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International Journal of ChemTech Research CODEN (USA): IJCRGG, ISSN: 0974-4290, ISSN(Online):2455-9555 Vol.10 No.4, pp 160-171, 2017
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Formulation and Evaluation of Solid Dispersion of Furosemide in Poly vinyl Pyrollidone K 30
Meenakshi1, Azhar Danish Khan2*
1Department of Pharmaceutics, College of Pharmaceutical Sciences, R.K.G.I.T Ghaziabad .(U.P), India
2Dept of Pharmaceutics RamEesh Institute of Vocational and Technical Education , Greater Noida (U.P), India
Abstract : This investigation was carried out to determine if a solid dispersion of Furosemide in Poly vinyl pyrollidone ( PVP K-30) will enhance the dissolution and permeation properties of the drug.Solid dispersion of Furosemide in PVP K 30 was prepared in ratios by Solvent Evaporation Method amongst which 1:4 was the optimized batch. Permeation study was also performed. In this case, the solid dispersion was characterized by Fourier transform Infrared spectroscopy, differential scanning calorimetry (DSC) to ascertain if there were any physicochemical interactions between drug and carrier that would effect dissolution. Mouth dissolving tablets containing solid dispersion were formulated. The dissolution studies were performed at 37+ 0.50 C and 50 rpm in simulated gastric fluid (pH 6.8).
FTIR spectroscopy and DSC showed a change in crystal structure toward an amorphous form of Furosemide. Dissolution data indicated that Furosemide dissolution was enhanced. FTIR,DSC spectroscopy and dissolution studies indicated that solid dispersion formulated in 1:4 ratio showed an increase in dissolution .Solid Dispersion technique can be used to improve the dissolution of Furosemide along with its permeation.
Keywords : Solid dispersion, Furosemide, Poly vinyl pyrollidone K-30, 0.1% Sodium lauryl sulphate, physicochemical characterization.
Introduction
Furosemide (FRMD) is 5-(aminosulphonyl)-4-chloro-2-[(2-funayl-methyl) amino] benzoic acid, and it is a potent high ceiling (loop) diuretic mainly used in treatment of hypertension. The drug has been classified as a class IV drug as per the biopharmaceutical classification system (BCS) as a result of its low solubility and oral bioavailability is its solubility1, 2,3.The present work aims to evaluate the potentials of the solid dispersion technique for the development of mouth dissolving tablets of FRMD using Poly vinyl pyrollidone K 30, as a hydrophilic carrier4, 5.
Oral bioavailability of a drug depends on its solubility and/or dissolution rate, and dissolution may be the rate determining step for the onset of therapeutic activity. Therefore efforts to increase drug dissolution of drug are often needed. Salt formation, micronization and addition of solvent or surface active agents are the methods to improve dissolution. Solid dispersion is one the such methods and it involves a dispersion of one of one or more active ingredients in an inner carrier or matrix in solid state prepared by solvent evaporation method6, 7. This technique has been used for a wide variety of poorly soluble drugs such as carbamazepine, celecoxib , Ibuprofen, Meloxicam, Nevirapine, Terbinafine, Rofecoxib, Valdecoxib.
The present work aims to evaluate the potential of solid dispersion technique for development of mouth dissolving tablets of FRMD using PVP K 30 as the hydrophilic carrier5, 6. The method used is Solvent evaporation method in which both the drug and the Hydrophilic polymer are dissolved in a common solvent later allowed for the evaporation of the solvent so the residue left over is the solid dispersion. Later these are analzed through the analytical tools such as Fourier Transform infrared (FTIR), Differential scanning calorimetry. Furthermore the dissolution was investigated.
Experimental
Materials and Method
Materials
Furosemide was gift sample from Hem Deep Organics Pvt. Ltd mfg of Bulk drugs and intermediates, Plot No.3801/2, G.I.D.C., Ankleshwar. Dist. Bharuch , Gujarat , India. Polyvinyl pyrollidone K 30 and Ethanol was used.
Preparation of Furosemide-PVP K 30 solid dispersion
A mixture (20mg) of Furosemide and PVP K 30 (1:4) by weight, respectively. The polymer was first dissolved in ethanol, to get a clear solution later the drug was dissolved in the polymer solution. The resultant mixture was than stirred to evaporate the volatile substance. Than the material was passed through sieve no 60. Than the formed material was stored in the desiccator till the further use. Therefore the solid dispersion was used to prepare the mouth dissolving tablets5, 11.
Evaluation
Content uniformity study:
The solid dispersions containing an equivalent amount of 10 mg of Furosemide was added to a volumetric flask (25 ml) containing phosphate buffer (pH 6.8), the flask was shaken for 15 min and final volume was made with phosphate buffer (pH 6.8). The sample was filtered and assayed for Furosemide spectrophotometrically (Shimadzu 1700 at 227.4 nm) 15.
Solubility studies:
Solubility measurement were performed according to Higuchi and corners method (Higuchi and corners.1965): The solubility of solid dispersions is usually determined by the equilibrium solubility method, which employs a saturated solution of the material, obtained by stirring an excess of material in the solvent for a prolonged period (24 hr) until equilibrium is achieved. The solutions were filtered and absorbance was checked at 227.4 nm using spectrophotometer.
Fourier transform infrared (FTIR) spectroscopy
FTIR spectra were recorded on samples prepared in potassium bromide (KBr) disksusing a Shimadzu Corporation facility (model - 8400S) from Punjab. Samples were prepared in KBr disks in a hydrostatic press at6-8 tons pressure. The scanning range was500 to 4000 cm.
Differential scanning calorimetry (DSC)
The DSC analysis was performed with Universal V4.5A TA Instruments, from IIT Delhi. It was found that the melting point of the Drug-Polymer Complex was lower in comparison of the pure Drug. This shows Amorphization of the Drug in Solid Dispersion.
Dissolution rate studies
The dissolution was studied with accurately weighed amount of the formulations(containing approx. 20 mg of furosemide)using a USP apparatus II in 900 ml of simulated gastrointestinal fluid (SGF, pH 6.8)for one hour. The rotational speed of thepaddle was set at 50 rpm at 37 ± 0.5ºC.Aliquots (5ml each) were withdrawn at
predetermined time intervals for 1h; sink conditions were maintained. The samples were analyzed for drug content using a double beam UV spectrophotometer at 227.4 nm.
Tablet preparation and characterization
Tablets containing an equivalent of 110 mg of Furosemide (SD2) were compressed on a 16-station single rotary tabletting press (Type –CMD3 – 16, using an 8-mm standard flatpunch by direct compression technique, at a compression pressure of 6 tons. The tablet formulation were code as S1, S2, S3, S4, S5, S6, S7 which were at different ratios of super disintegrant of 7, 8, 9, 10, 11 12, 13 respectively. Amongst all S6 is the best batch. It contains 110 mg of Furosemide, 24 mg of Sodium Starch Glycolate, 25 mg of Mannitol, 10 mg of starch, 25 mg of Microcrystalline cellulose, 2 mg of Magnesium Sterate, 2 mg of Talc, and 2mg of sodium lauryl sulphate and was punched of 200 mg tablet. Tablet was evaluated for hardness (Pfizer/Monsanto Hardness tester), Friability(Roche friabilator), weight variation, and drug content. In vitro dissolution studies were performed among different batches and a comparative study was performed as in fig.3.
Table 3. Comparative study of Mouth dissolving tablet dissolution
Time(min) |
% drug release of S1 |
% drug release of S2 |
% drug release of S3 |
% drug release of S4 |
% drug release of S5 |
% drug release of S6 |
% drug release of S7 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
2 |
40.099 |
25.99 |
25.248 |
28.218 |
39.356 |
34.901 |
45.297 |
4 |
56.658 |
50.639 |
60.289 |
58.078 |
54.427 |
68.511 |
58.915 |
6 |
62.17 |
61.316 |
65.821 |
61.37 |
61.411 |
88.197 |
68.152 |
8 |
69.196 |
69.823 |
69.897 |
87.698 |
68.432 |
98.337 |
86.349 |
10 |
68.833 |
76.147 |
79.934 |
88.923 |
91.085 |
100.363 |
91.279 |
15 |
65.495 |
78.791 |
81.114 |
90.153 |
95.297 |
99.427 |
99.204 |
|
|
|
|
|
|
|
|
Figure 3 : In-vitro dissolution S1 (♦), S2 (▀), S3 (▲), S4 (×), S5 (Ӿ), S6 (●), S7 (+)
Permeation studies:
Permeation studies were performed using using 0.1%, 0.5%, 1%.Sodium lauryl sulphate as the permeation enhancer. Amongst which 1% showed the best result. The assembly was set using Franz diffusion cell. In which the donor was filled with 15 ml drug isotonic solution in pH 6.8. And the recipient was filled with the same isotonic solution of pH6.8. The git membrane of rat was used for the permeation study under the College registration code-992/a/06/CPCSEA. The sample was withdrawn at regular intervals and sink
condition was maintained. The samples were analyzed for drug content using a double beam UV spectrophotometer at 227.4 nm. As in Tab 2 and Fig 2.
Figure 2 : In-vitro permeation Furosemide(▲), Solid dispersion(▀), mouth dissolving tablet(♦).
Table 2. Comparitive study of permeation-
Time(min) |
% Cum release of Furosemide |
% Cum release of solid dispersion |
% Cumlative release of mouth dissolving tablet |
0 |
0 |
0 |
0 |
15 |
0.5 |
0.65 |
2.95 |
30 |
1.24 |
1.85 |
4.65 |
60 |
2.56 |
2.96 |
7.27 |
90 |
4.2 |
5.2 |
9.35 |
120 |
7.54 |
8.24 |
12.65 |
150 |
14.78 |
15.78 |
20.64 |
180 |
31.25 |
32.05 |
46.25 |
Results
FTIR spectroscopy
IR spectra of Furosemide and its binary systems with PVP K 30 are presented in Figure 1.Pure Furosemide spectra showed sharp characteristic peaks at 3398.34, 3122.54,1665, and 1560 cm–1. See Fig 4,5,6.The above characteristic peaks appear in the spectra of all binary systems at the same wave number indicating no interaction between the drug and the carrier (PVP K 30).
Table 4: Evaluation Properties of Mouth dissolving tablets.
Evaluation Parameter |
S1 |
S2 |
S3 |
S4 |
S5 |
S6 |
S7 |
Weight variation |
Within Limit |
Within Limit |
Within Limit |
Within Limit |
Within Limit |
Within Limit |
Within Limit |
Hardness (kg/cm2) |
2.4 |
2.4 |
2.5 |
2.5 |
2.4 |
2.5 |
2.5 |
Friability (%) |
0 .61 |
0.62 |
0.60 |
0.62 |
0.62 |
0.60 |
0 .61 |
Uniformity of Content (%) |
98.32 |
98.30 |
98.61 |
98.92 |
98.61 |
98.92 |
98.30 |
Water absorption rate |
70.6 |
74.0 |
74.5 |
76.6 |
|
74.0 |
74.5 |
70.6 |
|||||||
Wetting time (sec) |
24 |
25 |
23 |
22 |
25 |
23 |
22 |
Disintegration Time (sec) in vitro |
24 |
23 |
24 |
24 |
23 |
22 |
25 |
In vitro drug release (%) |
65.495 |
78.791 |
81.114 |
90.153 |
95.297 |
99.427 |
99.204 |
Figure 4. Fourier transform infrared (FTIR) spectroscopy of Furosemide (F).
Figure 5. Fourier transform infrared (FTIR) spectroscopy of Polyvinyl pyrrolidone K30 (PVP K30).
Figure 6. Fourier transform infrared (FTIR) spectroscopy of Solid dispersion (SD)
Figure 7: Differential Scanning Calorimetry of Bulk drug Furosemide (F)
Figure 8: Differential Scanning Calorimetry of Polyvinyl pyrrolidone K30 (PVP K30)
Figure 9: Differential Scanning Calorimetry of Poly vinyl pyrrolidone K30 (PVP K30)
Figure 10: Differential Scanning Calorimetry of Solid dispersion (SD)
Differential scanning calorimetry (DSC)
DSC Thermograms of Furosemide, PVP K30, Physical mixture of both as well as their solid dispersions prepared by Solvent evaporation method are shown in Figure 7, 8,9,10. Furosemide exhibited a characteristic, sharp exothermic peak at 206.23oC which is associated with the melting point of the drug and indicates the crystalline nature of the drug; degradation was indicated by anendothermic peak at 280.2 oC. However, the characteristic exothermic peak, corresponding to drug melting was broadened and shifted towards a lower temperature to 179.120C with reduced intensity in both physical mixtures and solid dispersions. DSC
studies also showed that there no interaction between drug and carrier at a molecular level in both the solid dispersions and physical mixtures.
Dissolution studies
The dissolution profiles of the pure drug, carrier (PVP K 30) and binary systems are presented in Figure 1 and Tab 1. It is evident that the solid dispersion (SD) technique improved the dissolution rate of the drug to a great extent .The results indicate that SD2 (101.73% of drug dissolved in 60 min) showed the highest dissolution rate, followed by SD1 with 85% of drug dissolved over the same period. Physical mixtures (PM) also improve dissolution rate significantly. The PM2 showed an increment of 80% and that PM1 increased by 53%. The order of dissolution rate is SD2 >SD1 > PM2 > PM1 > drug alone. To formulate a tablet of furosemide, the SD2binary mixture was selected based on its invitro dissolution performance. S6 tablets showed the fastest disintegration (24 seconds)and this is attributed to inclusion of the disintegrant, Sodium starch glycolate, in the formulation. In vitro dissolution studies for S6 confirmed the results obtained with solid binary mixtures.S6 tablets, like the corresponding binary mixture, showed good dissolution (100%) in 12 min. So this indicates.
Figure 1: Dissolution profiles of Furosemide and its binary systems with PVP K 30. (♦)- Furosemide, (■) - PM 1, (▲) - PM 2, (×) - SD 1, (Ӿ)-SD 2
Table 1. Percent drug release of Bulk drug (F), Physical mixture (PM 1), Solid dispersion (SD1), (PM2), (SD2).
Time(min) |
% Drug release of Furosemide |
% Drug release of PM1 |
% Drug release of SD1 |
% Drug release of PM2 |
%Drug release of SD2 |
0 |
0 |
0 |
0 |
0.000 |
0.000 |
10 |
8.316 |
18.119 |
82.426 |
69.282 |
101.733 |
20 |
13.115 |
30.101 |
82.884 |
70.929 |
97.842 |
30 |
16.900 |
40.515 |
84.084 |
75.777 |
94.670 |
40 |
23.306 |
47.570 |
84.546 |
76.936 |
91.477 |
50 |
27.889 |
52.139 |
85.008 |
78.842 |
89.006 |
60 |
31.755 |
53.092 |
85.470 |
80.014 |
85.776 |
Discussion
The solid dispersion was prepared and characterized and the results showed that 1:4 solid dispersion (SD2) had a higher dissolution profile compared to other formulations. The order of dissolution rate is SD2 > SD1 > PM2> PM1 > FRMD.As shown in FTIR spectroscopic studies, the spectra of pure drug, Furosemide and solid dispersion were similar and the peak for pure Furosemide was also appeared in all the spectra of the binary mixtures. Thus, there was no interaction between the drug and the carrier (PVP K 30). DSC studies, on the basis of the melting peak of Furosemide ( 206.230C ),also indicate that there was not interaction between the drug and carrier. However, the characteristic melting peak broadened and shifted toward a higher temperature with reduced intensity for both the physical mixtures as well as solid dispersions. This may be attributed to high polymer concentration and uniform distribution of the drug in the crust of the polymer, resulting incomplete miscibility of the molten drug in the polymer. Enhancement of the dissolution of Furosemide from the solid dispersions can be ascribed to several factors which affect the mechanism of dissolution rate improvement in solid dispersion. Lack of Crystallinity, i.e., Amorphization, increased Wettability and Dispersibility and particle size reduction are considered to be important factors for dissolution rate enhancement. As indicated by the dissolution data of the physical mixtures, improvement could be attributed to higher wettability and dispersibility. Dry mixing of drug with a hydrophilic carrier results in greater wetting and increases surface available for dissolution by reducing interfacial tension between hydrophobic drug and is solution media.
Conclusion
This study shows that the dissolution rate of Furosemide can be enhanced considerably by formulating in it as a solid dispersion in PVP K 30 using a solvent evaporation method. Incorporation of superdisintegrants in the solid dispersions played a critical role in dissolution enhancement. It may be feasible to prepare suitable formulations of Furosemide solid dispersions as mouth dissolving tablets.
Acknowledgement
The Authors are thankful to Hem Deep Organics Pvt. Ltd mfg of Bulk drugs and intermediates, Ankleshwar. Dist. Bharuch, Gujarat, India., for the gift sample of Furosemide.
References
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