Abstract
The present study is regarding, Glimepiride is one derivatives of sulfonyl urea used in the treatment of Type II DM which classified as class-II (BCS) of high permeability and low degree of solubility. The endeavor is to improve its solubility by solvent vaporization method to enhance the rate of dissolution of glimepiride. Soluplus (Polyvinyl caprolactampolyvinyl acetate-polyethylene glycol graft co-polymer), PVP k40 (Polyvinylpyrrolidone) and PEG k5 are blended with the drug in various proportions (1:1,1:3) and prepared Soluplus1, Soluplus2, PEG1, PEG2, PVP1 and PVP2 as solid dispersion. The optimized formula of solid dispersion PVP1 is added to sodium starch glycolate and cross-carmellose. The disintegration profile will appear diminished in the drug release from the dosage form at a determined period of time. Differential scanning calorimetry appeared to a reduction in its crystallinity in solid dispersions. Scanning electron microscope and particle size analysis show a reduction in the drug particle size as solid dispersions. Fourier transform infrared spectroscopy does not show an interaction between them. Hence, that PVP1 batch will be considered from nine oral dissolving tablets dosage form. Finally, orally disintegrating tablets are estimated for various parameters; for instance, disintegration time, the content of the drug, wetting time, and in vitro release profile show a conventional result. The selected formula F6 shows a good result in disintegration time during 13-second and in-vitro drug release profile achieves 96% at the end of 40 minutes.
Keywords: Glimepiride, orodispersible tablets, solid dispersions and solvent evaporation technique
INTRODUCTION
Orodispersible tablets (ODTs) are important in the pharmaceutical formulation for both over-the-counter drugs and prescription; they improve patient acceptability, low cost and simple methods. The disintegration of such dosage form is determined by the size and hardness of tablets.[1] Thus the goal of current study is to compress the component into tablet that characterized by fast dissolving through rapid disintegration and high drug release from the formula during a short period of time.[2] It is also considered as a single dose solid dispersion that used orally inside the mouth cavity, which dissolves in saliva with rapid onset of action. ODTs are produced by adding cross-povidone, sodium cross-carmellose, and sodium starch-glycolate.[3] There are different techniques used in the production of ODTs like lyophilization, mass extrusion, spray drying, molding, sublimation, and direct compression.[4]
The preparation of solid dispersion relies on the disintegration rate which can be enhanced by improve surface area to avoid the precipitation within the carrier, solid including in the solution and improve the wetting properties due to direct interaction with hydrophilic polymer carrier, to take a shape of a metastable crystalline structure.[5] Therefore adjusting the drug/polymer ratio and selecting the suitable method have direct effect on the type of solid dispersion and drug release behavior[6]
The polyethylene glycol (PEG) 5k, Soluplus, and polyvinylpyrrolidone (PVP) 40k are the foremost utilized polymer to carry solid dispersion and their capability to form atomic adduct compounds.[7] The presence of hydroxyl and carbonyl group tends to enhance water solubility, bioavailability, and stability.[8] Hence, the use of such polymers has a crucial role in improving the dissolution rate profile for the drug and consequently the absorption.[9] Glimepiride has low water solubility (<0.004 mg/ml) and dissolution properties may cause poor bioavailability.[10] Additionally, Glimepiride is a weak acid (pKa 6.2), and has low solubility in acidic media, so it is a challenge to overcome this issue by formulating Glimepiride as ODTs to obtain rapid release of the drug in the oral cavity with a few second to achieve a high percent of drug release from the formula.[11] Subsequently, to improve the therapeutic efficacy by enhancement of solubility and dissolution rate of Glimepiride.[12]
MATERIALS AND METHODS
Materials
Glimepiride was a gift from Al Warqaa Medical Store for Chemicals Baghdad and Soluplus, PVP 40k, and PEG 5k were purchased from Al-Noor Medical Store for Chemicals. Sodium starch glycolate and sodium croscarmellose are purchased from Al-Noor Medical store.
Method of preparation
Solvent evaporation technique was used in the preparation of glimepiride solid dispersion, where various formulas of glimepiride were prepared by solid dispersion technique and arranged into two proportions with each polymer PEG 5k, PVP 40k, and Soluplus. Precisely weighed amount of the drug with polymer; then homogenously mixed with an adequate volume of alcohol. The prepared solution was evaporated at room temperature to get dry solid dispersion at that point dried in a desiccator; the batches of solid dispersion are shown in Table 1. The yield solid was sieved through 65 meshes to ensure the equal consistency of particle size within the required range.[13]
Table 1.
Solid dispersion batches preparation ratio of drug-polymer
| Polymer | Formula | Ratio |
|---|---|---|
| PEG 5k | PEG1 | 1:1 |
| PEG2 | 1:3 | |
| PVP 40k | PVP1 | 1:1 |
| PVP2 | 1:3 | |
| Soluplus | Soluplus 1 | 1:1 |
| Soluplus 2 | 1:3 |
PEG: Polyethylene glycol, PVP: Polyvinylpyrrolidone
Estimation of solid dispersion
Taking 10mg of prepared Glimepiride/polymer solid dispersion of (1:1 and 1:3) ratio and dilute with 50mL Ethanol of 95% using magnetic stirred for 1-hour then scanning at 217nm UV absorbance to obtain λmax as shown in [Figure 1] UV.[14] Then performing the solubility study, percentage yield, FTIR Spectroscopy, In-vitro study, scanning electron microscopy and thermal analysis (differential scanning calorimetry) to estimate the formulation of solid dispersion that assist in the selection of the optimize formula.[15]
Figure 1.
UV spectrum of Glimepiride in ethanol, UV: Ultraviolet
Preparation of orally disintegrating tablets
Glimepiride ODTs are prepared by combination of Na-starch glycolate and super-Na-crosscarmellose through direct compression method. The component are accurately weighed and passed through 50# sieve prior blending and placed into a glass mortar to mix consistently as shown in Table 2 the component of Glimepiride ODTs formula. The blend at that point is estimated for precompression parameters before the compression process.[16]
Table 2.
Formula for preparing orally disintegrating tablets of glimepiride
| Material | F1 | F2 | F3 | F4 | F5 | F6 | F7 | F8 | F9 |
|---|---|---|---|---|---|---|---|---|---|
| Batch PVP1 (mg) | 85 | 85 | 85 | 85 | 85 | 85 | 85 | 85 | 85 |
| Cross-Carmellose Na | - | - | 10 | 15 | 10 | 15 | 10 | 12.5 | 15 |
| SSG | 12.5 | 10 | - | - | 10 | 5 | 5 | 5 | - |
| MCC | 117.5 | 120 | 120 | 115 | 110 | 110 | 115 | 112.5 | 115 |
| Mannitol | 33 | 33 | 33 | 33 | 33 | 33 | 33 | 33 | 33 |
| Magnesium stearate | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 |
| Talc powder | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 |
| Na-saccharin | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
| Total | 250 | 250 | 250 | 250 | 250 | 250 | 250 | 250 | 250 |
PVP: Polyvinylpyrrolidone, SSG: Sodium starch glycolate, MCC: Microcrystalline cellulose
Estimation of precompression powder
The characterization study is performed by determining the angle of repose, tapped and bulk density, Carr's Index and Hausner ratio; to estimate the properties of the blend before compression.[17]
Estimation of orally disintegrating tablets
Weight variation test is carried out for the prepared tablets to determine the total differences in weight. The percentage of weight variation is obtained by taking the total weight of 20 tablets and the average weight difference with mean value of ±S.D.[18]
The hardness test was performed to determine the driving force required to break the tablet over an applied pressure. The hardness was obtained in kg about 3–5 kg/cm2, which is palatable for uncoated tablets. The hardness test device was Monsanto hardness analyzer.[19]
Friability test is performed to determine the weight loss from the tablet and comparing the final weight with the original tablet. This test is important obtain the surface resistance during the packaging and transport. The device used is Roche Friabilator.[20]
Dissolution time analysis
The dissolution test apparatus type II USP was used to determine the rate of dissolution of the ODTs.[21] One tablet was set in each vessel of 1 liter 0.1 M HCL at 37 ± 2°C, and the sample is scanned at 217nm UV to obtain the average percent of drug release during 25-minute.[25]
Wetting test
The test was used to determine the wetting time by placing a tablet in a beaker; Each table should be weighted before and after fluid absorption to determine the difference in weight using sensitive electronic balance to obtain the percent of wetting according to the equation 1.[23]
R = Wa - Wd / Wd × 100
Where Wa is tablet after water after and Wd is dry tablet.
In vitro study
The study was conducted in vitro to determine the drug release profile in phosphate-buffered saline (PBS) of pH 7 for 25.[24] Eight samples are tested triplicate using dissolution test apparatus type II (Digital DT 950 Series Dissolution Tester); the tablet is placed in 900mL phosphate buffer solution at 37±2°C and the sample is scanned at 217nm UV to obtain the average percent of drug release during 25-minute.[25]
RESULTS AND DISCUSSION
Solvent evaporation method is used to produce Glimepiride ODTs and the preformulation studies are performed for all the formula to obtain the data of organoleptic properties, angle of repose, Carr's 48. index, solubility analysis, λmax and calibration curve; which assist in the selection of best formula.
Preformulation studies
Characterization: Organoleptic properties were studied and are placed in Table 3.
Table 3.
Identification and characterization of glimepiride
| Tests | Results |
|---|---|
| Appearance | White to yellowish |
| Melting point | 188-192°C |
| Nature | Crystalline powder |
| Solubility | In acid media at 25°C (<0.004 mg/ml) |
λ max determination
UV spectrophotometer is used to determine λmax of the drug in different solvents as shown in Figure 1; the data of λmax in ethanol, water and PBS are placed in Table 4.
Table 4.
λmax of maximum absorbance in various solvents
| Solvent | λmax (nm) |
|---|---|
| Phosphate buffer solution 7 | 219 |
| Water | 218 |
| Ethanol | 217 |
Calibration curve determination
The solution of 0.1mg/mL Glimepiride shows linear relation at maximum UV absorption, the data of the intercept, slope and R2 are placed in Table 5; and the calibration curve of Glimepiride in PBS, water and ethanol are shown in [Figures 2-4].
Table 5.
Glimepiride calibration curve in different solvents
| Solvent | Slope | Intercept | R 2 |
|---|---|---|---|
| Phosphate buffer 7 | 0.177 | 0.024 | 0.999 |
| Water | 0.086 | 0.016 | 0.999 |
| Ethanol | 0.075 | 0.095 | 0.999 |
Figure 2.
Drug/PBS calibration curve, PBS: Phosphate-buffered saline
Figure 4.
Fourier transform infrared spectroscopy pure glimepiride
Figure 3.
Drug/ethanol calibration curve
Fourier transform infrared spectroscopy spectroscopy
The characterizations of Glimepiride are appeared in Table 6. The data of wave numbers of Glimepiride are placed Table 7. FTIR stretching of C=O group at 1656-1715cm-1 and stretching of C-H bond at 2922 cm-1; which slightly shifted in batch PEG1, PEG2, PVP1, PVP2, Soluplus1 and Soluplus2 at 2954, 2873,2837, 2886, 2939, 2933 cm-1 respectively. The boarded peak indicates a great interaction of H- bonds with PEG1, PVP1and Soluplus1 which cause a shift into the amorphous form; thus there is no change in the internal structure due to the compatibility of drug and polymers. FTIR analysis for Glimepiride, PVP1, PVP2, PEG1, PEG2, Soluplus 1 and Soluplus 2 are shown in [Figures 4-10] respectively.
Table 6.
Percentage yield and drug content
| Formula | Drug content | Percentage yield |
|---|---|---|
| PEG1 | 80.2 | 23.32 |
| PEG2 | 81.3 | 25.90 |
| PVP1 | 69.2 | 35.21 |
| PVP2 | 64.6 | 33.43 |
| Soluplus 1 | 75.4 | 22.32 |
| Soluplus 2 | 85.6 | 18.26 |
PEG: Polyethylene glycol, PVP: Polyvinylpyrrolidone
Table 7.
Peaks characterization for pure glimepiride
| Functional group | Reference wave number (cm−1) | Obtained wave number (cm−1) |
|---|---|---|
| OH | 3250-3400 | 3371.215 |
| C-H Stretch | 2750-3100 | 2922.876 |
| C=O (carbonyl) | 1656-1715 | 17165.657 |
| -C=C-Aromatic | 1450-1650 | 1592.022 |
| Para substituted | 825-935 | 822.112 |
Figure 10.
Fourier transform infrared spectroscopy Soluplus 2
Figure 5.
Fourier transform infrared spectroscopy PVP1. PVP: Polyvinylpyrrolidone
Figure 6.
Fourier transform infrared spectroscopy PVP2. PVP: Polyvinylpyrrolidone
Figure 7.
Fourier transform infrared spectroscopy PEG1. PEG: Polyethylene glycol
Figure 8.
Fourier transform infrared spectroscopy PEG2. PEG: Polyethylene glycol
Figure 9.
Fourier transform infrared spectroscopy Soluplus 1
Saturated solubility of Glimepiride/Solid-dispersion
Solubility study is performed to enhance the bioavailability of poor water solubility drug.[19,20] Here, glimepiride solubility is compared with polymers solubility in water as shown in Figure 11 where the polymers appear higher solubility in water. The solid dispersion of PVP1 and PVP2 have higher solubility than other batches due to formation of H-bonds with water to form amorphous structure to improve the drug release. The data of saturated solubility are recorded in [Table 5] with mean value of ±S.D.
Figure 11.
Saturation solubility of glimepiride and batches PEG1, PEG2, PVP1, PVP2, Soluplus 1, and Soluplus 2, PEG: Polyethylene glycol, PVP: Polyvinylpyrrolidone
Percentage yield and drug content of the formulas
The obtained data of drug content and percentage yield by detecting the amount of drug in each formula using UV absorbance at 217nm where Soluplus 2 was the higher drug content than others because of the stuck nature of the polymer as shown in Table 8.
Table 8.
Glimepiride and solid dispersion batches (saturation solubility)
| Formula | Saturated solubility |
|---|---|
| Glimepiride | 0.1202±0.008 |
| PEG1 | 0.3972±0.008 |
| PEG2 | 0.3628±0.005 |
| PVP1 | 0.9571±0.005 |
| PVP2 | 0.9121±0.003 |
| Soluplus 1 | 0.3309±0.002 |
| Soluplus 2 | 0.6298±0.005 |
PEG: Polyethylene glycol, PVP: Polyvinylpyrrolidone
In vitro study
The drug release in PBS alone is 53.13% within 10 min, while with polymer PVP K-40 the percent of release profile increased to 73.4% and 58.2% for PVP1 and PVP2, respectively [Figure 12].
Figure 12.
Drug release profile of glimepiride
Thermal study differential scanning calorimetry
The test is important to determine the compatibility between the drug and excipients to obtain an accurate data about their interactions.
Interpretation of DSC thermograms data is shown in [Figures 13-16] for pure drug, PVP1, PEG1 and S1 respectively below, the information about melting point shows a decline in PVP1 with less M. P than pure drug; 75.3°C and 191.8°C that's mean the endothermic reaction of the formula PVP1 with reduction in the temperature of the thermograms peak area; that gives an indication in the faster dissolution rate because of the reduction in crystallinity and rapid dissolving, when compared with a pure drug, on the other hand, there is the same change in the thermograms shows in [Figures 13-16]; show a reduction in M. P of Soluplus 1 as compared to the unadulterated Glimepiride likely due to diminish in the size crystillinty. The melting point of formula Soluplus 1 and PEG1 is found to be 174.23°C and 168.17°C. The inhibition in crystallinity is ascribed to interaction drug particles with polymer matrix through using the solvent evaporation technique which gives a result about the compatibility of both together.
Figure 13.
Differential scanning calorimetry pure glimepiride
Figure 16.
Differential scanning calorimetry Soluplus
Figure 14.
Differential scanning calorimetry polyvinylpyrrolidone
Figure 15.
Differential scanning calorimetry polyethylene glycol
Estimation of orally disintegrating tablets formulas
Study of precompression parameters
Table 9 shows the results of precompression parameters of compression technique in the presence of super disintegrant at various ratios. The reduction in size of granules and angle of repose can improve the flowability and increase in the surface area; the data have determined with mean value of ±S.D.
Table 9.
Values of precompression study
| Batches | Angle repose (θ) | Hausner’s ratio | Bulk (g/ml) | Tapped (g/ml) | Carr’s index |
|---|---|---|---|---|---|
| F1 | 29.2 | 1.22 | 0.54 | 0.69 | 17.91 |
| F2 | 28.1 | 1.12 | 0.56 | 0.66 | 16.32 |
| F3 | 27.4 | 1.23 | 0.53 | 0.64 | 16.61 |
| F4 | 26.5 | 1.19 | 0.58 | 0.68 | 15.43 |
| F5 | 28.3 | 1.17 | 0.61 | 0.67 | 18.45 |
| F6 | 27.8 | 1.18 | 0.57 | 0.67 | 16.82 |
| F7 | 24.9 | 1.24 | 0.59 | 0.70 | 14.99 |
| F8 | 28.5 | 1.16 | 0.56 | 0.71 | 15.37 |
| F9 | 26.6 | 1.17 | 0.55 | 0.69 | 15.48 |
Estimation of glimepiride orally disintegrating tablets
The obtained data of ODTs are shown in Table 10; the thickness ranges between 2.23±0.45 to 3.88±0.24 mm, the less the thickness shows a good product quality. The hardness test is not more than 4.00 ± 0.200 kg/cm2 for accepted range. Weight variation is within the accepted limit of 248 ± 1.030–252 ± 1.23 mg. The friability values for all formulas are less than 1.0% which fall in range of 0.37%-0.78% and have good mechanical strength. Table 11 illustrates the values for the estimation study.
Table 10.
Preformulation values
| Formulas | Thickness (mm) | Hardness (kg/cm2) | Weight (mg) | Friability | Disintegration time (s) |
|---|---|---|---|---|---|
| F1 | 3.26±0.12 | 3.41±0.167 | 248±1.02 | 0.37±0.010 | 18±1.22 |
| F2 | 2.74±0.27 | 3.49±0.124 | 251±1.05 | 0.43±0.023 | 22±1.35 |
| F3 | 2.91±0.13 | 3.50±0.100 | 248±1.10 | 0.78±0.113 | 17±1.11 |
| F4 | 3.88±0.25 | 3.60±0.200 | 251±1.32 | 0.62±0.311 | 17±1.40 |
| F5 | 2.92±0.35 | 3.60±0.200 | 248±1.23 | 0.65±0.336 | 22±1.00 |
| F6 | 2.32±0.42 | 3.36±0.057 | 250±1.15 | 0.42±0.007 | 13±1.72 |
| F7 | 2.73±0.24 | 3.43±0.057 | 248±1.03 | 0.73±0.100 | 14±0.64 |
| F8 | 2.23±0.45 | 3.40±0.264 | 252±1.23 | 0.75±0.025 | 20±1.00 |
| F9 | 3.63±0.37 | 3.62±0.154 | 250±1.35 | 0.47±0.005 | 21±1.26 |
Table 11.
Oral dispesrable tablets estimation values
| Formula | Percentage drug content | Wetting time | Percentage H2O absorption ratio | Percentage drug release |
|---|---|---|---|---|
| F1 | 98.23±0.774 | 21±1.12 | 52.32 | 42±5 |
| F2 | 96.54±0.253 | 23±1.46 | 59.65 | 39±1 |
| F3 | 97.32±0.422 | 18±1.32 | 57.72 | 31±7 |
| F4 | 98.74±0.567 | 13±1.15 | 59.52 | 45±3 |
| F5 | 96.76±0.321 | 25±1.23 | 57.61 | 37±1 |
| F6 | 99.36±0.582 | 15±1.54 | 59.85 | 44±1 |
| F7 | 98.81±0.518 | 20±0.21 | 59.65 | 36±2 |
| F8 | 98.21±0.773 | 21±0.78 | 59.69 | 28±3 |
| F9 | 97.39±0.691 | 19±1.22 | 58.43 | 31±2 |
The disintegration time for all formulas is ranged between 13 to 22 seconds, F6 shows the rapid disintegration time within 13 seconds.
Figure 17 shows water absorption of the ODTs. The data have determined with mean value of ±S.D., percentage of drug release from 28 to 44% for F6 as shown in [Table 11].
Figure 17.
Water absorption. (a) Before, (b) After water absorption
In vitro orally disintegrating tablets release profile
Figure 18 illustrates the Release profile in-vitro study by using dissolution rate apparatus USP2 test to obtain the dissolution time for the ODTs in PBS 7 media at 37°C, for F6 about 69% after 10 minutes and maximum release achieved 95.3% after 40 minutes; figure 18 illustrates the release profile, while the remaining formulas the burst release is started after 10 minutes less than 40% and the maximum release after 40 minutes is less than 90% as shown in Table 12.
Figure 18.
Percentage release profile
Table 12.
Drug release profile
| Time (min) | F1 | F2 | F3 | F4 | F5 | F6 | F7 | F8 | F9 |
|---|---|---|---|---|---|---|---|---|---|
| 10 | 66 | 63 | 65 | 67 | 60 | 69 | 59 | 64 | 62 |
| 20 | 70 | 67 | 73 | 75 | 65 | 66 | 61 | 66 | 73 |
| 30 | 90 | 88 | 87 | 85 | 78 | 96 | 75 | 88 | 78 |
| 40 | 92 | 90 | 89 | 88 | 83 | 94 | 78 | 90 | 89 |
| 50 | 89 | 87 | 86 | 90 | 82 | 93 | 80 | 85 | 83 |
| 60 | 88 | 85 | 85 | 88 | 80 | 90 | 77 | 81 | 80 |
| 70 | 85 | 84 | 83 | 87 | 79 | 89 | 76 | 80 | 77 |
CONCLUSION
Glimepiride ODT is prepared by using direct compression method as solid dispersion in the presence of super-disintegrant to enhance the dissolution rate of the tablets in oral cavity and increase the drug release profile through initial burst release from the matrix due to the swelling of the polymer in the presence of fluid to disintegrate the ODTs with a few second. The selection of F6 as a best formula is based on the collected data regarding high drug content and rapid drug release from the formula.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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