INTRODUCTION:

Biopharmaceutical aspects in the formulation of medicinal preparations are always influenced by physicochemical factors, one of which is solubility. Solubility has an important role in predicting the degree of drug absorption in the gastrointestinal tract. Drugs that have little solubility in water (poorly soluble drugs) have low bioavailability and low dissolution¹. Quercetin is included in the BCS (Biopharmaceutical Classification System) or class II biopharmaceutical classification system where its solubility is low but its permeability is high (low solubility drugs)^2,3.

Quercetin with the chemical name (3,3', 4', 5,7-pentahydroxyflavone) is a flavone which is a secondary metabolite known as a flavonoid. Quercetin can provide many effects such as antioxidant ^4,5, anti-carcinergic ⁶, anti-inflammatory⁷, antibacterial ⁸, antiviral ⁹, anti-obesity ¹⁰, nephronprotector¹¹.

One way to increase the solubility of quercetin which has low solubility in water is to use the freeze-drying technique. The drying technique known as "spray freeze-drying", has several uses in both food and pharmaceutical technologies ¹². The present study employed the freeze-drying (lyophilization) method as its production approach owing to its ease of use and the low/mild temperatures at which drying takes place, resulting in less mechanical or thermal stress on the drug particles in comparison to the spray- drying technique ¹³.

Several studies have been carried out to improve the physicochemical properties of quercetin, such as the quercetin crystal technique with liquid assisted grinding methods, the results of this research, the physical mixture and the cocrystalline phase showed an increase in the dissolution rate compared to pure quercetin, respectively 1.02 and 1.25 higher¹⁴. Increasing the dissolution rate of quercetin in vitro using quercetin - malonic acid cocrystals, the results of this research are that the cocrystals effectively increase the dissolution rate and dissolution efficiency compared to pure quercetin and a physical mixture of quercetin - malonic acid ¹⁵. Another study made co-crystallization of quercetin and isonicotinamide using the solvent evaporation method. The results obtained were quercetin-isonicotinamide co-crystals with better physicochemical and in-vitro dissolution characteristics ¹⁶.

Crystal-forming molecules or coformers that will be used in cocrystallization must have conditions such as being non-toxic, having better polarity compared to the active substance, being a pharmaceutical excipient or other drug and being able to bond non-covalently with the active substance ¹⁷. Based on the description above, the effect of forming quercetin-succinic acid cocrystals using the freeze-drying technique can improve the dissolution rate. X-Ray Diffraction (XRD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FT-IR), assay, solubility test can be carried out. and dissolution test

MATERIALS AND METHODS:

Materials:

Quercetin (Sigma, America), succinic acid (Merck, Germany), Ethanol pa (Merck, Germany), Aquadest (PT Novalindo, Indonesia), HCl (Sigma, America).

Making Quercetin-Succinic Acid Cocrystals Freeze-Drying Technique:

Curcetin and succinic acid were mixed in a ratio of 1:1 mole (3.02236g:1.1809g). Quercetin was added with 2 mL of 0.1 N NaOH, while succinic acid was dissolved in 48 ml of distilled water. The two solutions were mixed then homogenized on a magnetic stirrer. Once homogeneous, dissolve the sample first, freeze it in liquid nitrogen. Then proceed with the freeze-drying process (Christ Alpha 1-2 LD Plus) at a drying temperature of -80ºC. The freeze-drying process is carried out until the sample is dry from water. The drying results are stored in a tightly closed container and placed in a desiccator^{13 18}.

X-Ray Diffraction (XRD) Analysis:

X-ray diffraction analysis using a Philips X'Pert Pro-PANalytical in the Netherlands, analysis was carried out at room temperature using an x-ray diffractometer. measurement conditions as follows: metal target cu, voltage 40 kV, filter kɑ, current 20 mA measurement analysis range 2 theta 5 - 35°. This analysis was carried out on quercetin, succinic acid, physical mixtures, and cocrystals^{18 19}.

Differential Scanning Calorimetry (DSC) Analysis:

Analysis was carried out on quercetin, succinic acid, physical mixtures and cocrystals using a Setaram DSC 131 Evo, France. A sample of 5 mg was placed in a crucible pan, covered with a cover and immediately pressed. A small quantity of each sample was positioned in an aluminum housing, and the instrument's temperature was programmed within the range of 50°C to 300°C, with a heating rate set at 10°C per minute ^{18 20}.

Fourier Transform Infrared (FT-IR) Analysis:

Approximately 1-2 mg of powder is placed in the die mold, the sample is compressed in a disc under vacuum conditions with a pressure of 800 kPa. The absorption spectrum was recorded at wave numbers 4000-400 cm^-1. This analysis shows the functional groups of the compounds quercetin, succinic acid, physical mixtures, and cocrystals using the Perkin Elmer L1600300 Spectrum Two, USA ^21,22.

Solubility Test:

Solubility tests were carried out on quercetin, physical mixtures, and cocrystals made into saturated solutions. Each formula was weighed equivalent to 10 mg of quercetin, then put into a 100 mL Erlemeyer. Then add 100 mL of CO₂-free distilled water. Then the sample was placed in an orbital shaker for 24 hours at 25ºC., filtered using 0.45 μm filter paper (Whatman filter paper). The results were analyzed using a UV-Vis spectrophotometer (Shimadzu ED23 1800®, Japan) ^23,24.

Dissolution Rate Profile Study:

Determination of the dissolution profile using the paddle method was carried out by weighing the quercetin, physical mixture, and cocrystal equivalent to 50 mg of quercetin. Each sample and quercetin were inserted into each chamber of the paddle type dissolution tester which had been filled with dissolution media. The temperature was set at 37ºC ± 5ºC and the stirring speed was 50 rpm. The dissolution test process was carried out for 60 minutes. Each sample was taken at 5 mL at 5, 10, 15, 30, 45 and 60 minutes. After each sampling, 5 mL of 0.1 N HCl solution was added so that the volume of the dissolution medium remained constant. The solution samples that had been obtained were then measured for their absorbance using a UV-Vis spectrophotometer (Shimadzu ED23 1800®, Japan). The level of quercetin dissolved in each pipetting can be calculated using the regression equation ^14,15.

RESULT AND DISCUSSION:

This research began by examining the quercetin raw material, the examination was carried out based on the requirements in The Merck Index ²⁵. The results of the organoleptic examination showed that quercetin was in the form of a crystalline powder, pale yellow. Quercetin is practically insoluble in water and readily soluble in ethanol. Then the examination of the raw material for succinic acid was carried out based on the requirements stated in The Merck Index. From organoleptic examination, succinic acid was in the form of a white crystalline powder. Solubility succinic acid is soluble in water, soluble in ethanol, soluble in methanol and soluble in acetone. After examining the raw materials, proceed with making quercetin – succinic acid cocrystals in a ratio of 1:1 mole. Quercetin, physical mixtures, and cocrystals were characterized using XRD, DSC, FT-IR, solubility tests, and dissolution profiles.

The results of XRD analysis are used to characterize crystalline materials, which will provide information about structural parameters such as crystallinity, strain, crystal orientation and defects in the crystal ^26,27. In this study, XRD analysis was used to evaluate the influence of the degree of crystallinity of the sample. In the XRD test, quercetin shows a sharp and clear peak at an angle of 2θ, namely 12.8651° with an intensity of 782.8598; 26.4631° with an intensity of 2019.463; 27.2431° with an intensity of 1669.758 (Table 1, figure 1a). The diffractogram of succinic acid shows a peak at an angle of 2θ at an angle of 16.1671° with an intensity of 4528.692; 20.1191° with an intensity of 12296.17; 26.1771° with an intensity of 3857.917; 32.5211° with an intensity of 4230.414; 38.4231° with an intensity of 2481.774 (Table 1, figure 1b). The diffractogram results of quercetin show a crystalline phase that is more towards amorphous because there are not many sharp peaks, while succinic acid shows high and sharp peaks which show a crystalline for ²⁸. In the physical mixture, freeze-drying cocrystals resulted in a decrease in the peak intensity of succinic acid, this was due to the interaction between succinic acid and quercetin resulting in a decrease in the intensity of quercetin. However, in the results of the X-ray diffractogram analysis, it is estimated that the formation of crystals is due to the presence of a new peak at an angle of 2θ at an angle of 12.5011° with an intensity of 3555.649 which can be seen in table 1 and figure 1d. This indicated the physical interaction between quercetin and succinic acid and the formation of a new crystalline phase, known as co-crystalline phase (molecular compounds or molecular complexes) in materials sciences ²⁹.

Table 1. XRD Analysis Results

2θ	quercetin	succinic acid	physical mixture	cocrystal
12.8651°	782.8598	-	668.9701	540.9704
26.4631°	2019.463	-	1826.609	712.0372
27.2431°	1669.758	-	1415.958	1668.468
16.1671°	-	4528.692	405.7729	873.2555
20.1191°	-	12296.17	433.2476	756.8508
26.1771°	-	3857.917	2961.465	1100.807
32.5211°	-	4230.414	283.5219	573.0041
38.4231°	-	2481.774	731.2652	731.514
12.5011°				3555.649

Figure 1. Overlay X-ray diffraction analysis (a) quercetin, (b) succinic acid, (c) physical mixture, (d) cocrystal

Differential Scanning Calorimetry (DSC) is a thermal analyzer that can be used to determine the heat capacity and enthalpy of a material. DSC is able to measure the amount of heat absorbed or released during these transitions^27,30. The data obtained from this DSC analysis is the enthalpy and melting point of the endothermic peak. In this study, the results of DSC analysis of quercetin showed a single and sharp endothermic peak, namely at a temperature of 121.864°C, and an enthalpy of 20.637 J/g which can be seen in Figures 2a and 3a. The succinic acid thermogram shows an endothermic peak with an enthalpy of 323.227 J/g at a melting point of 191.676°C which can be seen in Figure 3b. The physical mixture thermogram shows an endothermic peak with an enthalpy of 14.962 J/g with a melting point of 188.937°C and another peak with an enthalpy of 19.658 J/g and a melting point of 116.609°C can be seen in Figure 3c. Meanwhile, in the thermogram of the quercetin - succinic acid cocrystal there is a peak showing an endothermic peak with an enthalpy of 70.011J/g with a melting point of 120.304°C and another peak with an enthalpy of 20.89 J/g and a melting point of 186.865°C which can be seen in Figures 2b and 3d. Melting point has a close relationship with solubility, the higher the melting point, the smaller the solubility, conversely, if the melting point is lower, the solubility will be greater. The results of this analysis show that the melting point of the cocrystal formula decreases due to the formation of an amorphous form, the amorphous form is formed when the melting point decreases and the cocrystal form is formed when the melting point increases. DSC can be used in multicomponent formation to identify polymorphic alterations of the drug or coformer, to select appropriate coformers to make cocrystals with the required molecule, and to identify the development of novel phases, such as cocrystals ³¹.

(a) quercetin

(b) cocrystal

Figure 2. Differential scanning calorimetry analysis of (a) quercetin, (b) cocrystal

Figure 3. Differential scanning calorimetry analysis of (a) quercetin, (b) succinic acid, (c) physical mixture, (d) cocrystal

Qualitative analysis with FT-IR Spectroscopy was carried out to obtain structural information on the compound. IR spectroscopy is often used to determine interactions between drugs and complexors. Infrared spectroscopy can detect the presence of hydrogen bonds or not ³². Infrared spectroscopy analysis is carried out to determine the functional group of an organic compound and determine the structure of the organic compound by comparing fingerprint areas. The results of the analysis are in the form of a graph showing the varying transmittance percentages at each infrared radiation frequency ³³. The infrared spectrum of quercetin can be seen in table 2 and figure 4a, it can be seen that there are OH functional groups, C=O functional groups, C=C functional groups and C–O–C functional groups with wave numbers of 3350.78cm^-1, 1655.78cm^-1, 1612.50cm^-1, and 1164.00cm^-1¹⁶. The FT-IR spectrum of succinic acid can be seen in Figure 2 and Figure 4b, the presence of OH functional groups and C=O functional groups at wave numbers 3013.69cm^-1 and 1705.50cm^-1²⁸. The infrared spectrum of the physical mixture can be seen in table 2 and figure 4c, it can be seen that there are OH functional groups, C=O functional groups, C=C functional groups, and C–O–C functional groups with wave numbers of 3400.49cm^-1, 1666.73cm^-1, 1612.16cm^-1, and 1168.00cm^-1. The infrared spectrum of the cocrystal can be seen in table 2 and figure 4d, it can be seen that there are OH functional groups, C=O functional groups, C=C functional groups, and C–O–C functional groups with wave numbers of 3410.84cm^-1, 1666.52 cm^-1, 1612.11 cm^-1, and 1169.27 cm^-1. From the FT-IR bond it can be concluded that there is a significant chemical interaction between quercetin and succinic acid after cocrystal formation, due to a shift in functional groups ¹⁶.

Table 2. FT-IR spectrum analysis of quercetin, succinic acid, physical mixture, and cocrystal.

Sample		Wave Number (cm^-1)
Sample	OH (3000-3750)	C=O (1650-1900)	C=C (1500-1675)	C-O-C (1000-1300)
Quercetin	3350.78	1655.78	1612.50	1164.00
Succinic acid	3013.69	1705.50	-	-
Physical mixture	3400.49	1666.73	1612.16	1168.00
Cocrystal	3410.84	1666.52	1612.11	1169.27

Figure 4. FT-IR analysis of (a) quercetin, (b) succinic acid, (c) physical mixture, (d) cocrystal

In the solubility test carried out on quercetin, a physical mixture, and quercetin – succinic acid cocrystals, the test results can be seen in table 3. The purpose of the solubility test is to see the effect of cocrystal formation on solubility ²⁸. The solubility of quercetin in CO₂-free distilled water was 0.459mg/mL, the physical mixture was 0.919mg/mL, and the cocrystal was 1.179mg/mL. From the results obtained it can be seen that the solubility of cocrystal (1:1) increases 3 times higher than quercetin. This is compared with the results of XRD, DSC and FTIR characterization.

Table 3. Solubility test results of quercetin, physical mixture, and cocrystal in CO₂-free distilled water solvent

Compound	Solubility (mg/mL)	Enhancement (times)
Quercetin	0.459 ± 0.02	-
Physical mixture	0.919 ± 0.022	2
Cocrystal	1.179 ± 0.095	3

[mean±SD, n= 3]

Determination of the dissolution profile of quercetin, physical mixture and cocrystal was carried out using 0.1 N HCl medium for 60 minutes. The results show an increase in the percent dissolution of pure quercetin, physical mixtures and cocrystals, which can be seen in Figure 5, Table 4. The results of the percent dissolution of pure quercetin at 5, 10, 15, 30, 45 and 60 minutes respectively are 25.43%, 25.82%, 26.24%, 26.48%, 26.9%, and 27.26%. The results of the percent dissolution of the physical mixture at 5, 10, 15, 30, 45 and 60 minutes respectively were 27%, 27.39%, 27.57%, 27.75%, 27.99% and 28.23%. The results of percent dissolution of cocrystals at 5, 10, 15, 30, 45 and 60 minutes respectively were 28.71%, 29.07%, 29.32%, 29.74%, 30.28% and 30.76 %. From the results obtained, it can be seen that the quercetin - succinic acid cocrystals have a good dissolution rate using the freeze-drying method. This shows that there has been a significant increase in the dissolution percentage of quercetin after it was formulated with succinic acid in a 1:1 mole ratio using the freeze-drying method. Another factor that causes an increase in the dissolution rate is that the drug's solubility and lower melting point will have a weaker lattice energy, thereby increasing the solubility and dissolution rate of a substance³⁴.

Figure 5: Dissolution rate profile of quercetin, physical mixture, and cocrystal [mean±SD, n= 3]

Table 4: Dissolution efficiency of quercetin, physical mixture, and cocrystal

Compound	Dissolution efficiency (%)	Enhancement (times)
Quercetin	19.896 ± 0.973	-
Physical mixture	26.890 ± 1.842	1.3
Cocrystal	28.550 ± 0.561	1.4

[mean±SD, n= 3]

The parameter used to evaluate dissolution is dissolution efficiency³⁵. The average calculation of dissolution efficiency obtained from the area under the curve shows the dissolution efficiency value for quercetin is 19.896%, the physical mixture is 26.890% and the quercetin – succinic acid cocrystal formula is 28.550% (Table 4).

CONCLUSION:

Based on research, 1:1 mol quercetin - succinic acid cocrystals can improve the physicochemical properties of quercetin as seen from XRD, DSC and FTIR characterization. The cocrystals showed an increase in solubility and percent dissolution compared to pure quercertin.

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 16.10.2024 Revised on 17.05.2025

Accepted on 01.09.2025 Published on 13.01.2026

Available online from January 17, 2026

Research J. Pharmacy and Technology. 2026;19(1):352-357.

DOI: 10.52711/0974-360X.2026.00051

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.