INTRODUCTION:

Etoricoxib (as seen Figure. 1) is an oral analgesic and non-steroidal anti-inflammatory drug (NSAID) that notably inhibits cyclooxygenase-2 (COX-2) which relieve pain, fever, and inflammatory conditions¹. In comparison to other COX-2 selective NSAIDs (e.g. rofecoxib, valdecoxib, or celecoxib), etoricoxib has higher selectivity and a lower risk of gastrointestinal toxicity².

However, etoricoxib is classified as class II based on BCS (Biopharmaceutical Classification System) with low solubility and high permeability³, in which its solubility in water is 76.7 μg/mL⁴. Therefore, efforts are needed to enhance the solubility of etoricoxib in order to maximize the performance of etoricoxib so that it can provide a more effective therapeutic effect^4,5.

Figure 1. Chemical structure of etoricoxib

Solubility is one of the determining factors that affects the process in manufacturing and formulating pharmaceutical dosage forms ⁶. By improving the solubility, it is expected that greater dose of the drug can be administered without the risk of precipitation or loss of therapeutic effect^7-9. A number of methods have been carried out to modify the solubility and dissolution of etoricoxib, including the formation of etoricoxib solid dispersion which showed an increase in etoricoxib solubility significantly ^10-12. However, the solid dispersion is likely sensitive to temperature and humidity during storage, which may trigger changes in crystallinity and impact the dissolution ¹³. Another study reported the formation of inclusion complex of etoricoxib with beta-cyclodextrin that showed an increase in the dissolution rate in 30 minutes¹⁴, yet the inclusion complexes tend to have a long preparation method and difficulty in preparing into dosage formulations ¹⁵.

One of recent strategies in increasing the solubility of etoricoxib is the by altering the solid phase into amorphous phase which known as co-amorph ¹⁶. Co-amorphs consist of active pharmaceutical substances with one or more coformers in the form of either drugs or excipients that have lower molecular weights. The use of coformers in the preparation of co-amorphs can improve the physical stability, solubility and dissolution rate of the co-amorphic form compared to the amorphous form alone ¹⁷. Co-amorphs are formed due to strong hydrogen bonding in the stoichiometric ratio between the active substance and excipients. The co-amorphous form shows markedly improved both solubility and also dissolution rate of the active compound compared to the crystalline phase ¹⁸.

Figure 2. Chemical Structure of Citric Acid

In this research, the solubility of etoricoxib is expected to be increased by preparing into co-amorphs phase with citric acid. The chosen coformer have to get the approval of Food Drug Administration (FDA) with the qualification of Generally Recognized as Safe (GRAS) material which is declared safe for human consumption ¹⁹. Citric acid can be used as the coformer because it is a weak organic acid, has high solubility in water, approximately 0.592 g/mL and pKa value of 4.76. Organoleptically, citric acid is a white crystal with a molecular weight of 192.123 g/mol at melt at temperature of 153°C ²⁰. In previous studies, citric acid has been made using active substances such as piroxicam, ketoconazole and loratadine ^21,22.

The co-amorphs of etoricoxib and citric acid is proposed to prepare by the Liquid Assisted Grinding (LAG) method, in which it offers simplify the manufacturing process and using a small amount of solvent that could promote in accelerating the formation the of co-amorph. In addition, this method requires less mechanical energy compared to the dry grinding method because the solvent acts as a lubricant which reduces friction and heat generated during the grinding process ²³. The co-amorphs were then characterized by several solid state characterizations including thermal analysis by Differential Scanning Calorimetry (DSC), crystallinity analysis by Powder X-ray Diffraction (PXRD), chemical composition analysis by Fourier Transform Infra-Red (FTIR) spectrophotometry, morphology analysis by Scanning Electron Microscope (SEM), and solubility and dissolution test ²⁴.

MATERIALS AND METHODS:

Materials:

Etoricoxib (PT Metrochem API Private Limited, Indonesia), Piperine (Tokyo Chemical Industry, Jepang), ethanol pro analysis (Merck, Germany), acetonitrile gradient grade for liquid chromatography (Merck, Germany), methanol gradient grade for liquid chromatography (Merck, Germany), KH₂PO₄ (Merck, Germany), and distilled water.

Methods:

Preparation of co-amorphous etoricoxib and citric acid

Etoricoxib and citric acid were prepared with a mole ratio of 1:1 (0.358 g: 0.192 g). The mixture of the two samples was grinding while adding ethanol pro analysis (98%) approximately 137.5 μL. Then, the sample was stored in a tightly closed container in a desiccator.

Preparation of co-amorphous etoricoxib and citric acid:

Physical mixture of etoricoxib and citric acid were prepared at the same amount as co-amorphous and mixed homogenously in a jar. Then, the powder was kept in a desiccator.

Solid state characterization:

For analysis below, the samples processed were etoricoxib, citric acid, physical mixture and co-amorphous of etoricoxib and citric acid, unless otherwise specified.

Differential Scanning Calorimetry (DSC) analysis:

Thermal analysis was carried out using DSC (Shimadzu DSC-60 Plus, Japan) instrument. Samples were prepared in an aluminum pan and the DSC was set at a temperature range of 10-160℃ with a heating rate of 10℃ per minute.

X-ray Diffraction (XRD) analysis:

XRD analysis was performed using a Powder X-Ray Diffraction apparatus (PANalytical MPD PW3040/60 type X' Pert Pro, Netherlands). Measurements were carried out under the following conditions: Cu metal target, Kα filter, 40 kV voltage, mA current, and analysis was carried out in the 2θ range of 5°C - 45°C.

Fourier transform infrared (FT-IR) spectroscopy analysis:

FTIR analysis (Thermo Fisher Scientific, USA) was carried out by placing on top of the ATR crystal until it covered all the crystal surfaces. The sample was covered by applying slight pressure and IR absorption spectra at a wavelength of 4000 - 400 cm^-1 were performed.

Scanning Electron Microscopy (SEM) analysis:

The morphology of the samples was analyzed using SEM (Hitachi FLEXSEM 100, Japan) at a voltage of 10 kV. The samples were placed in a sample holder and sprayed with a thin layer of gold-palladium. The measurement conditions were set at 10 kV and 12 mA.

Solubility test:

Saturated etoricoxib, physical mixture, and co-amorphous of etoricoxib and citric acid were put into an Erlenmeyer, 100 mL of CO₂-free distilled water was added. The test was carried out using an orbital shaker (Memmert WNB 29, Germany) for 24 hours. The solution was filtered (0.22 μm PTFE filter) then 20 µL was injected into the HPLC ²⁵ (Agilent LC 1220 Infinity II, USA) with a 250 x 4.6 mm C18 column device under analytical conditions including the mobile phase of phosphate-buffered saline pH 3.5 and acetonitrile with a ratio of 55:45 with the flow rate was 1 mL/minute. The solubility test was carried out triplicated.

Dissolution Test:

Etoricoxib, a physical and co-amorphous mixture of etoricoxib weighed equivalent to 60 mg of etoricoxib and placed in a dissolution flask containing 900 mL phosphate-buffered medium. The temperature was set at 37°C ± 0.5°C at 100 rpm for 45 minutes. This dissolution test used a paddle-type dissolution test kit (SR8 Plus Dissolution Test Hanson Instrument, USA). The dissolution solution was pipetted 5 mL, at the 5th, 10th, 15th, 30th, and 45th minutes. Each solution that was pipetted was put into a vial, then the sample solution was filtered (0.22 μm PTFE filter) and 20 µL of sample was injected into the HPLC (Agilent LC 1220 Infinity II, USA) with a 250 x 4.6 mm C18 column device under analytical conditions using phosphate-buffered saline pH 3.5 and acetonitrile with a ratio of 55:45 as the mobile phase. The flow rate used was 1 mL/minute. The dissolution test was done triplicated.

RESULT:

Differential Scanning Calorimetry (DSC) Analysis:

In Figure 3 and Table 1 the DSC thermogram of etoricoxib and citric acid shows a very sharp endothermic peak indicated the crystalline phase, in which the melting point of etoricoxib and citric acid were 131.70°C and 157.96°C, respectively. In addition, the physical mixture has melting point at 146.58°C, while the co-amorphous etoricoxib - citric acid at 126.52°C.

Figure 3. DSC Thermograms of (a) Etoricoxib, (b) Citric Acid, (c) Physical Mixtures and (d) Co-amorphous

Table 1. Thermal analysis of Etoricoxib, Citric Acid, Physical Mixture, and Co-amorphous

Samples	Melting point (°C)	ΔH Fusion (J/g)
Etoricoxib	131.70	30.36
Citric acid	157.96	725.57
Physical mixture	146.8	45.54
Co-amorphous	126.52	11.98

X-ray Diffraction (XRD) Analysis:

Figure 4. depicted the diffractogram of etoricoxib, citric acid, physical mixture and the co-amorphous etoricoxib and citric acid. Etoricoxib, citric acid and physical mixture show sharp diffraction peaks, the indicating the crystalline phase. The physical mixture presents the sharp intensity peaks as result of a merging two intact compounds, while co-amorphous shows a decrease in the intensity of the diffraction peaks.

Figure 4. XRD Patterns of (a) Etoricoxib, (b) Citric Acid, (c) Physical Mixtures and (d) Co-amorphous of Etoricoxib and Citric Acid

Table 2. Peak Intensity of Etoricoxib, Citric Acid, Physical Mixture, and Co-amorphous

Position 2θ	Peak Intensity
Position 2θ	Etoricoxib	Citric acid	Physical mixture	Co-amorphous
7.0101	350.86	-	553.52	116.91
9.6642	373.27	-	516.98	184.04
11.7313	261.91	-	409.6	124.85
12.3699	138.32	-	223.08	-
14.0459	-	548.53	-	-
15.4607	818.61	-	1308.21	275.18
16.538	2388.48	-	3726.85	867.54
17.9738	-	1901.8	-	-
18.0988	1466.91	-	2487.62	586.02
19.4365	-	1471.87	-	185.61
20.0051	235.61	-	216.92	178.74
22.7164	955.79	-	1322.62	392.88
23.2896	452.48	-	496.65	281.6
25.9802	-	1317.55	-	-
26.3511	280.7	-	279.79	124.7
28.7638	-	201.61	-	-
29.2608	563.26	-	571.2	327.49
30.7498	133.67	-	214.59	48.28
31.8302	20.73	170.02	86.65	-
34.7059	102.37	-	146.4	46.27
35.7559	158.67	-	215.13	205.2
37.4877	-	207.23	-	-
39.2231	156.73	47.7	-	57.86
40.9831	-	1843.06	-	-
42.0203	-	41.79	-	-
43.3242	134.05	-	118.26	39.5
49.2557	-	43.48	-	-

Fourier Transform Infrared (FTIR) Spectroscopy Analysis:

The infra-red spectrum of etoricoxib, citric acid, physical mixture and co- amorphous of etoricoxib-ciric acid is seen and Figure 5, and the wavelength of functional groups in each sample shown in Table 2.

Figure 5. FTIR Spectrum of (a) Etoricoxib, (b) Citric Acid, (c) Physical Mixtures and (d) Co-amorphous of Etoricoxib and Citric Acid

Scanning Electron Microscopy (SEM) Analysis:

The morphology of etoricoxib, citric acid, physical mixture and co-amorph of etoricoxib and citric acid is seen Figure 6. Based on the observation, it can be seen that etoricoxib has a morphological shape a long rod ¹⁴, and citric acid has an irregular shape and an uneven surface. The physical mixture has a combined morphology of etoricoxib and citric acid. Meanwhile, the co-amorphs have a slightly different shape where the particle size is smaller, irregular and aggregate-shaped.

Figure 6. SEM morphology of (a) Etoricoxib, (b) Citric Acid, (c) Physical Mixtures and (d) Co-amorphous of Etoricoxib and Citric Acid

Solubility Test:

The result of solubility test is shown in Table 3, in which there is the increase in solubility of the co-amorphous of etoricoxib and citric acid compared to intact etoricoxib, and the physical mixture.

Table 3. Solubility Test Results of Etoricoxib, Physical Mixture, and Co-amorphous Etoricoxib and Citric Acid

Sample	Dissolved Etoricoxib (mg/100 mL) ± SD	Increased Solubility
Etoricoxib	8.333 ± 0.011	-
Physical Mixture	10.936 ± 0.022	1.312
Co-amorphous of Etoricoxib and Citric Acid	13.275 ± 0.023	1.592

Dissolution test:

The result of dissolution test is seen in Figure 7 and Table 3, in which present an increase in the dissolution efficiency of co-amorphs etoricoxib and citric acid compared to intact etoricoxib and the physical mixture.

Figure 7. Dissolution test of Etoricoxib, Physical Mixture, and Co-amorphous Etoricoxib and Citric Acid

Table 4. Dissolution efficiency of Etoricoxib, Physical Mixture, and Co-amorphous Etoricoxib and Citric Acid

Samples	% Dissolution Efficiency	Enhancement
Etoricoxib	70.086	-
Physical Mixture	77.625	1.107
Co-amorphous	80.858	1.153

DISCUSSION:

DSC analysis is used to inspect changes in the thermodynamic properties of the sample when given heat energy characterized by the presence of endothermic and exothermic peaks in the thermogram. In Figure 3. the DSC thermogram of etoricoxib and citric acid has a very sharp endothermic peak which is pure crystal while the co-amorphous etoricoxib - citric acid has a wide endothermic peak in suggested that formation of co-amorphous. In the physical mixture there is more than one endothermic peak which indicates that the two components in the physical mixture have not melted together. In addition to the decrease in melting point, there is a decrease in the enthalpy of fusion (heat of fusion) value of the co-amorphous. The enthalpy value is the amount of energy required for the melting of a substance ²⁶. This explains the energy required to fuse the active substance is greater than the co-amorph. It can be concluded that a decline in the melting point value and enthalpy value of a compound likely indicate a reduction in the crystallinity so that it can increase the solubility of etoricoxib as described in the XRD analysis below.

XRD analysis is an analytical approach that used to characterize the structure of materials regarding the crystallinity. In addition, XRD analysis also can identify the degree and change in crystallinity which produced through the diffractogram by existence of amorphous and crystalline phases. Figure 4 and Table 2. depicted the diffractogram of the co-amorphous etoricoxib and citric acid which shows a decrease in the intensity of the diffraction peaks. While in the physical mixture there is a sharp diffraction peak indicating the merging of the two compounds. Because the crystal structure of amorphous materials is irregular, the XRD diffraction pattern does not show a sharp diffraction peak so that it can be used to confirm the amorphous phase. This is similar to the study of co-amorphous creatine formation with citric acid where there is a decline in peak intensity compared to the XRD results of pure creatine ²⁷. This indicates that the formation of co-amorphous etoricoxib with citric acid that show lower peak intensities, means a decrease in crystallinity likely contribute to the enhancement the solubility of the active substance ²⁸.

FTIR analysis is generally utilized to identify the chemical interactions that may occur between active substances and coformer through the presence of functional groups of samples. This analysis is carried out to observe the shift in the spectrum and the functional groups from the wave number value. This wave number shift is still in the same functional group indicates no chemical interaction, but rather a physical interaction between etoricoxib - citric acid as seen Figure 5 and Table 3. Both physical mixture and co-amorphous etoricoxib - citric acid show the presence of hydrogen bonds due to O-H groups of intact citric acid. To ensure the wave number shifts, it can be seen from the carbonyl group of etoricoxib (C = O) that shifts to a lower frequency, which imply that the carbonyl group contribute to hydrogen bonding with citric acid, because hydrogen bonding likely weaken the strength of the C = O bond. Moreover, the hydroxyl group (O-H) of citric acid shows a shift and change in wave number of physical mixture and co-amorph but still in the wavenumber range. Through intermolecular hydrogen bonds that presence in this study, it is expected the enhancement of the solubility and dissolution rate of co-amorphs etoricoxib with citric acid ²⁹.

Scanning Electron Microscopy (SEM) analysis is used to notice the surface morphology of the sample microscopically and provide information about the texture and shape of the sample surface. Based on the observation, it can be seen that etoricoxib has a morphological shape a long rod ¹⁴, citric acid has an irregular shape and an uneven surface, the physical mixture has a combined morphology of etoricoxib and citric acid as seen Figure 6. Meanwhile, the co-amorphs have a slightly different shape where the particle size is smaller, irregular and aggregate-shaped. This is likely due to the shape of the co-amorphs which produces pores on the surface. In research on the formation of atorvastatin co-amorphs with maleic acid, there is a co-amorphic form with a smaller particle size and a porous surface ³⁰. The presence of pores in the co-amorphs can increase the surface area so that it is likely to increase solubility and dissolution³¹.

The enhancement in solubility of etoricoxib in the co-amorphs phase was supported by prominent solid state characterization including analysis of DSC, PXRD, FTIR and SEM results. Table 3. shows the increase in solubility of the co-amorphous of etoricoxib and citric acid compared to intact etoricoxib, and the physical mixture. Particle size, wettability, microcrystalline structure, thermodynamic properties, and hydrophilic coformers are some of the factors that influence the solubility enhancement of co-amorphs³². Etoricoxib is categorized in BCS class II with a solubility of 76.7 μg/mL in water while citric acid has a solubility of 0.592 g/mL. The use of coformers that are highly soluble in water will increase the wettability and solubility of the active substance³³. Co-amorphous formation results in increased solubility, due to the higher mobility of amorphous phase molecules in solvent media than in crystalline form. In the research of Jin Wang, et al, the formation of co-amorphous loratadine with citric acid provided an increase in solubility by 50 times ³⁴. Similarly, in the study of Kyle, et al, the formation of creatine co-amorphs with citric acid gave an increase in solubility of 2.5 times²⁷. So, it can be concluded that the use of coformers affects the solubility of active substances in the formation of co-amorphs.

One of parameter that used in dissolution test is dissolution efficiency (DE), in which it is used to evaluate the performance of a solid pharmaceutical product in terms of its ability to release the active ingredient over time ³⁵. The increase in dissolved and dissolution efficiency of etoricoxib in the co-amorphs was correlated to the solubility result. Figure 7 and Table 4 show that there is an increase in the dissolution efficiency of co-amorphs etoricoxib and citric acid compared to intact etoricoxib and the physical mixture. The results showed that the % dissolution of etoricoxib at the 45th minute was 79.102%± 3.95%, while in the physical mixture it was 83.435 ± 3.75% and co-amorphous it was 86.789 ± 2.61%, respectively. The amount of etoricoxib dissolved is significantly greater in co-amorphous compared to the physical mixture. As previously describe, the increase in the dissolution rate of co-amorphous is supported by a decrease in the degree of crystallinity seen in the analysis results using XPRD and DSC. The decrease in the intensity of the diffraction peak in co-amorphous is lower than that of intact etoricoxib, so that the dissolution rate in the form of co-amorphous is greater than that of pure etoricoxib. In addition, the DSC results determine a decrease in the endothermic peak which indicates a decrease in crystallinity. The results of the etoricoxib and co-amorphous dissolution tests were then processed statistically to obtain a significance value = 0.000 (sig <0.05). This indicates that the formation of co-amorphous has a significant effect on increasing the levels of etoricoxib dissolved for 45 minutes.

CONCLUSION:

This research shows that the incorporation of etoricoxib and citric acid with a mole ratio of 1:1 using the liquid assisted grinding method can form co-amorphs with confirmation by thermal analysis, X-ray diffraction, and FTIR spectroscopy. The co-amorphs of etoricoxib and citric acid can increase the solubility by 1.592 times and can increase the dissolution efficiency for 45 minutes by 1.153 times compared with pure etoricoxib.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would thank to Faculty of Pharmacy Universitas Andalas for granting this research under scheme Riset Dasar (No. 09/UN16.10.D/PJ.01/2024).

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Received on 11.11.2024 Revised on 15.03.2025

Accepted on 26.05.2025 Published on 08.11.2025

Available online from November 13, 2025

Research J. Pharmacy and Technology. 2025;18(11):5358-5364.

DOI: 10.52711/0974-360X.2025.00772

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Functional groups		Wavenumber Range (cm^-1)	Wavenumber (cm^-1)
Functional groups		Wavenumber Range (cm^-1)	Etoricoxib	Citric Acid	Physical Mixture	Co-amorphous
Alkyl Halide	C-Cl bend	850 – 550	835.714	-	838.436	840.046
Sulfonyl	S=O stretch	1160 – 1120	1138.775	-	1141.7	1397.753
Amina	C=N stretch	1650 – 1550	1594.897	-	1598.766	1599.922
Amina	N-H stretch	3750 – 3000	3054.768	-	3064.772	3056.749
Amina	C-N stretch	1250 – 1000	1080.612	-	1011.326	1087.529
Carboxylic Acid	C=O stretch (conj.)	1900 – 1650	1850.457	1742.050	1826.854	1726.711
Hydrogen bonding	O-H	3300 – 2500	-	3283.353	3298.942	3137.200