- Email: [email protected]
Nanoemulsions: A review on low energy formulation methods, characterization, applications and optimization technique
Materials Today: Proceedings xxx (xxxx) xxx
Contents lists available at ScienceDirect
Materials Today: Proceedings journal homepage: www.elsevier.com/locate/matpr
Nanoemulsions: A review on low energy formulation methods, characterization, applications and optimization technique M. Safaya a,⇑, Y.C. Rotliwala b a b
Department of Chemical Engineering, Gujarat Technological University, Ahmedabad 382424, India Department of Chemical Engineering, Pacific School of Engineering, Surat 394305, India
a r t i c l e
i n f o
Article history: Received 25 July 2019 Received in revised form 22 November 2019 Accepted 24 November 2019 Available online xxxx Keywords: Nanoemulsion High energy method Phase inversion composition Phase inversion temperature Hydrophilic-lipophilic balance Surfactant
a b s t r a c t Nanoemulsions are emulsions with droplet size in the order of 100 nm and are kinetically stabilized dispersions formulated by combination and stabilization of two immiscible phases using a surfactant. They exhibit useful properties due to small droplet size leading to high surface area per unit volume, higher stability, optically transparent appearance, flexible fluidity and increased bioavailability of lipophilic components. Recently, interdisciplinary applications of nanoemulsions in consumer products, i.e. pharmaceuticals, pesticides, cosmetics, food, paint and environmental applications have attracted interest in its research. Various authors have focussed on preparing nanoemulsions through different methods, including high-energy and low-energy. High energy methods mainly includes microfluidization, high pressure homogenization and ultrasonication whereas, low energy methods comprise of phase transition temperature, phase inversion composition, spontaneous emulsification, micro emulsion dilution and recently developed approach such as D phase emulsification (DPE). In this review article, we address the growing usefulness of low energy method due to ease in its scale-up, less consumption of energy and increased stability in formulation of nanoemulsions. It also includes review on characterization techniques, applications of nanoemulsions and optimization studies for industrial scale up. Ó 2019 Elsevier Ltd. All rights reserved. Selection and Peer-review under responsibility of the scientific committee of the First International Conference on Recent Advances in Materials and Manufacturing 2019.
1. Introduction Nanoemulsions have gained popularity in recent times for their widespread usability in pharmaceuticals, pesticides, cosmetics, food, paint and environmental applications [1]. Nanoemulsions are kinetically stable systems (droplet size range in the order of 100 nm) exhibiting multiphase colloidal dispersion with longer shelf life [2]. Due to their small size they enhance penetration, spreading and uniform distribution on the targeted area. As shown in Fig. 1, nanoemulsions are mainly classified as water based known as oil in water (o/w) and oil based known as water in oil (w/o) which have been reviewed extensively. It is a mixture of two immiscible liquids stabilized by emulsifier, soluble in the continuous phase [3,4]. Adoptability of o/w or w/o type depends upon the use of nanoemulsion in the area of specific application [5]. The emulsifier used is generally a surfactant, effective in the preparation of nanoemulsions. Surfactant play major role in deformation ⇑ Corresponding author. E-mail address: [email protected] (M. Safaya).
and break-up of droplet and prevent coalescence during emulsification. Surfactants are classified on the bases of hydrophiliclipophilic balance (HLB). As shown in Fig. 2, when dispersed oil droplets coated with surfactants, come close to one another then a thin film of water forms between the droplets. The similar charges of surfactant layer on the oil droplets repel each other. This phenomenon stabilizes the film rupturing of the oil droplet and does not allow the droplets to coalesce [6]. The most effective surfactants are non-ionic surfactants used to emulsify o/w or w/o [7,8]. Numerous research papers have focussed on preparing nanoemulsions through various methods, including high-energy and low-energy methods. For the formulation of nanoemulsions, high energy consumption is the major constraint during the methods such as microfluidization, high pressure homogenization (HPH) and ultrasonication [9]. Conversely, low energy methods i.e., phase transition temperature, phase inversion composition, micro emulsion dilution and D phase emulsification method consume significantly less energy for the formulation of nanoemulsions [10,11]. The property of the formulated nanoemulsion is determined by various characterization techniques.
https://doi.org/10.1016/j.matpr.2019.11.267 2214-7853/Ó 2019 Elsevier Ltd. All rights reserved. Selection and Peer-review under responsibility of the scientific committee of the First International Conference on Recent Advances in Materials and Manufacturing 2019.
Please cite this article as: M. Safaya and Y. C. Rotliwala, Nanoemulsions: A review on low energy formulation methods, characterization, applications and optimization technique, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.11.267
2
M. Safaya, Y.C. Rotliwala / Materials Today: Proceedings xxx (xxxx) xxx
Fig. 1. (a) oil by water (o/w) nanoemulsion, (b) water by oil (w/o) nanoemulsion.
Fig. 2. Droplet stabilized by surfactant.
These characterization methods analyse the droplet size, shape of droplet, rheology as well as system stabilizing factors, i.e. conductivity, pH, zeta potential. Though nanoemulsions are kinetically stable, destabilization mechanism such as flocculation, coalescence, ostwald ripening and creaming might lead to phase separation. Among these, the effect of ostwald ripening is required to be controlled to overcome the issue of nanoemulsion instability. Ostwald ripening leads to formation of larger droplets of oil from a smaller one in a continuous phase [12,13]. Effect of parameters like nanoemulsion composition and temperature on destabilization rates of nanoemulsions has also been reviewed extensively [14]. The current review focuses on the applications of nanoemulsions through low energy methods and optimization studies that are being explored for smooth scale up of low energy methods. 2. Methods of preparation of nanoemulsions The preparation of nanoemulsions can be carried out either by high energy dissipation or low energy dissipation method. These two methods differ by the amount of energy used. The high energy method use mechanical devices to generate large disruptive forces. Whereas, low energy method alters the physiochemical properties of the system to generate nanosized particles [15]. Since the development of nanoemulsions, due to ease of production, high energy methods were the only choice for the researchers. Recently low energy methods have become appealing approach due to the requirement of components that are temperature sensitive such as pharmaceutical ingredients [16].
2.1. High-Energy method The nanoemulsions prepared by high energy method utilize mechanical devices such as micro fluidizers, high pressure homogenizers (HPH) and ultrasonicators. Fig. 3, shows that these mechanical devices use large disruptive forces to produce nanodroplets [17]. They are industrially scalable but consume large amount of energy leading to high production costs. The working principles of these devices included functioning of colloidal mill, high frequency sound waves (20 kHz and high) and influence of high pressure displacement pump (500–50,000 psi) for microfluidizer, ultrasonicators and HPH respectively. Studies have shown that High Pressure Valve Homogenizers are being used in the food industry as they are able to reduce droplet sizes in pre-existing coarse emulsion by passing it through valve under environment of disruptive forces like turbulence, shear and cavitation. This led to design of different nozzles to generate desired droplet sizes. In this method, increase in homogenization pressure is cause for small droplet size. Microfluidizers are similar to HPH with the only change in design of channels. Ultrasonicators are widely used in research laboratories. They convert electrical waves into pressure waves leading to size reduction of droplets with increasing sonication time, power level and emulsifier concentration [18]. The high energy methods can be used with any kind of oil to prepare nanoemulsions and is mostly favoured for oils that are highly viscous and with high molecular weight. There is less consumption of surfactants by this method and ease in selection of surfactant. However, this method seems to be inconvenient during drug delivery systems due to heat sensitive ingredients [19].
Please cite this article as: M. Safaya and Y. C. Rotliwala, Nanoemulsions: A review on low energy formulation methods, characterization, applications and optimization technique, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.11.267
M. Safaya, Y.C. Rotliwala / Materials Today: Proceedings xxx (xxxx) xxx
3
Fig. 3. Schematic diagram of formation of nanoemulsion using high energy method like high pressure homogenisation and ultrasonication.
2.2. Low energy method Nanoemulsions are prepared by utilizing the internal chemical energy of the system (or chemical potential of components) called as low energy method. Chemical energy released during the emulsification is believed to be responsible phenomenon that occurs in low energy method. This happens as a consequence of change in the spontaneous curvature of the surfactant molecules from negative to positive (o/w) or from positive to negative (w/o) [20]. This method includes spontaneous emulsification, phase inversion composition, phase inversion temperature, microemulsion dilution and D phase emulsification. Low energy method involves use of mere stirring at a slower rate (1600 rpm) leading to less energy consumption. In principle, low energy method is classified as isothermal and thermal method. Isothermal methods are suitable for bioactive compounds which are thermally sensitive [21]. It mainly includes spontaneous emulsification, phase inversion composition, microemulsion dilution and D phase emulsification. Thermal method is mainly applicable to solid lipid nanoparticles where heating is essential to maintain liquid phase [22]. 2.2.1. Spontaneous emulsification This method is based on movement of water miscible components like solvent, surfactant and co-surfactant from an organic phase into aqueous phase. The process starts with addition of an organic phase like oil and surfactant into an aqueous phase of water and co-surfactant. The fast migration of water-miscible components into the aqueous phase causes an immense turbulence at the interface of two phases leading to increase in oil–water interfacial area [23,24,25]. This results into spontaneous generation of fine oil droplets when the bicontinuous microemulsion phase breaks up. Use of solvents can promote this process either in the presence or absence of surfactants. In absence of surfactants this process is called ouzo effect [26]. The order of mixing the components have not shown critical effect in the process as the nanoemulsions are formed spontaneously [27]. 2.2.2. Phase inversion composition (PIC) Phase inversion composition (PIC) is an extended form of spontaneous emulsification method. This method produces nanoemulsions at room temperature, which does not involve energy intensive equipment like high energy method or use of solvent like spontaneous emulsification method. Laboratory scale magnetic stirrer is used for agitation of oil and surfactant at room tempera-
ture in which water is fed in a drop wise manner. Fig. 4, shows that upon increasing the amount of water, initially w/o nanoemulsion is formed followed by o/w at inversion point without consumption of significant energy [28]. The formation of nanoemulsion is attributed to interfacial tension, bulk viscosity, phase transition region, surfactant structure and its concentration. This method is also known as catastrophic inversion as it involves increasing the volume fraction of dispersed phase [29]. 2.2.3. Phase transition temperature (PIT) In the year 1969, Shinoda and Saito reported that temperature is the key parameter in the formation of o/w nanoemulsion by PIT method [30]. In the following year, the same group reported study of w/o nanoemulsions using PIT and described the importance of optimum hydrophilic chain length in procuring stable emulsions [31]. Few years later w/o nanoemulsions with same method and highlighting the importance of fast temperature change has been reported [32]. Surfactant, oil and water are stirred and heated gradually at room temperature continuously till phase inversion temperature. Then the solution is rapidly cooled by transferring the mixture to ice bath leading to formation of o/w nanoemulsions. It has been found that when the PIT of the system is approximately 20–65 0C higher than the storage temperature, nanoemulsions formed are of o/w type. Whereas w/o type nanoemulsions are obtained at temperature range of 10–40 0C lower than the storage temperature. It is observed that the stability of the system formed by this method is sensitive at the temperature near the PIT, so another way of stabilizing this system is addition of co-surfactants. Use of non-ionic surfactants (whose molecular geometry changes with temperature) in the systems prepared by PIT method showed stabilized nanoemulsions [33]. In some cases, inorganic salts have been used to adjust the PIT of the system [34,35]. The complete solubilisation of oil phase in the bicontinuous microemulsion leads to o/w nanoemulsion with low droplet size in PIT method [36]. The PIT method usually exhibits high emulsification efficiency and low Polydispersity Index (PDI) compared to PIC method [23]. 2.2.4. Microemulsion dilution This method is also known as self-emulsification method. The nanoemulsion is prepared by using a dilution process at constant temperature. The microemulsion of oil-in-water is rapidly diluted with large amount of water thereby lowering the surfactant concentration responsible for maintaining thermodynamic stability.
Please cite this article as: M. Safaya and Y. C. Rotliwala, Nanoemulsions: A review on low energy formulation methods, characterization, applications and optimization technique, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.11.267
4
M. Safaya, Y.C. Rotliwala / Materials Today: Proceedings xxx (xxxx) xxx
Fig. 4. Phase inversion composition method.
This method can be scaled-up with ease. It has low energy consumption as there is no change in temperature and no high stirring rates are required [37,38]. 2.2.5. D phase emulsification (DPE) D phase emulsification method had been first reported by Sagitani, Hattori, Nabeta and Nagai in 1983 [39]. Thereafter, very less studies on this method have been reported for last three decades. The D phase system consists of surfactant, water and oil like other methods but it also involves the use of an alkyl polyol as an extra component to form o/w nanoemulsion. Compared to other low energy methods, the DPE method requires low surfactant concentration, no strict adherence to hydrophilic-lipophilic scale or proper mixture of surfactant, no requirement of solvent and reportedly less energy consumption compared to PIC method [10,40,41]. In 2004, researchers have reported addition of less soluble oil phase to oil, water and surfactant to prepare o/w nanoemulsion which is in accordance to the DPE method [5]. 3. Characterization of nanoemulsions Nanoemulsions exhibit properties i.e., nano sized droplet, high transparency, variable viscosity and high stability which are characterized by using analytical methods such as dynamic light scattering (DLS), small angle neutron scattering (SANS), viscosity, atomic force microscopy (AFM), zeta potential and stability. For determining droplet size of nanoemulsion, DLS is considered to be a useful method. By measuring droplet size as a function of time with DLS, the physical stability of nanoemulsion can be assessed. DLS has been reported to be used for assessment of Ostwald ripening rate [12]. Neutron wavelengths can probe nanoscale structures, thereby making SANS method useful for obtaining bulk structure of nanoemulsions [42]. At macroscopic level nanoemulsion, methods such as viscosity, conductivity and dielectric testing provide appropriate results. Nanoemulsion exhibited low viscosity when increasing water content and higher viscosity when content of surfactant and co-surfactant is lowered. Change in viscosity helps in evaluating the stability of nanoemulsion systems. To predict whether the prepared nanoemulsions formed are o/w or w/o and
monitor the phase inversion phenomena, the use of conductivity tests are made [43]. Structural and dynamic features of nanoemulsions are evaluated by dielectric measurements. The droplet shape of nanoemulsions system can be determined using Atomic Force Microscopy method. The stability of nanoemulsions systems are probed by performing a set of stability tests such as centrifugation assay, freeze thaw cycle, heating–cooling tests and ambient conditions. These tests analyze the time period for which the nanoemulsions systems can remain stable without exhibiting ostwald ripening, coalescence, creaming and sedimentation. Thus providing an estimate of the shelf life of the prepared system [44].
4. Application of nanoemulsions Over the last few decades, nanoemulsions have found their significant contribution in various sectors. Based on the usage of nanoemulsions over the last decade, it has been observed that higher percentage of involvement of nanoemulsions is in pharmaceutics and cosmetics followed by food industry and other miscellaneous industries [45]. Nanoemulsions are acting as delivery system to allow appropriate dosage of pesticide. Commercial application in the area of pesticide delivery is yet to explore due to poor stability of nanoemulsions. Use of nanoemulsions formulation (water/non-ionic surfactant/ methyl decanoate) for the production of pesticide (b-cypermethrin) by phase inversion composition has been reported for commercial use [37]. Number of authors has reported significant benefit for the use of oral nanoemulsion formulations in contrast to regular oral formulations. Till date, pharmaceutical applications have majorly benefited by the formulation of nanoemulsions. It is due to important characteristics exhibited by nanoemulsions formulated drug in the body. It mainly includes, reduced drug resistance, dose, and enhanced anticancer activity [9]. For the treatment of arthritic conditions, an o/w lipid nanoemulsion of diclofenac using high pressure homogenizer method and droplet size of 200 nm has been studied. Oral delivery of lipophilic drugs like antibiotics, hormones, steroids, cytotoxics, diuretics and antifungals too benefited with the use of nanoemulsion. Some authors have reported the use of phase inversion composition method for oral delivery of protein drugs like Bovine
Please cite this article as: M. Safaya and Y. C. Rotliwala, Nanoemulsions: A review on low energy formulation methods, characterization, applications and optimization technique, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.11.267
M. Safaya, Y.C. Rotliwala / Materials Today: Proceedings xxx (xxxx) xxx
Serum Albumin (BSA) and was found to conserve the bioactivity and conformational structure of encapsulated BSA. The droplet size of 21.8 nm showed high encapsulation efficiency of the drug [46]. Many drugs pose difficulty for topical application when dispersed in carriers like gels, creams, or patches leading to skin irritability. In this area, nanoemulsions have proved to be effective by exhibiting enhanced penetration due to altered lipid bilayers and as small reservoirs for drugs by concentration gradient. It is also highlighted the combination of low and high energy method for the formulation of hydrogel nanoemulsion based on ingredients such as soybean lecithin, tween and poloxamer. Spontaneous emulsification method reported for paclitaxel nanoemulsion to treat deep skin delivery for psoriasis [47]. Another case study reports formulation of caffeine o/w nanoemulsion with droplet size between 20 and 100 nm prepared by phase inversion composition [48]. Cosmetics require good sensorial properties which is provided by nanoemulsions thereby some papers reported stable formulations by using different oils or oil mixtures[49,50].The use of edible coating to preserve fruits and vegetables have been made possible by nanoemulsions. Reports of food matrix redesigned by application of nanoemulsions can be found. Fast moving consumer goods (FMCG) industries have realised specific use of nanoemulsions for the reduction of fat content in ice-cream and uniform melting of frozen foods. [51]. Remarkable application of nanoemulsions have been analysed for the manufacturing of beverages, i.e. fortified waters and soft drinks by low energy methods. Improvement in shelf life of food has been exhibited with the use of nanoemulsions. Bitumin emulsions are stable when kept in containers and on being applied on road, they coalesce to form uniform film. Nanoemulsions have been used to assist in removal of oil spillage in seas and also used as regenerating fluids [8]. 5. Optimization of nanoemulsion system The large scale application of nanoemulsion needs study of optimization for different variables (mainly composition, speed of agitation and duration of formulation process) to achieve the desired properties of formulated nanoemulsions including minimum droplet size or minimum polydispersity, stability and the specific utility [52]. Effect of number of variables on properties of nanoemulsions seems to be the area of future research. Variables such as composition and preparation technique have been reported as an optimisation tool for controlling droplet size. In order to obtain the scale-up values of variables affecting the preparation of nanoemulsion, the use of experimental design has been explored. Experimental optimization is referred for the involvement of more number of variables affecting on the properties of nanoemulsions. Plackett-Burman experimental design by Minitab Software has been reported to determine the influence of seven independent qualitative variables for preparation of nanoemulsions [53,54]. Studies using response surface methodology (RSM) based on Central Composite Design (CCD) have altered the traditional methodology of maintaining all variables constant during the experiment [55,56]. These studies work on the assumption that all variables are independent of each other. Extent of mixing is also identified as key parameter in PIC method. It is stated that good vessel geometry can help achieve the desired extent of mixing leading to control droplet size [57]. Apart from above mentioned variables, some of the authors have shown the advantage of optimization studies for other variables such as influence on dilution, temperature of analysis, surfactant: oil weight ratio (S/O), temperature of preparation and HLB [58,59]. Statistical analysis involved in the experimental design shows clear indication of effect of variables in the preparation of nanoemulsions [60].
5
6. Conclusion Nanoemulsions are expected to gradually become the area of research and development. However, many challenges still need to be overcome in terms of extensive energy use. Due to cost implications, scaling up nanoemulsion production at laboratory bench scale to commercial market in the various areas of application yet need more attention. To overcome the issues, emulsion formulation by low energy methods become the suitable option. CRediT authorship contribution statement M. Safaya: Investigation, Data curation. Y.C. Rotliwala: Conceptualization. Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] C. Solans, P. Izquierdo, J. Nolla, N. Azemar, M.J. Garcia-Celma, Nano-emulsions, Curr. Opin. Colloid Interface Sci. 10 (2005) 102–110, https://doi.org/10.1016/ j.cocis.2005.06.004. [2] K. Meleson, S. Graves, T.G. Mason, Formation of concentrated nanoemulsions by extreme shear, Soft Mater. 2 (2004) 109–123, https://doi.org/10.1081/ SMTS-200056102. [3] Encyclopedia of Emulsion Technology: Volume 4, in: P. Becher (Ed.) Marcel Dekker, Inc., New York, 1996. pp xi + 359. $199.00 (ISBN 0-8247-9380-3), J. Dispers. Sci. Technol. 18 (1997) 459–460. doi: 10.1080/01932699708943748. [4] M. Robins, A. Fillery-Travis, Colloidal dispersions, in: W. B. Russel, D. A. Saville, W. R. Schowalter (Eds.), Cambridge University Press, Cambridge, UK, 1989, xvii + 506 pp., price: £60.00. ISBN 0 521 34188 4, J. Chem. Technol. Biotechnol. 54 (1992) 201–202. doi:10.1002/jctb.280540216. [5] T. Tadros, P. Izquierdo, J. Esquena, C. Solans, Formation and stability of nanoemulsions, Adv. Colloid Interface Sci. 108–109 (2004) 303–318, https://doi. org/10.1016/j.cis.2003.10.023. [6] T.G. Mason, S.M. Graves, J.N. Wilking, M.Y. Lin, Extreme emulsification : Formation and structure of nanoemulsions, 9 (2006) 193–199. [7] M.M. Fryd, T.G. Mason, Nanoinclusions in cryogenically quenched nanoemulsions, Langmuir. 28 (2012) 12015–12021, https://doi.org/10.1021/ la301834x. [8] A. Gupta, H.B. Eral, T.A. Hatton, P.S. Doyle, Nanoemulsions: Formation, properties and applications, Soft Matter. 12 (2016) 2826–2841, https://doi. org/10.1039/c5sm02958a. [9] Y. Singh, J.G. Meher, K. Raval, F.A. Khan, M. Chaurasia, N.K. Jain, M.K. Chourasia, Nanoemulsion: Concepts, development and applications in drug delivery, J. Control. Release. 252 (2017) 28–49, https://doi.org/10.1016/j. jconrel.2017.03.008. [10] M.N. Yukuyama, P.L.F. Oseliero, E.T.M. Kato, R. Lobënberg, C.L.P. de Oliveira, G. L.B. de Araujo, N.A. Bou-Chacra, High internal vegetable oil nanoemulsion: Dphase emulsification as a unique low energy process, Colloids Surfaces A Physicochem. Eng. Asp. 554 (2018) 296–305, https://doi.org/10.1016/ j.colsurfa.2018.06.023. [11] C. Anjali, Y. Sharma, A. Mukherjee, N. Chandrasekaran, Neem oil (Azadirachta indica) nanoemulsion – A potent larvicidal agent against Culex quinquefasciatus, Pest Manag. Sci. 68 (2012) 158–163, https://doi.org/ 10.1002/ps.2233. [12] T.J. Wooster, M. Golding, P. Sanguansri, Ripening stability, Langmuir 24 (2008) 12758–12765, https://doi.org/10.1021/la801685v. [13] R. Buscall, S.S. Davis, D.C. Potts, The effect of long-chain alkanes on the stability of oil-in-water emulsions. The significance of ostwald ripening, Colloid Polym. Sci. 257 (1979) 636–644, https://doi.org/10.1007/BF01548833. [14] S. Setya, S. Talegaonkar, B.K. Razdan, Nanoemulsions: Formulation methods and stability aspects, World J. Pharm. Pharceutical Sci. 3 (2014) 375–394. [15] K. Çinar, A Review on nanoemulsions: Preparation methods and stability, Track. Univ. J. Eng. Sci. 18 (2017) 73–83. [16] M.Y. Koroleva, E.V. Yurtov, Nanoemulsions: The properties, methods of preparation and promising applications, Russ. Chem. Rev. 81 (2012) 21–43, https://doi.org/10.1070/rc2012v081n01abeh004219. [17] N. Anton, J.P. Benoit, P. Saulnier, Design and production of nanoparticles formulated from nano-emulsion templates – A review, J. Control. Release (2008), https://doi.org/10.1016/j.jconrel.2008.02.007. [18] D.J. McClements, Edible nanoemulsions: Fabrication, properties, and functional performance, Soft Matter. 7 (2011) 2297–2316, https://doi.org/ 10.1039/C0SM00549E.
Please cite this article as: M. Safaya and Y. C. Rotliwala, Nanoemulsions: A review on low energy formulation methods, characterization, applications and optimization technique, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.11.267
6
M. Safaya, Y.C. Rotliwala / Materials Today: Proceedings xxx (xxxx) xxx
[19] Cmbebih 2017, 62 (2017) 317–322. doi: 10.1007/978-981-10-4166-2. [20] C. Jadhav, V. Kate, S.A. Payghan, Investigation of effect of non-ionic surfactant on preparation of griseofulvin non-aqueous nanoemulsion, J. Nanostructure Chem. 5 (2015) 107–113, https://doi.org/10.1007/s40097-014-0141-y. [21] N. Anton, T.F. Vandamme, The universality of low-energy nano-emulsification, Int. J. Pharm. 377 (2009) 142–147, https://doi.org/10.1016/j. ijpharm.2009.05.014. [22] C. Solans, I. Solé, Nano-emulsions: Formation by low-energy methods, Curr. Opin. Colloid Interface Sci. 17 (2012) 246–254, https://doi.org/10.1016/ j.cocis.2012.07.003. [23] A. Jintapattanakit, Preparation of nanoemulsions by phase inversion temperature (PIT), Pharm. Sci. Asia. 42 (2018) 1–12, https://doi.org/ 10.29090/psa.2018.01.001. [24] G. Lefebvre, J. Riou, G. Bastiat, E. Roger, K. Frombach, J.-C. Gimel, P. Saulnier, B. Calvignac, Spontaneous nano-emulsification: Process optimization and modeling for the prediction of the nanoemulsion’s size and polydispersity, Int. J. Pharm. 534 (2017) 220–228, https://doi.org/10.1016/j. ijpharm.2017.10.017. [25] A.H. Saberi, Y. Fang, D.J. McClements, Thermal reversibility of vitamin Eenriched emulsion-based delivery systems produced using spontaneous emulsification, Food Chem. 185 (2015) 254–260, https://doi.org/10.1016/ j.foodchem.2015.03.080. [26] J.S. Komaiko, D.J. Mcclements, Formation of food-grade nanoemulsions using low-energy preparation methods: A review of available methods, Compr. Rev. Food Sci. Food Saf. 15 (2016) 331–352, https://doi.org/10.1111/15414337.12189. [27] S. Shafiq-un-Nabi, F. Shakeel, S. Talegaonkar, J. Ali, S. Baboota, A. Ahuja, R.K. Khar, M. Ali, Formulation development and optimization using nanoemulsion technique: A technical note, AAPS PharmSciTech. 8 (2007) E12–E17, https:// doi.org/10.1208/pt0802028. [28] I. Solè, C.M. Pey, A. Maestro, C. González, C. Solans, J.M. Gutiérrez, Nanoemulsions prepared by the phase inversion composition method: Preparation variables and scale up, J. Colloid Interface Sci. 344 (2010) 417–423, https://doi. org/10.1016/j.jcis.2009.11.046. [29] A. Forgiarini, J. Esquena, C. González, C. Solans, Formation of nano-emulsions by low-energy emulsification methods at constant temperature, Langmuir 17 (2001) 2076–2083, https://doi.org/10.1021/la001362n. [30] K. Shinoda, H. Saito, The Stability of O/W type emulsions as functions of temperature and the HLB of emulsifiers: The emulsification by PIT-method, J. Colloid Interface Sci. 30 (1969) 258–263, https://doi.org/10.1016/S0021-9797 (69)80012-3. [31] H. Saito, K. Shinoda, The stability of W/O type emulsions as a function of temperature and of the hydrophilic chain length of the emulsifier, J. Colloid Interface Sci. 32 (1970) 647–651, https://doi.org/10.1016/0021-9797(70) 90158-X. [32] K. Ozawa, C. Solans, H. Kunieda, Spontaneous formation of highly concentrated oil-in-water emulsions, J. Colloid Interface Sci. (1997), https://doi.org/10.1006/ jcis.1997.4761. [33] J. Rao, D.J. McClements, Stabilization of phase inversion temperature nanoemulsions by surfactant displacement, J. Agric. Food Chem. 58 (2010) 7059–7066, https://doi.org/10.1021/jf100990r. [34] Z. Mei, J. Xu, D. Sun, O/W nano-emulsions with tunable PIT induced by inorganic salts, Colloids Surf. A Physicochem. Eng. Asp. 375 (2011) 102–108, https://doi.org/10.1016/j.colsurfa.2010.11.069. [35] H.M. Hasan, J. Leanpolchareanchai, A. Jintapattanakit, Preparation of virgin coconut oil nanoemulsions by phase inversion temperature method, Pharm. Formul. Dev (2015) 99–102, https://doi.org/10.4028/www.scientific.net/ AMR.1060.99. [36] D. Morales, J.M. Gutiérrez, M.J. García-Celma, Y.C. Solans, A Study of the relation between bicontinuous microemulsions and oil/water nano-emulsion formation, Langmuir 19 (2003) 7196–7200, https://doi.org/10.1021/ la0300737. [37] L. Wang, X. Li, G. Zhang, J. Dong, J. Eastoe, Oil-in-water nanoemulsions for pesticide formulations, J. Colloid Interface Sci. 314 (2007) 230–235, https:// doi.org/10.1016/j.jcis.2007.04.079. [38] J. Feng, Q. Zhang, Q. Liu, Z. Zhu, D.J. McClements, S.M. Jafari, Application of Nanoemulsions in Formulation of Pesticides, Elsevier Inc., 2018. doi: 10.1016/ B978-0-12-811838-2.00012-6. [39] H. Sagitani, T. Hattori, K. Nabeta, M. Nagai, Formation of O/W emulsion having fine and uniform droplets by the surfactant (D) phase emulsification method, Nippon Kagaku Kaishi 1983 (1983) 1399–1404, https://doi.org/10.1246/ nikkashi.1983.1399.
[40] T. Kawanami, K. Togashi, K. Fumoto, S. Hirano, P. Zhang, K. Shirai, S. Hirasawa, Thermophysical properties and thermal characteristics of phase change emulsion for thermal energy storage media, Energy 117 (2016) 562–568, https://doi.org/10.1016/j.energy.2016.04.021. [41] H. Sagitani, K. Nabeta, M. Nagai, A new preparing method for fine O/W emulsions by D phase emulsification and their application to cosmetic industry, J. Japan Oil Chem. Soc. 40 (1991) 988–994, https://doi.org/10.5650/ jos1956.40.988. [42] S. Graves, K. Meleson, J. Wilking, M.Y. Lin, T.G. Mason, Structure of concentrated nanoemulsions, J. Chem. Phys. (2005), https://doi.org/10.1063/ 1.1874952. [43] M. Chiesa, J. Garg, Y.T. Kang, G. Chen, Thermal conductivity and viscosity of water-in-oil nanoemulsions, Colloids Surf. A Physicochem. Eng. Asp. (2008), https://doi.org/10.1016/j.colsurfa.2008.05.028. [44] D.Q.M. Craig, S.A. Barker, D. Banning, S.W. Booth, An investigation into the mechanisms of self-emulsification using particle size analysis and low frequency dielectric spectroscopy, Int. J. Pharm. (1995), https://doi.org/ 10.1016/0378-5173(94)00222-Q. [45] A. Maali, M.T.H. Mosavian, Preparation and application of nanoemulsions in the last decade (2000–2010), J. Dispers. Sci. Technol. (2013), https://doi.org/ 10.1080/01932691.2011.648498. [46] H. Sun, K. Liu, W. Wang, B. Tang, J. Gu, J. Zhang, X. Mao, Q. Zou, H. Zeng, W. Liu, C. Guo, H. Li, Development and characterization of a novel nanoemulsion drugdelivery system for potential application in oral delivery of protein drugs, Int. J. Nanomedicine. 7 (2012) 5529, https://doi.org/10.2147/IJN.S36071. [47] S. Khandavilli, R. Panchagnula, Nanoemulsions as versatile formulations for paclitaxel delivery: Peroral and dermal delivery studies in rats, J. Invest. Dermatol. 127 (2007) 154–162, https://doi.org/10.1038/sj.jid.5700485. [48] O. Sonneville-Aubrun, J.-T. Simonnet, F. L’Alloret, Nanoemulsions: A new vehicle for skincare products, Adv. Colloid Interface Sci. 108–109 (2004) 145– 149, https://doi.org/10.1016/j.cis.2003.10.026. [49] N. Dasgupta, S. Ranjan, M. Gandhi, Nanoemulsions in food: Market demand, Environ. Chem. Lett. (2019), https://doi.org/10.1007/s10311-019-00856-2. [50] V.P. Chavda, D. Shah, A review on novel emulsification technique: A nanoemulsion, J. Pharmacol. Toxicol. Stud. 5 (2017) 29–37. [51] M. Sessa, G. Ferrari, F. Donsì, Novel edible coating containing essential oil nanoemulsions to prolong the shelf life of vegetable products, 2015. doi: 10.3303/CET1543010. [52] J.M. Gutiérrez, C. González, A. Maestro, I. Solè, C.M. Pey, J. Nolla, Nanoemulsions: New applications and optimization of their preparation, Curr. Opin. Colloid Interface Sci. 13 (2008) 245–251, https://doi.org/10.1016/ j.cocis.2008.01.005. [53] M.E.I. Badawy, A.F.S.A. Saad, E.S.H.M. Tayeb, S.A. Mohammed, A.D. Abd-Elnabi, Optimization and characterization of the formation of oil-in-water diazinon nanoemulsions: Modeling and influence of the oil phase, surfactant and sonication, J. Environ. Sci. Heal. – Part B Pestic. Food Contam. Agric. Wastes. 52 (2017) 896–911, https://doi.org/10.1080/03601234.2017.1362941. [54] I. Solè, A. Maestro, C. González, C. Solans, J.M. Gutiérrez, Optimization of nanoemulsion preparation by low-energy methods in an ionic surfactant system, Langmuir (2006), https://doi.org/10.1021/la0613676. [55] M. Hesseien, N. Singh, C.-H. Kim, E. Prouzet, Stability and tunability of O/W nanoemulsions prepared by PIC, Langmuir 27 (2011) 2299–2307. [56] E.I. Taha, A.M. Samy, A.A. Kassem, M.A. Khan, Response surface methodology for the development of self-nanoemulsified drug delivery system (SNEDDS) of all-trans-retinol acetate, Pharm. Dev. Technol. (2005), https://doi.org/10.1081/ PDT-65675. [57] A.S. Zidan, O.A. Sammour, M.A. Hammad, N.A. Megrab, M.J. Habib, M.A. Khan, Quality by design: Understanding the formulation variables of a cyclosporine A self-nanoemulsified drug delivery systems by Box-Behnken design and desirability function, Int. J. Pharm. (2007), https://doi.org/10.1016/j. ijpharm.2006.09.060. [58] R.B. Shah, A.S. Zidan, T. Funck, M.A. Tawakkul, A. Nguyenpho, M.A. Khan, Quality by design: Characterization of self-nano-emulsified drug delivery systems (SNEDDs) using ultrasonic resonator technology, Int. J. Pharm. (2007), https://doi.org/10.1016/j.ijpharm.2007.04.009. [59] Y. Chang, D.J. McClements, Optimization of orange oil nanoemulsion formation by isothermal low-energy methods: influence of the oil phase, surfactant, and temperature, J. Agric. Food Chem. 62 (2014) 2306–2312, https://doi.org/ 10.1021/jf500160y. [60] Z. Du, C. Wang, X. Tai, G. Wang, X. Liu, Optimization and Characterization of Biocompatible Oil-in-Water Nanoemulsion for Pesticide Delivery, ACS Sustain. Chem. Eng. 4 (2016) 983–991, https://doi.org/10.1021/acssuschemeng.5b01058.
Please cite this article as: M. Safaya and Y. C. Rotliwala, Nanoemulsions: A review on low energy formulation methods, characterization, applications and optimization technique, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.11.267
Contents lists available at ScienceDirect
Materials Today: Proceedings journal homepage: www.elsevier.com/locate/matpr
Nanoemulsions: A review on low energy formulation methods, characterization, applications and optimization technique M. Safaya a,⇑, Y.C. Rotliwala b a b
Department of Chemical Engineering, Gujarat Technological University, Ahmedabad 382424, India Department of Chemical Engineering, Pacific School of Engineering, Surat 394305, India
a r t i c l e
i n f o
Article history: Received 25 July 2019 Received in revised form 22 November 2019 Accepted 24 November 2019 Available online xxxx Keywords: Nanoemulsion High energy method Phase inversion composition Phase inversion temperature Hydrophilic-lipophilic balance Surfactant
a b s t r a c t Nanoemulsions are emulsions with droplet size in the order of 100 nm and are kinetically stabilized dispersions formulated by combination and stabilization of two immiscible phases using a surfactant. They exhibit useful properties due to small droplet size leading to high surface area per unit volume, higher stability, optically transparent appearance, flexible fluidity and increased bioavailability of lipophilic components. Recently, interdisciplinary applications of nanoemulsions in consumer products, i.e. pharmaceuticals, pesticides, cosmetics, food, paint and environmental applications have attracted interest in its research. Various authors have focussed on preparing nanoemulsions through different methods, including high-energy and low-energy. High energy methods mainly includes microfluidization, high pressure homogenization and ultrasonication whereas, low energy methods comprise of phase transition temperature, phase inversion composition, spontaneous emulsification, micro emulsion dilution and recently developed approach such as D phase emulsification (DPE). In this review article, we address the growing usefulness of low energy method due to ease in its scale-up, less consumption of energy and increased stability in formulation of nanoemulsions. It also includes review on characterization techniques, applications of nanoemulsions and optimization studies for industrial scale up. Ó 2019 Elsevier Ltd. All rights reserved. Selection and Peer-review under responsibility of the scientific committee of the First International Conference on Recent Advances in Materials and Manufacturing 2019.
1. Introduction Nanoemulsions have gained popularity in recent times for their widespread usability in pharmaceuticals, pesticides, cosmetics, food, paint and environmental applications [1]. Nanoemulsions are kinetically stable systems (droplet size range in the order of 100 nm) exhibiting multiphase colloidal dispersion with longer shelf life [2]. Due to their small size they enhance penetration, spreading and uniform distribution on the targeted area. As shown in Fig. 1, nanoemulsions are mainly classified as water based known as oil in water (o/w) and oil based known as water in oil (w/o) which have been reviewed extensively. It is a mixture of two immiscible liquids stabilized by emulsifier, soluble in the continuous phase [3,4]. Adoptability of o/w or w/o type depends upon the use of nanoemulsion in the area of specific application [5]. The emulsifier used is generally a surfactant, effective in the preparation of nanoemulsions. Surfactant play major role in deformation ⇑ Corresponding author. E-mail address: [email protected] (M. Safaya).
and break-up of droplet and prevent coalescence during emulsification. Surfactants are classified on the bases of hydrophiliclipophilic balance (HLB). As shown in Fig. 2, when dispersed oil droplets coated with surfactants, come close to one another then a thin film of water forms between the droplets. The similar charges of surfactant layer on the oil droplets repel each other. This phenomenon stabilizes the film rupturing of the oil droplet and does not allow the droplets to coalesce [6]. The most effective surfactants are non-ionic surfactants used to emulsify o/w or w/o [7,8]. Numerous research papers have focussed on preparing nanoemulsions through various methods, including high-energy and low-energy methods. For the formulation of nanoemulsions, high energy consumption is the major constraint during the methods such as microfluidization, high pressure homogenization (HPH) and ultrasonication [9]. Conversely, low energy methods i.e., phase transition temperature, phase inversion composition, micro emulsion dilution and D phase emulsification method consume significantly less energy for the formulation of nanoemulsions [10,11]. The property of the formulated nanoemulsion is determined by various characterization techniques.
https://doi.org/10.1016/j.matpr.2019.11.267 2214-7853/Ó 2019 Elsevier Ltd. All rights reserved. Selection and Peer-review under responsibility of the scientific committee of the First International Conference on Recent Advances in Materials and Manufacturing 2019.
Please cite this article as: M. Safaya and Y. C. Rotliwala, Nanoemulsions: A review on low energy formulation methods, characterization, applications and optimization technique, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.11.267
2
M. Safaya, Y.C. Rotliwala / Materials Today: Proceedings xxx (xxxx) xxx
Fig. 1. (a) oil by water (o/w) nanoemulsion, (b) water by oil (w/o) nanoemulsion.
Fig. 2. Droplet stabilized by surfactant.
These characterization methods analyse the droplet size, shape of droplet, rheology as well as system stabilizing factors, i.e. conductivity, pH, zeta potential. Though nanoemulsions are kinetically stable, destabilization mechanism such as flocculation, coalescence, ostwald ripening and creaming might lead to phase separation. Among these, the effect of ostwald ripening is required to be controlled to overcome the issue of nanoemulsion instability. Ostwald ripening leads to formation of larger droplets of oil from a smaller one in a continuous phase [12,13]. Effect of parameters like nanoemulsion composition and temperature on destabilization rates of nanoemulsions has also been reviewed extensively [14]. The current review focuses on the applications of nanoemulsions through low energy methods and optimization studies that are being explored for smooth scale up of low energy methods. 2. Methods of preparation of nanoemulsions The preparation of nanoemulsions can be carried out either by high energy dissipation or low energy dissipation method. These two methods differ by the amount of energy used. The high energy method use mechanical devices to generate large disruptive forces. Whereas, low energy method alters the physiochemical properties of the system to generate nanosized particles [15]. Since the development of nanoemulsions, due to ease of production, high energy methods were the only choice for the researchers. Recently low energy methods have become appealing approach due to the requirement of components that are temperature sensitive such as pharmaceutical ingredients [16].
2.1. High-Energy method The nanoemulsions prepared by high energy method utilize mechanical devices such as micro fluidizers, high pressure homogenizers (HPH) and ultrasonicators. Fig. 3, shows that these mechanical devices use large disruptive forces to produce nanodroplets [17]. They are industrially scalable but consume large amount of energy leading to high production costs. The working principles of these devices included functioning of colloidal mill, high frequency sound waves (20 kHz and high) and influence of high pressure displacement pump (500–50,000 psi) for microfluidizer, ultrasonicators and HPH respectively. Studies have shown that High Pressure Valve Homogenizers are being used in the food industry as they are able to reduce droplet sizes in pre-existing coarse emulsion by passing it through valve under environment of disruptive forces like turbulence, shear and cavitation. This led to design of different nozzles to generate desired droplet sizes. In this method, increase in homogenization pressure is cause for small droplet size. Microfluidizers are similar to HPH with the only change in design of channels. Ultrasonicators are widely used in research laboratories. They convert electrical waves into pressure waves leading to size reduction of droplets with increasing sonication time, power level and emulsifier concentration [18]. The high energy methods can be used with any kind of oil to prepare nanoemulsions and is mostly favoured for oils that are highly viscous and with high molecular weight. There is less consumption of surfactants by this method and ease in selection of surfactant. However, this method seems to be inconvenient during drug delivery systems due to heat sensitive ingredients [19].
Please cite this article as: M. Safaya and Y. C. Rotliwala, Nanoemulsions: A review on low energy formulation methods, characterization, applications and optimization technique, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.11.267
M. Safaya, Y.C. Rotliwala / Materials Today: Proceedings xxx (xxxx) xxx
3
Fig. 3. Schematic diagram of formation of nanoemulsion using high energy method like high pressure homogenisation and ultrasonication.
2.2. Low energy method Nanoemulsions are prepared by utilizing the internal chemical energy of the system (or chemical potential of components) called as low energy method. Chemical energy released during the emulsification is believed to be responsible phenomenon that occurs in low energy method. This happens as a consequence of change in the spontaneous curvature of the surfactant molecules from negative to positive (o/w) or from positive to negative (w/o) [20]. This method includes spontaneous emulsification, phase inversion composition, phase inversion temperature, microemulsion dilution and D phase emulsification. Low energy method involves use of mere stirring at a slower rate (1600 rpm) leading to less energy consumption. In principle, low energy method is classified as isothermal and thermal method. Isothermal methods are suitable for bioactive compounds which are thermally sensitive [21]. It mainly includes spontaneous emulsification, phase inversion composition, microemulsion dilution and D phase emulsification. Thermal method is mainly applicable to solid lipid nanoparticles where heating is essential to maintain liquid phase [22]. 2.2.1. Spontaneous emulsification This method is based on movement of water miscible components like solvent, surfactant and co-surfactant from an organic phase into aqueous phase. The process starts with addition of an organic phase like oil and surfactant into an aqueous phase of water and co-surfactant. The fast migration of water-miscible components into the aqueous phase causes an immense turbulence at the interface of two phases leading to increase in oil–water interfacial area [23,24,25]. This results into spontaneous generation of fine oil droplets when the bicontinuous microemulsion phase breaks up. Use of solvents can promote this process either in the presence or absence of surfactants. In absence of surfactants this process is called ouzo effect [26]. The order of mixing the components have not shown critical effect in the process as the nanoemulsions are formed spontaneously [27]. 2.2.2. Phase inversion composition (PIC) Phase inversion composition (PIC) is an extended form of spontaneous emulsification method. This method produces nanoemulsions at room temperature, which does not involve energy intensive equipment like high energy method or use of solvent like spontaneous emulsification method. Laboratory scale magnetic stirrer is used for agitation of oil and surfactant at room tempera-
ture in which water is fed in a drop wise manner. Fig. 4, shows that upon increasing the amount of water, initially w/o nanoemulsion is formed followed by o/w at inversion point without consumption of significant energy [28]. The formation of nanoemulsion is attributed to interfacial tension, bulk viscosity, phase transition region, surfactant structure and its concentration. This method is also known as catastrophic inversion as it involves increasing the volume fraction of dispersed phase [29]. 2.2.3. Phase transition temperature (PIT) In the year 1969, Shinoda and Saito reported that temperature is the key parameter in the formation of o/w nanoemulsion by PIT method [30]. In the following year, the same group reported study of w/o nanoemulsions using PIT and described the importance of optimum hydrophilic chain length in procuring stable emulsions [31]. Few years later w/o nanoemulsions with same method and highlighting the importance of fast temperature change has been reported [32]. Surfactant, oil and water are stirred and heated gradually at room temperature continuously till phase inversion temperature. Then the solution is rapidly cooled by transferring the mixture to ice bath leading to formation of o/w nanoemulsions. It has been found that when the PIT of the system is approximately 20–65 0C higher than the storage temperature, nanoemulsions formed are of o/w type. Whereas w/o type nanoemulsions are obtained at temperature range of 10–40 0C lower than the storage temperature. It is observed that the stability of the system formed by this method is sensitive at the temperature near the PIT, so another way of stabilizing this system is addition of co-surfactants. Use of non-ionic surfactants (whose molecular geometry changes with temperature) in the systems prepared by PIT method showed stabilized nanoemulsions [33]. In some cases, inorganic salts have been used to adjust the PIT of the system [34,35]. The complete solubilisation of oil phase in the bicontinuous microemulsion leads to o/w nanoemulsion with low droplet size in PIT method [36]. The PIT method usually exhibits high emulsification efficiency and low Polydispersity Index (PDI) compared to PIC method [23]. 2.2.4. Microemulsion dilution This method is also known as self-emulsification method. The nanoemulsion is prepared by using a dilution process at constant temperature. The microemulsion of oil-in-water is rapidly diluted with large amount of water thereby lowering the surfactant concentration responsible for maintaining thermodynamic stability.
Please cite this article as: M. Safaya and Y. C. Rotliwala, Nanoemulsions: A review on low energy formulation methods, characterization, applications and optimization technique, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.11.267
4
M. Safaya, Y.C. Rotliwala / Materials Today: Proceedings xxx (xxxx) xxx
Fig. 4. Phase inversion composition method.
This method can be scaled-up with ease. It has low energy consumption as there is no change in temperature and no high stirring rates are required [37,38]. 2.2.5. D phase emulsification (DPE) D phase emulsification method had been first reported by Sagitani, Hattori, Nabeta and Nagai in 1983 [39]. Thereafter, very less studies on this method have been reported for last three decades. The D phase system consists of surfactant, water and oil like other methods but it also involves the use of an alkyl polyol as an extra component to form o/w nanoemulsion. Compared to other low energy methods, the DPE method requires low surfactant concentration, no strict adherence to hydrophilic-lipophilic scale or proper mixture of surfactant, no requirement of solvent and reportedly less energy consumption compared to PIC method [10,40,41]. In 2004, researchers have reported addition of less soluble oil phase to oil, water and surfactant to prepare o/w nanoemulsion which is in accordance to the DPE method [5]. 3. Characterization of nanoemulsions Nanoemulsions exhibit properties i.e., nano sized droplet, high transparency, variable viscosity and high stability which are characterized by using analytical methods such as dynamic light scattering (DLS), small angle neutron scattering (SANS), viscosity, atomic force microscopy (AFM), zeta potential and stability. For determining droplet size of nanoemulsion, DLS is considered to be a useful method. By measuring droplet size as a function of time with DLS, the physical stability of nanoemulsion can be assessed. DLS has been reported to be used for assessment of Ostwald ripening rate [12]. Neutron wavelengths can probe nanoscale structures, thereby making SANS method useful for obtaining bulk structure of nanoemulsions [42]. At macroscopic level nanoemulsion, methods such as viscosity, conductivity and dielectric testing provide appropriate results. Nanoemulsion exhibited low viscosity when increasing water content and higher viscosity when content of surfactant and co-surfactant is lowered. Change in viscosity helps in evaluating the stability of nanoemulsion systems. To predict whether the prepared nanoemulsions formed are o/w or w/o and
monitor the phase inversion phenomena, the use of conductivity tests are made [43]. Structural and dynamic features of nanoemulsions are evaluated by dielectric measurements. The droplet shape of nanoemulsions system can be determined using Atomic Force Microscopy method. The stability of nanoemulsions systems are probed by performing a set of stability tests such as centrifugation assay, freeze thaw cycle, heating–cooling tests and ambient conditions. These tests analyze the time period for which the nanoemulsions systems can remain stable without exhibiting ostwald ripening, coalescence, creaming and sedimentation. Thus providing an estimate of the shelf life of the prepared system [44].
4. Application of nanoemulsions Over the last few decades, nanoemulsions have found their significant contribution in various sectors. Based on the usage of nanoemulsions over the last decade, it has been observed that higher percentage of involvement of nanoemulsions is in pharmaceutics and cosmetics followed by food industry and other miscellaneous industries [45]. Nanoemulsions are acting as delivery system to allow appropriate dosage of pesticide. Commercial application in the area of pesticide delivery is yet to explore due to poor stability of nanoemulsions. Use of nanoemulsions formulation (water/non-ionic surfactant/ methyl decanoate) for the production of pesticide (b-cypermethrin) by phase inversion composition has been reported for commercial use [37]. Number of authors has reported significant benefit for the use of oral nanoemulsion formulations in contrast to regular oral formulations. Till date, pharmaceutical applications have majorly benefited by the formulation of nanoemulsions. It is due to important characteristics exhibited by nanoemulsions formulated drug in the body. It mainly includes, reduced drug resistance, dose, and enhanced anticancer activity [9]. For the treatment of arthritic conditions, an o/w lipid nanoemulsion of diclofenac using high pressure homogenizer method and droplet size of 200 nm has been studied. Oral delivery of lipophilic drugs like antibiotics, hormones, steroids, cytotoxics, diuretics and antifungals too benefited with the use of nanoemulsion. Some authors have reported the use of phase inversion composition method for oral delivery of protein drugs like Bovine
Please cite this article as: M. Safaya and Y. C. Rotliwala, Nanoemulsions: A review on low energy formulation methods, characterization, applications and optimization technique, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.11.267
M. Safaya, Y.C. Rotliwala / Materials Today: Proceedings xxx (xxxx) xxx
Serum Albumin (BSA) and was found to conserve the bioactivity and conformational structure of encapsulated BSA. The droplet size of 21.8 nm showed high encapsulation efficiency of the drug [46]. Many drugs pose difficulty for topical application when dispersed in carriers like gels, creams, or patches leading to skin irritability. In this area, nanoemulsions have proved to be effective by exhibiting enhanced penetration due to altered lipid bilayers and as small reservoirs for drugs by concentration gradient. It is also highlighted the combination of low and high energy method for the formulation of hydrogel nanoemulsion based on ingredients such as soybean lecithin, tween and poloxamer. Spontaneous emulsification method reported for paclitaxel nanoemulsion to treat deep skin delivery for psoriasis [47]. Another case study reports formulation of caffeine o/w nanoemulsion with droplet size between 20 and 100 nm prepared by phase inversion composition [48]. Cosmetics require good sensorial properties which is provided by nanoemulsions thereby some papers reported stable formulations by using different oils or oil mixtures[49,50].The use of edible coating to preserve fruits and vegetables have been made possible by nanoemulsions. Reports of food matrix redesigned by application of nanoemulsions can be found. Fast moving consumer goods (FMCG) industries have realised specific use of nanoemulsions for the reduction of fat content in ice-cream and uniform melting of frozen foods. [51]. Remarkable application of nanoemulsions have been analysed for the manufacturing of beverages, i.e. fortified waters and soft drinks by low energy methods. Improvement in shelf life of food has been exhibited with the use of nanoemulsions. Bitumin emulsions are stable when kept in containers and on being applied on road, they coalesce to form uniform film. Nanoemulsions have been used to assist in removal of oil spillage in seas and also used as regenerating fluids [8]. 5. Optimization of nanoemulsion system The large scale application of nanoemulsion needs study of optimization for different variables (mainly composition, speed of agitation and duration of formulation process) to achieve the desired properties of formulated nanoemulsions including minimum droplet size or minimum polydispersity, stability and the specific utility [52]. Effect of number of variables on properties of nanoemulsions seems to be the area of future research. Variables such as composition and preparation technique have been reported as an optimisation tool for controlling droplet size. In order to obtain the scale-up values of variables affecting the preparation of nanoemulsion, the use of experimental design has been explored. Experimental optimization is referred for the involvement of more number of variables affecting on the properties of nanoemulsions. Plackett-Burman experimental design by Minitab Software has been reported to determine the influence of seven independent qualitative variables for preparation of nanoemulsions [53,54]. Studies using response surface methodology (RSM) based on Central Composite Design (CCD) have altered the traditional methodology of maintaining all variables constant during the experiment [55,56]. These studies work on the assumption that all variables are independent of each other. Extent of mixing is also identified as key parameter in PIC method. It is stated that good vessel geometry can help achieve the desired extent of mixing leading to control droplet size [57]. Apart from above mentioned variables, some of the authors have shown the advantage of optimization studies for other variables such as influence on dilution, temperature of analysis, surfactant: oil weight ratio (S/O), temperature of preparation and HLB [58,59]. Statistical analysis involved in the experimental design shows clear indication of effect of variables in the preparation of nanoemulsions [60].
5
6. Conclusion Nanoemulsions are expected to gradually become the area of research and development. However, many challenges still need to be overcome in terms of extensive energy use. Due to cost implications, scaling up nanoemulsion production at laboratory bench scale to commercial market in the various areas of application yet need more attention. To overcome the issues, emulsion formulation by low energy methods become the suitable option. CRediT authorship contribution statement M. Safaya: Investigation, Data curation. Y.C. Rotliwala: Conceptualization. Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] C. Solans, P. Izquierdo, J. Nolla, N. Azemar, M.J. Garcia-Celma, Nano-emulsions, Curr. Opin. Colloid Interface Sci. 10 (2005) 102–110, https://doi.org/10.1016/ j.cocis.2005.06.004. [2] K. Meleson, S. Graves, T.G. Mason, Formation of concentrated nanoemulsions by extreme shear, Soft Mater. 2 (2004) 109–123, https://doi.org/10.1081/ SMTS-200056102. [3] Encyclopedia of Emulsion Technology: Volume 4, in: P. Becher (Ed.) Marcel Dekker, Inc., New York, 1996. pp xi + 359. $199.00 (ISBN 0-8247-9380-3), J. Dispers. Sci. Technol. 18 (1997) 459–460. doi: 10.1080/01932699708943748. [4] M. Robins, A. Fillery-Travis, Colloidal dispersions, in: W. B. Russel, D. A. Saville, W. R. Schowalter (Eds.), Cambridge University Press, Cambridge, UK, 1989, xvii + 506 pp., price: £60.00. ISBN 0 521 34188 4, J. Chem. Technol. Biotechnol. 54 (1992) 201–202. doi:10.1002/jctb.280540216. [5] T. Tadros, P. Izquierdo, J. Esquena, C. Solans, Formation and stability of nanoemulsions, Adv. Colloid Interface Sci. 108–109 (2004) 303–318, https://doi. org/10.1016/j.cis.2003.10.023. [6] T.G. Mason, S.M. Graves, J.N. Wilking, M.Y. Lin, Extreme emulsification : Formation and structure of nanoemulsions, 9 (2006) 193–199. [7] M.M. Fryd, T.G. Mason, Nanoinclusions in cryogenically quenched nanoemulsions, Langmuir. 28 (2012) 12015–12021, https://doi.org/10.1021/ la301834x. [8] A. Gupta, H.B. Eral, T.A. Hatton, P.S. Doyle, Nanoemulsions: Formation, properties and applications, Soft Matter. 12 (2016) 2826–2841, https://doi. org/10.1039/c5sm02958a. [9] Y. Singh, J.G. Meher, K. Raval, F.A. Khan, M. Chaurasia, N.K. Jain, M.K. Chourasia, Nanoemulsion: Concepts, development and applications in drug delivery, J. Control. Release. 252 (2017) 28–49, https://doi.org/10.1016/j. jconrel.2017.03.008. [10] M.N. Yukuyama, P.L.F. Oseliero, E.T.M. Kato, R. Lobënberg, C.L.P. de Oliveira, G. L.B. de Araujo, N.A. Bou-Chacra, High internal vegetable oil nanoemulsion: Dphase emulsification as a unique low energy process, Colloids Surfaces A Physicochem. Eng. Asp. 554 (2018) 296–305, https://doi.org/10.1016/ j.colsurfa.2018.06.023. [11] C. Anjali, Y. Sharma, A. Mukherjee, N. Chandrasekaran, Neem oil (Azadirachta indica) nanoemulsion – A potent larvicidal agent against Culex quinquefasciatus, Pest Manag. Sci. 68 (2012) 158–163, https://doi.org/ 10.1002/ps.2233. [12] T.J. Wooster, M. Golding, P. Sanguansri, Ripening stability, Langmuir 24 (2008) 12758–12765, https://doi.org/10.1021/la801685v. [13] R. Buscall, S.S. Davis, D.C. Potts, The effect of long-chain alkanes on the stability of oil-in-water emulsions. The significance of ostwald ripening, Colloid Polym. Sci. 257 (1979) 636–644, https://doi.org/10.1007/BF01548833. [14] S. Setya, S. Talegaonkar, B.K. Razdan, Nanoemulsions: Formulation methods and stability aspects, World J. Pharm. Pharceutical Sci. 3 (2014) 375–394. [15] K. Çinar, A Review on nanoemulsions: Preparation methods and stability, Track. Univ. J. Eng. Sci. 18 (2017) 73–83. [16] M.Y. Koroleva, E.V. Yurtov, Nanoemulsions: The properties, methods of preparation and promising applications, Russ. Chem. Rev. 81 (2012) 21–43, https://doi.org/10.1070/rc2012v081n01abeh004219. [17] N. Anton, J.P. Benoit, P. Saulnier, Design and production of nanoparticles formulated from nano-emulsion templates – A review, J. Control. Release (2008), https://doi.org/10.1016/j.jconrel.2008.02.007. [18] D.J. McClements, Edible nanoemulsions: Fabrication, properties, and functional performance, Soft Matter. 7 (2011) 2297–2316, https://doi.org/ 10.1039/C0SM00549E.
Please cite this article as: M. Safaya and Y. C. Rotliwala, Nanoemulsions: A review on low energy formulation methods, characterization, applications and optimization technique, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.11.267
6
M. Safaya, Y.C. Rotliwala / Materials Today: Proceedings xxx (xxxx) xxx
[19] Cmbebih 2017, 62 (2017) 317–322. doi: 10.1007/978-981-10-4166-2. [20] C. Jadhav, V. Kate, S.A. Payghan, Investigation of effect of non-ionic surfactant on preparation of griseofulvin non-aqueous nanoemulsion, J. Nanostructure Chem. 5 (2015) 107–113, https://doi.org/10.1007/s40097-014-0141-y. [21] N. Anton, T.F. Vandamme, The universality of low-energy nano-emulsification, Int. J. Pharm. 377 (2009) 142–147, https://doi.org/10.1016/j. ijpharm.2009.05.014. [22] C. Solans, I. Solé, Nano-emulsions: Formation by low-energy methods, Curr. Opin. Colloid Interface Sci. 17 (2012) 246–254, https://doi.org/10.1016/ j.cocis.2012.07.003. [23] A. Jintapattanakit, Preparation of nanoemulsions by phase inversion temperature (PIT), Pharm. Sci. Asia. 42 (2018) 1–12, https://doi.org/ 10.29090/psa.2018.01.001. [24] G. Lefebvre, J. Riou, G. Bastiat, E. Roger, K. Frombach, J.-C. Gimel, P. Saulnier, B. Calvignac, Spontaneous nano-emulsification: Process optimization and modeling for the prediction of the nanoemulsion’s size and polydispersity, Int. J. Pharm. 534 (2017) 220–228, https://doi.org/10.1016/j. ijpharm.2017.10.017. [25] A.H. Saberi, Y. Fang, D.J. McClements, Thermal reversibility of vitamin Eenriched emulsion-based delivery systems produced using spontaneous emulsification, Food Chem. 185 (2015) 254–260, https://doi.org/10.1016/ j.foodchem.2015.03.080. [26] J.S. Komaiko, D.J. Mcclements, Formation of food-grade nanoemulsions using low-energy preparation methods: A review of available methods, Compr. Rev. Food Sci. Food Saf. 15 (2016) 331–352, https://doi.org/10.1111/15414337.12189. [27] S. Shafiq-un-Nabi, F. Shakeel, S. Talegaonkar, J. Ali, S. Baboota, A. Ahuja, R.K. Khar, M. Ali, Formulation development and optimization using nanoemulsion technique: A technical note, AAPS PharmSciTech. 8 (2007) E12–E17, https:// doi.org/10.1208/pt0802028. [28] I. Solè, C.M. Pey, A. Maestro, C. González, C. Solans, J.M. Gutiérrez, Nanoemulsions prepared by the phase inversion composition method: Preparation variables and scale up, J. Colloid Interface Sci. 344 (2010) 417–423, https://doi. org/10.1016/j.jcis.2009.11.046. [29] A. Forgiarini, J. Esquena, C. González, C. Solans, Formation of nano-emulsions by low-energy emulsification methods at constant temperature, Langmuir 17 (2001) 2076–2083, https://doi.org/10.1021/la001362n. [30] K. Shinoda, H. Saito, The Stability of O/W type emulsions as functions of temperature and the HLB of emulsifiers: The emulsification by PIT-method, J. Colloid Interface Sci. 30 (1969) 258–263, https://doi.org/10.1016/S0021-9797 (69)80012-3. [31] H. Saito, K. Shinoda, The stability of W/O type emulsions as a function of temperature and of the hydrophilic chain length of the emulsifier, J. Colloid Interface Sci. 32 (1970) 647–651, https://doi.org/10.1016/0021-9797(70) 90158-X. [32] K. Ozawa, C. Solans, H. Kunieda, Spontaneous formation of highly concentrated oil-in-water emulsions, J. Colloid Interface Sci. (1997), https://doi.org/10.1006/ jcis.1997.4761. [33] J. Rao, D.J. McClements, Stabilization of phase inversion temperature nanoemulsions by surfactant displacement, J. Agric. Food Chem. 58 (2010) 7059–7066, https://doi.org/10.1021/jf100990r. [34] Z. Mei, J. Xu, D. Sun, O/W nano-emulsions with tunable PIT induced by inorganic salts, Colloids Surf. A Physicochem. Eng. Asp. 375 (2011) 102–108, https://doi.org/10.1016/j.colsurfa.2010.11.069. [35] H.M. Hasan, J. Leanpolchareanchai, A. Jintapattanakit, Preparation of virgin coconut oil nanoemulsions by phase inversion temperature method, Pharm. Formul. Dev (2015) 99–102, https://doi.org/10.4028/www.scientific.net/ AMR.1060.99. [36] D. Morales, J.M. Gutiérrez, M.J. García-Celma, Y.C. Solans, A Study of the relation between bicontinuous microemulsions and oil/water nano-emulsion formation, Langmuir 19 (2003) 7196–7200, https://doi.org/10.1021/ la0300737. [37] L. Wang, X. Li, G. Zhang, J. Dong, J. Eastoe, Oil-in-water nanoemulsions for pesticide formulations, J. Colloid Interface Sci. 314 (2007) 230–235, https:// doi.org/10.1016/j.jcis.2007.04.079. [38] J. Feng, Q. Zhang, Q. Liu, Z. Zhu, D.J. McClements, S.M. Jafari, Application of Nanoemulsions in Formulation of Pesticides, Elsevier Inc., 2018. doi: 10.1016/ B978-0-12-811838-2.00012-6. [39] H. Sagitani, T. Hattori, K. Nabeta, M. Nagai, Formation of O/W emulsion having fine and uniform droplets by the surfactant (D) phase emulsification method, Nippon Kagaku Kaishi 1983 (1983) 1399–1404, https://doi.org/10.1246/ nikkashi.1983.1399.
[40] T. Kawanami, K. Togashi, K. Fumoto, S. Hirano, P. Zhang, K. Shirai, S. Hirasawa, Thermophysical properties and thermal characteristics of phase change emulsion for thermal energy storage media, Energy 117 (2016) 562–568, https://doi.org/10.1016/j.energy.2016.04.021. [41] H. Sagitani, K. Nabeta, M. Nagai, A new preparing method for fine O/W emulsions by D phase emulsification and their application to cosmetic industry, J. Japan Oil Chem. Soc. 40 (1991) 988–994, https://doi.org/10.5650/ jos1956.40.988. [42] S. Graves, K. Meleson, J. Wilking, M.Y. Lin, T.G. Mason, Structure of concentrated nanoemulsions, J. Chem. Phys. (2005), https://doi.org/10.1063/ 1.1874952. [43] M. Chiesa, J. Garg, Y.T. Kang, G. Chen, Thermal conductivity and viscosity of water-in-oil nanoemulsions, Colloids Surf. A Physicochem. Eng. Asp. (2008), https://doi.org/10.1016/j.colsurfa.2008.05.028. [44] D.Q.M. Craig, S.A. Barker, D. Banning, S.W. Booth, An investigation into the mechanisms of self-emulsification using particle size analysis and low frequency dielectric spectroscopy, Int. J. Pharm. (1995), https://doi.org/ 10.1016/0378-5173(94)00222-Q. [45] A. Maali, M.T.H. Mosavian, Preparation and application of nanoemulsions in the last decade (2000–2010), J. Dispers. Sci. Technol. (2013), https://doi.org/ 10.1080/01932691.2011.648498. [46] H. Sun, K. Liu, W. Wang, B. Tang, J. Gu, J. Zhang, X. Mao, Q. Zou, H. Zeng, W. Liu, C. Guo, H. Li, Development and characterization of a novel nanoemulsion drugdelivery system for potential application in oral delivery of protein drugs, Int. J. Nanomedicine. 7 (2012) 5529, https://doi.org/10.2147/IJN.S36071. [47] S. Khandavilli, R. Panchagnula, Nanoemulsions as versatile formulations for paclitaxel delivery: Peroral and dermal delivery studies in rats, J. Invest. Dermatol. 127 (2007) 154–162, https://doi.org/10.1038/sj.jid.5700485. [48] O. Sonneville-Aubrun, J.-T. Simonnet, F. L’Alloret, Nanoemulsions: A new vehicle for skincare products, Adv. Colloid Interface Sci. 108–109 (2004) 145– 149, https://doi.org/10.1016/j.cis.2003.10.026. [49] N. Dasgupta, S. Ranjan, M. Gandhi, Nanoemulsions in food: Market demand, Environ. Chem. Lett. (2019), https://doi.org/10.1007/s10311-019-00856-2. [50] V.P. Chavda, D. Shah, A review on novel emulsification technique: A nanoemulsion, J. Pharmacol. Toxicol. Stud. 5 (2017) 29–37. [51] M. Sessa, G. Ferrari, F. Donsì, Novel edible coating containing essential oil nanoemulsions to prolong the shelf life of vegetable products, 2015. doi: 10.3303/CET1543010. [52] J.M. Gutiérrez, C. González, A. Maestro, I. Solè, C.M. Pey, J. Nolla, Nanoemulsions: New applications and optimization of their preparation, Curr. Opin. Colloid Interface Sci. 13 (2008) 245–251, https://doi.org/10.1016/ j.cocis.2008.01.005. [53] M.E.I. Badawy, A.F.S.A. Saad, E.S.H.M. Tayeb, S.A. Mohammed, A.D. Abd-Elnabi, Optimization and characterization of the formation of oil-in-water diazinon nanoemulsions: Modeling and influence of the oil phase, surfactant and sonication, J. Environ. Sci. Heal. – Part B Pestic. Food Contam. Agric. Wastes. 52 (2017) 896–911, https://doi.org/10.1080/03601234.2017.1362941. [54] I. Solè, A. Maestro, C. González, C. Solans, J.M. Gutiérrez, Optimization of nanoemulsion preparation by low-energy methods in an ionic surfactant system, Langmuir (2006), https://doi.org/10.1021/la0613676. [55] M. Hesseien, N. Singh, C.-H. Kim, E. Prouzet, Stability and tunability of O/W nanoemulsions prepared by PIC, Langmuir 27 (2011) 2299–2307. [56] E.I. Taha, A.M. Samy, A.A. Kassem, M.A. Khan, Response surface methodology for the development of self-nanoemulsified drug delivery system (SNEDDS) of all-trans-retinol acetate, Pharm. Dev. Technol. (2005), https://doi.org/10.1081/ PDT-65675. [57] A.S. Zidan, O.A. Sammour, M.A. Hammad, N.A. Megrab, M.J. Habib, M.A. Khan, Quality by design: Understanding the formulation variables of a cyclosporine A self-nanoemulsified drug delivery systems by Box-Behnken design and desirability function, Int. J. Pharm. (2007), https://doi.org/10.1016/j. ijpharm.2006.09.060. [58] R.B. Shah, A.S. Zidan, T. Funck, M.A. Tawakkul, A. Nguyenpho, M.A. Khan, Quality by design: Characterization of self-nano-emulsified drug delivery systems (SNEDDs) using ultrasonic resonator technology, Int. J. Pharm. (2007), https://doi.org/10.1016/j.ijpharm.2007.04.009. [59] Y. Chang, D.J. McClements, Optimization of orange oil nanoemulsion formation by isothermal low-energy methods: influence of the oil phase, surfactant, and temperature, J. Agric. Food Chem. 62 (2014) 2306–2312, https://doi.org/ 10.1021/jf500160y. [60] Z. Du, C. Wang, X. Tai, G. Wang, X. Liu, Optimization and Characterization of Biocompatible Oil-in-Water Nanoemulsion for Pesticide Delivery, ACS Sustain. Chem. Eng. 4 (2016) 983–991, https://doi.org/10.1021/acssuschemeng.5b01058.
Please cite this article as: M. Safaya and Y. C. Rotliwala, Nanoemulsions: A review on low energy formulation methods, characterization, applications and optimization technique, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.11.267