Self Nanoemulsifying Solid of Atorvastatin Calcium –
Development, Characterization and Evaluation
Department of Pharmaceutics, PSG College of Pharmacy, Peelamedu, Coimbatore – 641004, India.
*Corresponding Author E-mail: subbu3j@gmail.com
ABSTRACT:
The aim of the present study is development and characterization of SNEDDS to enhance the bioavailability of anti-hyperlipidemic agent Atorvastatin calcium. The solubility was estimated in various solvent to find maximum solubility of drug in solvent. Vegetable oil (as vehicle), non-ionic surfactant (as surfactant, co-surfactant) and water is used to construct pseudo-ternary phase diagram (identify nanoemulsifying region). Stability, dispersibility and robustness to dilution to be performed for optimize formulations using phase diagram. Different formulations are prepared with various composition of vegetable oil, non-ionic surfactant. At one globule size of optimized system is expected to accept nano emulsion size range for improving the dissolution of Atorvastatin calcium. There by we may enhance the bio-availability of Atorvastatin.
KEYWORDS: SNEDDS, Dissolution, Atorvastatin calcium, Surfactant.
INTRODUCTION:
Atorvastatin BCS Class II having high permeability with low aqueous solubility. Oral route of atorvastatin administration is the most preferred, convenient and recommended way, but the usage in oral route has poor aqueous solubility with recorded low bioavailability. Lipid-based drug delivery system like self-emulsifying formulations delivers the drug into solution form to GIT directly which enhances bioavailability.1-4 SNEEDS are isotropic mixture of oils, surfactant and co-surfactant which emulsify to produce fine O/W emulsion when introduced into aqueous phase (GI fluid). It enhance solubility and absorption of lipophilic drugs by increasing the surface area and decreasing the size of droplets that are readily digested and incorporated into micelles that can pass through lumen.5-8
Preformulation Studies
Melting point of Atorvastatin calcium is determined by capillary tube method and solubility is identified in different solvents like water, methanol, ethanol to form a saturated solution9.
The solubility of Atorvastatin in various oils, surfactants and co-surfactants is done by the vial shake method. 5 ml of oil with excess of atorvastatin is added to the vial and then heated to 40°C followed by centrifuged at 3000 rpm for 10 min. After the process, it is filtered and analyzed in UV spectrophotometer.10,11,12
The Pseudo ternary phase diagram is constructed without using of Atorvastatin calcium to identify the nano-emulsifying region and to optimise the percentage of oil, surfactant/co-surfactant. Surfactant and co-surfactant with different ratio are added to oil phase and it is titrated with water until it becomes turbid.13-16
Table 1: Size reduction process of Atorvastatin formulation
|
Bath sonicator |
1st cycle - 5min |
|
High speed homogenizer |
1st cycle - 5min @ 20000rpm |
|
High speed homogenizer |
2nd cycle - 5min @ 20000rpm |
The atorvastatin is weighed accurately and formulated as 10mg/ml, then it is mixed with specified proportion of the oil, surfactant and co-surfactant are picked out from the pseudo ternary phase diagram. The above formulation of prepared SNEDDS is heated at 40˚C followed by different particle size reduction process (Table 1).11,17
Table 2: Guidelines for Visibility Grade18,19
|
Grade |
Visibility |
|
I |
Clear or slightly bluish in appearance within 1 minute |
|
II |
Slightly less clear; Bluish white in appearance < 2 minutes |
|
III |
Milky in appearance within 3 minutes |
|
IV |
Dull white which is slightly oily in appearance, slow to emulsify > 3 minutes |
|
V |
Turbid in appearance > 3 minutes |
The rate and extends of atorvastatin release determined by globule size of the formulation. Distilled water is used to made 100ml from 1ml of formulation and sonicated for 15mins and produces nano emulsion. Droplet size, PDI and Zeta potential of nano emulsion is determined using Malvern Zeta sizer.20-24
The Morphology of the prepared SNEDDS is observed by PCM. The atorvastatin formulation is diluted with distilled water and it is mounted on glass slide. Then it is viewed and photographed in phase contrast microscope.25
The prepared SNEDDS is taken and sprinkled on Avicel PH101 adsorbent bed until a free flowing powder is obtained. The formulation is added with starch as bulking agent, talc 2% as glidant and magnesium stearate 1% as lubricant. The formulation is converted to self nano-emulsifying tablets of Atorvastatin by tablet punching machine.
In-Vitro Dissolution Study
In paddle type apparatus with 900ml of phosphate buffer pH=7.4 as dissolution medium.14 The temperature and speed of the apparatus are adjusted into 37˚C±0.4˚C and 75 rpm respectively. 5mL of the sample are withdraw at 15, 20, 30, 45, 60 minutes and replaced the same by fresh medium and it is filtered, diluted and analysed spectrophotometrically.21
Preformulation Studies of Melting Point and Solubility
The melting point of Atorvastatin calcium is found to be 174˚C and soluble in methanol, slightly soluble in ethanol and insoluble in water.
Among oils, neem oil has higher solubility for Atorvastatin but it is less acceptable for oral route of administration. So, sesame oil is selected for the SNEDDS formulation.19 Span 80 and PEG 400 are used as surfactant and co-surfactant which shows the best emulsification stability. HLB value of sesame oil is 4.9, for Span 80 is 4.3 and for PEG 400 is 9.7. In order to satisfy the required HLB value of 4.9, 4.8 part of span 80 (surfactant) and 0.6 part of PEG 400 (co-surfactant) are used in the SNEDDS formulation.
The point at shaded area gives the concentration of oil, surfactant and co-surfactant (Smix). Better emulsification is seen with concentrations of surfactant above 50% and oil below 30%. Above these concentrations either phase separation or turbidity will be seen.
The SNEDDS formulation (Table 3) is prepared with the specified composition which has been determined from the pseudo ternary phase diagram.
Table 3: Compositions of Atorvastatin SNEDDS
|
Formulation |
Drug (mcg/ ml) |
Oil (%) |
Surfactant (%) |
Co-Surfactant (%) |
|
F1 |
10 |
30 |
26.6 |
3.3 |
|
F2 |
10 |
50 |
44.4 |
5.5 |
|
F3 |
10 |
70 |
62.2 |
7.7 |
SNEDDS formulation should have ability to disperse completely when it is subjected to dilution under mild agitation. F1, F2, F3 formulations shows no phase separation. The formulation F1 will be appeared as slightly less clear and bluish white in appearance within
<2 minutes, it comes under the visual assessment of Grade II (Table 4).
Table 4: Visibility Grade of Atorvastatin SNEDDS Formulation
|
Formulation |
Visibility Grade |
Precipitation |
|
F1 |
II |
NO |
|
F2 |
III |
NO |
|
F3 |
III |
NO |
Droplet size of nano-emulsion is most the important for determining the rate and extends of drug release because it affects the absorption the drugs. Smaller droplets have larger surface area which increases the absorption of drug. PDI is the ratio of standard deviation to the mean droplet size which indicates the uniformity of size range in the formulation. Zeta potential indicates the charge repulsion among the particles.1,16 For F1 formulation, the Z-average size is found to be 405.2nm with PDI value of 0.376 shows the narrow size distribution. The Zeta potential of F1 formulation is determined to be -32.5mV which indicates the good quality formulation.
The morphology of formulation F1 of atorvastatin SNEDDS was evaluated by phase contrast microscopy and evidence that irregular spherical shape of formulation F1 of SNEDDS atorvastatin.
The prepared liquid SNEDDS is sprinkled on the adsorbent bed, which is prepared by using Avicel PH 101 but it does not yield free flowing powder. Then it added with talc and magnesium stearate to yield free flowing powder further it is dried in an oven. Tablets are punched with required amount of solid SNEDDS preparation and some binding agents. 2% starch used as binding agent for hardness property.
Weight variation, thickness, diameter, friability, hardness, drug content uniformity of Atorvastatin SNEDDS – F1 formulation is presented in (Table 5).
Table 5: Evaluation of SNEDDS Atorvastatin F1 formulation tablets
|
Formulatio n code |
Weight variatio n (mg) |
Thickness (mm) |
Diamete r (mm) |
Friabilit y (%) |
Hardness (Newton ) |
Drug content uniformity (%) |
|
F1 |
495 |
4 |
6 |
1.02 |
29 |
98.78 ± 0.03 |
In-Vitro Dissolution Study:
The dissolution profile of Atorvastatin SNEDDS F1 formulation and marketed formulation are compared. Marketed tablet shows only 39.7 ± 0.68% of drug release within 30 mins but in the Atorvastatin SNEDDS formulation F1 shows 93.45 ± 0.72% of drug release within 30 mins and maximum drug release was achieved but in marketed tablet maximum drug release was attained only by 60 mins.. In comparison with the marketed tablet, SNEDDS showed a 2.35 fold increase in the dissolution rate by 30 mins . Thus, result indicates the spontaneous nano-emulsion is formed with better in vitro dissolution.
From the experimental study, we concluded that the poorly aqueous soluble atorvastatin calcium into SNEDDS formulation yields the product with good nanoparticles size range and PDI of uniform size distribution and zeta potential of acceptable stability (405.2 nm with PDI 0.375 and Zeta potential -32.5mV), which helps in increasing aqueous solubility of atorvastatin and thereby enhances the dissolution rate. Irregular spherical vesicles are proved in phase contrast microscopy study. The liquid SNEDDS are converted into powder by spreading into Avicel PH 101 and then compressed into tablet form for better stability. Physico-chemical properties of prepared tablets also confirm the suitability of formulation to scale up. The prepared tablets of Formulation F1 atorvastatin SNEDDSshown 1.4 fold increase in in-vitro dissolution when compare to marketed tablet. This may enhance the bioavailability of atorvastatin calcium and can be proved by further extension of studies.
The author would like to express sincere thanks to PSG College of Pharmacy, Coimbatore for facilitating infrastructure to carry out the experimental
CONFLICT OF INTEREST:
No conflict of interest in the manuscript.
All authors are equally contributed in experimental investigations.
REFERENCE:
1. Kuralarasan K, Subramanian S. Influence of Different Stabilizers on Dissolution of Cilnidipne Nanosupension. Asian Journal of Pharmaceutics. 2020; 14 (1): 26. DOI: https://doi.org/10.22377/ajp.v14i1.3472
2. Subramanian S. Codestm drug delivery: design and evaluation of metronidazole tablets. International Journal Green Pharmacy. 2021; 15 (4): 400-405. DOI: https://doi.org/10.22377/ijgp.v15i4.3187
3. Subramanian S, Monisha V. Investigating the use of liquisolid compact technique for pioglitazone HCI. Research Journal of Pharmacy and Technology. 2022; 15(3): 1013-7. DOI : 10.52711/0974-360X.2022.00169
4. Bhairav B.A., J.K. Bachhav, R.B. Saudagar. Review on Solubility Enhancement Techniques. Asian J. Pharm. Res. 2016; 6(3): 147-152.
5. Hiral A. Makadia, Ami Y. Bhatt, Ramesh B. Parmar, Ms. Jalpa S. Paun, H.M. Tank. Self-nano Emulsifying Drug Delivery System (SNEDDS): Future Aspects. Asian J. Pharm. Res. 2013; 3(1): 20-26.
6. Wadhwa J, Nair A, Kumria R. Emulsion forming drug delivery system for lipophilic drugs. Acta Pol Pharm. 2012; 69(2):179-91. PMID: 22568032.
7. Singh B, Khurana L, Bandyopadhyay S, Kapil R, Katare OO. Development of optimized self-nano-emulsifying drug delivery systems (SNEDDS) of carvedilol with enhanced bioavailability potential. Drug Deliv. 2011; 18(8): 599-612. DOI: 10.3109/10717544.2011.604686. Epub 2011 Oct 18. PMID: 22008038.
8. Thomas N, Holm R, Müllertz A, Rades T. In vitro and in vivo performance of novel supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS). J Control Release. 2012 May 30; 160(1): 25-32. DOI: 10.1016/j.jconrel.2012.02.027. Epub 2012 Mar 3. PMID: 22405903.
9. Pandurang N Dhabale, Vijay Jadhav, Chandrakant Raut. UV-Spectrophotometric Estimation of Atorvastatin Calcium in Tablet Dosage Form. Asian J. Research Chem. 2010; 3(2): 339-341.
10. Mandal S, Mandal SS, Sawant KK. Design and development of microemulsion drug delivery system of atorvastatin and study its intestinal permeability in rats. International Journal of Drug Delivery. 2010; 2(1). DOI:10.5138/ijdd.2010.0975.0215.02014
11. Patel J, Patel A, Raval M, Sheth N. Formulation and development of a self-nanoemulsifying drug delivery system of irbesartan. Journal of advanced pharmaceutical technology and research. 2011; 2(1): 9. DOI: 10.4103/2231-4040.79799
12. Ponnaganti H, Abbulu K. Enhanced dissolution of repaglinide: SMEDDS formulation and in-vitro evaluation. Research Journal of Pharmacy and Technology. 2014; 7(11): 1246-52.
13. Beg S, Swain S, Singh HP, Patra CN, Rao MB. Development, optimization, and characterization of solid self-nanoemulsifying drug delivery systems of valsartan using porous carriers. Aaps Pharmscitech. 2012; 13: 1416-27.
14. Khan F, Islam MS, Jalil RU. Study of Solubility of Atorvastatin using Ternary Phase Diagram for the Development of Self-Emulsifying Drug Delivery Systems (SEDDS). Dhaka University Journal of Pharmaceutical Sciences. 2012; 11(2): 3-91.
15. Doaa Elsegaie. Formulation and In-vitro Characterization of Self Nano-emulsifying Drug Delivery System (SNEDDS) for enhanced Solubility of Candesartan Cilexetil. Research J. Pharm. and Tech. 2019; 12(6): 2628-2636. DOI: 10.5958/0974-360X.2019.00440.2
16. Patil P, Mahajan VR. Self-Emulsifying Drug Delivery Systems (SEDDS): A Brief Review. Research Journal of Pharmaceutical Dosage Forms and Technology. 2014; 6(2): 134-9. DOI: 10.3390/ph15091064
17. Jyothi BJ, Sreelakshmi K. Design and evaluation of self-nanoemulsifying drug delivery system of flutamide. Journal of young pharmacists. 2011; 3(1): 4-8.
18. Reddy MS, Sravani B. Formulation and evaluation of solid self nano emulsifying drug delivery system of olanzapine to enhance aqueous solubility and dissolution rate. Asian Journal of Pharmaceutical Research. 2021; 11(4): 227-38. DOI: 10.52711/2231-5691.2021.00040
19. Venkatesh M, Mallesh K. Self-nano emulsifying drug delivery system (SNEDDS) for oral delivery of atorvastatin-formulation and bioavailability studies. Journal of Drug Delivery and Therapeutics. 2013; 3(3): 131-40.
20. Chandrakar A, Sahu B, Sahu H, Dewangan J, Kumar N, Singh R, et al. Review on the formulation considerations needed to produce a stable Self micro Emulsifying Drug Delivery System (SMEDDS). Research Journal of Pharmacy and Technology. 2017; 10(5): 1563-70. DOI: 10.5958/0974-360X.2017.00275.X.
21. Nan Z, Lijun G, Tao W, Dongqin Q. Evaluation of carbamazepine (CBZ) supersaturatable self-microemulsifying (S-SMEDDS) formulation in-vitro and in-vivo. Iranian journal of pharmaceutical research. 2012; 11(1): 257.
22. Tripathi S, Kushwah V, Thanki K, Jain S. Triple antioxidant SNEDDS formulation with enhanced oral bioavailability: Implication of chemoprevention of breast cancer. Nanomedicine: Nanotechnology, Biology and Medicine. 2016 Aug 1; 12(6): 1431-43. DOI: 10.1016/j.nano.2016.03.003
23. Uddin MS, Millat MS, Siddiqui SA. Formulation and evaluation studies of Atorvastatin calcium sustained release tablet. PharmaTutor. 2019 Sep 1; 7(9): 1-5.
24. Rahul P. Jadhav, Vikranti W. Koli, Amruta B. Kamble, Dr. Mangesh A. Bhutkar. A Review on Nanoemulsion. Asian J. Res. Pharm. Sci. 2020; 10(2): 103-108. DOI: 10.5958/2231-5659.2020.00020.X
25. Kumar DV, Jat RK, Kumar GV. Formulation and In-vitro Evaluation of Floating Drug Delivery System for Piretanide. International Journal of Pharmaceutical Research (09752366). 2020; 12(4). DOI: 10.31838/ijpr/2020.12.04.712
26. Namayandeh SM, Kaseb F, Lesan S. Olive and sesame oil effect on lipid profile in hypercholesterolemic patients, which better?. Int J Prev Med. 2013; 4(9): 1059-62. PMID: 24130948; PMCID: PMC3793488.
27. Debjit Bhowmik, Amerandra singh, Praveen Khirwadker, Nishu Shukla, et al. Formulation andamp; Evaluation of Methyl Phaenidate Sustained Release Tablets. Res J.Pharm. Dosage Formandamp; Tech. 2016; 8(3): 199-206. DOI: 10.5958/0975-4377.2016.00027.6
Received on 09.06.2023 Modified on 18.11.2023
Accepted on 27.02.2024 © RJPT All right reserved
Research J. Pharm. and Tech 2024; 17(5):2031-2034.
DOI: 10.52711/0974-360X.2024.00321