INTRODUCTION:

Gemfibrozil is a compound that regulates blood fat levels because it reduces serum triglyceride levels, total cholesterol, VLDL (very low density lipoprotein) cholesterol, LDL (low density lipoprotein) cholesterol, and increases the clearance of apoliprotein B as a VLDL carrier so that VLDL levels are reduced and increases HDL (high density lipoprotein) through increasing the HDL subfraction and apoliprotein AI and AII¹.

Gemfibrozil is categorized as belonging to BCS class II in the Biopharmaceutics Classification System. Medications classified as BCS class II have low solubility and high permeability in the human body, which presents challenges for the creation of pharmaceutical products¹^,². With a molecular weight of 250.33 grammes per mole and a pKa of 4.75, gemfibrozil is essentially insoluble in water (less than 0.1mg/mL), however it is soluble in ethanol (1:10) and methanol (1:10)³.

Solubility enhancement techniques have an important role in increasing the dissolution rate of drugs with low solubility. Various techniques can be used to increase the solubility of poorly soluble drugs including physical modification, drug chemistry, and other methods such as solid dispersions⁴^,⁵, inclusion complexation⁶, spherical agglomerates⁷, nanoparticles⁸, spray drying⁹^,¹⁰, crystal modification¹¹, liquisolid compacts technique¹², and polymorphism¹³. Multicomponent crystals in the form of crystal, salts, solvents and hydrates is one of the crystal engineering techniques in forming new phases and changing the physicochemical properties of a drug, so that it can be used to increase solubility, dissolution rate, physical and chemical stability and compressibility¹⁴^,¹⁵.

A dicarboxylic acid with two hydrogen bond donor groups is succinic acid (COOH). Succinic acid weighs 118.1 grams per mole and has the chemical formula C₄H₆O₄. Succinic acid is a crystalline powder that is white or colorless and odorless. Absorbent in acetone (1:36), methanol (1:16.3), ethanol (1:18.5), and water (1:13). Its pKa is 4.21, and its melting and boiling points are 185 and 235 degrees Celsius, respectively¹⁶.

Other researchers have attempted to improve the solubility and rate of dissolution of gemfibrozil. One such researcher created a solid dispersion of gemfibrozil using PEG 6000 polymer and demonstrated the effects of raising the solid dispersion gemfibrozil's dissolution rate in comparison to pure gemfibrozil¹⁷. According to research by Bastami et al., the solubility of pure gemfibrozil utilizing wet milling procedures was lower than that of gemfibrozil nanosuspension employing the stabilizers PVP K-30 and Tween 80². In an attempt to accelerate the dissolution rate of ketoconazole, other researchers have also conducted study employing succinic acid coformers. Their findings, obtained by the solvent evaporation method, demonstrate a higher dissolution rate in a ratio of 1:1 (molar) when compared to pure ketoconazole¹⁸.

In this work, the solvent drop grinding process was used to produce multicomponent gemfibrozil crystals using succinic acid coformer at a ratio of 1:1 mol. When the difference in pKa value (difference in value <3) between succinic acid (pKa = 4.21) and gemfibrozil (pKa = 4.75) is 0.54, it is projected that the multicomponent will be cocrystalline. X-Ray Diffraction (XRD), Differential Scanning Calorimetric (DSC), Fourier Transform-InfraRed (FT-IR), solubility, and dissolution rate tests will all be used to describe the multicomponent crystal.

MATERIALS AND METHODS:

Materials:

Ingredients used include: gemfibrozil (Zhejiang excel pharmaceutical CO LTD, China), succinic acid (Merck, Germany), distilled water (PT Novalindo, Indonesia), Methanol pa (PT Brataco, Indonesia) Potassium Dihydrogen Phosphate (KH₂PO₄) (PT Novalindo, Indonesia), Sodium Hydroxide (NaOH) (PT Novalindo, Indonesia), and Phosphate Buffer (Merck, Germany).

Getting Ready for a Multicomponent Crystal Drop Grinding with Gemfibrozil-Succinic Acid Solvent:

The ratio of the multicomponent gemfibrozyl-succinic acid crystals was 1:1 mole (2.503 grams:1.181 grams). In a mortar, gemfibrozil and crystal succinic acid were crushed for +15 minutes while 4 mL of methanol was added. Once the mixture of gemfibrozil and succinic acid starts to dry, add an additional 4 milliliters of methanol solution and grind for an additional 15 minutes or until a dry mass forms. Store in a desiccator for ten days¹⁹.

Analysis of X-ray Diffraction (XRD):

Room temperature was used for the X-ray diffraction analysis (Philips X'Pert Pro-PANalytical, The Netherlands). Cu metal target, Kα filter, 40 kV voltage, 30 mA current, and measurement analysis in the 2 theta 5–35° range are the requirements for the measurement. During sample preparation, the sample is leveled and put in a glass sample container to stop particle orientation. The diffraction patterns of succinic acid, multicomponent crystals, physical mixes, and single compound gemfibrozil will all be displayed in this analysis²⁰^,²¹.

Differential Scanning Calorimetry (DSC) Analysis:

DSC analysis was carried out on samples of gemfibrozil, succinic acid, physical mixtures, and multicomponent crystal using Differential Scanning Colorimetry (Setaram DSC 131 Evo, France). Each sample in a small amount was placed in an aluminum container and the temperature of the instrument was set in the range from 50^oC to 300^oC at a heating rate of 10^oC per minute²¹^,²².

Infrared Fourier Transform (FT-IR) Spectroscopy:

FT-IR analyses were performed on gemfibrozil, succinic acid, physical mixes, and multicomponent crystal samples using a Perkin Elmer L1600300 Spectrum Two, USA instrument. After combining about 1-2mg of sample powder with 10mg of KBr in a mortar and grinding the mixture until it was homogenous, the sample was moved to a die and compressed into a disc at an 800 kPa vacuum. Wave numbers 400–4000cm^-1 were used to record the absorption spectra. The spectra obtained from this investigation will depict the functional groups of succinic acid, gemfibrozil as a single compound, the physical mixing, and the multicomponent crystal that is created²¹^,²³.

Test of Solubility:

Samples of gemfibrozil, physical mixes, and multicomponent crystal that were converted into saturated solutions using CO₂-free distilled water were subjected to solubility experiments. After weighing 10 mg of gemfibrozil and the equivalent of 10mg for physical mixes and multicomponent crystals, 100mL of CO₂-free distilled water was added to an Erlenmeyer, and the combination was agitated for 24hours using an orbital shaker. After passing the samples through a 0.45 µm filter (Whatman filter paper), the absorbance was determined at the wavelength of maximum absorption using a UV-Vis spectrophotometer (Shimadzu ED23 Type 1800, Japan). The dissolved gemfibrozil content is ascertained by inserting the acquired absorbance into the calibration curve's regression equation²⁴.

Study of Dissolution Rate Profile

Apparatus II (paddle type) was used to perform the dissolving test (Copley Scientific NE4-COPD, UK) at a stirring speed of 50rpm. A pH 7.5 phosphate buffer solution in 900mL was utilized as the medium, and the temperature was maintained at 37°C±0.5°C. Once the desired temperature has been attained, add 50mg of gemfibrozil or a sample amount to the dissolution container. Pipettes of 5mL of the dissolving solution were used at 5, 10, 15, 30, 45, and 60 minutes. Dissolution medium was used in its stead during pipetting (with the same volume and temperature). At the maximum wavelength, the absorbance of the solution that was pipetted out of the dissolution media is measured. The level of gemfibrozil dissolved at any time can be calculated using a calibration curve/regression equation²²^,²⁵.

RESULT AND DISCUSSION:

Gemfibrozil is a drug that works to reduce triglyceride levels and helps reduce LDL levels and increase HDL levels in the blood. This drug is practically insoluble in water, resulting in a slow dissolution rate and poor bioavailability²⁶. Based on these problems, researchers are interested in making multicomponent crystal using the solvent drop grinding method. The multicomponent crystal that have been made are then subjected to characterization tests including X-Ray Diffraction (XRD), Differential Scanning Calorimetric (DSC), Fourier Transform-InfraRed (FT-IR), solubility and dissolution rate tests.

X-Ray Diffraction (XRD) analysis is used to evaluate the effect of changing the degree of crystallinity of the sample. Gemfibrozil shows a crystalline solid because the diffractogram shows a typical and sharp gemfibrozil crystalline peak at an angle of 2θ, namely (11.4871º, 13.8011º, 17.9351º, 24.1751º) with an intensity of 5304.4, 2793.977, 1811.543, 1803.511 in (figure 1a). In the X-ray diffraction results, it can be seen that the crystalline peak of the physical mixture shows an interference peak at a typical 2θ angle (11.4871º, 13.8011º, 17.9351º, 24.1751º) with an intensity of 3453.233, 2808.734, 1572.93, 1578.888 in (figure 1c). In the X-ray diffraction results, it can be seen that the crystalline peak of the multicomponent crystal shows an interference peak at a typical 2θ angle (11.4871º, 13.8011º, 17.9351º, 24.1751º) with an intensity of 1669.195, 1029.095, 800.0831, 1897.636 on (figure 1d). The physical mixture and multicomponent crystal exhibit a decrease in the intensity of the degree of gemfibrozil crystallinity, as indicated by these two investigations. This is because succinic acid, a new crystal peak coformer in gemfibrozil, has an impact on this. Sharp peaks appear, indicating the presence of crystal, where the solvent or water used enters the crystal lattice of gemfibrozil. This suggests that multicomponent crystal produces a new crystallinity phase (molecular compound) or that the change from anhydrous to hydrate occurs. Interactions take place during freezing, leading to the creation of new crystal peaks²⁷. From the X-ray diffraction results, it can be seen that the crystalline peak of succinic acid shows an interference peak at a typical 2θ angle (19.9631º and 26.0991º). namely 18540.43 and 5425.341 in (figure 1b). In the physical mixture at angles 2θ: 19.9631º and 26.0991º, namely 11058.05 and 1854.346 in (figure 1c). Meanwhile, the multicomponent crystal at an angle of 2θ is 19.9631º and 26.0991º, namely 1723.107 and 2311.761 in (figure 1d).

Figure 1. XRD overlay of (a) gemfibrozil, (b) succinic acid, (c) physical mixture, and (d) multicomponent crystal.

Based on the analysis data, it shows that there is a decrease in the intensity of the degree of crystallinity of succinic acid in physical mixtures and multicomponent crystal. This indicates that the multicomponent crystal between gemfibrozil and succinic acid produces a new crystalline phase (molecular compound) or is suspected of changing from anhydrous to hydrate, where sharp peaks appear due to the solvent or water used entering the crystal lattice. gemfibrozil and the freezing process then an interaction occurs so that a new crystal peak appears. From the diffractogram results on the overlay, the typical peak of gemfibrozil is not as sharp as the peak of the coformer, the physical mixture and multicomponent crystal indicate that the gemfibrozil is evenly mixed into the succinic acid coformer and the results obtained have led to a crystalline form²⁷.

Analysis of the degree of crystallinity is tested using the DSC "differential scanning colorimetry" tool which is used to determine the heat capacity and enthalpy of a material and is able to measure the amount of heat absorbed or released during the transition²⁸. The gemfibrozil thermogram results show a sharp endothermic peak at 62.407℃ which is the melting point with an enthalpy value of 49.585J/g (Figure 2a). The results of the succinic acid thermogram show a sharp endothermic peak with a melting point of 191.67 ℃ with an enthalpy value of 323.227J/g (Figure 2b). The thermogram of the physical mixture shows two endothermic peaks with melting points of 62.725℃ and 184.601℃ with enthalpy values of 64.628 J/g and 18.447 J/g (Figure 2c). In the multicomponent crystal thermogram there are also two endothermic peaks, namely with melting points of 60.742^oC and 179.307^oC with enthalpy values of 154.64J/g and 16.29 J/g (Figure 2d). From the results of the DSC thermogram analysis, there are 2 peaks that appear due to the mixture of gemfibrozil and succinic acid which have different melting points. A crystalline solid requires more energy during the melting process, which raises the heat of fusion. This is indicated by the DSC thermogram's endothermic transition, which shows that the more crystalline a solid is, the more energy is needed to melt it²⁹.

Figure 2. DSC overlay of (a) gemfibrozil, (b) succinic acid, (c) physical mixture, and (d) multicomponent crystal.

Figure 3. FT-IR overlay of (a) gemfibrozil, (b) succinic acid, (c) physical mixture, and (d) multicomponent crystal.

Table 1. FT-IR spectrum analysis of gemfibrozil, succinic acid, physical mixtures, and multicomponent crystal.

Formulas	Functional Groups and Wave Number (cm^-1)
Formulas	O-H (1317-1286)	C=O (1708-1613)	C=C (1675-1500)
Gemfibrozil	1286.81	1708.00	1612.79
Succinic acid	1309.93	1693.77	-
Physical Mixture	1286.80	1613.01	1613.01
Multicomponent Crystal	1315.97	1613.07	1613.07

Functional group analysis using an FT-IR (Fourier Transform-Infrared) Spectrophotometer in multicomponent evaluation aims to identify functional groups in a compound and to determine the structure of a compound by comparing fingerprint areas and to determine whether or not there is a chemical interaction between gemfibrozil - succinic acid³⁰. Results of infrared spectrum analysis on gemfibrozil (Figure 3a, Table 1). It can be seen that the presence of the O-H functional group at the wave number 1286.81cm^-1 indicates that there is a stretch of the O-H functional group because in the range 1317-1286 cm^-1, the C=O group at the wave number 1708.00 cm^-1 indicates that there is a stretch of the C=O functional group because in the range 1708-1613 cm^-1, the C=C functional group at a wave number of 1612.79 cm^-1 indicates the existence of a stretch of the C=C functional group because it is in the range 1675-1500 cm^-1. The infrared spectrum of succinic acid (Figure 3b, Table 1) shows the presence of the O-H functional group at wave number 1309.93 cm^-1, the C=O group at wave number 1693.77 cm^-1, indicating the presence of functional group stretching because it is in the range. The characteristics of the infrared spectrum in the physical mixture (Figure 3c, Table 1) show the presence of the O-H group at the wave number 1286.80 cm^-1, the C=O functional group at the wave number 1613.01 cm^-1, the C=C functional group at the wave 1613.01 cm^-1. The results of the infrared spectrum characteristics of multicomponent crystal (Figure 3d, Table 1) show the presence of the O-H group at wave number 1315.97 cm^-1, the C=O functional group at wave number 1613.07 cm^-1, the C=C functional group at wave number 1613.07 cm^-1. From the results of FT-IR analysis it can be concluded that there is a shift in wave numbers in physical mixtures and multicomponent crystal.

Solubility tests were carried out on pure gemfibrozil, physical mixtures and multicomponent crystal (Table 2). The solubility results of pure gemfibrozil in CO₂-free distilled water were 0.2953µg/mL, physical mixtures were 3.5764µg/mL, and multicomponent crystal were 7.4653µg/mL. From the results obtained it can be seen that the solubility of the multicomponent crystal increases 25 times higher than that of pure gemfibrozil, while the physical mixture increases 12 times higher. This is directly proportional to the particle size, where the smaller the particle size, the more surface area the particle has to interact with the solvent, the higher the solubility.

Table 2. Results of solubility test of gemfibrozil, physical mixtures, and multicomponent crystal in CO₂-free distilled water.

Compound	Solubility (µg/mL)	Enhancement (times)
Gemfibrozil	0,295 ± 0,100	-
Physical Mixture	3,576 ± 0,574	12
Multicomponent crystal	7,465 ± 0,909	25

[mean±SD, n= 3]

Determination of the gemfibrozil dissolution profile obtained the results sequentially at 5, 10, 15, 30, 45 and 60 minutes, namely 10.71%, 11.51%, 12.9%, 16.95%, 20.47% and 25, 99%. The results of the physical mixture dissolution profile sequentially at 5, 10, 15, 30, 45 and 60 minutes were 21.02%, 22.83%, 24.12%, 26.51%, 31.12% and 35.46%. The results of the multicomponent crystal dissolution profiles sequentially at 5, 10, 15, 30, 45 and 60 minutes were 30.37%, 32.49%, 34.02%, 40.46%, 44.36% and 46.13% can be seen in Figure 4.

Table 3. Dissolution efficiency of gemfibrozil, physical mixtures, and multicomponent crystal with phosphate buffer pH 7.5.

Compound	Dissolution Efficiency (%)	Enhancement (times)
Gemfibrozil	16,60% ± 0,1077	-
Physical Mixture	26,51% ± 0,1090	1.6
Multicomponent crystal	37,88% ± 0,1027	2.3

[mean±SD, n= 3]

Figure 4. Dissolution profile curves of gemfibrozil, physical mixtures, and multicomponent crystal with phosphate buffer pH 7.5.

From the results obtained, it can be seen that the multicomponent crystal has a good dissolution rate using the solvent drop grinding method. This shows that there has been a significant increase in the dissolution percentage of gemfibrozil after it was formulated with succinic acid in a 1:1 mole ratio using the solvent drop grinding method. Another factor that causes an increase in the dissolution rate is between drug solubility and melting point, where a solid that has a lower melting point will have a weak lattice energy, thereby increasing the solubility and dissolution rate of a substance³¹.

According to Abdou, 1989, another parameter used to evaluate dissolution is dissolution efficiency³². Dissolution efficiency was used to compare the amount of gemfibrozil dissolved in the dissolution medium of pure gemfibrozil, physical mixtures and multicomponent crystal. The dissolution efficiency value is the AUC (Area Under Curve) value of the amount of drug dissolved per time. The calculation of the average dissolution efficiency is the comparison between the area under the dissolution curve at time (t) and the area of the rectangle when the dissolution of the active substance reaches 100%.

From the dissolution efficiency tests carried out, it shows that the dissolution efficiency of pure gemfibrozil is 16.60%, the physical mixture is 26.51%, and the multicomponent crystal is 37.88% (Table 3). From this data it can be seen that there has been an increase in the dissolution efficiency value of gemfibrozil by 2.3 times after the formation of multicomponent crystal.

CONCLUSION:

Multicomponent gemfibrozyl-succinic acid crystal can improve the physicochemical properties seen from the XRD, DSC, and FT-IR results. Multicomponent crystal can increase the solubility and dissolution rate of gemfibrozil.

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 16.05.2024 Revised on 14.09.2024

Accepted on 20.12.2024 Published on 10.04.2025

Available online from April 12, 2025

Research J. Pharmacy and Technology. 2025;18(4):1831-1836.

DOI: 10.52711/0974-360X.2025.00262

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