|Year : 2019 | Volume
| Issue : 3 | Page : 262-267
Study of gliclazide solid dispersion systems using PVP K-30 and PEG 6000 by solvent method
Febriyenti Febriyenti, Suraiya Rahmi, Auzal Halim
Faculty of Pharmacy, Universitas Andalas, Padang, Indonesia
|Date of Web Publication||9-Jul-2019|
Dr. Febriyenti Febriyenti
Faculty of Pharmacy, Kampus Limau Manis, Universitas Andalas (UNAND), Padang 25163
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Gliclazide is a second-generation hypoglycemic sulfonylurea, which is useful in the treatment of non-insulin-dependent diabetes mellitus. It has low bioavailability because of its limited water solubility and slow dissolution rate. In this study, solid dispersions of gliclazide were prepared by solvent method. Drug and carriers weight ratio were 1:9; 2:8; 3:7; 4:6; and 5:5. The weight ratio of carriers (polyvinyl pyrrolidone K-30 and polyethylene glycol 6000) was 1:1. The properties of solid dispersions were evaluated using scanning electron microscopy (SEM), Fourier-transform infra red (FTIR) spectroscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and solubility and dissolution studies. SEM result showed that gliclazide was highly dispersed and was present as amorphous state in the solid dispersions. The FTIR spectroscopy showed no chemical interaction between gliclazide and carriers. DSC studies indicated melting point of gliclazide was decreased. The XRD studies indicated that crystallinity degree of gliclazide was decreased. Rate of dissolution and solubility of solid dispersions was increased than pure gliclazide (F < 0.05).
Keywords: Gliclazide, PEG 6000, PVP K-30, solid dispersion, solvent method
|How to cite this article:|
Febriyenti F, Rahmi S, Halim A. Study of gliclazide solid dispersion systems using PVP K-30 and PEG 6000 by solvent method. J Pharm Bioall Sci 2019;11:262-7
|How to cite this URL:|
Febriyenti F, Rahmi S, Halim A. Study of gliclazide solid dispersion systems using PVP K-30 and PEG 6000 by solvent method. J Pharm Bioall Sci [serial online] 2019 [cited 2019 Aug 24];11:262-7. Available from: http://www.jpbsonline.org/text.asp?2019/11/3/262/262200
| Introduction|| |
The bioavailability of the oral dosage form depends on the solubility and dissolution rate of the drug. The dissolution rate of drug determines its effect. Some efforts to increase the solubility of the drug need to be carried out. There are many methods to improve the solubility, such as salt formation, micronization, and the addition of solvents or surfactants. Solid dispersion is a method that involves the dispersion of one or more active substances in an inert carrier or matrix in the solid state. This system can be produced by melt, solvent, and combination of melt–solvent methods.
Gliclazide is a second generation of oral antidiabetic sulfonylurea that is used in the treatment of type 2 diabetes mellitus. Gliclazide showed good tolerability and a low incidence of hypoglycemic. These properties make gliclazide as the drug of choice in the long-term therapy of type 2 diabetes mellitus. Gliclazide is an active compound belonging to the second group of Biopharmaceutics Classification System, which means gliclazide has a low solubility in water but has a high permeability.,
Increased oral bioavailability of poorly soluble drugs in water is a challenge for the development of a formulation. A solid dispersion of poorly soluble drugs in water and a water-soluble polymer can increase drug solubility and even bioavailability. The increase in dissolution rate of solid dispersion systems is caused by a reduction in the particle size as a drug carrier solubilization effect, the improvement of wettability, and the formation of the metastable dispersion system. Some researchers have used surfactants to improve the dissolution rate. Surfactants will cooperate with the carrier used by lowering the surface tension and by increasing the wettability of the drug. This is what that makes the dissolution rate of poorly soluble drugs in water larger.,
In a solid dispersion with two components, a third component could be added to increase the rate of dissolution or to overcome the limitations in the manufacture and stability. The use of polyethylene glycol 6000 (PEG 6000) in increasing the dissolution rate of gliclazide has been carried out. PEG 6000 could reduce drug particle aggregation and increase wettability and formation of drug microcrystalline. Therefore, the aim of this study was to see the effect of polyvinyl pyrrolidone K-30 (PVP K-60) and PEG 6000 in the characterization of solid dispersions of gliclazide. PEG 6000 and PVP K-30 have a good solubility in various organic solvents. These properties are the advantages in the manufacture of solid dispersions. Besides as a dispersant, PEG 6000 also can act to inhibit recrystallization on gliclazide.
| Materials and Methods|| |
Materials used in this study are gliclazide (PT. Pyridam, Indonesia), PVP K-30 (PT. Dexa Medica, Indonesia), PEG 6000 (PT. Dexa Medica, Indonesia), NaOH (PT. Brataco, Indonesia), KH2PO4 (PT. Brataco, Indonesia), ethanol (PT. Brataco, Indonesia), methanol (PT. Brataco, Indonesia), CO2-free Aquadest, Digital scales analytic (AUX220®; Shimadzu, Japan), 250 μm sieve, magnetic stirrer, hotplate, water bath, desiccators, Whattman filter paper, pH meter, X-ray diffractometer (Rigaku, Japan), FTIR spectrophotometer (Perkin Elmer, Germany), UV-Vis spectrophotometer (Shimadzu 1700 series, Japan), scanning electron microscopy (SEM; JEOL, Japan), dissolution testing apparatus (NE4-COPD; Copley Scientific), differential scanning calorimetry (Perkin Elmer, Germany), and glassware..
Solid dispersion preparation
Gliclazide solid dispersion system, PVP K-30, and PEG 6000 were made with the following comparison [Table 1] with a final weight of 20g.
Solid dispersions were prepared by solvent method. Gliclazide, PVP K-30, and PEG 6000 were dissolved respectively in 96% ethanol, and then mixed and stirred with a magnetic stirrer. The solution formed was evaporated and dried over water bath to obtain dried dispersion. Solid dispersion that formed was collected and stored in desiccators before use. For comparison, there were also prepared physical mixture of gliclazide with the carriers with a ratio of 1: 1.
Scanning electron microscopy analysis
Gliclazide powder, physical mixtures, and solid dispersions formula were placed on an aluminum sample holder and coated with gold to a thickness of 10nm, then observed on the various magnifications. SEM instrument (JEOL) was set at 20kV and 12 mA current.
Fourier-transform infrared spectroscopy analysis
Approximately 1–2mg of gliclazide powder, physical mixtures, and solid dispersions formula were placed in a mortar and then crushed until homogeneous then formed pellets with a pressure of 800 mPa under vacuum and analyzed by Fourier-transform infrared (FTIR) spectrophotometer. Absorption spectra were recorded at wave number 500–4000cm−1.
X-ray diffraction analysis
Some gliclazide powders, physical mixtures, and solid dispersions formula were placed on glass slides, spreaded them homogeny in order to prevent particle orientation during sample preparation and incorporated into the diffractometer. X-ray diffraction (XRD) was carried out with a scan speed of 2°/mm and a chart speed of 2°/2cm per 2θ.
Differential scanning calorimetry analysis
Approximately 5mg of sample was placed on an aluminum cylinder and the sample was introduced into the differential scanning calorimetry (DSC) instrument. Heating was performed with dry nitrogen gas flow rate of 20mL/min and a heating rate of 10°C/min. Heated temperature ranges were between 10°C and 250°C. Empty aluminum plate was used as a reference. Endothermic and exothermic processes that occur in the sample were recorded on a recorder. Melting temperature and enthalpy of each particle were recorded.
Recovery of gliclazide in solid dispersions
The wavelength of maximum absorption in phosphate buffer pH 7.4 was determined using gliclazide solution (250 µg/mL). Calibration curve of gliclazide was used at concentrations 6, 8, 10, 12, and 14mg/mL. Physical mixture and solid dispersion samples were weighted, which was equivalent to 80mg of gliclazide, and then dissolved with 10mL methanol and phosphate buffer of pH 7.4 up to 100mL. Absorbance was measured at a wavelength of maximum absorption. Gliclazide concentration could be determined using a calibration curve.
Samples that equal with 50mg gliclazide were weighted and dissolve with 25mL phosphate buffer (pH 7.4) in Erlenmeyer. Samples were put in orbital shaker for 24 hours. After the samples were filtered using filter paper (Whattman [0.45 µm]), absorbance of filtrates were measured using UV spectrophotometer at the maximum wavelength.
Dissolution test was run using dissolution apparatus type 1 (basket) at 100rpm for 2 hours. Dissolution medium was 900mL phosphate buffer (pH 7.4) and temperature of the medium was set at 37°C ± 0.5°C. Dissolution test was performed with a test sample that was equivalent to 80mg gliclazide. Samples were taken about 5mL at 5, 10, 15, 30, 45, 60, 90, and 120 minutes. In order to maintain a fixed volume, 5mL of dissolution medium was added at the same temperature. Absorptions of liquid samples were determined using UV spectrophotometer at maximum wavelength.
| Results and Discussion|| |
Morphology of samples were observed using SEM. The results have been shown in [Figure 1]. Crystal gliclazide has a rod-like shape; PVP K-30 looks spherical with a smooth surface texture and PEG 6000 looks like flakes. On the physical mixture, morphology of gliclazide, PVP K-30, and PEG 6000 still can be distinguished. The solid dispersion formula indicates that the morphology of gliclazide has not seen specifically. It means that a solid dispersion system has formed where gliclazide has been dispersed in PVP K-30 and PEG 6000.
|Figure 1: Morphology of (A) gliclazide, (B) PVP K-30, (C) PEG 6000, (D) physical mixture, (E) F1, (F) F2, (G) F3, (H) F4, and (I) F5|
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FTIR spectroscopic analysis was performed to see the spectrum formed from solid dispersions of gliclazide and carriers (PVP K-30 and PEG 6000) compared to the spectrum of pure gliclazide. Each bond in a compound absorbs infrared light. Gliclazide provides peak at wave number 1707.53cm−1, which shows the carbonyl group (C = O). Peaks absorption at 1162.02cm−1 and 1345.90cm−1 shows the sulfonyl group. Peak at 3270.26cm−1 proves the amino group. The results can be seen in [Figure 2].
Physical mixtures and solid dispersions of all formulas still provide absorption in the same area and also a similarity of fingerprint region with the spectrum of gliclazide. It shows that no chemical reaction occurred during the manufacture of solid dispersions. The slight change in the wave numbers proves the physical interaction between gliclazide and polymers in the solid state. This is caused by hydrogen bonds between the amine group on gliclazide with one oxygen atom–ion pair in PEG 6000 or oxygen atom on gliclazide sulfonyl group with a hydrogen atom in PVP K-30 or PEG 6000.
Analysis by XRD was carried out to see the diffraction pattern of gliclazide, physical mixtures, and solid dispersion formulas. Peak position (angle of diffraction) shows the crystal structure and the height of the peak indicated the crystallinity. The result has been shown in [Figure 3].
|Figure 3: X-ray diffractogram of PVP K-30 (A), PEG 6000 (B), gliclazide (C), physical mixture (D), F1 (E), F2 (F), F3 (G), F4 (H), and F5 (I)|
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X-ray diffraction pattern of the gliclazide provides typical diffraction peaks and high peaks, which indicated that the drug is in the crystalline state. The peaks 2θ are at 10.40°, 14.79°, 17.06°, 18.05°, 20.60°, 21.03°, 21.88°, and 26.06°. Crystallinity levels have affected the drug dissolution. Amorphous or metastable state will dissolve most rapidly because of higher internal energy and movement of larger molecules. Change or shift in the peak position of gliclazide can be observed in the solid dispersion formulas. Sharp peak in pure gliclazide is clearly visible at the same position in the solid dispersion formulas, but overall the intensity is reduced. This means that the crystalline nature of the drug is still there but the intensity is decreased. A change in the location of the diffraction peaks in the solid dispersion formula allegedly occurred because of the physical interaction between gliclazide with the polymer, namely polymorphic transformation or change from one state into another polymorph state during the evaporation of the solvent in the manufacture of solid dispersion systems.
Thermal analysis using a DSC was performed to see the melting point and the interactions that occur between gliclazide and carriers (PVP K-30 and PEG 6000).
Thermogram showed a shift in temperature at endothermic peak of gliclazide solid dispersion compared with gliclazide. Thermogram of gliclazide showed an endothermic reaction that indicated the melting process. Sharp peak at 166.4°C is the melting point of gliclazide. The results could be seen in [Figure 4].
|Figure 4: DSC thermogram of gliclazide (A), physical mixture (B), F1 (C), F2 (D), F3 (E), F4 (F), and F5 (G)|
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There are two endothermic peaks in the thermogram of physical mixture and solid dispersion systems F2, F4, and F5. The peaks are the melting point of PEG 6000 and gliclazide. Endothermic peak of PEG 6000, which has a melting point of 65.14°C, has decreased in the thermogram of solid dispersion system. Gliclazide endothermic peak is also wider and decrease. It shows a decrease in the degree of crystallinity of the drug. DSC thermogram of solid dispersion F1 has not seen the peak of gliclazide. This is presumably because gliclazide in solid dispersion F1 has dissolved completely in the melted polymer during the DSC measurement. Overall, data from DSC have shown that the components of PVP K-30 and PEG 6000 solid dispersion systems affect the position of the endothermic peak and endothermic peak sharpness. This indicates the physical interaction between the dispersed drug (gliclazide) and the carriers. These data reinforce the results of XRD that have been described previously.
The wavelength of maximum absorption is 223nm. Equation of the calibration curve is y = 0.041x + 0.064 with a regression value of 0.999. Recovery of gliclazide in solid dispersions F1, F2, F3, F4, and F5 are 97.76%, 102.44%, 103.96%, 105.39%, and 99.01%, respectively. The results are not much different from the requirements listed in the British Pharmacopoeia 2009 of 95%–105%. This shows the resulting solid dispersion system has been created meticulously and carefully so that retrieval of gliclazide is obtained in accordance with the requirements.
Solubility study results
The results of the solubility study showed an increase in the solubility of gliclazide in physical mixtures and solid dispersions formulas. F4 has the highest (1.478mg/mL) solubility of gliclazide [Table 2]. The increase in the solubility to the gliclazide was due to the wetting effect of the PVP K-30 and PEG 6000 in the solid dispersion system.
Dissolution study results
The solid dispersion system could improve the dissolution rate of gliclazide when compared to pure gliclazide. F4 has higher percentage of dissolution than the F1, F2, F3, and F5. The results could be seen in [Figure 5]. Percentages of gliclazide dissolve at 120 minutes from F1, F2, F3, F4, and F5 are 44.73%, 47.15%, 43.35%, 60.85%, and 45.63%, respectively. These results indicate that the addition of PVP K-30 and PEG 6000 plays an important role in the dissolution of solid dispersions.
|Figure 5: Dissolution curve of gliclazide, physical mixture, and solid dispersion system|
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| Conclusions|| |
There are physical interactions between gliclazide and carriers (PVP K-30 and PEG 6000) in solid dispersion system. There are hydrogen bonds between the amine group on gliclazide with one oxygen atom–ion pair in PEG 6000 or oxygen atom on gliclazide sulfonyl group with a hydrogen atom in PVP K-30. Solid dispersion system of gliclazide and carriers used could improve the solubility and dissolution rate of gliclazide.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]