmaceutics Classification System) class II and IV drugs³^,4,5.

The liquisolid technique involves dissolving hydrophobic drugs in non-volatile, non-toxic, and hydrophilic solvents such as propylene glycol, polyethylene glycol, glycerin, or polysorbate-80. These are then mixed with carriers, such as microcrystalline cellulose, lactose, or starch, along with coating materials like silica, in optimized proportions. This method is known to increase the surface area and wettability of the drug. For drugs with low solubility in water, liquisolid systems are expected to enhance drug release and bioavailability when administered orally⁴^,5,6. The liquisolid tablet formulation can be applied to various drugs that are poorly soluble or almost insoluble in water, especially those with small doses (less than 100 mg)^5,6,7. There are three mechanisms for increasing drug release from the liquisolid system: increasing the drug's surface area, enhancing its solubility, and improving its wettability properties^7,8,9.

Fenofibric acid is an antihyperlipidemic agent that can reduce cholesterol levels in patients at risk of cardiovascular disease by lowering LDL and triglyceride levels while increasing HDL levels. However, fenofibric acid is insoluble in water, resulting in a low dissolution rate in gastrointestinal fluids. It is an active metabolite of fenofibrate and belongs to BCS class II, characterized by low water solubility but high permeability in the intestine^10,11.

Efforts to increase the dissolution of fenofibric acid include the addition of MgCO3 and carrageenan as catalysts¹¹, the formation of surface solid dispersions with crosscarmellose sodium¹², self-nanoemulsifying drug delivery system (SNEDDS)^13,14, and the development of multicomponent crystals using nicotinamide and nicotinic acid coformers¹⁵. One of the techniques to increase the dissolution of fenofibric acid, namely the solid SNEDDS, has also been proven to increase its bioavailability (the rate of drug entering the systemic circulation)¹⁶.

The purpose of this study was to determine the characteristics of the solid-state properties of fenofibric acid in a liquisolid system. The characterization carried out included chemical structure characterization, thermal analysis, crystal property analysis, and microscopic analysis.

MATERIALS AND METHODS:

Materials:

Fenofibric acid (BOC Sciences USA), Transcutol® HP (Gattefossé, France), Neusilin® (Fuji Chemical, Japan), Aerosil® 200 (Evonik Industries, Germany).

Liquisolid Design^17,18

The dosage of fenofibric acid is 35 mg. The ɸ values for Neusilin® US2 and Aerosil® 200 with Transcutol® HP are 1.6 and 1.4, respectively. The calculation of the liquid load factor (Lf) for the excipient ratio (R) is 20, using the following equation:

Lf = ɸCa + ɸCo / R

Lf = 1.6 + (1.4/20) = 1.67

Note:

Lf: Liquid load factor

ɸCa: Carrier material value

ɸCo: Coating material value

R: Excipient ratio

Calculation of the Amount of Carrier Material (Neusilin® US2)

The amount of carrier material is calculated using the equation:

Q = W / Lf, where W is the amount of drug in a non-volatile solvent, and Lf is the liquid load factor. For the different formulations:

F1: 0.035 + 0.14 = 0.175

F2: 0.035 + 0.28 = 0.315

F3: 0.035 + 0.42 = 0.455

The amount of Neusilin® US2 is then calculated as:

F1: 0.175 / 1.67 = 0.104g

F2: 0.315 / 1.67 = 0.188g

F3: 0.455 / 1.67 = 0.272g

Calculation of the Amount of Coating Material (Aerosil® 200)

The amount of coating material is calculated using the equation: q = Q/R, where Q is the amount of carrier material and R is the excipient ratio.

For the different formulations:

F1: 0.104 / 20 = 0.005g

F2: 0.188 / 20 = 0.009g

F3: 0.272 / 20 = 0.013g

Preparation of Liquisolid:

Fenofibric acid and the non-volatile solvent (Transcutol® HP) were mixed until fully dissolved. A binary mixture of carrier (Neusilin® US2) and coating material (Aerosil® 200) was then prepared in a 20:1 ratio. This binary mixture was gradually added to the drug solution until the mixture formed a dry powder mass.

Table 1. Liquisolid of Fenofibric Acid

Materials	Function	F1	F2	F3
Fenofibric acid (g)	Active ingredient	0.035	0.035	0.035
Transcutol® HP (ml)	Solvent	0.140	0.280	0.420
Neusillin® US2 (g)	Carrier material	0.104	0.188	0.272
Aerosil® 200 (g)	Coating material	0.005	0.009	0.013

Characterization of Fenofibric Acid Liquisolid^17,18,20

Fourier Transform Infrared (FTIR):

The functional group spectra were obtained using an FTIR spectrophotometer (Agilent Cary 630, USA) with the ATR (Attenuated Total Reflection) method. The sample was placed on the light source at the center of the object table and covered with a cone-shaped metal. Percent transmittance was then measured in the wave number range of 4500 to 450 cm⁻¹.

Scanning Electron Microscope (SEM):

The powder sample was mounted on an aluminum sample holder and coated with a 10nm thick layer of gold. The sample was then observed at various magnifications under the SEM (Hitachi SU3500, Japan). The voltage was set to 20kV, and the current was maintained at 12mA.

Powder X-Ray Diffraction (PXRD):

X-ray diffraction analysis of the sample powder was performed using an X-ray diffractometer (Bruker D8 Advance, Germany) at room temperature using a diffractometer. The measurement conditions were as follows: Cu metal target, Kα filter, 40kV voltage, and 40 mA current. The analysis was carried out in the 2θ range of 5º to 35º. The sample was placed in a sample holder and leveled to avoid particle orientation during preparation.

Differential Scanning Calorimetry (DSC):

The sample was thermally analyzed using a DSC device (DSC-60, Japan) calibrated with indium. Samples weighing 3-5mg were placed on a coated aluminum plate. The DSC device was programmed to heat the sample in a temperature range of 30–200ºC, with a heating rate of 10 ºC per minute.

Polarization Microscopy:

Liquisolid formulations were observed microscopically using a polarizing microscope (BestScope, China) and compared with fenofibric acid and Neusilin® US2. Sample testing was carried out by placing the samples on a glass slide and observing them under a polarizing microscope with 10X magnification.

RESULT:

Fourier Transform Infrared Spectroscopy (FTIR):

Fourier Transform Infrared Spectroscopy (FTIR) was used in this study to analyze the functional groups of chemical compounds. In the FTIR spectrum of pure fenofibric acid, a peak at 2990 cm-¹ indicates O-H stretching vibrations of the carboxylic group in the fenofibric acid structure. A sharp peak at 1702 cm-¹ corresponds to C=O stretching vibrations, suggesting the presence of a ketone functional group. The peak at 1643 cm-¹ represents the symmetrical C=C stretching vibration, indicating the presence of an alkene functional group. A peak at 1592 cm-¹ shows the symmetrical stretching of the aromatic ring. At 1300 cm⁻¹, the presence of C-O vibrations suggests an ester functional group, while the peak at 720 cm⁻¹ indicates the presence of an alkyl halide (C-Cl) functional group¹⁴. The FTIR characterization results for the third formulation (F3) showed slight peak shifts compared to the pure fenofibric acid. In F1, a peak at 3396 cm-¹ indicates the presence of the O-H group of the carboxylic acid functional group from fenofibric acid's chemical structure. The same peak at 1651 cm-¹ was observed, corresponding to C=O stretching vibrations, which indicates a ketone functional group. A peak at 1596 cm⁻¹ represents the symmetrical C=C stretching vibration, suggesting the presence of aromatic ring vibrations. At 1100 cm⁻¹, the C-O stretching vibration suggests an ester functional group, and peaks at 761 cm⁻¹ and 669 cm⁻¹ correspond to an alkyl halide (C-Cl) group. In F2, a slight peak shift was observed at 2977 cm⁻¹, indicating the presence of the O-H group of the carboxylic acid. The peak at 1596 cm-¹ corresponds to C=C symmetry stretching, indicating aromatic ring vibrations. A peak at 1199 cm⁻¹ corresponds to a C-O stretch, indicating the presence of an ester functional group, and a peak at 761 cm⁻¹ indicates an alkyl halide group. In F3, slight shifts were observed in the peaks at 3396, 2976, and 2878 cm⁻¹, indicating the presence of the O-H carboxylic group. The peak at 1558 cm-¹ corresponds to a C=C symmetry stretch, indicating aromatic ring vibrations. The peak at 1100 cm⁻¹ suggests the presence of an ester functional group, and the peak at 761 cm⁻¹ indicates an alkyl halide group.

Figure 1. FTIR spectrum of fenofibric acid liquisolid formulation

Differential Scanning Calorimetry (DSC):

Thermal analysis using Differential Scanning Calorimetry (DSC) was performed on fenofibric acid, Neusilin® US2, and the liquisolid formulation of fenofibric acid (Figure 2). The DSC analysis was conducted over a temperature range of 30–300˚C, with a heating rate of 10˚C/min. The DSC thermogram of pure fenofibric acid showed a single endothermic peak with a melting point at 185.76°C. In contrast, the DSC thermograms of the liquisolid formulations of fenofibric acid (F1, F2, and F3) displayed two endothermic peaks.

Figure 2. DSC thermogram of fenofibric acid liquisolid formulation

Powder X-Ray Diffraction (PXRD):

The diffractogram of pure fenofibric acid revealed a distinct crystal pattern characteristic of the compound. The PXRD pattern of the pure fenofibric acid in Fig. 3 showed peaks at 2 theta 5.49°, 7.88°, 15.85°, 18.41°, 23.08°, and 30.16°, indicating the crystalline nature of the fenofibric acid. However, the PXRD diffractograms of the liquisolid formulations of fenofibric acid showed the disappearance of the crystalline peaks.

Figure 3. PXRD patterns of fenofibric acid, Neusillin® US2, Aerosil® 200, F1, F2, and F3

Scanning Electron Microscope (SEM):

The SEM examination results provide additional information regarding the morphology of liquisolid (Figure 4). Microscopic characterization of liquisolid shows a difference in morphology compared to pure fenofibric acid. Pure fenofibric acid has a microscopic shape in the form of irregular plates^12,14. The surface of Neusilin® US2 is round with many pores.

(a) (b)

(c) (d)

(e) (f)

Figure 4. SEM images of (a) Fenofibric acid (magnification x2500) (b) Neusillin® US2 (magnification x800), (c) Aerosil® 200 (magnification x20,000), (d) F1, (e) F2, (f) F3 (magnification 500x)

(a) (b)

(e) (f)

Figure 5. Polarizing microscope images of (a) fenofibric acid, (b) Neusillin® US2, (c) Aerosil® 200, (d) F1, (e) F2, (f) F3

Polarization Microscopy:

Polarizing microscopy is a valuable tool for identifying crystalline structures and distinguishing between amorphous and crystalline phases²¹, allowing for confirmation whether fenofibric acid remains in a crystalline form or has completely dissolved in the liquisolid formulation. Characterization results using a polarization microscope showed that fenofibric acid has a crystalline shape, Neusilin® US2 is in porous spheres, and Aerosil® 200 appears as fine particles. In F1, the microscopic results reveal spherical particles of Neusilin® US2, with a few remaining crystals of fenofibric acid, as F1 contains a mixture of fenofibric acid slightly soluble in Transcutol® HP. In F2, the microscopic results show spherical particles with fewer crystals of fenofibric acid compared to F1, as F2 contains a mixture of fenofibric acid that is more soluble in Transcutol® HP. In F3, the microscopic results show spherical particles, and the crystals of fenofibric acid are no longer visible, as fenofibric acid has completely dissolved in Transcutol® HP in this formulation (Figure 5).

DISCUSSION:

A liquisolid system of fenofibric acid was successfully developed using Transcutol® HP as the solvent, Neusilin® US2 as the adsorbent, and Aerosil® 200 as the coating agent. Transcutol was used as the solvent due to its high capacity to dissolve fenofibric acid¹³. Meanwhile, Neusilin and Aerosil were employed as coating materials because of their excellent liquid adsorption capacity^14,22. The formulations were prepared with varying ratios of fenofibric acid to Transcutol® HP, namely 1:4 (F1), 1:8 (F2), and 1:12 (F3). These variations were based on the solubility profile of fenofibric acid in Transcutol® HP. F1 represents a ratio in which fenofibric acid is only partially dissolved in the solvent. In F2, a larger portion of the drug is dissolved, although not completely. In contrast, F3 represents a condition in which fenofibric acid is fully dissolved in Transcutol® HP. These variations led to differences in solid-state properties, which were evaluated using SEM, PXRD, and polarized light microscopy.

FTIR analysis revealed no new peaks in the liquisolid spectra of fenofibric acid, indicating that its chemical structure remained unchanged in the formulations¹⁴. The FTIR spectra of pure fenofibric acid, individual liquisolid components, and the final formulations are shown in Figure 1. This finding confirms that no chemical interaction occurred between fenofibric acid and the excipients used in the liquisolid system. These results are also consistent with previous studies¹⁴, where fenofibric acid in a solid SNEDDS system using the same excipients (Transcutol® HP and Neusilin® US2) exhibited similar findings, despite being formulated in a different delivery system.

The DSC thermogram of F1 displayed two endothermic peaks at 138.18 °C and 211.04 °C, suggesting a shift in melting behavior compared to pure fenofibric acid. Similarly, F2 exhibited peaks at 152.66 °C and 220.57 °C, while F3 showed peaks at 139.02 °C and 217.68 °C. These downward shifts in endothermic peak temperatures suggest a reduction in crystallinity, indicating partial transformation of the drug into an amorphous form within the liquisolid matrix^21,22. PXRD analysis, used to detect the crystallinity of compounds through their diffraction patterns^23,24,25. The results showed the disappearance of characteristic crystalline peaks in all liquisolid formulations. This disappearance indicates that fenofibric acid was molecularly dispersed in Transcutol® HP and adsorbed onto Neusilin® US2, resulting in an amorphous form. The PXRD diffractograms exhibited broadened peaks, consistent with amorphous characteristics^14,26,27. Quantitative analysis revealed that F1 contained 68.5% amorphous and 31.5% crystalline content, F2 had 69.1% amorphous and 30.9% crystalline content, and F3 showed the highest amorphous content at 82.4%, with only 17.6% crystalline content (Figure 3).

SEM examination showed that the surface morphology of F1, F2, and F3 was spherical, similar to that of Neusilin® US2, and no visible fenofibric acid was observed^14,17. This could be due to the dissolution of fenofibric acid in Transcutol® HP, resulting in only Neusilin® US2 particles being visible in the SEM images^14,17. Polarized light microscopy confirmed that fenofibric acid was not completely soluble in any of the liquisolid systems (F1, F2, or F3). The characterization results using polarized light microscopy indicated that the visibility of undissolved fenofibric acid was related to the ratio of Transcutol® HP used as the solvent. A higher ratio of Transcutol® HP (F3) resulted in greater dissolution of fenofibric acid, as indicated by the absence of visible drug crystals under the polarized light microscope.

CONCLUSION:

This study has revealed the solid-state properties of fenofibric acid in the liquisolid system. The liquisolid technique successfully converted fenofibric acid from a crystalline to an amorphous form without causing any chemical changes in its molecular structure. The degree of amorphization in the liquisolid formulations was determined by the ratio of fenofibric acid to the solvent (Transcutol® HP). A higher amount of solvent, as observed in formulation F3, resulted in a greater extent of amorphization. These amorphous solid-state characteristics of fenofibric acid in the liquisolid system are expected to enhance its dissolution rate.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would like to thank Sekolah Tinggi Ilmu Farmasi Riau (STIFAR), Bandung Institute of Technology (ITB), and Gadjah Mada University (UGM), Indonesia, for their kind support for all other lab studies.

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Received on 25.06.2025 Revised on 15.11.2025

Accepted on 22.01.2026 Published on 01.07.2026

Available online from July 04, 2026

Research J. Pharmacy and Technology. 2026;19(7):3151-3156.

DOI: 10.52711/0974-360X.2026.00447

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