Novel technologies to enhance solubility of food-derived bioactive
compounds: A review

, Muhammad Riaz

, Sanghoon Ko

, Sungkwon Park

Department of Food Science and Bio-technology, Sejong University, 209 Neundong-ro, Gwangjin-gu, Seoul 05006, Republic of Korea

Institute of Food Science & Nutrition, Bahauddin Zakariya University, Multan 60800, Pakistan

a r t i c l e i n f o

Article history:
Received 12 June 2017
Received in revised form 1 October 2017
Accepted 2 October 2017
Available online 17 October 2017

Keywords:
Natural bioactive compounds
Solubility
Inclusion complexation
Supercritical fluids
Emulsification

a b s t r a c t

Food-derived multifunctional bioactive compounds, such as carotenoids, fat soluble vitamins, phytos-
terols, polyunsaturated lipids, curcuminoids and flavonoid compounds provide promising therapeutic
health benefits. However, the efforts in identifying their mode of action and applying them into food
industry are still unsuccessful because majority of these compounds are water-insoluble and ingested
are not delivered to the site of action, therefore, less bioavailable. Several strategies to enhance the water
solubility have been developed over the years. There has been active research in the area during recent
times. The present review will comprehensively discuss about novel technologies which have used to
improve the aqueous solubility of bioactives.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

1.1.

The role of bioactive substance solubility in development of functional foods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

1.2.

Factors that affect solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
1.2.1.

Influence of particle size and shape . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

1.2.2.

Influence of temperature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

1.2.3.

Influence of molecular weight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

1.2.4.

Influence of molecular polarity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

1.2.5.

Influence of physical forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

1.2.6.

Influence of pH of the medium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

1.2.7.

Influence of stabilizers/emulsifiers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Techniques for enhancing solubility of poorly water-soluble bioactive natural products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

2.1.

Nanosuspension technologies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
2.1.1.

Preparation of nanosuspensions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

2.1.2.

Application of nanosuspensions to enhance solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

2.2.

Emulsion-based delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
2.2.1.

Microemulsions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

2.2.2.

Self-emulsifying drug delivery systems (SEDDS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

2.2.3.

Nanoemulsions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

2.3.

Inclusion complexation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
2.3.1.

Techniques to prepare inclusion complexation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

2.3.2.

Applications of cyclodextrins to improve the solubility of bioactive compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

2.4.

Super critical fluid (SCF) technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
2.4.1.

Common techniques to prepare particles in SCF technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

https://doi.org/10.1016/j.jff.2017.10.001

1756-4646/

⇑

Corresponding author.
E-mail addresses:

neeruphysio39@gmail.com

(N. Recharla),

riaz@bzu.edu.pk

(M. Riaz),

sanghoonko@sejong.ac.kr

(S. Ko),

sungkwonpark@sejong.ac.kr

(S. Park).

Co-corresponding author.

Journal of Functional Foods 39 (2017) 63–73

Contents lists available at

ScienceDirect

Journal of Functional Foods

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / j f f

2.5.

Co-solvency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

2.6.

Nanoprecipitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

2.7.

Cryogenic techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
2.7.1.

Spray freezing into liquid (SFL) process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

2.7.2.

Ultra-rapid freezing (URF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

2.7.3.

Spray freezing into vapor over liquid (SFV/L) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

2.8.

Solid dispersions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
2.8.1.

Techniques for preparing solid dispersions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

2.8.2.

Application of solid dispersions to enhance solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

2.9.

Micellar solubilization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
2.9.1.

Mixed micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

2.9.2.

Polymeric micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

2.10.

Reducing particle size by milling techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

2.10.1.

Milling techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

2.11.

Hydrotropy method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

Conclusions and future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

1. Introduction

In light of consumer perception and preferences toward health

promoting foods, the development of new functional food is a lead-
ing trend in food industry. Various bioactive compounds have been
obtained from natural sources and classified into different cate-
gories based on their chemical structure and functions: phenolic
compounds, vitamins, carotenoids, alkaloids, and organosulfur
compounds (

Hamri, Zeghichi, Chibane, Kallithraka, & Benhalima,

2011; Jeong et al., 2015; Lim et al., 2017

). Many of bioactive com-

ponents were identified and isolated from vegetables, fruits,
legumes, oils, nuts, and whole grains and have shown numerous
beneficial effects on human health including antioxidant, anti-
inflammatory, antibacterial, and immunomodulatory activities
(

Hsieh, Yang, Sethi, & Hu, 2015; Imm, Kim, & Imm, 2014; Kris-

Etherton et al., 2002

). Therapeutic effects of these compounds for

instance; allicin (from garlic), curcumin (from turmeric), catechi-
nes (from tea polyphenols) helps to prevent diseases including
cancer, cardiovascular illness, neuronal degenerative diseases, dia-
betes, etc. (

Pandey & Rizvi, 2009; Pham-Huy, He, & Pham-Huy,

2008

). However, the incorporation of these bioactive molecules

into commercial food products is a challenging task due to their
poor stability and low rate of solubility (

Lee et al., 2015; Teleki,

Hitzfeld, & Eggersdorfer, 2013; Yousuf, Gul, Wani, & Singh, 2016

Furthermore, the therapeutic health effects of orally administered
bioactive compound depend on several factors such as solubility in
an aqueous environment and permeability through the epithelial
cell membrane, concentration of bioactive compounds in blood/
plasma and molecular interactions in gastro intestinal fluids.
Numerous technologies and novel food delivery systems have been
developed to overcome these solubility and permeability issues.

1.1. The role of bioactive substance solubility in development of
functional foods

Solubility is one of the important parameters to achieve the

desired concentration of drug/bioactive substance in systemic cir-
culation for therapeutic response (

Vemula, Lagishetty, & Lingala,

2010

). The aqueous solubility is a major indicator for the solubility

in the intestinal fluids and its potential contribution to bioavail-
ability issues (

Stegemann, Leveiller, Franchi, De Jong, & Lindén,

2007

). Extracted bioactive compounds from plant resources can

be used in cosmetics and medicines. For instance, antioxidants
derived from plant sources are used in skin and hair care products

that affect the biological function of skin and hair and enhance the
beauty and health. More than 40% of newly developed drugs in the
pharmaceutical industry are practically insoluble in water (

Savjani,

Gajjar, & Savjani, 2012

). The limited aqueous solubility of these

compounds results in a low absorption rate in the gut, leading to
decreased bioavailability but increased side effects such as gas-
trointestinal tract irritation because of using high doses or high
concentration of surfactants in emulsions (

Sivakumar, Tang, &

Tan, 2014; Wang et al., 2014

). In this context, powerful solubilizing

methods have been developed for improved absorption and
bioavailability with lower manufacturing cost. The solubility of
bioactive compounds can be altered through particle engineering
techniques and several formulation approaches. Particle engineer-
ing techniques are developed to produce defined particles to modify
phycochemical properties of poorly soluble substances (

Kale et al.,

2014; Koshy, Pacharane, Chaudhry, Jadhav, & Kadam, 2010

). Particle

engineering, which includes mechanical particle-size reduction
techniques (wet-milling, dry-milling, and high-pressure homoge-
nization), cryogenic particle engineering techniques (lyophiliza-
tion, spray freezing), and other micro/nanoparticle preparation
methods such as nano-precipitation, supercritical fluid processing
(

Kale et al., 2014; Morales, Watts, & McConville, 2016

). In formula-

tion strategy, the drugs or bioactive compounds are formulated in
solutions which consist of water/oil, stabilizer, drug, and other
excipients. General formulations include solid formulations, lipid
formulations (for example, emulsion based drug delivery systems)
and amorphous formulations (example, amorphous solid disper-
sions) (

Merisko-Liversidge, Liversidge, & Cooper, 2003; Pouton,

2006

). These formulations are prepared using spray drying, milling

and other techniques.

1.2. Factors that affect solubility

The amount of solute that can be dissolved in a solvent depends

on various factors, including temperature, pressure, chemical nat-
ure, and physico-chemical forms of substances.

1.2.1. Influence of particle size and shape

The smaller the particle size, the greater the dissolution rate.

The thickness of the diffusion layer around each particle reduced
with particle specific surface area increases. Therefore, a decrease
in particle size with high surface area results in an increase in dis-
solution rate (

Mosharraf & Nyström, 1995; Niebergall, Milosovich,

& Goyan, 1963

). Furthermore, symmetrical molecules are less

N. Recharla et al. / Journal of Functional Foods 39 (2017) 63–73

soluble than unsymmetrical ones (

Pinal, 2004

). Solubility of

hydrophobic molecules can be increased by disruption of molecu-
lar symmetry without any increase of molecular weight (

Ishikawa

& Hashimoto, 2011

1.2.2. Influence of temperature

The solubility for many solids and liquids usually increases with

temperature increases. The kinetic energy increases with tempera-
ture and it allows the solvent molecules to more effectively break
apart the solute molecules that are held together by intermolecular
attractions (

Feriyanto, Idris, & Sebayang, 2014

1.2.3. Influence of molecular weight

Generally greater molecular weight substance will be less solu-

ble. In the case of organic compounds, the solubility increases with
the amount of carbon branching. The solubility of branched poly-
mer will be higher than the linear polymer of same molecular
weight. Because the branched chains have smaller radius of gyra-
tion (Rg), and decreased degree of chain entanglement, thus the
branched-chain molecules exhibit smaller volume/dimension in
solution and dissolve more readily (

Harris, 2006; Jadhav &

Pandey, 2013; Ravve, 2013, chap. 1

1.2.4. Influence of molecular polarity

Generally Polar solutes/substances are dissolve in polar sol-

vents, and nonpolar substances dissolve in nonpolar solvents. The
solvent particles hold the solute particles by intermolecular attrac-
tive forces. Polar and ionic solutes generally cannot dissolve in
non-polar solvents and vice versa.

1.2.5. Influence of physical forms

Amorphous forms of bioactives have greater aqueous solubility

than the crystalline form. Polymorphs have different solubilities.
The physical arrangements of the constituents in the crystal lattice
have immense potential to influence the physicochemical proper-
ties of the bioactive substance and subsequently therapeutic out-
comes. Therefore, the study of polymorphic forms has become
important (

Raza, Kumar, Ratan, Malik, & Arora, 2014

1.2.6. Influence of pH of the medium

The pH of a solution can influence the solubility of solute, there-

fore, the state of solute can be changed by changing the pH of solu-
tion. Many hydrophilic and lipophilic compounds exhibit different
solubilities at different pHs. Weak acids and weak bases undergo
an ionization reaction in solution. The ionized form of substance
will be more soluble in water.

1.2.7. Influence of stabilizers/emulsifiers

An emulsifier referred as surface-active compounds (i.e., surfac-

tants) which contain both hydrophilic head group and lipophilic
tail. The role of stabilizers or emulsifiers reduce the interfacial ten-
sion between the oil and water interface and increase the solubility
(

Krog, 1977

2. Techniques for enhancing solubility of poorly water-soluble
bioactive natural products

The solubility of poorly water-soluble bioactive compounds can

be improved by modifying their physical and chemical properties.
The physical and chemical modification of bioactive molecules
may be achieved by various traditional and novel techniques,
which are discussed in this review. Developing nanoparticle for-
mulations in food industry by using nanotechnology is an innova-
tive approach for substantial improvement of solubility and
bioavailability of bioactive ingredients (

Acosta, 2009; Magnuson,

Jonaitis, & Card, 2011; Wang et al., 2014

). We summarized here

about the nanotechnology-based approaches with applications. In
addition, we provided an overview of various preparation tech-
niques for each approach.

2.1. Nanosuspension technologies

Reduction of particle size into micro or nano range may

enhance solubility by increased surface area of substance to inter-
act aqueous medium. Nanosuspensions are colloidal dispersions of
nanosized particles in an aqueous media, these particles stabilized
by surfactants and polymers (

Rabinow, 2004

). The advantages of

nanosuspensions include improved drug dispersibility and solubi-
lization, increased therapeutic efficacy and reduced toxicity.

2.1.1. Preparation of nanosuspensions

Nanosuspentions are mainly prepared by using top-down and

bottom-up approaches (

Gao et al., 2011

). A top-down method

involves starting with large materials to reduce nanoscale size.
These methods include media milling, high pressure homogeniza-
tion, and super critical fluid method. In contrast, the bottom-up
approach implies that self-association and self-organization of
molecules form the materials. Example of bottom-up technologies
are precipitation, and melt emulsification. Various methods for
preparation of nanosuspensions are shown below:

(a) Precipitation technique (Bottom-up): In this method, the

bioactive compound is dissolved in a miscible solvent and
then the mixer will add with antisolvent in the presence of
surfactants. Rapid addition of active ingredient solution to
the antisolvent leads to increase in super saturation of a solu-
tion and produce amorphous nanoparticles (

Patel & Agrawal,

2011

(b) Homogenization in aqueous media (Top-down, Dissocubes pro-

cess): High pressure homogenization (HPH) performed with
piston-gap homogenizers, which can be described as
homogenization performed in aqueous media at room tem-
perature (

Keck & Müller, 2006

). The preparation of a coarse

suspension containing the mixture of bioactive compound,
water, and surfactants. This mixture is pushed with a piston
through a very tiny homogenization gap. The nano-sized
particles generated by cavitation forces, shear forces and
particle collision.

technology): In this technique, the same piston-gap homoge-
nization performed using water reduced or even completely
water-free dispersion media (

Keck & Müller, 2006

(d) Jet stream homogenizers (Top-down, IDD-P technology): A sus-

pension or an emulsion is pumped into collision chamber
under high pressure (up to 1700 bar) and high shear forces,
which leads to form small sized particles. The particle size is
preserved by using phospholipids or other surfactants and
stabilizers. The collision chamber designed as Z-type or the
Y-type (

Salazar, Müller, & Möschwitzer, 2014

(e) Media milling technique (Top-down approach): In media

milling, nanoparticle can produce by collision of milling
media and excipients sample. The particle size may be
decreased by high shear forces (

Ghosh, Bose, Vippagunta, &

Harmon, 2011

2.1.2. Application of nanosuspensions to enhance solubility

De Paz et al. (2012)

encapsulated beta carotene in nanosuspen-

sions using modified n-octenyl succinate starch to improve dis-
persibility, coloring strength and bioavailability of this compound.
The solubility of quercetin was enhanced by high-pressure homog-
enized (HPH) quercetin nanosuspensions (

Karadag, Ozcelik, &

N. Recharla et al. / Journal of Functional Foods 39 (2017) 63–73

Huang, 2014

). The combination of HPH with spray-drying would be

more potential approach for the development of quercetin-based
functional

food

products.

Alpha-tocopherol

solubility

and

bioavailability were improved by nanosuspensions formulations.

Campardelli and Reverchon (2015)

were used supercritical assisted

process for the production of alpha-tocopherol stable aqueous sus-
pensions with mean diameter of 150 nm.

2.2. Emulsion-based delivery systems

Emulsion-based delivery systems have been used to enhance

bioavailability of poorly water-soluble bioactive agents and drugs.
Emulsion technology is particularly suitable for encapsulating, pro-
tecting, and controlled release of active lipophilic compounds via
the oral route for both pharmaceutical drugs and functional food
applications

McClements & Li, 2010

). These emulsion based delivery systems

can be divided into various types based on emulsion size and char-
acteristics such as microemulsions, nanoemulsions, and self-
emulsifying delivery systems.

2.2.1. Microemulsions

Microemulsions have greater efficiency to solubilize the poorly

soluble guest molecules such as active ingredients, food additives,
cosmetic compounds and drugs. Microemulsions are a special kind
of colloidal dispersions either of water-in-oil (w/o) or of oil-in-
water (o/w) with the internal or dispersed phase are <0.1

droplet diameter with thermodynamically stable, transparent iso-
tropic solution of two immiscible liquids in presence of amphiphi-
lic compounds (surfactant and stabilizers). Emulsions formed
spontaneously by self-assembly of the hydrophobic parts and
hydrophilic parts with amphiphilic surfactant molecules. Surfac-
tants and co-surfactants play an important role to minimize the
interfacial tension in emulsion formation. Lecithins (phosphatidyl-
choline,

phospatidylethanolamine,

and

phospatidylinositol),

saponins, sorbitan esters of fatty acids (sorbatin monostearate/
monolaurate)

are

commonly

used

food-grade

surfactants.

Microemulsions, as food-derived bioactive emulsions can improve
both solubility and bioavailability of molecules (

Flanagan & Singh,

2006

Microemulsions preparation methods: The arrangement of the

emulsifier molecules occurs spontaneously by combining water,
oil and surfactant. However, in some cases energy is needed to
speed up the process, or to overcome an energy barrier. There
are three principle methods which may be used in microemulsion
formation (

Flanagan & Singh, 2006

A. Low energy emulsification method: Microemulsion can be

prepared without using any energy device by adding oil
phase, water phase and surfactant with or without
co-surfactant/co-solvent under mild stirring, which depends
on desired emulsion like O/W emulsion or W/O emulsion. It
involves the spontaneous self-assembly of all components.

B. Phase inversion temperature (PIT) method: The PIT method

used for ethoxylated non-ionic surfactants containing emul-
sions. These surfactant properties are dependent on temper-
ature, increasing temperature can cause dehydration of
polyethyleneoxide chain and the surfactants get more lipo-
philic. Then, cooled down the solution quickly in order to
produce water-in-oil (w/o) or oil-in-water (o/w) emulsions.

C. High pressure homogenization: Homogenizer equipment also

used to prepare small sized emulsion droplets. The limita-
tion of this method is high pressure homogenizers are not
suitable for highly viscous liquids.

2.2.2. Self-emulsifying drug delivery systems (SEDDS)

SEDDS are very attractive approach for oral delivery of func-

tional food compounds and drugs. These systems have an ability
to disperse and form spontaneous colloidal structures by combin-
ing the target compounds with water or gastro intestinal fluids
(

Patel & Velikov, 2011

). Self-emulsifying drug delivery system is

an anhydrous pre-concentration system which contain a mixture
of oil, surfactant, co-surfactant/co-solvent, and lipophilic drug or
functional food compound. SEDDS can be classified into two groups
such as self-nanoemulsifying drug delivery systems (SNEDDS) and
Self-microemulsifying drug delivery systems (SMEDDS) based on
droplet size. Droplet size of SMEDDS ranging from 100 and 200
nm, while that of SNEDDS are less than 100 nm (

Singh,

Bandopadhyay, Kapil, Singh, & Katare, 2009

). These formulations

can take orally by either filled with gelatin capsules or mixed with
water. Self-emulsified, fine oil in water droplets will form when it
mixed with water by small agitation or with gastro intestinal fluids
by the digestive motility of the stomach and intestine. Recently
self-double emulsifying drug delivery systems (SDEDDS) have been
developed with improved emulsification efficiency and thermody-
namic stability. The SDEDDS are novel self-emulsifying formula-
tions, which are prepared by modification of conventional SEDDS
(

Singh, Beg, Khurana, Sandhu, & Kaur, 2014

). Like SEDDS, SDEDDS

can self-emulsify and form water-in-oil-in-water (w/o/w) double
emulsions with gastrointestinal fluids.

Hu, Zhao, Xia, and Sun

(2015)

have

successfully

prepared

SDEDDS

loaded

with

epigallocatechin-3-gallate (EGCG) and a-lipoic acid to enhance
the photostability of EGCG.

2.2.3. Nanoemulsions

Nanoemulsions are one of the promising and novel carrier sys-

tems for poorly soluble lipophilic compounds, consisting of oil and
water phase with stabilizers. The mean size of emulsion droplet is
from 50 to 100 nm, which exist either as water-in-oil (w/o) or oil-
in-water (o/w) form (

Chime, Kenechukwu, & Attama, 2014

Nanoemulsion is considered to be an isotropic, transparent, kinet-
ically stable liquid dispersion of an oil phase and a water phase
along with surfactants. Reduced particle size in nanoemulsions
may enhance the solubility by increasing the surface area of parti-
cles and improve the stability of food ingredients by encapsulating
(

Odriozola-Serrano, Oms-Oliu, & Martín-Belloso, 2014

Nanoemulsions can be prepared by using low energy techniques

or high energy techniques. Phase behavior of emulsion and con-
stituent’s properties plays a major role in low energy methods.
These low-energy techniques include phase inversion temperature
method, phase transition, and self-assembly of emulsion droplets.
In high-energy methods, emulsions can be prepared by utilizing
mechanical devices such as microfluidisers (ultra-high-pressure
homogenizers), ultrasonicators and high-pressure homogenizers.
Additionally, ultra-high-pressure homogenization (UHPH) is a
novel potential technology for production of nano-sized droplets
(

Magnuson et al., 2011; Zamora & Guamis, 2015

). These high energy

mechanical devices provide large disruptive forces to break up the
interphase between oil and water and to form fine droplets. The
droplet size depends on the type of device using and their operating
conditions along with sample components properties (

Qian &

McClements, 2011

). Emulsion based delivery systems for food

derived functional ingredients are given in

Table 1

2.3. Inclusion complexation

Inclusion complexation is the molecular level interaction

between the core and wall material. These complexes generally
do not have any adhesive forces working between their molecules

N. Recharla et al. / Journal of Functional Foods 39 (2017) 63–73

and are performed host-guest interactions. Inclusion complexation
can be divided into several types based on alignment of host and
guest molecules like channel type, lattice type, layer type,
monomolecular type, and macromolecular type (

Frank, 1975

). In

Monomolecular inclusion complex type cyclodextrins (CDs) are
commonly used as a host molecule. CDs are cyclic oligosaccharides
consisting of six

-cyclodextrin, seven

b-cyclodextrin, eight

-cyclodextrin or more glucopyranose units which are linked by

-(1,4) bonds (

Del Valle, 2004

). Cyclodextrins can accommodate

the hydrophobic molecules by their truncated cone structure,
which have hydrophobic interior cavity and hydrophilic outer sur-
face due to the presence of CH

and hydroxyl groups in inner side

and outer side of cyclodextrin respectively. The CDs have large
number of hydroxyl groups, showing greater water solubility. In
addition to improving the solubility of compounds, other advan-
tages of complexation with cyclodextrin are improvement of
chemical stability, protection of bioactive compounds from exter-
nal environment, taste modification and controlled release of drugs
(

Marques, 2010

). Toxicologically, low doses of CDs are well toler-

ated by humans, however high doses may cause some adverse
effects such as diarrhea and soft stools.

b-cyclodextrins are com-

monly used for practical use because of the lipophilic cavity, and
the diameter is suitable for non-polar guest molecules. Further-
more, the purification of

b-CDs is cheaper than

- and

-CDs

(

Astray, Gonzalez-Barreiro, Mejuto, Rial-Otero, & Simal-Gándara,

2009; Del Valle, 2004; Marques, 2010

). Cyclodextrins due to their

above unique properties, inclusion complexation of bioactive
ingredients with CDs should be considered as interesting applica-
tion in the development of novel formulations for functional foods.

2.3.1. Techniques to prepare inclusion complexation

Different methods are available to prepare the inclusion com-

plexes of poorly water soluble bioactive molecules with cyclodex-
trins (

Patil, Kadam, Marapur, & Kamalapur, 2010

). Those are

described below;

a. Physical blending: Physical mixture of CDs and guest mole-

cule are prepared by simple mechanical mixing (

Nakai,

Yamamoto, Terada, & Watanabe, 1987

b. Kneading method (Complexation as a paste): In this method

cyclodextrin paste is prepared by mixing with water or
hydroalchoholic solutions in a kneading machine. Then the
bioactive compounds are added to this paste and proceed
kneading process for a specified time. Then the kneaded
mixture is dried.

c. Co-precipitation method: To prepare inclusion complexes by

co-precipitation method, the bioactive compounds dissolved
into miscible solvent and the mixture will add to the
cyclodextrin aqueous solution under agitation. The obtained
precipitate is filtered and dried (

Marques, 2010

d. Milling technique: Solid state inclusion complexes can be pre-

pared by co-grinding the active ingredients and excess
amounts of cyclodextrins in mechanical oscillatory mills.
Ball milling technique is commonly used among other
milling techniques.

e. Spray drying method: Cyclodextrin with bioactive compound

complexes can also prepare by spray drying method. In this
method, the cyclodextrin and bioactive solutions added in
spray drier and sprayed for specific time through nozzle.
This technique is not suitable for thermolabile guest com-
pounds (

Marques, 2010

f. Lyophilization/freeze-drying technique: The guest molecule

and CDs solution is dried by freeze drying. The final products
including amorphous and porous powder enhances the
aqueous solubility of bioactive compounds. Freeze drying
is mainly used for thermo sensitive compounds. This tech-
nique is alternative method for solvent evaporation
(

Marques, 2010; Patil et al., 2010

g. Supercritical antisolvent technique: In this technique, CO

used as anti-solvent for the solute. It is used as an alternative
solvent to the organic solvent. The high solvating power of
Supercritical carbon dioxide is suggested as a new complex-
ation medium.

2.3.2. Applications of cyclodextrins to improve the solubility of
bioactive compounds

CDs are used as carriers in food applications, pharmaceutical

industry, and cosmetics. Especially,

b-CDs are most suitable when

host molecules entrap guest molecules (

Astray et al., 2009; Szejtli,

1997

). Many researchers have been reported the potential applica-

tions of inclusion complexation for bioactive compounds and in
food processing (

Szente & Szejtli, 2004

;

Astray et al., 2009;

Cravotto, Binello, Baranelli, Carraro, & Trotta, 2006

). Most of these

studies concerned the encapsulation of flavonoids with

b-CDs to

enhance the stability and protection as well as water solubility of
hydro phobic core material.

Pinho, Grootveld, Soares, and

Henriques (2014)

were given in detailed overview of cyclodextrins

and their applications for plant bioactive compounds.

Hadaruga

et al. (2006)

studied the thermal stability of the linoleic acid by

b-cyclodextrin complexation method and they observed

Table 1
Emulsion based delivery systems for food derived functional ingredients.

Component
solubilized

Preparation method

Surfactant(s) employed

Results of study

Ref.

Carotenoid

(paprika
oleoresin)

Solid self-microemulsifying carotenoid
systems (S-SMECS)

Polyethoxylated sorbitan
ester (Tween80)

Increased solubility

Chow, Gue, Leow, and Goh (2015)

Lutein

Microemulsions

Tween 80 (POE-SM)

Amar, Aserin, and Garti (2003)

Self-nanoemulsifying drug delivery
system (SNEDDS)

Labrasol, TranscutolHP/
Lutrol-E400
(cosurfactant)

Increased solubility, and
bioavailability

Yoo et al. (2010), Shanmugam et al.
(2011)

Polymetho-

xyflavones
(PMFs)

Nanoemulsion-based delivery systems by
using high pressure homogenization

Tween 20/Tween 85

Increased the solubilization
capacity

Li, Zheng, Xiao, and McClements
(2012)

b-Carotene

O/W nanoemulsions by high pressure
homogenization method

Tween 20

Optimization of conditions for b-
carotene nanoemulsion stability

Yuan, Gao, Mao, and Zhao (2008)

Solubilize the molecule and
increased bioaccessibility

Qian, Decker, Xiao, and McClements
(2012)

Lycopene

Microemulsion-based delivery systems

Ethoxylated sorbitan
esters, 3GIO, SML

Increased solubility

Spernath, Yaghmur, Aserin, Hoffman,
and Garti (2002), Ha et al. (2015)

Quercetin

SNEDDS

Tween 80, PEG 400

Enhanced solubility

Tran, Guo, Song, Bruno, and Lu (2014)

Abbreviations: POE-SM – polyoxyethylene (20) sorbitan monooleate, 3GIO – triglycerol monooleate, SML – sucrose monooleate, PEG – polyethylene glycol.

N. Recharla et al. / Journal of Functional Foods 39 (2017) 63–73

increased thermal stability and a good protection against the envi-
ronmental degradation factors. The stability and solubility of
resveratrol were improved by resveratrol–cyclodextrin inclusion
complexes formation by

b-CDs (

Lucas-Abellán, Fortea, López-

Nicolás, & Núñez-Delicado, 2007

De Lima Petito, da Silva Dias,

Costa, Falcão, and de Lima Araujo (2016)

were encapsulated caro-

tenoids from red bell pepper extracts by 2-hydroxypropyl-

b-cyclo

dextrin to enhance water solubility of carotenoids.

Nerome et al.

(2013)

have prepared nano-sized lycopene-

b-cyclodextrin com-

plexes by supercritical antisolvent precipitation technique.

2.4. Super critical fluid (SCF) technology

Supercritical fluids, which have higher temperature and pres-

sure than the corresponding critical values were discovered by
Hannay and Hogarth in 1879 (

Tom & Debenedetti, 1991

). Super-

critical fluids have the properties of both liquid and gas i.e., gas-
like compressibility, liquid-like density and viscosity and higher
diffusivity than liquids (

Kumar & Johnston, 1988; Tom &

Debenedetti, 1991

). Moreover, the density and other physical

properties (such as dielectric constant and polarity) will be modi-
fied by changing in operating pressure, temperature, or both
around the critical points. Due to their high pressure and high tem-
peratures, the SCFs exhibit greater solvating capabilities than the
normal liquids (

Matson, Petersen, & Smith, 1987

). The most com-

monly used SCF is supercritical carbon dioxide (SC-CO

). Carbon

dioxide is a very attractive supercritical fluid because of its low
critical temperature (Tc = 31.10

°C) and pressure (Pc = 7.3 MPa). It

is nontoxic, low cost, readily available, and an alternative solvent
for many hazardous solvents.

2.4.1. Common techniques to prepare particles in SCF technology

(a) Rapid expansion of supercritical solutions (RESS): RESS is com-

monly used method to obtain fine particles through super
critical fluid technology. The fine particles can be produced
by rapid expanding of the super critical solution with solute,
then depressurized to low pressure and room temperature
conditions (

Jung & Perrut, 2001

). A well-designed apparatus

is used to achieve rapid expansion/depressurization, which
consist of nozzle, temperature, and pressure regulator. This
rapid expansion of supercritical solutions leads to super sat-
uration of the solute in it and subsequent precipitation of
solute particles with narrow particle size distributions. SCFs
are also used for thermo-sensitive compounds by adding
polymer (

Reis, Neufeld, Ribeiro, & Veiga, 2006

(b) Precipitation with supercritical antisolvent: In this process the

functional core materials dissolved into miscible solvent and
then the mixture is added to supercritical antisolvent to
precipitate.

technique the drug solution and the SCF are introduced
simultaneously into the arrangement causing rapid disper-
sion, mixing and extraction of the drug solution solvent by
SCF leading to very high super saturation ratios. The temper-
ature and pressure together with accurate metering of flow
rates of drug solution and SF through a nozzle provide uni-
form condition for particle formation. This helps to control
the particle size of the product and by choosing an appropri-
ate liquid solvent it is possible to manipulate the particle
morphology.

In food industry, the SCF process is an advantageous method for

extraction of bioactive components, because it improves the yield,
solubility and inexpensive (

Palmer & Ting, 1995; Pereira &

Meireles, 2010; Wang & Weller, 2006

). There are different

SCF-based processes to produce reduced size particles, which gen-
erally exhibit enhanced aqueous solubility. Commonly SC-CO

used as a dispersion medium to improve the solubility of
hydrophobic materials.

Jin, Xia, Jiang, Zhao, and He (2009)

were

used supercritical antisolvent to encapsulation of lutein with
hydroxypropylmethyl cellulose phthalate (HPMCP) to maintain
its bioactivity and to avoid thermal/light degradation.

Santos and

Meireles (2013)

used SC CO

as antisolvent via SAS (supercritical

anti-solvent) for micronization of beta carotene (a type of carote-
noids) and quercetin (one type of flavonoids).

2.5. Co-solvency

The aqueous solubility of hydrophobic natural bioactive com-

pounds can be increased by adding water-miscible organic sol-
vents. Co-solvents are mixture of miscible solvents, it may
contain organic solvent and water (binary mixture) or may also
contains more than two organic solvents (ternary or higher cosol-
vent mixture) (

Strickley, 2004

). The common co-solvents used in

the pharmaceutical industry include ethanol, propylene glycol,
glycerin, glycofural and (PEG 400) polyethylene glycols (

Jouyban,

2008

). In food industry, food grade solvents such as ethanol, water,

lipids, and vegetable oils can be used as co-solvents. Co-solvent
system makes solvent blending by reducing the interfacial tension
between the polar solvent and non-polar solute. It is also com-
monly referred to as solvent blending (

Jain & Yalkowsky, 2007

Most of co-solvents have hydrogen bond donating or hydrogen
bond accepting ability at their hydrocarbon regions. Their hydro-
philic hydrogen bonding groups ensure water miscibility, while
their hydrophobic hydrocarbon regions interfere with waters
hydrogen bonding network, reducing the overall intermolecular
attraction of water. By disrupting waters self-association, co-
solvents reduce waters ability to squeeze out non-polar, hydropho-
bic compounds, thus increasing solubility.

In food applications, co-solvents commonly used along with

surfactants to prepare emulsion based delivery systems such as
in nanoemulsions and in self-emulsification systems. The nano-
sized self-assembled emulsions are composed of oil phase, water
phase, surfactant, and co-solvent/co-surfactant (

Garti, Aserin,

Spernath, & Amar, 2007

). The solubility of ginger bioactive com-

pounds can be enhanced 20–50% by adding ethanol co solvent
(

Jaapar, Iwai, & Morad, 2014

2.6. Nanoprecipitation

Nanoprecipitation is also called solvent displacement method.

This method is a simple, more facile, less complex, comparatively
cheaper, less energy consuming and easy for scaling-up to produce
nanoparticle of poorly aqueous soluble drugs by inserting or mix-
ing a drug solution with an anti-solvent (

Hitanga, Sharma, Chopra,

& Kumar, 2015

). In this liquid-liquid precipitation method first the

drug/bioactive compound and polymer dissolved in organic solu-
tion (solvent) then the solution mixed into an aqueous water solu-
tion under the influence of sonication or stirring. The nano
particles are obtained as dispersed in the water solution. It is based
on the spontaneous emulsification of the organic internal phase
containing the dissolved drug, polymer, and organic solvent into
the aqueous external phase. Nanoprecipitation technique involves
the precipitation of polymer from an organic solution and the dif-
fusion of the organic solvent in the aqueous medium (

Galindo-

Rodriguez, Allemann, Fessi, & Doelker, 2004

Nanoprecipitation technique has been used for the encapsula-

tion of bioactive compounds. This is an efficient method to nanoen-
capsulate lipophilic drugs because of the miscibility of the solvent
with the aqueous phase (

Ezhilarasi, Karthik, Chhanwal, &

Anandharamakrishnan, 2013

Noronha, de Carvalho, Lino, and

N. Recharla et al. / Journal of Functional Foods 39 (2017) 63–73

Barreto (2014)

have used nanoprecipitation method to prepare

tocopherol nanocapsules for incorporation of alpha tocopherol
with methylcellulose films which enhance the solubility and pro-
tect them from oxidation. Nanoprecipitation is a suitable method
for the preparation of

-tocopherol loaded PCL (poly ethyl capro-

lactone) nanocapsules to produces nano sized particles and
improve the encapsulation efficacy (

Noronha et al., 2013

2.7. Cryogenic techniques

Amorphous nanoparticles can be produced by utilizing cryo-

genic technologies. These amorphous nanostructures bearing high
dissolution rate and larger surface area of drug particles signifi-
cantly enhance the solubility. After cryogenic processing, dry pow-
der can be obtained by various freeze-drying methods (

Derle, Patel,

Yeole, Patel, & Pingle, 2010

2.7.1. Spray freezing into liquid (SFL) process

Liquid-liquid impingement between the pressurized feed solu-

tion exiting the nozzle and the cryogenic liquid is the basic princi-
ple of SFL (

Hu, Johnston, & Williams, 2003

). Feed solution that

contain active ingredient and excipients is atomized directly into
a compressed liquid, such as compressed fluid CO

, propane,

ethane helium or the cryogenic liquids nitrogen, hydrofluroethers.
This may produce atomized microdroplets. The atomized feed dro-
plets instantly solidified after they formed. This technique is
widely used in the pharmaceutical sector to enhance the dissolu-
tion rate of poorly water soluble drugs. In encapsulation of bioac-
tives, SFL is beneficial technique to produce micro sized
amorphous structures. In this SFL technique the phase separation
of feed solution components is prevented by the very fast freezing
rate.

2.7.2. Ultra-rapid freezing (URF)

Submicron sized amorphous high surface area powders can pro-

duce by ultra-rapid freezing techniques (

Overhoff et al., 2007

). URF

involves freezing an active substance or polymer solution directly
onto the cryogenic substrate surface with a thermal conductivity.

2.7.3. Spray freezing into vapor over liquid (SFV/L)

The main difference between SFL and SFV/L is in the atomiza-

tion process. The feed solution is atomized through a nozzle posi-
tioned at a distance above the boiling refrigerant and the atomized
droplets fall into the refrigerant and are solidified on contact with
the cryogen. The frozen powder is then collected.

2.8. Solid dispersions

The absorption rate of orally administered drug or natural

bioactive compound is directly proportional to their dissolution
rate in gastro intestinal fluids. Solid dispersions with water-
soluble carriers have been attracting strategy to improve the disso-
lution rate of poorly water soluble bioactive substance. Solid dis-
persion is a group of solid products with consist of a hydrophilic
matrix and a hydrophobic compound. The hydrophobic substance
can be dispersed in amorphous matrix (

Kaur, Aggarwal, Singh, &

Rana, 2012

Amorphos solid dispersions (ASD) are more suitable to increase

drug solubility because the dissolution rate and solubility of
amorphous form compounds are higher than the corresponding
crystalline forms. However, rapid dissolution leads to the drug
super-saturation, followed by precipitation, therefore amorphous
form of drug is more prone to recrystallization (

Lee, Boersen,

Yang, & Hui, 2014

). To reduce such crystallization tendency, vari-

ous Polymeric additives such as polyethylene glycol (PEG400),
Polyvinylpyrrolidone

(PVP),

methylcellulose,

hydroxypropyl

methylcellulose (HPMC) have been used to increase the solubility
or decrease the supersaturation level of the drug in the ASD sys-
tem. These polymer additives also have the capability to improve
the amorphous system’s physical stability (

Alonzo, Zhang, Zhou,

Gao, & Taylor, 2010; Raghavan, Trividic, Davis, & Hadgraft, 2001

Li, Konecke, et al. (2013)

were used PVP polymers to enhance sta-

bility and solubility of quercetin amorphous solid dispersions.

2.8.1. Techniques for preparing solid dispersions

Different techniques used for preparation of solid dispersions

are given below:

(a) Solvent evaporation method: In solvent evaporation process,

both drug and matrix material are dissolved in miscible
organic solvent and then the solvent is allowed to evaporate
and form solid dispersions (

Dogra, Dhyani, & Juyal, 2015

(b) Co-precipitation method: In this process interested guest sub-

stance is added to the solution of carrier and then the system
is kept under magnetic agitation to form precipitation. The
formed precipitate is separated by vacuum filtration and
dried at room temperature to avoid the loss of the structure
(

Moyano, Arias-Blanco, Gines, & Giordano, 1997

cule and carrier is heated at or above the melting point
and then cooled rapidly in an ice bath. Rapid cooling leads
to form fine solid particles by supersaturation (

Leuner &

Dressman, 2000

). In this system, the melting temperature

of a binary system is dependent on thermoresistance of their
composition.

(d) Melt extrusion method: In this method, Solid dispersions are

prepared similarly as hot melt method with using a co-
rotating twin-screw extruder at high rotational speed
(

Vasconcelos, Sarmento, & Costa, 2007

(e) Melt agglomeration process: In melt agglomeration method,

the meltable binders are used as carriers. The binders (car-
rier) are added to mixture of bioactive compounds and
heated to above melting temperature point of the binder
by using a high shear mixer (

Drooge et al., 2005; Sharma,

2016

(f) Spray-drying method: It is an effective and well-established

method to prepare amorphous solid dispersions (

Baghel,

Cathcart, & O’Reilly, 2016

). The guest molecules and excipi-

ents are dissolved into a solvent and the fine solid particles
generated by atomizing the solution into a drying process.
The operating conditions and dryer design depends upon
the drying characteristics of the product and require powder
specifications (

Sharma, 2016

(g) Freeze-drying/lyophilization technique: Lyophilization has

been thought of a molecular mixing technique where the
drug and carrier are dissolved in a solvent, frozen and sub-
limed to obtain a lyophilized molecular dispersion. This
technique was proposed as an alternative technique to sol-
vent evaporation (

Sharma, 2016

2.8.2. Application of solid dispersions to enhance solubility

Li, Harich, Wegiel, Taylor, and Edgar (2013)

studied stability and

solubility of ellagic acid (bioactive natural flavonoid compound) in
cellulose ester solid dispersions. They found that hydroxypropyl-
methylcellulose acetate succinate (HPMCAS) is more suitable to
form amorphous solid dispersions (ASD) with ellagic acid to
enhance solubility than other carboxyl-containing cellulose deriva-
tives. The solubility and bioavailability of apigenin were enhanced
by carbon nanopowder solid dispersion (

Ding et al., 2014

N. Recharla et al. / Journal of Functional Foods 39 (2017) 63–73

2.9. Micellar solubilization

Micelles are amphiphilic, self-assembling nanosized colloidal

particles

with

hydrophobic

core

and

hydrophilic

shell

(

Torchilin, 2007

). The size of micelles can range from around 10

nm–100 nm in diameter. Micelle shape and size can be controlled
by changing the surfactant chemical structure as well as by varying
solution conditions such as temperature, overall surfactant con-
centration, surfactant composition (in the case of mixed surfactant
systems), ionic strength and pH (

Rangel-Yagui, Pessoa, & Tavares,

2005

). Based on particle size and stability, micellar systems are

considered as effective delivery system. However, they have lim-
ited solubilization capacity which is determined by specificity of
surfactant and its concentration (

Patel & Velikov, 2011

). Micellars

are divided into two categories.

2.9.1. Mixed micelles

Mixed micelles formed by using a combination of hydrophobic

and hydrophilic surfactants.

2.9.2. Polymeric micelles

Polymeric micelles are characterized by a core-shell structures

formed by self-assembly of amphiphilic block copolymers. Forma-
tion of micelles in aqueous solution occur when the concentration
of the block copolymer increases above a certain concentration
named the critical aggregation concentration (CAC) or critical
micelle concentration (CMC) (

Xu, Ling, & Zhang, 2013

). The poly-

meric micelles generally comprise of a relatively hydrophobic
block such as polylactic acid, polycaprolactone and poly-aspartic
acid, with a hydrophilic PEG segment (

Boyd, 2008

). Micelles have

been successfully used as drug delivery nanocarriers in pharma-
ceutical applications for solubilization of a wide variety of
hydrophobic drugs.

There are several reports shown the applications of micelles in

food ingredient formulations and food delivery systems. The stabil-
ity and bioavailability of vitamin D has been improved by ultra-
high-pressure

homogenization

treated

re-assembled

casein

micelles (rCM) encapsulation (

Haham et al., 2012

). Casein micelles

(CM) are potential natural nano-vehicles for entrapment, protec-
tion, and delivery of sensitive hydrophobic nutraceuticals with in
food products (

Semo, Kesselman, Danino, & Livney, 2007

Curcumin (polyphenol) was solubilized in natural casein micelles
(CM) and used as a nanocarrier for drug delivery to cancer cells
resulting in enhanced solubility and stability of curcumin (

Leuner

& Dressman, 2000; Sahu, Kasoju, & Bora, 2008

). The aqueous solu-

bility of quercetin can be enhanced by polyethylene glycol (PEG)-
lipid nanomicelles formulation (

Tan, Liu, Chang, Lim, & Chiu, 2012

2.10. Reducing particle size by milling techniques

The conventional methods of particle size reduction such as

grinding, hammer and jet milling have long been employed to
enhance solubility and bioavailability of drugs. Milling techniques
may enhance dissolution rate and solubility by changing shape,
size and surface area (

Loh, Samanta, & Heng, 2015

). The conven-

tional milling techniques can only produce coarse particles. How-
ever, micro- and nano-sized particles can be achieved by using
rotor stator colloid mill, jet mills and wet milling techniques
(

Vimalson, 2016

2.10.1. Milling techniques

Common milling techniques to produce micro- and nano-sized

particles are given hereunder:

(a) Air jet milling/fluid energy milling: In this micronization

method, high velocity jets of compressed air injected into a
raw material feed chamber. As the particles enter the air
stream, they are accelerated and caused to collide with each
other and the wall of the milling chamber with high veloci-
ties. Particle size reduction is brought about by a combina-
tion of impact and attrition (

Vimalson, 2016

). The average

particle size can achieve in fluid energy mill is 1–5

(

Saleem & Smyth, 2010

(b) Ball milling: A ball mill is a cylindrical chamber containing

balls, or rods, constructed from a variety of materials such
as ceramic, agate, silicon nitride, sintered corundum, zirco-
nia, chrome steel, Cr–Ni steel, tungsten carbide or plastic
polyamide (

Khadka et al., 2014; Loh et al., 2015

). The mate-

rial to be milled is placed inside the vessel, which is made to
rotate or vibrate at a particular speed or frequency. The
movement of the vessel causes the balls to move in a pat-
tern, colliding with each other and with the opposing inner
wall of the vessel (

Loh et al., 2015

). During the high-

energy ball milling process, the powder particles are sub-
jected to high energetic impact.

ized version of the ball mill (

Vimalson, 2016

). Nano sized

particles or nanosuspensions are prepared by using high-
shear media mills. In this method, the milling chamber is
loaded with aqueous suspension of the bioactive compound,
stabilizer and milling media. Then the chamber is rotated at
a very high shear rate under controlled temperatures. Fine
particles are produced by collisions of the milling media
and the suspension. The milling media is generally con-
structed from a variety of materials such as glass, zirconium
oxide, and ceramics or highly cross-linked polystyrene
resins.

2.11. Hydrotropy method

The term hydrotropy was coined by Carl Neuberg in 1916 but

the practical implications were introduced as late as 1976 by
Thoma and coworkers (

Nidhi, Indrajeet, Khushboo, Gauri, & Sen,

2011

). In this method by adding large amount of secondary solute

increase the aqueous solubility of water insoluble drug. In hydro-
tropy technique the solubility of poorly water-soluble compound
enhanced with use of hydrotopes like sodium benzoate, sodium
citrate, urea, niacinamide, etc. Employing a hydrotropic agent is
an alternative for the use of an organic solvent.

Hydrotropic solubilization technique is a one of the most poten-

tial methods used in pharmaceutical sector to prepare formula-
tions of poorly water-soluble drugs. There are very few studies
shown the role of hydrotropic agents in extraction and solubility
of bioactive compounds. Sodium salicylate (Na-Sal) and sodium
cumene sulphonate (Na-CuS) were used to extract limonin bioac-
tive compound (belongs to

limonoids) from sour orange

(

Dandekar, Jayaprakasha, & Patil, 2008

3. Conclusions and future prospects

In early twentieth-century, functional foods were mainly

focused to prevent or reduce the risk of nutritional deficiency dis-
eases such as iron deficiency anemia, rickets, and scurvy diseases.
The examples include vitamin C, vitamin D and iron fortified bev-
erages. Later, consumer awareness of health and wellness are
increased rapidly and they interested to consume healthier food
products to avoid chronic diseases. Thus, food companies shifted
their focus to develop fortified foods with various bioactive ingre-
dients which offer multiple health benefits. Therefore, research

N. Recharla et al. / Journal of Functional Foods 39 (2017) 63–73

now focuses on developing new functional foods. The incorpora-
tion of bioactive compounds into foods is challenging to research-
ers and food industry, the major challenges includes poor aqueous
solubility, disagreeable sensory characteristics of bioactive ingredi-
ents (for example unpleasant flavors and aromas), chemical insta-
bility of bioactives and changes in antioxidant activity during
processing. Aqueous solubility is one of the basic requirements
for the formulation and development of beverages and other food
products fortified with bioactive compounds. Nanotechnology
have the potential to overcome low solubility problems in the
development of functional foods. The various techniques described
above can be used alone or in combination to enhance the solubil-
ity of lipophilic bioactive compounds. The selection of appropriate
solubility technique depends on physical and chemical properties
of bioactive compound and mode of delivery system. The pub-
lished studies to estimate the potential risks and human toxicity
of these nanomaterials are insufficient, further research should
be needed and studies on food components-bioactive compound
interactions are necessary to prepare commercial functional food
products. In particular, the following investigations are required
to design and develop potential innovative functional food prod-
ucts: (1) the identification and quantification of bioactive com-
pounds, (2) the establishment of appropriate dosage and delivery
systems to incorporate the bioactive compounds into foods, (3)
the analysis of absorption and bioavailability of incorporated
ingredient, (4) testing the safety of bioactive compound incorpo-
rated foods, (4) the product storage stability studies, (5) Investiga-
tion of possible interactions between active ingredients and other
food components. In the future, improvements in nanotechnology
by extensive research will provide new delivery systems to incor-
porate bioactive compounds into foods and more safe and effective
functional foods will enter the market.

Conflict of interest

The authors confirm that this article content has no conflict of

interest.

Acknowledgement

This work was carried out with the support of ‘‘Cooperative

Research Program for Agriculture Science & Technology Develop-
ment (Project No. PJ012615)” Rural Development Administration,
South Korea.

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