INTRODUCTION:

In aqueous solutions, crystalline medications frequently have extremely low solubility and dissolution rates¹. The Biopharmaceutical Classification System (BCS) states that drugs classified as "class II" should have their dissolution enhanced and/or accelerated. If the dosage of class II medications is not excessively large, an in vitro/in vivo correlation for dissolving rates can be anticipated.

Because of this, investigations on the dissolving of drugs in vitro offer valuable insights into their bioavailability²

Ketoprofen (KPN) is one of the non-steroidal anti-inflammatory drugs (NSAIDs) that is widely used in musculoskeletal and joint disorders such as osteoarthritis and rheumatoid arthritis³. Based on the Biopharmaceutics Classification System (BCS), ketoprofen is included in the BCS class II drug group which has low solubility ie 0.010 mg/ml. Drugs that have low solubility will result in a low dissolution rate so that absorption is less than perfect and has low bioavailability^4,5.

Extract is the result of extraction from the contents of plant cells. To obtain an extract, a solvent is needed, because extracts are usually soluble in certain solvents that are compatible with the polarity of the compound to be extracted. The most common solvents are volatile organic chemicals, particularly petroleum and petroleum derivatives, the majority of which are hazardous to the environment and public health⁶. In this study, we will conduct testing on EKBD which we have standardized⁷ ⁸. In the realm of pharmaceuticals, solubility is a crucial thermodynamic characteristic from both a theoretical and practical standpoint. This characteristic plays a role in a number of pharmaceutical processes, including drug identification, drug purification, and homogenous dosage form design. Despite being a macroscopic feature, solubility is utilized to examine the specific molecular interactions that take place throughout the dissolving process⁹. A compound's solubility affects its bioavailability, rate and degree of bloodstream absorption, and, ultimately, its therapeutic efficacy¹⁰. Furthermore, solubility has a significant impact on medication formulation stability, which impacts shelf life and storage conditions^11,12. Significant difficulties arise from poor solubility, which raises the need for higher doses to achieve therapeutic levels and raises the possibility of adverse consequences¹³. Consequently, a great deal of work goes into analyzing, estimating, and modifying the solubility of compounds by pharmaceutical scientists.

Strategies like salt formation, cosolvent systems, cyclodextrin-based formulations¹⁴, and nanoparticle delivery technologies^15,16 are used to boost solubility and, thus, improve medicine performance.^17,18. Researchers can choose the most promising drug candidates, improve drug delivery systems, and optimize formulation tactics with the aid of accurate solubility prediction.

The aforementioned demand for better pharmaceutical products both in terms of patient safety and environmental considerations has prompted a broad acceptance of the "green chemistry" paradigm¹⁹. Particularly the use of ecologic solvents in the pharmaceutical sector might be seen as a paradigm change toward environmental responsibility and sustainability²⁰. The low toxicity, renewable source, and biodegradability of green solvents make them a desirable substitute for conventional organic solvents, which frequently present serious risks to human health and the environment²¹.

One well-known class of procedures and substances that are frequently used to satisfy the demands of the green chemistry concept are deep eutectic solvents (DES)²². Most of these systems are made up of two or more components, such as a hydrogen bond donor (HBD) and an acceptor (HBA), which can be either liquid or solid. Because the melting point of the finished mixture is lower than the melting points of its component parts, the mixture remains liquid even at room temperature²³. Low toxicity, biodegradability, and above all physicochemical features are just a few of the special qualities that make DES stand out in a variety of pharmaceutical applications, such as drug production, formulation, and extraction processes²⁴. Notably, DES have been shown to be effective solvents for ibuprofen ²⁵ and ketoprofen^26,27. There have been many studies examining the usefulness of DESs, including the solubility of tumeric assisted by Camphor:Menthol (1:1) (CM-DES) and Menthol:Thymol (1:1) (MT-DES)²⁸, NADES can extract more philanthine compounds than using ethanol as a solvent²⁹, the use of green solvent as a safe solvent in spectrophotometric testing of anticancer drugs³⁰.

However, not all DES systems are the same. Each DES system has its own advantages and disadvantages depending on the components used. In this case, DES based on fatty acids and menthol offers several advantages compared to other potential DES systems. Below is a comparison of fatty acid and menthol-based DES with other systems like choline chloride and urea or glycerol-based DES. The combination of fatty acids and menthol effectively enhances the solubility of lipophilic compounds (such as ketoprofen) because both components have lipophilic properties. Menthol acts as an excellent solvent for bioactive compounds that are insoluble in conventional solvents. Choline chloride combined with urea or glycerol is often used in DES, but has limited ability to dissolve lipophilic compounds. These systems are more effective for hydrophilic compounds due to their higher polarity. Choline chloride and urea are more suited for enhancing the solubility of water-soluble substances³¹. One of the main reasons for selecting fatty acids and menthol in this study is their thermophysical properties. Fatty acids and menthol can form DES with a low melting point, making them stable at room temperature and easy to store. This makes fatty acid and menthol-based DES ideal for pharmaceutical applications that require good temperature control, especially in topical drug formulations. Choline chloride and urea/glycerol-based DES often have higher melting points, making them less stable at room temperature. This requires stricter temperature control to maintain stability, which can be more complicated and costly in large-scale production³². Both fatty acids and menthol are biocompatible and environmentally friendly. Fatty acids, derived from natural sources, are easily biodegradable and non-toxic to the environment. Menthol has been widely used in pharmaceutical and cosmetic products without causing adverse side effects. While choline chloride and glycerol have relatively safe and biodegradable profiles, some urea-based DES systems may have higher toxicity potential, especially if used in high concentrations or for long periods. This can be a concern in pharmaceutical applications, where safety and compatibility with the human body are paramount³³. Since menthol has penetration-enhancing properties and can facilitate drug absorption through the skin, fatty acid and menthol-based DES are ideal for topical drug delivery. Lipophilic drugs like ketoprofen can be absorbed more efficiently when formulated in a fatty acid and menthol-based DES. Choline chloride and glycerol-based DES are more commonly used for hydrophilic drug delivery and are less effective in enhancing the absorption of lipophilic drugs like ketoprofen through the skin³¹.

This research focuses on the development of a drug delivery system based on DES to enhance the solubility of KPN and EKBD. While DES has been extensively studied as an eco-friendly solvent, there are several gaps that need to be further explored. Most DES studies have used combinations of substances such as choline chloride and carboxylic acids or glycerol as hydrogen bond donors. However, studies that incorporate fatty acids and menthol as the main components of DES, particularly for pharmaceutical applications, are still limited. This combination could offer advantages in terms of solubility and the stability of bioactive compounds³¹. Lack of research on EKBD. The EKBD is known for its anti-inflammatory and analgesic properties. However, research on the solubility and stability of this extract in DES based on fatty acids and menthol is still scarce. Further studies are needed to evaluate the effectiveness of DES in enhancing the solubility and biological activity of degen bark extract ³³. Temperature can affect the viscosity and solubility of compounds in DES. However, research exploring the influence of temperature on the viscosity and solubility of KPN and EKBD in DES based on fatty acids and menthol is still limited. This study is crucial to determine the optimal conditions for the formulation of topical drugs³⁴.

The aim of this study was to design the solubility of KPN and EKBD with the DESs system using variations in the types of fatty acids and menthol.

MATERIALS AND METHODS:

Material:

This research is an experimental research where the tools used are tools that are The tools used in this study are glassware, a climatic chamber, magnetic stirrer, mortar and pestle, Brookfield viscometer, water bath, fine scales, thermometer, spectrophotometer. UV-Vis (Safas Moncoco), Centrifuge 5702 (Eppendorf), Homogenizer (IKA) T18 Digital Ultra Turrax), Scales Analytics. Materials that used in this study were Dengen bark, 96% ethanol, powder ketoprofen pro analysis Which obtained from Shaanxi Greenyo Biotech Xian China, Stearic acid, Palmitic acid, Myristic acid, Lauric acid, and menthol.

Method:

Extract Making:

The extract was obtained by extracting Dengen bark simplicia using the maceration method using 96% ethanol solvent and producing a concentrated extract.

Eutectic Phase Construction:

A eutectic binary phase mixture of Stearic acid+ menthol was created; Palmitic Acid+menthol; Myristic Acid+menthol and Lauric Acid+menthol in the following ratio

Table 1. Comparison of Fatty Acids and Menthol

Fatty acids (g)	Menthol (g)
1	1
0.25	1
0.5	1
2	1
1	2
1	0.5
1	0.25

Observations were made on whether the mixture formed a clear solution or not.

Solubility of Ketoprofen and Dengen Bark Extract in Eutectic Solvent:

Weighed 10mg of active substance that has been mixed with deep eutectic solvent with each formula consisting of menthol: lauric acid in a ratio of 1:1; 0.25:1; 0.5:1; 1:2. prepared at a concentration of 10ppm., ⁠ then measured at a maximum wavelength of 255.4nm for ketoprofen and 660.8nm for Dengen bark extract.

Viscosity Measurement:

A Brookfield viscometer (model DV1, Brookfield Engineering Laboratories, Inc.; Middleboro, MA, USA) with a thermocontainer, temperature controller, and spindle was used to measure the viscosity of the eutectic fluid mixture.

FTIR Fourier Transformed Infrared Spectrophotometry Analysis:

The mixture was analyzed using an infrared spectrophotometer using the KBr pellet method.

X-Ray Diffraction Testing:

Using a diffractometer and monochromatic graphite as the anode, the test was conducted at room temperature. The device was run at 40kV of voltage and 30 mA of current. The process parameters were set at a scan step size of 0.02° and a scan step time of 0.5s, and the samples were evaluated with a 2θ range of 5 to 70°.

RESULTS:

Eutectic Phase Construction:

Table 2. Observation of Fatty Acid and Menthol Mixtures

Dess	Treatment	Condition	24 Hours Condition
Lauric Acid : Menthol (1:1)	10 Minutes : 40 ̊C : 500rpm	Clear Liquid	Clear Liquid
Lauric Acid : Menthol (0.25:1)	30 Minutes : 40 ̊C : 500rpm	Clear Liquid	Clear Liquid
Lauric Acid : Menthol (0.5:1)	40 Minutes : 40 ̊C : 500rpm	Clear Liquid	Clear Liquid
Lauric Acid : Menthol (1:2)	15 Minutes : 40 ̊C : 500rpm	Clear Liquid	Clear Liquid
Lauric Acid : Menthol (2:1)	1 hour 40 ̊C : 500rpm	Not soluble	Not soluble
Lauric Acid : Menthol (1:0.25)	1 hour 40 ̊C : 500rpm	Not soluble	Not soluble
Lauric Acid : Menthol (1:0.5)	1 hour 40 ̊C : 500rpm	Not soluble	Not soluble
Stearic Acid: Menthol (1:1)	1 hour 40 ̊C : 500rpm	Not soluble	Not soluble
Stearic Acid: Menthol (0.25:1)	1 hour 40 ̊C : 500rpm	Not soluble	Not soluble
Stearic Acid: Menthol (0.5:1)	1 hour 40 ̊C : 500 rpm	Not soluble	Not soluble
Stearic Acid : Menthol (1:2)	1 hour 40 ̊C : 500 rpm	Not soluble	Not soluble
Stearic Acid : Menthol (2:1)	1 hour 40 ̊C : 500 rpm	Not soluble	Not soluble
Stearic Acid: Menthol (1:0.25)	1 hour 40 ̊C : 500 rpm	Not soluble	Not soluble
Stearic Acid: Menthol (1:0.5)	1 hour 40 ̊C : 500 rpm	Not soluble	Not soluble
Palmitic Acid : Menthol (1:0.5)	1 hour 40 ̊C : 500 rpm	Not soluble	Not soluble
Palmitic Acid: Menthol (0.25:1)	1 hour 40 ̊C : 500 rpm	Not soluble	Not soluble
Palmitic Acid : Menthol (0.5:1)	1 hour 40 ̊C : 500 rpm	Not soluble	Not soluble
Palmitic Acid : Menthol (1:2)	1 hour 40 ̊C : 500 rpm	Not soluble	Not soluble
Palmitic Acid: Menthol (2:1)	1 hour 40 ̊C : 500 rpm	Not soluble	Not soluble
Palmitic Acid : Menthol (1:0.25)	1 hour 40 ̊C : 500 rpm	Not soluble	Not soluble
Pamitatic Acid: Menthol (1:0.5)	1 hour 40 ̊C : 500 rpm	Not soluble	Not soluble
Myristic Acid: Menthol ( 1:0.5)	1 hour 40 ̊C : 500 rpm	Late	Freeze
Myristic Acid: Menthol ( 0.25:1)	1 hour 40 ̊C : 500 rpm	Late	Freeze
Myristic Acid: Menthol (0.5:1)	1 hour 40 ̊C : 500 rpm	Late	Freeze
Myristic Acid: Menthol (1:2)	1 hour 40 ̊C : 500 rpm	Not soluble	Not soluble
Myristic Acid: Menthol (2:1)	1 hour 40 ̊C : 500 rpm	Not soluble	Not soluble
Myristic Acid: Menthol (1:0.25)	1 hour 40 ̊C : 500 rpm	Not soluble	Not soluble
Myristic Acid: Menthol ( 1:0.5)	1 hour 40 ̊C : 500 rpm	Not soluble	Not soluble

Solubility of Ketoprofen and Dengen Bark Extract in Eutectic Solvent

Figure 1. Ketoprofen in DESs Solvent

Figure 2. Dengen Bark Extract in DESs Solvent

Solubility testing was used to see the ability of DESs solvents to dissolve ketoprofen compounds and Dengen bark extract. The solubility of Dengen bark extract was equated with gallic acid as a polyphenol compound. The results are illustrated in Table 3.

Table 3. Solubility level of binary mixture

Formula of DEss	Solubility
	Ketoprofen		Dengen
	Concentration (mg/ml)	%	Concentration (mg/ml)	%
Lauric Acid : Menthol (1:1)	10,02	99,15	6,92	82,19
Lauric Acid : Menthol (0.25:1)	9,53	94,34	3,50	41,51
Lauric Acid : Menthol (0.5:1)	10,04	99,42	6,77	80,37
Lauric Acid : Menthol (1:2)	10,67	105,63	7,51	89,14

Viscosity Measurement

Figure 3. Viscosity Diagram of Binary Mixture of Lauric Acid and Menthol EKBD

Figure 4. Viscosity Diagram of Binary Mixture of Lauric Acid and Menthol of Ketoprofen

FTIR Fourier Transformed Infrared Spectrophotometry Analysis:

FTIR analysis is used to analyze the identification of functional groups, whose signals can shift when molecular interactions are formed.

Figure 5. FTIR Spectra of Ketoprofen and Dengen Extract in Variations of Eutectic Solvents Lauric Acid + Menthol

From the results of the FTIR analysis, it was obtained that ketoprofen has aromatic combination bands (Aromatic ring (aryl)), namely at 1693 cm ^-1( (2000–1660 cm ^-1); at 1280 cm ^-1 = Aromatic secondary amine, CN stretch (Aromatic amino) 1350-1280 cm ^-1; at 963 cm ^-1 trans-CH out-of-plane bend (alkene) (970-960 cm ^-1) and at 710 cm ^-1= CH Monosubstitution (phenyl) ³⁵.

For FTIR testing of Dengen extract, the following functional group data were obtained at a wavelength of 1616 cm ^-1= Quinone or conjugated ketone (Carbonyl compound) (1690–1675 cm ^-1/(1650–1600 cm ^-1); 1443 cm ^-1= Methyl CH asym./sym. Bend (Methyl (−CH3 (1470–1430 cm ^-1/1380–1370 cm ^-1); 1207 cm ^-1= Aromatic CH in-plane bend (Aromatic ring (aryl)) (1225–950 cm ^-1); 1032 cm ^-1= Primary amine, CN stretch (Ether and oxy compound) (1090–1020 cm ^-1) ³⁵.

X-Ray Diffraction Testing:

Figure 6. XRD Spectra of Ketoprofen and Dengen Extract in Variations of Eutectic Solvent Lauric Acid + Menthol

DISCUSSION:

Eutectic Phase Construction:

In this study, a binary mixture of fatty acids and menthol has been carried out. This type of binary mixture is known as Deep Eutecticum Solvents (DESs) or eutectic solvents. This solvent is known as a green solvent (Green Solvent) because of its environmentally friendly properties³⁶. This solvent has the properties of being non-volatile, biodegradable, sustainable and non-toxic³⁷ so that it can replace organic solvents which are volatile and toxic.

When two or more elements are mixed in a specific molar ratio, the resultant mixture has a substantially lower melting point, which causes DES to form as a homogeneous liquid state component at ambient temperature³⁸. At a specific temperature, eutectic mixtures—combinations of at least two solid components—cause a phase shift from solid to liquid. This temperature is the minimal melting point for all conceivable compositions; it is sometimes referred to as the eutectic point temperature. The eutectic mixture has a lower melting point than the pure components as a result. These combinations are typically associated and identified by a decrease in freezing point relative to the original molecule³⁹. The hydrogen bond interaction between the donor (HBD) and acceptor (HBA) is what causes this occurrence.

The liquid aspect of the menthol mixture containing all the fatty acids was progressively acquired based on observations made during the preparation procedure. All four of the DES were still in their colorless liquid condition even after cooling. This is due to the proper ratio of menthol to fatty acids, as well as the appropriate heating temperature and time. The hydrogen bonds that have formed quite a bit have caused the equivalent amount of HBA and HBD to form a homogenous mixture, which causes the melting point to drop abruptly. Even after extended shaking at a high temperature, no DES will form and the mixture will remain heterogeneous if the amount of HBD is greater than the amount of HBA. This was supported by a study by Hayyan et al., which demonstrated that a solid mixture is created when the quantity of glucose is greater than the quantity of choline chloride⁴⁰.

In this research, menthol was employed as a base chemical or hydrogen bond acceptor for naturally hydrophobic DES. Menthol, a terpene that is believed to be derived from the Mentha species, has been mixed with different substances to create DES formulations⁴¹. The variety of biological applications for synthesized hydrophobic DES can be greatly increased, since it can enhance the stability of DES in water.

From the observation results of various concentration variations and types of fatty acids, lauric acid and menthol were obtained with a ratio of 1:1; 0.25:1; 0.5:1; 1:2 which formed a clear liquid.

Solubility of Ketoprofen and Dengen Bark Extract in Eutectic Solvent:

In every studied eutectic mixture of menthol and lauric acid, both medications were shown to be soluble. For KPN and EKBD, the maximum solubility was found in the 1:2 lauric acid/menthol mixture. The stated solubility of both medicines in water, which is 0.01mg/mL for ketoprofen and 0.07mg/mL for dengen extract, is far lower than these values. In this study, a 10mg concentration of ketoprofen was chosen for solubility testing for several reasons related to pharmaceutical application, practical standards, and the drug delivery system used. Ketoprofen is a lipophilic drug that is poorly soluble in conventional solvents. The 10mg concentration was selected to ensure that the DES system could significantly enhance the solubility of ketoprofen at a concentration that is representative and practical for therapeutic applications. Additionally, at a 10mg concentration, it is easier to evaluate the effect of various DES formulations on solubility without causing issues such as oversaturation or excessive solubility beyond the system's capacity³¹. The 10mg concentration was selected because it provides a good balance between solubility testing and the concentration that can be practically analyzed using common laboratory equipment. At this concentration, the sample size is efficient for testing using spectrophotometry or chromatography techniques, which are commonly used in solubility experiments³³.

The results obtained where the mixture of lauric acid: menthol can provide a solubility level of up to 10,67 mg/mL (105,63%). While for EKBD was 7,51mg/mL (89,14%). Although EKBD do not reach 100%, this binary mixture has increased the solubility by more than 50%. Compared to the solubility in traditional solvents such as methanol, which ketoprofen only reaches 0.158 mole fraction at 25°C, it can be concluded that DES offers a significant improvement in solubility⁴². In another study, the use of DES based on choline chloride and polyols such as ethylene glycol, glycerol, and triethylene glycol also showed improved solubility of ketoprofen compared to conventional solvents. However, the increase was not as substantial as that achieved with the fatty acid and menthol-based DES. Additionally, in another study by Filippa et al. (2016), organic solvent mixtures were used to enhance the solubility of ketoprofen, but they only reported a solubility of about 2-4mg/mL in the organic solvent mixture compared to the higher results obtained with the fatty acid and menthol-based DES⁴³. Jeliński et al. (2019) reported that DES based on choline chloride and glycerol is more effective for hydrophilic compounds, while DES based on fatty acids and menthol excels in enhancing the solubility of lipophilic compounds such as ketoprofen. When compared to traditional solvents such as ethanol or methanol, the solubility of EKBD bioactive compounds from plants, can only increase the solubility in the range of 2-5mg/mL (depending on the concentration and type of extract) (Jeliński et al., 2019). This indicates that fatty acid and menthol-based DES is much more effective in enhancing the solubility of the extract compared to conventional solvents like ethanol or methanol³¹.

This behavior makes sense given that both medications are highly soluble in water and are typically found in lipophilic systems. According to Lee et al. (2018), the medications' enhanced solubility can be linked to hydrogen bonding's dominating role in the drug's solubility⁴⁴. This approach, however, does not emphasize how fatty acids improve medication solubility through a molecular process. Silva et al. (2018) provide more explanation for the aforementioned, stating that hydrotropy is the phenomena responsible for fatty acids' ability to boost medication solubility⁴⁵.

Hydrotropes are composed of hydrophilic and hydrophobic components, just as surfactants, but the hydrophobic component does not lead to spontaneous self-aggregation. This suggests that the chemical self-association of lauric acid molecules as hydrotropes with the medication is responsible for the increase in solubility of ketoprofen and its dengen extract⁴⁶.

The results of FTIR characterization showed that the multicomponent ketoprofen-lauric acid experienced intermolecular interactions with the presence of hydrogen bonds in the proton donor group OH of ketoprofen bound to the proton acceptor group C=O of lauric acid. According to the reported mechanism, the most widely accepted theory holds that the hydroxyl group in DES has a strong internal interaction that facilitates its interaction with the drug and forms hydrophilic and hydrophilic-hydrophilic bonds, van der Waals forces, ion-dipole interactions, and dipole-dipole interactions, all of which increase the solubility of the drug^47,48. The findings of thermodynamic function calculations (enthalpy, Gibbs energy, and entropy) similarly supported the increase in drug solubility in aqueous DES (all genuine thermodynamic function values found were positive)⁴⁹. Additionally, menthol increased the solubility of the medicine by reducing the surface tension, contact angle, and viscosity of the system⁵⁰.

The extract's solubility in DESs may be attributed to a number of its ingredients, including polyphenolic chemicals. The connections that hold the solute and solvent together mediate solubility. Between the elements of the DESs and the compounds in the extract, hydrogen bonds and van der Waals forces are created. DESs may interact with polyphenolic components in particular and become more soluble in them. Further research is necessary to understand the precise connections that underlie solubility.^51,52.

Viscosity Measurement:

Viscosity measurement is very important in determining the stability of a preparation. This parameter greatly affects the rate of dissolution of the solute in the solvent, so that the viscosity value determines the method of drug delivery in the fluid system. ²⁶. As is known, temperature affects the viscosity value of a liquid. The viscosity value is inversely proportional to the increase in temperature. The viscosity value will decrease in the direction of increasing temperature (Indonesian Pharmacopoeia). This can be seen in the diagram below. Where temperature reduces the viscosity of the binary mixture.

From the viscosity measurement table, it can be seen that the binary mixture with a high concentration of menthol also increases the viscosity of the binary mixture. This is because menthol liquidates fatty acids by disrupting the packing state of lauric acid. This condition results in a high level of wetness so that the contact angle becomes small ⁵³.

All ratios (1:1, 0.25:1, 0.5:1, 1:2) show decreasing viscosity as temperature increases, which is typical for liquids with higher viscosity. This is due to increased molecular motion at higher temperatures. For topical applications (e.g., 1:1 and 1:2), higher viscosity at low temperatures may be beneficial, while for oral or injectable systems, 0.25:1 and 0.5:1 are preferable due to their lower viscosity at higher temperatures⁵⁴.

FTIR Fourier Transformed Infrared Spectrophotometry Analysis:

FTIR analysis is used to analyze the identification of functional groups, whose signals can shift when molecular interactions are formed. The FTIR spectrum revealed that there was no interaction between the medication and the binary solution. According to the FTIR spectrum analysis, the FTIR spectrum of every formulation containing the binary mixture of lauric acid and menthol showed all of the major peaks seen in the pure drug. Additionally, some additional peaks were seen with the physical mixture, which may have been caused by the presence of lauric acid and menthol. Since the drug absorption peaks were still discernible in the mixture, there was no drug-lauric acid-menthol interaction visible in the FTIR spectrum.

Based on results FTIR of ketoprofen show that ketoprofen has well-defined aromatic structures, with secondary amines and phenyl groups, which are important for its solubility in both aqueous and organic solvents. Hydrogen bonding interactions with solvents, such as water or polar solvents, may significantly enhance its solubility and bioavailability. The presence of carbonyl, aromatic, and amine groups in the Dengen extract suggests that it is biologically active, and these groups may interact favorably with the DES (fatty acid and menthol) system, leading to improved solubility. The FTIR spectrum of the physical mixture of ketoprofen, lauric acid, and menthol shows that all major peaks of the pure drug remain intact, and no significant new peaks appear that would indicate an interaction between the drug and the binary solution. This suggests that the ketoprofen, lauric acid, and menthol do not form any significant chemical interactions, such as covalent bonds or complexes, under the experimental conditions.

This observation is important because it means that the increase in solubility is likely due to physical changes such as solubility enhancement through the formation of a stable eutectic mixture (i.e., DES), rather than chemical interactions. Therefore, the DES system can still improve the solubility of ketoprofen without altering its chemical structure or causing unwanted side effects. From the FTIR analysis, it is clear that DES based on fatty acids and menthol plays a significant role in enhancing the solubility of both ketoprofen and Dengen extract. The ammonium and carbonyl groups in both substances are likely to interact with the hydrogen-bonding properties of lauric acid and menthol, forming a more homogeneous mixture that allows the drug and extract to be better solubilized.

X-Ray Diffraction Testing:

The XRD diagram above shows the X-ray diffraction patterns of various samples labeled F4, F3, F2, F1, and ketoprofen. F1 shows that hhis spectrum shows sharp diffraction peaks at specific 2-theta angles, indicating that ketoprofen is in a crystalline form. From F1, F2, F3, to F4 the intensity of the XRD peaks gradually decreases. This reduction in peak intensity suggests a decrease in crystallinity or a transformation to a more amorphous form. This change could result from mixing processes or structural modifications of ketoprofen in each formulation (F1 to F4). The F1 formulation shows some visible diffraction peaks, although lower in intensity compared to pure ketoprofen, indicating that some crystallinity of ketoprofen remains. In F2 and F3, the peak intensity is lower than in F1, suggesting a further reduction in crystallinity. F4 shows the most amorphous pattern, with almost no visible diffraction peaks, indicating that ketoprofen may be in a fully amorphous form or highly dispersed within its matrix. Overall, this XRD diagram demonstrates how modifications to ketoprofen (from F1 to F4) affect its crystal structure, with F4 showing the highest level of amorphousness compared to pure ketoprofen.

The displayed XRD diagram shows the X-ray diffraction patterns of various samples labeled F4, F3, F2, F1, and dengen extract. The dengen extract shows several sharp peaks at specific 2-theta angles, indicating that the extract is in a crystalline form. These peaks are characteristic of a stable and well-ordered crystalline structure. From F1, F2, F3, F4, the diffraction peak intensity remains visible with slight variations in intensity. The existing peaks indicate that the components in F1 to F4 have a relatively high degree of crystallinity. F1 has clear diffraction peaks with high intensity, indicating a significant level of crystallinity.F2 also shows distinct diffraction peaks, though with slightly lower intensity than F1, suggesting a slightly lower degree of crystallinity. F3 has a pattern similar to F1 and F2, but with even lower peak intensity, indicating a further reduction in crystallinity. F4 shows the lowest intensity diffraction pattern among all samples, indicating a lower degree of crystallinity or a possible transition to a more amorphous phase. This XRD pattern indicates a gradual decrease in crystallinity intensity from F1 to F4. This may suggest changes in formulation that lead to reduced crystallinity, possibly aiming to improve the solubility or bioavailability of the active compound from the dengen extract. Overall, this XRD diagram demonstrates how variations in the formulations F1 to F4 affect the degree of crystallinity of the dengen extract, with F4 appearing to be the most amorphous among all formulations.

Generally, formulations with lower crystallinity (such as F4) may have better solubility than those with higher crystallinity (such as F1). Therefore, F4, with the lowest intensity, may have higher solubility potential compared to F1 through F3. In the binary mixture sample with ketoprofen or with Dengen bark extract, it did not show the same peaks as pure ketoprofen or with Dengen bark extract. This explains why the DESs approach disperses the molecules of the extract and ketoprofen into a mixed solvent matrix, forming an amorphous structure. According to earlier research, the amorphous form has superior solubility qualities since it has less energy. This test demonstrates the ability of the DESs method to convert the crystal form to amorphous, which accounts for the notable improvement in the solubility of Dengen bark extract and ketoprofen.

CONCLUSION:

Lauric acid-menthol mixture has been shown to be an efficient eutectic system in increasing the solubility of ketoprofen and Dengen bark extract in optimal formulation Lauric acid : menthol = 1:2. This is due to the role of lauric acid in forming hydrogen bonds with both substances, along with the role of menthol in reducing the surface tension, contact angle, and viscosity of the system. There is no evidence of interaction between ketoprofen and Dengen bark extract with the lauric acid-menthol eutectic system as shown by FTIR analysis and the change of crystal form to amorphous form is shown from XRD analysis. Overall, these findings show that fatty acid and menthol-based DES are not only effective in enhancing the solubility of ketoprofen and degen tree bark extract, but also have the potential to change the way drugs are formulated in the future. With broader applications in drug delivery and a reduction in the use of synthetic organic solvents, natural-based DES can significantly contribute to the development of environmentally friendly and sustainable drugs. The next step in the research can be continued by formulating it into a suitable dosage form and proceeding with ex vivo and in vivo testing.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would like to thank the Poltekkes Ministry of Health Makassar (Poltekkes Kemenkes Makassar) for their kind financial support for this research.

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Received on 14.02.2025 Revised on 02.10.2025

Accepted on 16.02.2026 Published on 03.04.2026

Available online from April 06, 2026

Research J. Pharmacy and Technology. 2026;19(4):1567-1576.

DOI: 10.52711/0974-360X.2026.00224

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