INTRODUCTION:

According to the biopharmaceutical classification system (BCS), drugs with low solubility are grouped into classes II and IV¹. One example of a drug that is classified in the BCS class II is celecoxib²^,³. Celecoxib (C₁₇H₁₄F₃N₃O₂S) is an NSAID class of drug that works specifically to inhibit the cyclooxygenase-2 enzyme. This compound has therapeutic activity as a treatment for rheumatoid arthritis including idiopathic arthritis, osteoarthritis, ankylosing spondylitis, and in the adjuvant treatment of adenoma colorectal polyps. Celecoxib is also used in acute pain and dysmenorrhoea⁴.

Some drugs have problems with their solubility, one thing that can be done to improve the solubility of the drug is using a solid dispersion system⁵^,⁶. Solid dispersion is a solid product consisting of two different components, namely, a hydrophilic matrix which can be crystalline or amorphous, and a hydrophobic drug which will be molecularly dispersed in matrix particles, both amorphous and crystalline, to increase the dissolution speed⁷^,⁸. Solid disperses have been widely used to increase solubility including: Sulfasalazine⁹, Nifedipine¹⁰, Vericonazole¹¹, Ramipril¹², Terbinafine¹³, Pioglitazone¹⁴, Diacerein¹⁵.

One popular technique for reducing drug particle size and improving the bioavailability and rate of dissolving of hard-to-solve medications is co-grinding^16,17. One technique for improving the stability and solubility of hydrophobic medications is co-milling. The co-milling process outperforms other approaches due to its affordability, lack of harmful organic solvent requirements, and environmental friendliness¹⁸.

Previous studies have used a variety of techniques to try to speed up celecoxib's rate of disintegration. When compared to pure celecoxib, the solid dispersion approach using Polyvinylpyrrolidone (PVP)-K30 polymer shown an increase in the rate of dissolution and solubility. When comparing the solubility rate of the celecoxib nanosuspension with pure celecoxib, the D-alpha Tocopherol acid polyethylene glycol succinate (TPGS) polymer showed a considerable increase²^,¹⁹^.

Based on this problem, researchers intend to formulate water-insoluble celecoxib in the form of a solid dispersion using PEG-4000 as a polymer which is expected to increase the dissolution rate of celecoxib using the co-grinding method so that drug absorption and therapeutic effects can be achieved perfectly.

MATERIALS AND METHODS:

Materials:

The materials used in this research are Celecoxib (Shanghai Huirui Chemical Technology. Co.LTD, Hongkong), PEG-4000 (Indomedifa, Indonesia), methanol (Novalindo, Indonesia), HCl (Novalindo, Indonesia), distilled water (Novalindo, Indonesia).

Preparation of Solid Dispersions:

Each formula is weighed according to the weight ratio of 1:9, 2:8, 3:7, and 4:6, ground simultaneously using a planetary ball mill and 34 large balls and 34 small zirconium balls at a speed of 120 revolutions/minute. for 120 minutes. The results of the grinding are collected, weighed, and stored in a tightly closed container in a desiccator²⁰.

Scanning ElectronMicroscopy (SEM) Analysis:

The powder sample was placed in an aluminum sample holder and coated with 10mm of gold for SEM (Hitachi Type S-3400N®, Japan) analysis. After then, the samples were examined at different magnifications. The voltage is set at 20 kV, current 12mA. This investigation will demonstrate the particle morphology of pure celecoxib, PEG 4000, physical mixes, and solid dispersions²¹^,²².

Fourier Transform Infrared (FT-IR) Spectroscopic Analysis:

The procedure for performing FT-IR spectroscopy (Perkin Elmer L1600300 Spectrum Two, USA) involved combining 1-2mg of sample powder with 10mg of Kbr in a mortar, grinding the mixture until it was homogenous, moving it to a die, and pressing the mixture into a disc under vacuum pressure (800kPa). The wavelength range for the absorption spectrum is 450–4000 cm–1. Examine the sample's infrared absorption spectra. The spectra of PEG 4000, solid dispersions, physical mixes, and pure celecoxib compounds will all be displayed in this analysis along with their functional groups²³^,²⁴.

X-Ray Diffraction (XRD) Analysis:

Pure celecoxib compounds, PEG 4000, physical mixes, and solid dispersions were all subjected to analysis. A diffractometer-style device was used to do X-ray diffraction analysis (Philips X'Pert Pro-PANalytical, The Netherlands) at room temperature. The following conditions apply to measurements: Cu metal target, 40 kV voltage, 30mA current, and measurement analysis in the 2 theta 5–50° range are all included in this setup. During sample preparation, the sample is leveled and put in a glass sample container to stop particle orientation²¹.

Differential Scanning Calorimetry (DSC) Analysis:

A DSC device (Setaram DSC 131 Evo, France) was used to perform thermal analysis on the samples. An aluminum pan was closed and a 3mg sample was added. The DSC tool is set to heat at a rate of 10°C per minute throughout a temperature range of 30 to 220°C. The results of this analysis will display the thermal characteristics of solid dispersions, physical mixes, PEG 4000, and pure celecoxib²⁵^,²⁶.

Dissolution Rate Profile Study:

Using paddle-type dissolution test equipment (Copley Scientific NE4-COPD, UK), the dissolution profiles of solid dispersions, physical mixes, and celecoxib were determined. 900 mL of 0.1 N HCl dissolving medium were added to the dissolution flask. For one hour, the temperature was maintained at 37±0.5^oC and the rotation speed was set to 100rpm. After being weighed to the equivalent of 100mg, celecoxib, physical mixture, solid dispersion of formulas 1:9, 2:8, 3:7, and 4:6 are added to the dissolution medium. At 5, 10, 15, 30, 45, and 60 minutes, 5mL of the solution in the dissolution flask was pipetted. A fresh dissolution medium with the same volume and temperature was pipetted at each collection time. Each pipetted solution was placed in a vial and tested for absorbance using UV-Vis Spectrophotometry (Shimadzu ED23 1800®, Japan). Dissolution testing was carried out three times²⁷.

RESULT AND DISCUSSION:

Surface morphology tests using SEM were carried out on samples of celecoxib, PEG 4000, physical mixtures, and solid dispersions. The SEM results can be seen at 1000 times magnification showing rod-shaped solid crystals of celecoxib (Figure 1a). The surface morphology results of PEG 4000 can be seen at 1000 times magnification (Figure 1b) showing an irregular plate shape. The results of the analysis of the physical mixture viewed with a magnification of 1000 times (Figure 1c) show that the morphology changes shape to become irregular, but celecoxib is still visible in the form of solid, rod-shaped crystals which are more dominant. The results of the analysis of the solid dispersion in the 1:9 formula can be seen with a magnification of 1000 times (Figure 1d) and it shows that the morphology changes shape to become irregular but the plate shape of PEG 4000 and the rod-shaped solid crystals of celecoxib are still visible, the solid dispersion of the 2:8 formula is seen with a magnification of 1000 times (Figure 1e) has shown that the morphology changes shape to become irregular but the plate shape of PEG 4000 and celecoxib is still visible in the form of solid rod-shaped crystals, the solid dispersion of formula 3:7 seen with a magnification of 1000 times (Figure 1f) has shown The morphology changes shape to become irregular with the particle size becoming smaller but the solid crystal shape of the rod shape of celecoxib is still visible and the solid dispersion of formula 4:6 seen with 1000 times magnification (Figure 1g) shows the morphology changes shape to become irregular with the particle size becoming smaller but still visible solid rod-shaped crystal morphology of celecoxib. It can be seen in each formula that the morphology has changed to become irregular with the particle size becoming smaller but the solid crystals in the rod shape of celecoxib and irregular plates of PEG 4000 are still clearly visible. From the results obtained, it can be concluded that in the four formulas, it is estimated that celecoxib powder was dispersed in PEG 4000.

Figure 1. SEM morphology at 1000x magnification (a) celecoxib, (b) PEG 4000, (c) physical mixture, (d) formula 1:9, (e) formula 2:8, (f) formula 3:7, (g) formula 4:6

Figure 2. Fourier transform infrared spectroscopic analysis of (a) celecoxib, (b) PEG 4000, (c) physical mixture, (d) formula 1:9, (e) formula 2:8, (f) formula 3:7, (g) formula 4:6

When evaluating solid dispersions, functional group analysis with an FT-IR spectrophotometer seeks to identify functional groups in a compound, ascertain the structure of a compound by comparing the fingerprint areas, and ascertain whether or not celecoxib and PEG 4000 interact chemically²⁸. According to celecoxib's infrared spectrum analysis results, there are four functional groups: S=O at wave number 1347.73cm^-1, NH₂ at wave number 3339.83cm^-1, -CF₃ at wave number 1274.62cm^-1, and C-H at wave number 2927.88cm^-1 (Figure 2a).The C-H functional group is visible in the PEG 4000 infrared spectrum (Figure 2b) at wave number 2888.87cm^-1. The S=O group is located at wave number 1347.29 cm^-1, the NH₂ functional group is at wave number 3339.29 cm^-1, the –CF₃ functional group is at wave number 1275.90 cm^-1, and the C-H functional group is at wave number 2888.85 cm^-1 in the infrared spectrum of the physical combination (Figure 2c). The presence of the S=O group at wave number 1343.36 cm^-1, the NH₂ functional group at wave number 3435.07 cm^-1, the –CF₃ functional group at wave number 1280.80 cm^-1, and the C-H functional group at wave number 2889.42 cm^-1 is indicated by the infrared spectrum results on the solid dispersion of formula 1:9 (Figure 2d). The infrared spectrum results of formula 2:8 (Figure 2e) show the S=O group at wave number 1343.31 cm^-1, the NH₂ functional group at wave number 3435.78 cm^-1, the –CF₃ functional group at wave number 1280.69 cm^-1, the C-H function wave number 2890.51 cm^-1. The results of the solid dispersion infrared spectrum of formula 3:7 (Figure 2f) show the presence of the S=O group at wave number 1342.91 cm^-1, the NH₂ functional group at wave number 3435.67 cm^-1, the –CF₃ functional group at wave number 1279.74 cm^-1, C-H functional group wave number 2889.28 cm^-1. The results of the solid dispersion infrared spectrum of formula 4:6 (Figure 2g) contain the S=O group at wave number 1342.20 cm^-1, the NH₂ functional group at wave number 3435.85 cm^-1, the –CF₃ functional group at wave number 1273.95 cm^-1, C-H functional group wave number 2889.28 cm^-1. The peaks are identical to the functional groups of celecoxib and PEG 4000 and there is no wave number shift and no new functional groups are visible. From the results of FT-IR analysis, it was concluded that no interaction occurred between celecoxib and PEG 4000 after the formation of a physical mixture and solid dispersion system.

From the results of X-ray diffraction, the crystalline peak of celecoxib can be seen (Figure 3a-g). The celecoxib compound shows an interference peak at a typical 2ϴ angle (13.5216; 19.0726; 23.2066; 27.2496) with an intensity of 2202.97; 4065.881; 5088.14; 2314.001 (Figure 3a). PEG 4000 shows an interference peak at an angle of 2ϴ (13.5216; 19.0726; 23.2066; 27.2496) (Figure 3b) with an intensity of 324.5199; 264.3073; 453.0033; 181.1161. In the diffractogram results of the physical mixture, the crystalline peak of celecoxib can be seen at an angle of 2ϴ (13.5216; 19.0726; 23.2066; 27.2496) with an intensity of 564.7443; 1097.652; 2025.608; 783.0631 This diffractogram shows a decrease in the crystalline degree of celecoxib. In the solid dispersion of formula 1:9 (Figure 3d), the crystalline peak of celecoxib can be seen at an angle of 2ϴ (13.5216; 19.0726; 23.2066; 27.2496) with an intensity of 577.2892; 2055.936; 3143.991 and 680.6053 in this diffractogram shows a decrease in the degree of crystalline celecoxib. In the solid dispersion of formula 2:8 (Figure 3e), the crystalline peak of celecoxib can be seen at an angle of 2ϴ (13.5216; 19.0726; 23.2066; 27.2496) with an intensity of 930.895; 1691.81; 2991.75 and 942.678 diffractogram show a decrease in the degree of crystalline celecoxib. In the solid dispersion of formula 3:7 (Figure 3f), the crystalline peak of celecoxib can be seen at an angle of 2ϴ (13.5216; 19.0726; 23.2066; 27.2496) with an intensity of 399.4766; 1315.891; 2195.623 and 341.3355 This diffractogram shows a decrease in the crystalline degree of celecoxib. In the solid dispersion of formula 4:6 (Figure 3g), the crystalline peak of celecoxib can be seen at an angle of 2ϴ (13.5216; 19.0726; 23.2 066; 27.2496) with an intensity of 287.8721; 849.7628; 1581.46 and 228.2343 diffractogram shows a decrease in the degree of celecoxib crystalline. Based on the analysis data, it shows that there is a decrease in the intensity of the degree of crystallinity of celecoxib in the physical mixture and solid dispersion in each formula. This is due to the effect of adding PEG 4000 as a polymer on reducing the intensity of the degree of crystallinity. From the diffractogram results on the overlay, the typical peaks from the physical mixture and solid dispersion have begun to be less sharp than the peaks of the active substance, indicating that celecoxib has been dispersed into the PEG 4000 polymer and the results obtained have led to an amorphous form.

Figure 3. Overlay of XRD Diffractogram (a) celecoxib, (b) PEG 4000, (c) physical mixture, (d) formula 1:9, (e) formula 2:8, (f) formula 3:7, (g) formula 4:6

Figure 4. Differential scanning calorimetry analysis of (a) celecoxib, (b) PEG 4000, (c) physical mixture, (d) formula 1:9, (e) formula 2:8, (f) formula 3:7, (g) formula 4:6

DSC thermal analysis is used to determine the heat capacity and enthalpy of a material and can measure the amount of heat absorbed or released during the transition²⁹. A solid dispersion sample that has a melting point that is different from the pure compound indicates that a solid dispersion has been formed³⁰. The results of the celecoxib thermogram (Figure 4a) show a sharp endothermic peak at a temperature of 164.089^oC which is a melting event of celecoxib with an enthalpy of 64.874 J/g. The PEG 4000 (Figure 4b) thermogram results show an endothermic peak at a temperature of 60.75^oC with an enthalpy of 224.847 J/g. The physical mixture (Figure 4c) shows an endothermic peak at a temperature of 59.398^oC with an enthalpy of 62.042 J/g. The 1:9 formula (Figure 4d) shows an endothermic peak at a temperature of 61.422^oC with an enthalpy of 148.801 J/g. The 2:8 formula (Figure 4e) shows an endothermic peak at a temperature of 61.142^oC with an enthalpy of 58.949 J/g. The formula 3:7 (Figure 4f) shows an endothermic peak at a temperature of 60.915^oC with an enthalpy of 164.61 J/g. The 4:6 formula (Figure 4g) shows an endoermic peak at a temperature of 59.94^oC with an enthalpy of 115.2 09 J/g. From the results of the DSC thermograms it can be seen that the enthalpy value of the solid dispersion of celecoxib – PEG 4000 in each formula follows the enthalpy value of the PEG 4000 polymer, this is because the crystalline phase of celecoxib has been homogeneously dispersed into the PEG 4000 polymer matrix. From the results, DSC can also be seen that there is a decrease in the melting point in the solid dispersion of celecoxib - PEG 4000 where the melting point in each formula has followed the melting point of the PEG 4000 polymer. From the DSC results obtained, it can be seen that in the formula 2:8, the enthalpy value is the highest. low and these results indicate that in the diffractogram the formula 2:8 has led to an amorphous form. Apart from that, there is also a decrease in the enthalpy value which shows a reduction in the amount of energy needed to melt the substance associated with a decrease in intensity in the XRD examination³⁰.

Determining the dissolution profile of celecoxib, physical mixture, and solid dispersion of celecoxib - PEG 4000 was carried out using 0.1 N HCl medium. The increase in dissolution rate was due to the effect of adding PEG 4000 polymer to the physical mixture and solid dispersion. In the dissolution test, it was seen that the dissolution percentage at the 60^th minute of pure celecoxib was 55.58%, physical mixture 60.26%, formula 1:9 69.94%, formula 2:8 65.74%, formula 3:7 66. 94 % and formula 4:6 66.72 %. From the results obtained, it can be seen that the celecoxib – PEG 4000 solid dispersion has a good dissolution rate using the co-grinding method. This result was because the solid dispersion had been treated, whereas the physical mixture used as a comparison was without treatment. Apart from that, there are also several influencing factors such as particle size³¹. From the results of the dissolution profile, it can be seen that there is an increase in the dissolution rate in each formula and in the 1:9 formula, the dissolution rate increase is the best, this is because in the 1:9 formula the amount of PEG 4000 polymer is the highest, where the greater the amount of PEG 4000 polymer used. then the dissolution rate of celecoxib increases.

Figure 5: Dissolution rate profile of celecoxib, physical mixture, formula 1:9, formula 2:8, formula 3:7, formula 4:6 [mean±SD, n= 3]

Table 1: Dissolution efficiency of celecoxib, physical mixture, formula 1:9, formula 2:8, formula 3:7, formula 4:6

Compound	Dissolution efficiency
Celecoxib	50.83 ± 0,0071
Physical mixture	54.42 ± 0,0026
Formula 1:9	64.74 ± 0,0040
Formula 2:8	61.05 ± 0,0073
Formula 3:7	60.02 ± 0,0048
Formula 4:6	61.53 ± 0,0027

[mean±SD, n= 3]

CONCLUSION:

Characterization of celecoxib – PEG 4000 solid dispersion in SEM, FT-IR, XRD, DSC analysis with various comparisons can influence the physicochemical properties and increase the dissolution efficiency value of celecoxib.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would like to thank STIFARM PADANG for support in the use of the laboratory.

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Received on 23.04.2024 Revised on 14.07.2024

Accepted on 18.10.2024 Published on 27.03.2025

Available online from March 27, 2025

Research J. Pharmacy and Technology. 2025;18(3):1296-1301.

DOI: 10.52711/0974-360X.2025.00188

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