Design and Characterization of Self-Nanoemulsifying Drug Delivery Systems of Rosuvastatin

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1 4042 nt J Pharm Sci Nanotech Vol 11; ssue 2 March April 2018 nternational Journal of Pharmaceutical Sciences and Nanotechnology Volume 11 ssue 2 March April 2018 Research Paper MS D: JPSN PRYA Design and Characterization of Self-Nanoemulsifying Drug Delivery Systems of Rosuvastatin Keerthi Priya 1 and D.V. R. N. Bhikshapathi 1,2* 1 Mewar University, Chittorgarh, Rajasthan, ndia; and 2 Vijaya College of Pharmacy, Hayathnagar, Hyderabad , Telangana, ndia. Received January 2, 2017; accepted February 10, 2018 ABSTRACT Development of self-emulsifying drug delivery systems (SEDDS) are becoming more popular to improve the oral bioavailability of poorly water-soluble drugs. Rosuvastatin is a lipid-lowering agent used in patients suffering from dyslipidemia. t is a competitive inhibitor of 3-hydroxy 3- methyl glutaryl coenzyme A, which converts mevalonate to cholesterol. Rosuvastatin is a BCS class (poor solubility) drug; hence, SNEDDS are being formulated to enhance oral bioavailability of the drug. n the present study, rosuvastatin SNEDDS were formulated using different oils, surfactant and co-surfactant. The optimized formulation F9 has composition of Las (PEG-8-Caprylic glycerides), Maisine 35-1 and Tween 20 as oil phase, surfactant and co-surfactant respectively. Composition of SNEDDS was optimized using Pseudoternary phase diagram, where the formulations showed increased self-emulsification with increased concentration of surfactants. Formulation F9 was found to be best formulation based on evaluation parameters. The particle size of the optimized SNEDDS formulation was found to be 10.9 nm & Z-Average of 55.6 nm indicating all the particles were in the nanometer range. The zeta potential of the optimized SNEDDS formulation was found to be mv, which comply with the requirement of the zeta potential for stability. The developed rosuvastatin SNEDDS have the potential to minimize the variability in absorption and provide rapid onset of action of the drug. KEYWORDS: SNEDDS; Rosuvastatin; Las (PEG-8-Caprylic glycerides); Maisine 35-1; Tween 20; Pseudo-ternary phase diagram. ntroduction There is a need to design new formulations to enhance the solubility of modern day drugs as most of them have low water solubility (Ohara et al., 2005). SNEDDS are isotropic mixtures of an oil, surfactant and co-surfactant that form fine micro emulsions or nano emulsions upon mild agitation. Within the gastrointestinal tract, the source of agitation is peristaltic movements of the stomach and intestine (Pouton et al., 2006). SNEDDS are nano sized and hence pose as an alternative to conventional oral lipid formulations by having increased interfacial area for partitioning of drug between the oil and aqueous phases (Charman et al., 1992). There are three types of nano emulsions (Sandeep et al., 2010): water in oil (W/O) nano emulsion- droplets of water is dispersed in continuous phase of oil, oil in water (O/W) nano emulsion- oil droplets are dispersed in continuous phase of water and bi-continuous nano emulsion- surfactant is soluble in both oil and aqueous phase and droplets are dispersed in both water and oil phases (Raja Lakshmi et al., 2011). The ability of nano emulsion (SNEDDS) to dissolve large quantities of lipophilic drug, along with their ability to protect the drugs from hydrolysis and enzymatic degradation make them ideal vehicles for parenteral transport (Shafiq et al., 2007). SNEDDS provide ultra-low interfacial tension and large O/W interfacial areas thus enhancing the oral solubility and bioavailability of poorly water-soluble drugs (Ahmad et al., 2012). Rosuvastatin is a new generation 3-hydroxy 3-methyl glutaryl coenzyme A (HMG CoA) inhibitor. t reduces the total cholesterol, LDL (low-density lipoprotein), plasma triglycerides and apo lipoprotein B levels. t is a BCS class drug with low water solubility and low oral bioavailability of 20% (Luvai et al., 2012). About 80% of the drug is excreted in unchanged form in feces (Heba et al., 2017). Formulation of SNEDDS of Rosuvastatin helps in reduction of drug dose significantly thereby reducing the side effects of the drug. Materials and Methods Materials Rosuvastatin was obtained from Aurobindo Pharma limited, Hyderabad. LAS (PEG-8-Caprylic glycerides) were obtained from SDFCL, Mumbai. Capmul MCM, Capyrol 90, Captex 355, Lauroglycol and sesame oil were procured from Gattefosse Ltd., Mumbai. Maisine 35-1 and Lutrol E 400 were obtained from BASF, Mumbai. Cremophore RH 40, PEG 200, span 80, Polysorbate 20, Tween 20, Propylene glycol and Oleic acid were obtained 4042

2 Priya and Bhikshapathi: Design and Characterization of Self-Nanoemulsifying Drug Delivery Systems of Rosuvastatin 4043 from SDFCL, Mumbai. Polaxomer 407 and Soluphor are procured from Yarrow Chemical Products, Mumbai. Methods Solubility studies: An excess amount (10 mg) of Rosuvastatin was added into 2 ml of each excipient (Oils - LAS (PEG-8-Caprylic glycerides), Capmul MCM, Capyrol 90, Sesame oil. Surfactants Span 80, PEG 200, Lauroglycol, Cremophore RH 40, Maisine 35-1, Captex 355. Co-surfactants - Propylene glycol, Oleic acid, Lutrol E 400, Soluphor P, Polaxomer 407, Tween 20, Polysorbate 20 and kept in mechanical shaker for 24hrs and centrifuged at 10,000 rpm for 20 min using a centrifuge. Supernatant was filtered through membrane filter using 0.45μm filter disk. Filtered solution was appropriately diluted with methanol, and UV absorbance was measured at 243nm. Concentration of dissolved drug was determined spectrophotometrically. Solubility studies were used to find out the suitable oil, surfactant and co-surfactant that possess good solubilizing capacity for Rosuvastatin (Patel et al., 2011). Pseudo ternary phase diagram: Pseudo ternary phase diagram was constructed using water titration method at ambient temperature (25 0 C). Surfactant and cosurfactant (Smix) in each group were mixed in different volume ratio (1:1, 2:1, 3:1). Oil and surfactant/cosurfactant mixture (Smix) were mixed thoroughly in different volume ratios 1:9 to 9:1 (1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2 and 9:1) w/w for all the three S mix ratios 1:1, 2:1, 3:1. Pseudo ternary phase diagram helps in determining the solubility of Rosuvastatin. The mixture of oil, surfactant and co-surfactant at certain ratios were titrated with water by drop wise addition under gentle agitation. Deionized water was used as diluting medium and added into the formulation. The proper ratio of one excipient to another in the SNEDDS formulation was analyzed and Pseudo ternary plots were constructed using Chemix software (Sermkaew et al., 2013). TABLE 1 Formulation trials of liquid SNEDDS. Visual observation: n this method, a predetermined volume of mixture (0.2 ml) was added to 300 ml of water in a glass beaker under stirring and temperature was maintained at 37 0 C using a magnetic stirrer. The tendency of formation of emulsion was observed. f the droplet spreads easily in water was judged as good and judged as bad when there was milky or no emulsion or presence of oil droplets (Gurjeet et al., 2013). Development of SNEDDS formulation: SNEDDS formulations of Rosuvastatin were prepared based on solubility studies, pseudo ternary phase diagram and visual observation. LAS were used as oil phase and Maisine 35-1 and Tween 20 were used as surfactant and co-surfactant respectively (Table 1). n brief, Rosuvastatin (10 mg) was added in accurately weighed amount of oil into screw-capped glass vial and heated in a water bath at 40ºC. The surfactant and co-surfactant were added to the oily mixture using positive displacement pipette and stirred with magnetic bar. The formulation was further sonicated for 15mins and stored at room temperature for further study. Freeze thawing (Thermodynamic stability studies): The objective of thermodynamic stability is to evaluate the phase separation and effect of temperature variations on SNEDDS formulations. Formulations were subjected to freeze cycle (-20 C for 2 days followed by 40 C for 2 days). Only stable formulations were selected for further studies. (Gupta et al 2011). Centrifugation: Centrifugation was performed at 3000 rpm for 5 minutes. The formulations were then observed for phase separation. Only formulations that were stable to phase separation were selected for further studies. (Bhikshapathi et al 2013). % transmittance measurement: Various SNEDDS formulations were reconstituted with distilled water and the percent transmittance was measured at 243 nm using UV spectrophotometer against water as a blank. (Chirag et al., 2012) S mix (Surfactant: Co-surfactant) 1:1 2:1 3:1 Oil: S mix Formulation Code Drug (Rosuvastatin) (mg) Oil (LAS (PEG-8-Caprylic glycerides)) (ml) Surfactant (Maisine 35-1) (ml) Co-surfactant (Tween 20) (ml) 3:7 F :6 F :5 F :4 F :3 F :9 F :8 F :7 F :6 F :5 F :6 F :5 F :4 F :3 F :2 F

3 4044 nt J Pharm Sci Nanotech Vol 11; ssue 2 March April 2018 Determination of drug content: SNEDDS equivalent to 10mg of Rosuvastatin were weighed accurately and dissolved in 100 ml of phosphate buffer ph 6.8. The solution was filtered, diluted with phosphate buffer and drug content was analyzed at λ max 243 nm against blank by UV spectrometer. The actual drug content was calculated using the following equation as follows: % Drug content = Actual amount of drug in SNEDDS 100 Theoretical amount of drug in SNEDDS Percent entrapment efficiency: The contents of free drug were separated from nanoemulsions by ultrafiltration at 3500 Da with centrifugation at 3000g for 5 to 10 minutes, followed by qualification using HPLC method (Zhongcheng et al., 2016). The Entrapment Efficiency was calculated as follows. Entrapment efficiency = Total amount of drug in SNEDDS 100 Total weight of ingredients in nanoemulsions n-vitro dissolution studies: Using a US Pharmacopoeia Type dissolution apparatus, SNEDDS of Rosuvastatin (equivalent to 10 mg of Rosuvastatin) was filled in size 0 hard gelatin capsules. The dissolution media is phosphate buffer ph 6.8, and maintained at 37 0 C operated at 50 rpm. At predetermined time intervals, 5 ml sample was withdrawn at 2, 5, 10, 15, 20, 25, 30, 45, and 60 mins and filtered through 0.45-μm pore size membrane filters. Equivalent volume of buffer was replaced each time with 5 ml of fresh medium and the samples were assayed by spectrophotometry at 243 nm. Characterization of SNEDDS Drug-excipient compatibility studies: The Drug Excipient Compatibility Studies were carried out by Fourier Transform infrared spectroscopy (FTR) method. Fourier transform infrared spectroscopy (FTR): An FTR-8400S Spectrophotometer (Shimadzu, Japan) equipped with attenuated total reflectance (ATR) accessory was used to obtain the infrared spectra of drug in the isotropic mixtures of excipients. Analysis of pure drug i.e., Rosuvastatin and physical mixtures of the drug with the excipients were carried out using diffuse reflectance spectroscopy (DRS)-FTR with KBr disc. All the samples were dried under vacuum prior to obtaining any spectra to remove the influence of residual moisture. For each the spectrum, 8 scans were obtained at a resolution of 4 cm 1 from a frequency range of cm 1. Determination of droplet size: The average droplet size of Rosuvastatin SNEDDS formulations were determined by Photon correlation spectroscopy, able to measure sizes between 10 and 5000 nm. The selected formulations were diluted with deionized water and placed in an electrophoretic cell for measurement (Vanitha et al., 2013). Determination of zeta potential: The zeta potential of the diluted SNEDDS formulation was measured using a zeta meter system. The SNEDDS were diluted with a ratio 1:2500 (v/v) with distilled water and mixed with magnetic stirrer. Zeta-potential of the resulting micro emulsion was determined using a Zetasizer. Scanning electron microscopy: The shape and surface morphology of microspheres was studied using scanning electron microscopy (SEM). The SNEDDS after converting to emulsion were mounted on metal stubs and the stub was then coated with conductive gold with sputter coater attached to the instrument. (HTACH, S- 3700N) (Ruan et al., 2003). Stability studies: Stability testing was conducted at 40 C ± 2 C/75% RH ± 5% RH for 3 months using stability chamber (Thermo Lab, Mumbai). Samples were withdrawn at predetermined intervals 0, 30, 60 and 90 days period according to CH guidelines. Various in vitro parameters like % yield, entrapment efficiency and in vitro release studies were evaluated. (Lalit Kumar et al., 2014) Results and Discussion Solubility Studies nitially, preliminary solubility analysis was carried out to select the appropriate excipient from various (Oils - LAS, Maisine 35-1 and Tween 20 (Oil), (surfactant) and (co-surfactant), Capmul MCM, Capyrol 90, Sesame oil. Surfactants Span 80, PEG 200, Lauroglycol, Cremophore RH 40, Maisine 35-1, and Captex 355. Co-surfactants - Propylene glycol, Oleic acid, Lutrol E 400, Soluphor P, Polaxomer 407, Tween 20, Polysorbate 20. The solubility of pure drug was found to be mg/ml. Based on drug solubility LAS, Maisine 35-1 and Tween 20 were selected as oil, surfactant and co-surfactant respectively. The drug solubility values of these polymers were found to be highest when compared with the pure drug and other polymers. (Tables 2, 3, 4) (Figures 1, 2, 3). TABLE 2 Solubility studies of rosuvastatin in various oils. Oils Solubility (mg/ml) Capmul MCM 30.1 ± 0.17 LAS ± 0.27 Capyrol ± 0.11 Sesame oil ± 0.19 TABLE 3 Solubility studies of rosuvastatin in various surfactants. Surfactants Solubility (mg/ml) Span ± 0.16 PEG ± 0.09 Lauroglycol ± 0.19 Cremophore RH ± 1.11 Maisine ± 2.68 Captex ± 2.00 TABLE 4 Solubility studies of rosuvastatin in various co-surfactants. Co-surfactants Solubility (mg/ml) Propylene glycol ± 0.21 Oleic acid 45.6 ± 0.87 Lutrol E ± 1.22 Soluphor P ± 1.47 Polaxomer ± 0.68 Tween ± 3.24 Polysorbate ± 1.55

4 Priya and Bhikshapathi: Design and Characterization of Self-Nanoemulsifying Drug Delivery Systems of Rosuvastatin 4045 of Smix 2:1 and 4:6, 5:5, 6:4, 7:3, 8:2 of Smix 3:1 showed rapid formation of micro emulsion within a minute having a clear appearance. Therefore, these ratios were selected for the formulation of SNEDDS. The results are tabulated in Table 6. Fig. 1. Solubility studies of Rosuvastatin in oils. Fig. 4. Ternary phase diagram of LAS, Maisine 35-1 and Tween 20. Fig. 2. Solubility studies of Rosuvastatin in surfactant. Fig. 5. Visual observation test. TABLE 5 Visual observation test for Smix (Surfactant: Co-surfactant) ratio 1:1. Fig. 3. Solubility studies of Rosuvastatin in co-surfactants. Pseudo Ternary Phase Diagram From the solubility studies, LAS, Maisine 35-1 and Tween 20 were selected as oil, surfactant and codiagram surfactant respectively. From the ternary phase (Figure 4), it was observed that self emulsifying region was enhanced with increasing concentrations of surfactant and co-surfactant with oil. Efficiency of self- concentration increased. Visual Observation With the use of visual observation method, the emulsification was good when the surfactant tendency of formation of emulsion was observed. Visual observation test was performed for different ratios by keeping the surfactantt and co-surfactant ratio (Smix) as 1:1, 2:1 and 3:1. Grades were given to the ratios based on the tendency of formation of micro-emulsion. Ratios 6:4, 5:5, 3:7, 4:6 and 7:3 of Smix 1:1 and 1:9, 2:8, 3:7, 4:6, 5:5 Oil: Smix 1:9 2:8 3:7 4:6 5:5 6:4 7:3 8:2 9:1 Time of self-emulsification (min) TABLE 6 Visual observation test for Smix (surfactant: co-surfactant) ratio 2:1. Oil: Smix 1:9 2:8 3:7 4:6 5:5 6:4 7:3 8:2 9:1 Time of self-emulsification (min) Grade / / / Grade / /

5 4046 nt J Pharm Sci Nanotech Vol 11; ssue 2 March April 2018 Preparation of Rosuvastatin SNEDDS SNEDDS of Rosuvastatin were prepared by using LAS, Maisine 35-1 and Tween 20 (Oil), (surfactant) and (co-surfactant). n the present study, fifteen formulations were prepared, and their complete composition was shown in Table 1. All the formulations prepared were found to be clear and transparent. Pictorial representations of formulations F1 to F15 were shown in Figure 6. Percent Transmittance Measurement The micro emulsions were checked for transparency, measured in terms of transmittance (%T). SNEDDS forms o/w microemulsion since water is external phase Formulation F9 has % transmittance value greater than 99%. These results indicate the high clarity of microemulsion i.e., %T values were less than 99% suggesting less clarity of micro emulsions. This may be due to greater particle size of the formulation. Due to higher particle size, oil globules may reduce the transparency of microemulsion and thereby values of %T. (Table 9) TABLE 9 Percentage transmittance of different formulations. Fig. 6. Formulation no.1 to no 15. Thermodynamic Stability Studies There was no significant phase separation and effects of temperature variations on prepared formulations were not observed. There was no change in the visual description of samples after centrifugation freeze-thaw cycles. Formulations which are thermodynamically stable only were selected for further characterization (Table 8). TABLE 7 Visual observation test for Smix (Surfactant: Co-surfactant) ratio 3:1. Oil: Smix Time of self-emulsification (min) Grade 1:9 2:8 3:7 / 4:6 5:5 / 6:4 / 7:3 8:2 9:1 TABLE 8 Thermodynamic stability studies of the formulations. Formulation code Centrifugation Freeze thaw method -20 C for 2 days +40 C for 2 days F1 No phase separation No change No change F2 No phase separation No change No change F3 No phase separation No change No change F4 No phase separation No change No change F5 No phase separation No change No change F6 No phase separation No change No change F7 No phase separation No change No change F8 No phase separation No change No change F9 No phase separation No change No change F10 No phase separation No change No change F11 No phase separation No change No change F12 No phase separation No change No change F13 No phase separation No change No change F14 No phase separation No change No change F15 No phase separation No change No change S. No. Formulation Code Visual observation % Transmittance 1 F1 Transparent F2 Transparent F3 Transparent F4 Slightly clear F5 Turbid F6 Transparent F7 Slightly clear F8 Slightly clear F9 Transparent F10 Slightly clear F11 Slightly clear F12 Turbid F13 Slightly clear F14 Slightly clear F15 Slightly clear Drug Content of SNEDDS Actual drug content of all 15 formulations are shown in Table 10. The drug content of the prepared SNEDDS was found to be in the range of %. Maximum % drug content i.e % was found in the formulation F9. TABLE 10 Percentage drug content for different formulations of rosuvastatin SNEDDS. S. No. Formulation code % Drug content 1 F F F F F F F F F F F F F F F Percent Entrapment Efficiency The percent entrapment efficiency of the optimized formulation of Rosuvastatin F9 was found to be 98%, which is highly beneficial.

6 Priya and Bhikshapathi: Design and Characterization of Self-Nanoemulsifying Drug Delivery Systems of Rosuvastatin 4047 n-vitro Dissolution Studies of SNEDDS The faster dissolution from SNEDDS may be attributed to the fact that in this formulation, the drug is in a solubilized form and upon exposure to dissolution medium results in small droplet that can dissolve rapidly in the dissolution medium. The release from liquid SNEDDS formulation F9 was faster and highest amount than other SNEDDS formulations and pure drug substance indicating influence of droplet size on the rate of drug dissolution. (Tables 11, 12, 13) (Figures 7, 8, 9). nterpretation of FTR Data FT-R spectrums are mainly used to identify any interactions between the drug and any of the excipients used. The wave number 3416 cm 1 is due to stretching vibration of O-H; 2968 cm 1 due to C-H stretching vibrations; cm 1 due to C-F stretching vibrations and cm 1 due to C=C bending. The presence of all these peaks gives conformation about purity of the drug. The FTR spectra of optimized formulations were having similar fundamental peaks and pattern. Thus, there are no significant interactions among the drug and excipients. (Figure 10 & 11). Particle Size Analysis of SNEDDS Droplet size determines the rate and extent of drug release as well as drug absorption. Smaller the particle size, larger the interfacial surface area which may lead to more rapid absorption and improved bioavailability. SNEDDS with a mean droplet size below 200 nm exhibit excellent bioavailability. The particle size of the emulsion is a crucial factor in self-emulsification performance because it determines the rate and extent of drug release as well as absorption. The particle size of the optimized SNEDDS formulation was found to be 10.9 nm & Z- Average of 55.6 nm indicating all the particles were in the nanometer range. (Figure 12). Zeta Potential of SNEDDS Zeta potential is responsible for the degree of repulsion between adjacent, similarly charged, dispersed droplets. A zeta potential value of ± 30mV is sufficient for the stability of a micro emulsion. The zeta potential of the optimized SNEDDS formulation was found to be mv which comply with the requirement of the zeta potential for stability. (Figure 13) Scanning Electron Microscopy (SEM) for Rosuvastatin SNEDDS Scanning electron microscopy studies of optimized formulation (F9) revealed oval shaped globules. The size is within nanometers. There are clear liquid droplets without any pores (Figure 14). TABLE 11 Dissolution profiles of rosuvastatin SNEDDS from F1 to F5. Time (min) Dissolution media Phosphate buffer ph 6.8 (% drug release) Formulation Code F1 to F5 (1:1) Pure drug F1 F2 F3 F4 F ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 4.55 TABLE 12 Dissolution profiles of rosuvastatin SNEDDS from F6 to F10. Time (min) Dissolution media Phosphate buffer ph 6.8 (% drug release) Formulation Code F6 to F10 (2:1) Pure drug F6 F7 F8 F9 F ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 4.55

7 4048 nt J Pharm Sci Nanotech Vol 11; ssue 2 March April 2018 TABLE 13 Dissolution profiles of rosuvastatin SNEDDS from F11 to F15. Dissolution media Phosphate buffer ph 6.8 (% drug release) Time Formulation Code F11 to F15 (3:1) (min) Pure drug F11 F12 F13 F14 F ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 4.88 Fig. 7. Dissolution profiles of Rosuvastatin pure drug and formulations (F1 to F5). Fig. 8. Dissolution profiles of Rosuvastatin pure drug and formulations (F6 to F10). Fig. 9. Dissolution profiles of Rosuvastatin pure drug and formulations (F11 to F15) nterpretation of FTR Data.

8 Priya and Bhikshapathi: Design and Characterization of Self-Nanoemulsifying Drug Delivery Systems of Rosuvastatin 4049 Fig. 10. FTR Spectroscopy of Rosuvastatin pure drug. Fig. 11. FTR Spectroscopy of Rosuvastatin optimized formulation F9. Fig.12. Particle size analysis of optimized formulation F9.

9 4050 nt J Pharm Sci Nanotech Vol 11; ssue 2 March April 2018 Fig. 13. Zeta potential of the optimized formulation F9. Fig. 14. Scanning Electron Microscopic images of optimized formulations (F9). Stability Studies The Rosuvastatin SNEDDS F9 formulation was filled in hard gelatin capsules as the final dosage form and subjected to stability studies for 6 months. There was no significant change in the drug content and drug release. t was also seen that the formulation were compatible with the hard gelatin capsule shells, as there was no sign of capsule shell deformation. There was no significant change in the appearance, or micro emulsifying property. Summary and Conclusion Different formulations of Rosuvastatin were developed by using different polymers. From solubility studies it was observed that Rosuvastatin and showed good solubility in LAS (PEG-8-Caprylic glycerides), Maisine 35-1 and Tween 20 and hence these were selected as oil, surfactant and co-surfactant respectively. From Pseudo ternary phase diagram with LAS (PEG-8- Caprylic glycerides), Maisine 35-1 and Tween 20 as a surfactant and co-surfactant, it was observed that selfemulsifying region was enhanced with increasing concentrations of surfactant and co-surfactant with oil. The drug content of all the formulations was performed. Maximum drug content was found in the formulation F9. Formulation F9 was found to be best formulation based on evaluation parameters. The particle size of the optimized SNEDDS formulation was found to be 10.9 nm & Z-Average of 55.6 nm indicating all the particles were

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