SOLUBILITY ENHANCEMENT OF AZILSARTAN BY SELF- EMULSIFYING LIPID FORMULATIONS

Transcription

1 WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES Reddy et al. S SJIF Impact Factor Volume 6, Issue 3, Research Article ISSN SOLUBILITY ENHANCEMENT OF AZILSARTAN BY SELF- EMULSIFYING LIPID FORMULATIONS Dr. M. Sunitha Reddy* 1, Senigarapu Soumya 1 and S. Muhammad Fazal Ul Haq 1 1 Centre for Pharmaceutical Sciences, Institute of of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad, Telangana, India. Article Received on 14 January 2017, Revised on 05 February 2017, Accepted on 26 February 2017 DOI: /wjpps *Corresponding Author Dr. M. Sunitha Reddy Centre for Pharmaceutical Sciences, Institute of of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad, Telangana, India. ABSTRACT Azilsartan is a BCS class II drug with poor aqueous solubility. The present work mainly emphasized on the enhancement of solubility of Azilsartan by developing Self Emulsifying Lipid Formulations. The solubility of Azilsartan was determined in various lipid excipients by UV Spectroscopy analysis. Based on the solubility data and IR studies the excipients were selected. Labrafac Lipophile WL 1349(oil), Tween 80 (Surfactant) and Polyethylene glycol 400 (PEG 400) were Selected as co-surfactants and formulation were developed. A series of Pseudoternary phase diagrams were constructed by water titration method to determine the microemulsion region. Various compositions of oil and surfactant mixture were titrated with water to determine the limit of emulsification and microemulsion region. Two selected formulations were further evaluated for self emulsification time, phase separation, Thermodynamic stability studies, Droplet size distribution and zeta potential. None of these exhibited phase separation and drug precipitation. Thermo dynamic stability studies were satisfactory. Effect of dilution did not exhibit phase separation. Based on the above experiments, two formulations were optimized. Using the optimized self micro emulsifying mixture, Azilsartan loaded Liquid SELFS was prepared, evaluated for their selfmicroemulsification tendency and characterized. In vitro drug release studies showed nearly 83.42% drug release in first 60 minutes of dissolution by LLT3P1 liquid SELFs. The in-vitro release profiles of two formulations were good. They showed a significant increased rate of dissolution, when compared with the plain azilsartan drug. Among the two formulations, LLT3P1-2(2:8) formulation was found to exhibit better drug release with average droplet size of 119.1nm and zeta potential of mv. The self emulsifying Lipid formulations exhibited Vol 6, Issue 3,

2 improved dissolution characteristics of an Azilsartan. The present studies indicates that SELFs can be potentially used a drug delivery system for delivering poorly water soluble drugs. KEYWORDS: Azilsartan, Oils, Surfactants, Co-surfactants, Pseudo ternary phase diagram, solubility study. INTRODUCTION The oral route has always been preferred route for various formulations in treatment of different chronic diseases. The major problem in oral drug formulation is low and erratic bioavailability, which mainly results from poor aqueous solubility. This may lead to higher inter-and intra subject variability, lack of dose proportationality and therapeutic response. For such successfully oral delivery of such poorly soluble drugs it is necessary to improve their solubility. several strategies to improve the solubility and dissolution of poorly water soluble drugs like particle size reduction, salt formation, hydrotrophy, solid dispersions, ph adjustment, use of surfactants, complexation, super critical fluid process, co solvency etc. each strategy has its own limitations owing to development of other formulation strategies like lipid based formulations. Lipid based formulations offer a variety of options like solutions, suspensions, solid dispersions and self emulsifying lipid formulations. Self emulsifying lipid formulations usually improve the bioavailability of hydrophobic drugs. MATERIALS AND METHODS Materials: Azilsartan Gift samples from MSN company, Banglore, Castor oil, Capryol 90, Capmul PG-8, Captex 200, Oleic acid, Tween 80, Labrasol, Cremophore RH 40, Transcutol HP, Peceol, Polyethylene glycol 400(PEG 400), Lauroglycol 90,Labrafac Lipophile WL 1349, Methanol,Hydrochloric acid,potassium bromide, Capsules. Methods Solubility studies: The saturation solubility of Azilsartan was determined in various vehicles such as oils, surfactants and co-surfactants. The solubility of Azilsartan was determined by adding excess amount of drug to each screw capped glass vials containing 1 gram of excipient. The mixture was cyclomixed immediately using cyclo-mixer to facilitate drug Vol 6, Issue 3,

3 solubilisation. Then the mixtures were heated in thermostatic water bath at 40 o C for 5minutes further to increase Solubilization. Then, the mixtures were kept in rotary shaker at a speed of 100 rpm for 48hrs at 25 o C and kept for equilibration at room temperature for 24hrs. The supersaturated solutions were then centrifuged at a speed of 2000 rpm for 15 minutes to separate the undissolved drug from the supernatant liquid. Aliquots of supernatant liquid were withdrawn using a micropipette and diluted accordingly. The concentration of drug in solution was determined by UV-spectrometer at 250nm after dilution. Concentration of Azilsartan in each vehicle was calculated from calibration curve. Construction of pseudo-ternary Phase Diagrams: Pseudo-ternary phase diagrams were constructed for selected oil, surfactant, and co-surfactant with water at room Temperature by water titration method. The surfactant was mixed with co-surfactant in ratio 4:1, 3:1, 2:1 and 1:1 respectively. Aliquots of surfactant/co-surfactant mixture were then mixed with oil at ratios of 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, 1:9 in different vials and then titrated with water at room T o C. The samples were then equilibrated for 30seconds and visually observed after each addition. Based on visual observation the systems were classified as nano emulsion, micro emulsion and coarse dispersion and gel phases. Pseudo ternary phase diagrams were then constructed using Triplot software version The samples which were clear (or) bluish transparent in appearance were considered as micro emulsions. Preparation of SELFs: Varying ratio of oil, surfactant and co-surfactant were selected for formulation systems. Azilsartan was kept constant (40mg) for all formulations. Surfactant/cosurfactant mixture (S mix ) was prepared by mixing suitable proportions of surfactant, co surfactants and they were cyclomixed. Azilsartan was accurately weighed and dissolved in suitable proportions of oil/ S mix mixture. The formulations were cyclomixed for 1minute to facilitate uniform mixing and then heated in thermostatic water bath at 40 o C to facilitate drug Solubilization. Then all formulations were cyclomixed until transparent preparations were obtained. Finally prepared SELFs of Azilsartan were kept aside at room Temperature for 48 hrs and examined for signs of turbidity (or) phase separation and the formulation is characterised for various parameters Characterization of SMEDDS Self emulsification and visual assessment: The prepared emulsions were added drop wise to 250ml of water. Self emulsifying mixtures should quickly disperse in water with mild shaking. Vol 6, Issue 3,

4 Dispersibility test: Self emulsification property of SELFs was evaluated by visual assessment. Time taken for the formation of micro emulsion was determined by drop wise addition of formulation to 250mL of distilled water, simulated gastric fluid and phosphate buffer of ph 6.8 in separate glass beakers at 37 o C. The contents were gently stirred using magnetic stirrer at 100rpm. The tendency to form an emulsion was assessed as good when emulsification occurs rapidly in less than 1 minute with clear (or) transparent appearance. The tendency to form an emulsion was assessed as bad when there is less clear emulsion formation. Depending on visual appearance and time taken for self emulsification, formulations are graded as, Grade I: Rapidly forming (within 1min) nano emulsion having a clear (or) bluish appearance. Grade II: Rapidly forming, slightly less clear emulsion, having a bluish white appearance. Grade III: Fine milky emulsion that formed within 2 minutes. Grade IV: Dull, greyish white emulsion with a slight oily appearance that is slow to emulsify (more than 2 minutes). Phase separation and stability study of emulsions: Each Selected formulation (50µl) was added to a vials containing 5mL of double distilled water, simulated gastric fluid at room T o C and cyclomixed for 1 minute then each mixture was stored and observed for phase separation and precipitation of drug at intervals 2, 4, 6, 8, 12, 24 hours period of time. Effect on dilution: Prepared Selected formulations were subjected to dilution in ratios 1:100& 1:1000 folds with distilled water, 0.1 N HCl and phosphate buffer of ph 6.8. The diluted nano emulsions were stored for 24 hrs and visually observed for any signs of phase separation (or) precipitation of drug. Percentage Transmittance: Each Selected formulation (100µL) was added to a vial containing 10mL of double distilled water, 0.1 N HCl and phosphate buffer of ph 6.8 at room T o C and cyclomixed for 1minute. Each sample was observed for %Transmittance at 250nm. Drug loading efficiency: Drug content in formulation was determined UV- Spectrophotometrically. 50mg of each formulation was accurately weighed and dilute to 100mL with methanol. Resultant solutions were analyzed spectroscopically following suitable dilution. Vol 6, Issue 3,

5 Drug loading efficiency was calculated by equation Drug loading efficiency = Amount of drug in known amount of formulation X100 Initial drug load FT-IR Studies FT-IR Spectrum of pure drug and drug-excipients were obtained by FT-IR Spectrophotometer (Bruker-Alpha)... The spectrums of drug, excipients and drug-excipients were taken with the accumulation 24 scans and a resolution of 4cm -1 over the range of cm -1. The spectrum of drug-excipient mixtures so obtained was compared with spectrum of pure drug for any interactions. Thermodynamic stability studies The prepared SMEDDS formulations were subjected to thermodynamic stability studies to study the effect of centrifugation and temperature on stability of micro emulsions. Centrifugation study The formulations were added to deionised water in ratio 1:20 and centrifuged at 3500 rpm for 30minute and observed for phase separation (or) precipitation. Freeze thaw cycle The formulations which are stable under centrifugation were subjected to freeze thaw cycle. In this study, SELFs were diluted with deionised water in 1:20 ratio and subjected to two freeze thaw cycles between -20 o C and +25 o C by storing at each temperature for 48hrs and after 48hrs samples were observed for phase separation (or) precipitation. Invitro drug release study The in-vitro dissolution study of SELFs which were filled into suitable size capsule were carried out using USP-Type II dissolution test apparatus (DS1800 Lab India)(Figure 4.5) in 500mL buffer of ph 1.2 at 37±0.5 o C with 100rpm rotating speed. In Vitro drug release study was performed for 60 mins in 0.1NHCl. Samples were withdrawn at 0, 5, 10, 15, 30, 45, 60, minute s time intervals and filtered through 0.45μ filter. An equal volume of dissolution medium was replenished after every sampling to maintain constant volume. Samples were analyzed using UV-Spectrophotometer at 247nm. Percentage drug release and cumulative percentage drug release were calculated from absorbance and concentration that were obtained with the help of standard graph of Azilsartan. Vol 6, Issue 3,

6 Droplet size and Zeta potential determination SELF s formulations were diluted to 100 times with distilled water in beaker with constant stirring on a magnetic stirrer. The droplet size distributions and Zeta potential of resultant micro emulsion were determined after 1 hr by dynamic light scattering (DLS) spectroscopy using a Zetasizer Nano ZS Version 6.20 (Malvern Instruments, UK). Size analysis was performed at 25ºc by placing in an electrophoretic cell with an angle of detection of 90ºC for measurement. The droplet size and Zeta potential of formulations were obtained. RESULTS AND DISCUSSION Solubility of Azilsartan in various Oils Solubility of Azilsartan in various oils was determined by UV-spectrophotometer The saturation solubility of Azilsartan in various oils is shown in table 6.3. Labrafac lipophile WL 1349 oil was selected for the formulation which forms good. Table1: Solubility of Azilsartan in various oils S.NO EXCIPIENT CONCENTRATION mg/ml(am±sd) 1 Castor oil ± Sesame oil ± Soybean oil ± Oleic acid ± Peceol ± Labrafac Propylene glycol ± Labrafac Lipophile WL ± Capmul PG ± Captex ±2.45 All as values are expressed Mean, n=3 Fig: 1 Solubility of Azilsartan in various Oils Vol 6, Issue 3,

7 Solubility of Azilsartan in various Surfactants Solubility of Azilsartan was determined in various Surfactants. Surfactants Tween80 is selected for formulation which has highest solubility and good emulsifying ability among all other formulations. Results are shown in table 2. Table 2 Solubility of Azilsartan in various Surfactants S.NO EXCIPIENT CONCENTRATION(mg/ml) 1 Labrafac M1944 CS 26.84± Lauroglycol ± Tween ± Cremophore RH ± Labrasol 47.54± Capryol ±3.45 All as values are expressed Mean, n=3 Fig 2: Solubility of Azilsartan in various Surfactants Solubility of Azilsartan in various Co-Surfactants Solubility of Azilsartan in various Co-Surfactants was determined. PEG 400 is selected for the formulation which shows highest solubility than other co-surfactants. Solubilities of various Co-Surfactants are shown in table.3. Table 3 Solubility of Azilsartan in various Co-Surfactants S. No Excipient Concentration (mg/ml)±sd 1 Transcutol HP 55.09± Propylene glycol ± PEG ± Ethanol ±1.34 All values are expressed as Mean n=3 Vol 6, Issue 3,

8 Fig: 3 Solubility of Azilsartan in various Co-surfactants Selection of excipients: Based on the solubility studies done on various oils,surfactants and co surfactants, excipients which has shown more solubility was selected for the formulation. Oil: Labrafac Lipophile WL 1349 oil Surfactant: Tween 80 Co-Surfactant: PEG 400 Drug -Excipient compatibility studies by FTIR spectroscopy The spectrums of drug-excipient mixtures and the formulations so obtained were compared with spectrum of pure drug for any interactions.characteristic peaks were observed at 3237 cm -1,2985.6cm -1,2743.2cm -1,1768.5cm -1,1455cm -1 for NH stretching vibration, cm - 1,1154.7cm -1, cm -1,1223.2cm -1, cm -1 O-H stretching,ft-ir spectrum of pure drug and the formulation were almost similar because of same functional groups. It indicates there was no interaction between Azilsartan and Excipient used in the formulation. Fig 4: FT-IR Spectrum of pure drug (Azilsartan) Vol 6, Issue 3,

9 Fig 5: FT-IR Spectrum of Labrafac lipophilewl 1349 Fig 6: FT-IR Spectrum of Tween 80 Fig 7: FT-IR Spectrum of PEG 400 Pseudo ternary Phase Diagrams: Pseudo ternary Phase Diagrams are constructed to identify the microemulsion regions and to identify suitable composition of oil, surfactant and co-surfactant for the formulation of SELFs. From Pseudo ternary phase diagrams it has been found that the systems consisting of labrafac lipophile WL 1349 as oily phase, Tween 80 as surfactant and PEG 400 as co-surfactant showed good micro emulsify property though Vol 6, Issue 3,

10 the drug has been shown more solubility in systems containing Labrafac Lipophile WL 1349 oil as oil phase, Tween 80 as surfactant and PEG 400 as co- surfactant based on solubility studies. It was also found that systems containing Tween 80 as a surfactant showed appearance of micro emulsion. For S mix 1:4 and 1:3 ratio formulation LLT1P4,LLT1P3showed milky white emulsion for oil: S mix 3:7,4:6,5:5,6:4,7:3,8:2,9:1. For S mix 3:1 ratio formulation LLT3P1 showed bluish white Emulsion (BTE) for Oil: S mix 1:9, 2:8 and milky white Emulsion(MWE) for 3:7,4:6,5:5,6:4,7:3,8:2,9:1 For S mix 4:1ratio formulation LLT4P1 showed clear transparent Emulsion (CTE) for Oil: S mix: 1:9. for Oil: S mix 2:8 formulation LLT4P1 showed bluish white emulsion (BWE); milky white Emulsion(MWE) for 3:7,4:6,5:5,6:4,7:3,8:2,9:1. It was also found that for systems consisting of Labrafac Lipophile WL 1349 oil, Tween 80 as surfactant by increasing proportion in S mix systems had shown decreasing property of forming micro emulsion. From this observation it is also clear that Surfactant is playing role to form micro- emulsion in a proper range.micro emulsion region that is observed in the formulations. Percentage composition of Oil, S mix and water consumed during titration. Fig 8: Pseudo ternary phase diagram of formulation LLT4P1 Fig 9: Pseudo ternary phase diagram of LLT3P1 Formulation Vol 6, Issue 3,

11 SIZE AND ZETA POTENTIAL DETERMINATION Prepared formulations are analysed in zeta sizer for the determination of size and zeta potential values they are shown in various tables below. Table 4 Droplet size and Zeta potential and PDI of formulation LLT3P1-9 Oil:Smix Size of emulsion Region Zeta PDI droplets(dnm) Potential(mV) LLT3P1-1: Micro LLT3P1-2: Micro LLT3P1-3: Micro LLT3P1-4: Micro LLT3P1-5: Micro LLT3P1-6: Micro LLT3P1-7: Micro LLT3P1-8: Micro LLT3P1 9: Micro Table 5 Droplet size and Zeta potential and PDI of formulation LLT4P1-9 Oil:Smix Size of emulsion Region Zeta PDI Droplets(dnm) Potential(mV) LLT4P1-1: Micro LLT4P1-2: Micro LLT4P1-3: Micro LLT4P1-4:6 390 Micro LLT4P1-5: Micro LLT4P1-6: Micro LLT4P1-7: Micro LLT4P1-8: Micro LLT4P1 9: Micro Fig 10: Droplet size distribution of LLT3P1-2 formulation Vol 6, Issue 3,

12 Fig 11: Zeta potential of LLT3P1-2 formulation Fig 12: Droplet size of LLT4P1-2 formulation Fig 13: Zeta potential of LLT4P1-2 formulation Self emulsification and visual assessment: According to visual assessment formulations are graded for self-emulsification time. Self emulsifying mixtures should disperse rapidly in aqueous medium with mild shaking. Self emulsification time that was determined for Vol 6, Issue 3,

13 prepared SELFs given in Table 6. The prepared self -emulsifying lipid of Azilsartan emulsified less than 1min. The efficiency of all prepared emulsions was good. were Table 6 Self emulsification time (Seconds) S.No Formulation Emulsification time 1 LLT3P ±1.5 2 LLT4P ±1.25 All values are expressed as Mean ± SD (n=3) DISPERSIBILITY TEST The two formulations showed grade 1 emulsions when the test is performed in distilled water, 0.1N HCl and phosphate buffer 6.8. Table 7 Dispersibility test results Formulation name Distilled water 0.1NHCL Phosphate buffer of ph6.8 PTWT2 1:9 Grade 1 Grade 1 Grade1 PTWT2 2:8 Grade 1 Grade 1 Grade1 Phase separation and stability study of emulsions Prepared SMEDDS formulations are observed for precipitation and phase separation of drug at intervals 2, 4, 6, 8, 12, 24 hrs periods of time and it was found that all formulations showed neither precipitation nor phase separation of the drug. Table 8 Phase separation and precipitation of the drug (n = 3) Effect of Dilution S.no Formulation Precipitation Phase separation 1 LLT3P1-2 NO NO 2 LLT4P1-2 NO NO Formulations are diluted with excess of Water, 0.1N HCL and Phosphate buffer of ph 6.8 and the diluted samples are stored for 24hrs and visually observed for precipitation (or) phase separation of drug. No precipitation (or) phase separation is found which indicates. Table 9 Effect of Dilution (n = 3) S. No Formulation name Distilled water 0.1NHCL Phosphate buffer of ph6.8 1 PTWT2 1:9 No No No 2 PTWT2 2:8 No No No No indicates no phase separation and precipitation Vol 6, Issue 3,

14 Percentage Transmittance: Each diluted sample was observed for %Transmittance at 250nm. Results are given in Table 10. All formulations showed %transmittance more than 95% indicating clear emulsions. Table 10 Percentage Transmittance S. No Formulation name Distilled water 0.1N HCL Phosphate buffer ph6.8 1 LLT3P ± ± ± LLT4P ± ± ±0.45 All values are expressed as Mean ± SD (n=3) Drug loading efficiency 40mg of each SNEDDS formulation was diluted with 100mL Methanol. Resultant solutions are analyzed UV-Spectrophotometrically following suitable dilution. Absorbance of each solution is measured at 250nm. Results are given in Table It was found both formulations have drug loading efficiency more than 90%. Table 11 Drug loading efficiency of formulations S.no Formulation name Drug loading efficiency 1 LLT3P ± LLT4P ±1.01 All values are expressed as Mean ± SD (n=3) Thermodynamic stability studies Thermodynamic stability study is designed to identify metastable formulation. The prepared self -emulsifying lipid formulations are subjected to Centrifugation study and Freeze thaw cycle. The emulsions are stable during centrifugation at 3,500rpm and alternative temperature cycles of -20 o C and +25 o C. Table 12Thermodynamic stability studies S. No Formulation Name Centrifugation (3500rpm FOR 30 min) Freeze Thaw Cycle( C and ±25 0 C) 1 LLT3P1-2 Passed Passed 2 LLT4P1-2 Passed Passed *P-Passed IN VITRO DRUG RELEASE STUDY In Vitro drug release study was done for pure drug, and liquid SELFS of azilsartan. The percentage drug release from LIQUID SELF was found to be higher than that of pure drug. Percentage drug release and cumulative percentage drug release were calculated from Vol 6, Issue 3,

15 absorbance and concentration that were obtained with the help of standard graph of azilsartan (Fig6.4). After performing the drug release study for 60 min in 0.1 N HCl for LLT4P1 (2:8) % and the LLT3P1-2:8 showed %drug release and pure drug 71.55% showed. Table 13: Cumulative Percentage drug release from pure drug and liquid azilsartan SELFs in 0.1N HCL of p H Solubility of azilsartan is determined in various Oils, Surfactants and Co -surfactants by UV- S. NO TIME(mins) Pure drug LLT3P1- (Azilsartan) 2(2:8) LLT4P1-2(2:8) Fig14: Comparison of percentage drug release of pure drug and their selected formulations SUMMARY AND CONCLUSION The drug azilsartan which was poorly soluble drug was selected for SELFs due to its poor aqueous solubility and its oral bioavailability which is approximately less than 60%. Self emulsifying lipid formulation was developed to improve its solubility and dissolution rate. Spectrophotometric method. Azilsartan has been shown maximum solubility in oil Labrafac Lipophile WL 1349, co surfactant Tween 80 and co surfactant PEG Vol 6, Issue 3,

16 A series of Pseudo ternary phase diagrams are constructed to identify micro emulsion region. Various compositions of Oil and S mix are titrated with water to identify micro emulsion region. From pseudo ternary phase diagrams systems consisting of Labrafac lipophile WL 1349 oil as oily phase, Tween 80 surfactant, PEG 400 as co surfactant are selected for formulation. SELFs are prepared by selecting oil: S mix ratio 1:9,.9:1 and S mix ratio 3:1, 4:1. Two mixtures (LLT3P1-2(2:8), LLT4P1-2(2:8)) are selected for SELFs by keeping amount of drug constant (40mg) in all formulations. Prepared formulations are evaluated for Self emulsification and visual assessment, Phase separation and precipitation of the drug, Robustness to dilution, Percentage Transmittance, drug loading efficiency, FT-IR Studies, Thermodynamic stability studies, Droplet size, PDI and Zeta potential. All five formulations are emulsified in less than 1min. No formulation had showed precipitation and phase separation of drug. All formulation shows effect on dilution. All formulations showed percentage transmittance more than 95% indicating clear emulsions. All formulations have drug loading efficiency more than 90%. Thermodynamic stability studies had indicated that all formulations are stable after centrifugation and freeze thaw cycle. Droplet size was found to be 119.1nm and Zeta potential -7.94mV and drug-excipient compatability studies were done by FT-IR with selected formulations.cumulative drug release of selected formulation of azilsartan is 83.42% at the end of 1month indicating no change in % drug release after stability study. The SELFs clearly showed improved and increased drug dissolution for poorly soluble drug. This helps to keep the drug in soluble state in GIT. So the prepared SELFs have capability for delivering poorly water soluble drug azilsartan in soluble state in GIT. ACKNOWLEDGEMENT It is my proud privilege to express my heartfelt gratitude to my beloved institutional guide, Centre for Pharmaceutical Sciences, IST, and JNTUH for their valuable guidance, cooperation, affectionate encouragement and moral support throughout the course of this investigation. REFERENCES 1. Biopharmaceutical Classification system and Formulation Development. Particle sciences, 2011; 9. Vol 6, Issue 3,

17 2. Mohd Yasir; Mohd Asif; Ashwani Kumar; Abinav Aggarval. Biopharmaceutical classification system: An account. International Journal of Pharm Tech Research, 2010; 2(3): Guidance for Industry, waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Dosage Forms based on a Biopharmaceutics Classification System. U.S Department of Health and Human Services, Food and Drug Administration, Centre for Drug evaluation and Research (CDER), August 2000, BP. 4. Milind P Wagh; Jatin S Patel. Biopharmaceutical Classification System: Scientific basis for Biowaiver Extensions. International Journal of Pharmacy and Pharmaceutical Sciences, 2010; 2(1): Amit Chaudhary; Upendra Nagaich; Neha Gulati; V. K. Sharma; R. L. Khosa. Enhancement of Solubilization and bioavailability of poorly soluble drugs by physical and chemical modifications: A recent review. Journal of Advanced Pharmacy Education and Research, 2012, ISSN , 2(1): D.M.Brahmankar ; Sunil B. Jaiswal : Biopharmaceutics and Pharmacokinetics A Treatise: Martin s Physical Pharmacy and Pharmaceutical sciences Sixth edition Patrick J. Sinko: 48 52; More H.N; Hazare A.A: Practical Pharmaceutics (Physical Pharmacy) Manas Prakashan, Kolhapur, first edition, 2004; Pouton CW. Lipid formulation for oral administration of drugs, non-emulsifying, self emulsifying drug delivery systems. European Journal of Pharmaceutical sciences 2000; 11(2): S93 S Pouton CW. Formulation of poorly water soluble drugs for oral administration: Physicochemical and Physiological issues and formulation classification system. European Journal of Pharmaceutical Sciences, 2006; 29: Ms.Hiral A.Makadia ; Ms.Ami Y.Bhatt; Mr.Ramesh B.Parmar ; Ms.JalpaS.Paun; Dr. H.M.Tank. Self nanoemulsifying drug delivery system (SNEDDS) : Future Aspects. Asian journal of pharmacy. Res, 2013; 3(1): Kanika Sarpal ; Yogesh B.Pawar ; Arvind K.Bansal. Self-emulsifying drug delivery systems: a strategy to improve Oral Bioavailability. Current research and Information on Pharmaceutical Sciences (CRIPS), 2010; 11(3): Vol 6, Issue 3,

18 14. Patel Nitesh N ; Rathva Sunil R; Mr.Shah Viral H ; Dr.Upadhyay Umesh M. Review on self emulsifying drug delivery system : Novel approach for solubility enhancement. International Journal of Pharmaceutical Research and Allied Sciences, 2012; 1(3): M.G.Wakerly; CW Pouton ; B.J.Meakin ; F.S.Morton. Self emulsification of vegetable oil non- ionic surfactant mixtures. ACS Symp.Ser. 1986; 311: European pharmacopeia fifth edition: Indian pharmacopeia. Vol 6, Issue 3,