Elsevier

Journal of Functional Foods

Volume 39, December 2017, Pages 63-73
Journal of Functional Foods

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

https://doi.org/10.1016/j.jff.2017.10.001Get rights and content

Highlights

  • Food bioactives provide health benefits beyond their nutritional functions.

  • Low solubility is a major limitation for commercial application of bioactives.

  • Nanotechnology approaches can improve the solubility of lipophilic bioactives.

Abstract

Food-derived multifunctional bioactive compounds, such as carotenoids, fat soluble vitamins, phytosterols, 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.

Introduction

In light of consumer perception and preferences toward health promoting foods, the development of new functional food is a leading trend in food industry. Various bioactive compounds have been obtained from natural sources and classified into different categories based on their chemical structure and functions: phenolic compounds, vitamins, carotenoids, alkaloids, and organosulfur compounds (Hamri et al., 2011, Jeong et al., 2015, Lim et al., 2017). Many of bioactive components 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 et al., 2015, Imm et al., 2014, Kris-Etherton et al., 2002). Therapeutic effects of these compounds for instance; allicin (from garlic), curcumin (from turmeric), catechines (from tea polyphenols) helps to prevent diseases including cancer, cardiovascular illness, neuronal degenerative diseases, diabetes, etc. (Pandey and Rizvi, 2009, Pham-Huy et al., 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 et al., 2013, Yousuf et al., 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.

Solubility is one of the important parameters to achieve the desired concentration of drug/bioactive substance in systemic circulation 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 bioavailability 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 gastrointestinal tract irritation because of using high doses or high concentration of surfactants in emulsions (Sivakumar et al., 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 engineering techniques are developed to produce defined particles to modify phycochemical properties of poorly soluble substances (Kale et al., 2014, Koshy et al., 2010). Particle engineering, which includes mechanical particle-size reduction techniques (wet-milling, dry-milling, and high-pressure homogenization), cryogenic particle engineering techniques (lyophilization, spray freezing), and other micro/nanoparticle preparation methods such as nano-precipitation, supercritical fluid processing (Kale et al., 2014, Morales et al., 2016). In formulation 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 dispersions) (Merisko-Liversidge et al., 2003, Pouton, 2006). These formulations are prepared using spray drying, milling and other techniques.

The amount of solute that can be dissolved in a solvent depends on various factors, including temperature, pressure, chemical nature, and physico-chemical forms of substances.

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 dissolution rate (Mosharraf and Nyström, 1995, Niebergall et al., 1963). Furthermore, symmetrical molecules are less soluble than unsymmetrical ones (Pinal, 2004). Solubility of hydrophobic molecules can be increased by disruption of molecular symmetry without any increase of molecular weight (Ishikawa & Hashimoto, 2011).

The solubility for many solids and liquids usually increases with temperature increases. The kinetic energy increases with temperature 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).

Generally greater molecular weight substance will be less soluble. In the case of organic compounds, the solubility increases with the amount of carbon branching. The solubility of branched polymer will be higher than the linear polymer of same molecular weight. Because the branched chains have smaller radius of gyration (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 and Pandey, 2013, Ravve, 2013).

Generally Polar solutes/substances are dissolve in polar solvents, and nonpolar substances dissolve in nonpolar solvents. The solvent particles hold the solute particles by intermolecular attractive forces. Polar and ionic solutes generally cannot dissolve in non-polar solvents and vice versa.

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 properties of the bioactive substance and subsequently therapeutic outcomes. Therefore, the study of polymorphic forms has become important (Raza, Kumar, Ratan, Malik, & Arora, 2014).

The pH of a solution can influence the solubility of solute, therefore, the state of solute can be changed by changing the pH of solution. 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.

An emulsifier referred as surface-active compounds (i.e., surfactants) which contain both hydrophilic head group and lipophilic tail. The role of stabilizers or emulsifiers reduce the interfacial tension between the oil and water interface and increase the solubility (Krog, 1977).

Section snippets

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 formulations in food industry by using nanotechnology is an innovative approach for substantial improvement of solubility and bioavailability of bioactive ingredients (Acosta, 2009,

Conclusions and future prospects

In early twentieth-century, functional foods were mainly focused to prevent or reduce the risk of nutritional deficiency diseases such as iron deficiency anemia, rickets, and scurvy diseases. The examples include vitamin C, vitamin D and iron fortified beverages. 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

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 Development (Project No. PJ012615)” Rural Development Administration, South Korea.

References (128)

  • S.G. Frank

    Inclusion compounds

    Journal of Pharmaceutical Sciences

    (1975)
  • L. Gao et al.

    Preparation of a chemically stable quercetin formulation using nanosuspension technology

    International Journal of Pharmaceutics

    (2011)
  • I. Ghosh et al.

    Nanosuspension for improving the bioavailability of a poorly soluble drug and screening of stabilizing agents to inhibit crystal growth

    International Journal of Pharmaceutics

    (2011)
  • T.V.A. Ha et al.

    Antioxidant activity and bioaccessibility of size-different nanoemulsions for lycopene-enriched tomato extract

    Food Chemistry

    (2015)
  • N.G. Hadaruga et al.

    Thermal stability of the linoleic acid/α-and β-cyclodextrin complexes

    Food Chemistry

    (2006)
  • Y.S. Hsieh et al.

    Natural bioactives in cancer treatment and prevention

    Biomed Research International

    (2015)
  • J. Hu et al.

    Spray freezing into liquid (SFL) particle engineering technology to enhance dissolution of poorly water soluble drugs: Organic solvent versus organic/aqueous co-solvent systems

    European Journal of Pharmaceutical Sciences

    (2003)
  • P. Jain et al.

    Solubilization of poorly soluble compounds using 2-pyrrolidone

    International Journal of Pharmaceutics

    (2007)
  • H. Jin et al.

    Nanoencapsulation of lutein with hydroxypropylmethyl cellulose phthalate by supercritical antisolvent

    Chinese Journal of Chemical Engineering

    (2009)
  • J. Jung et al.

    Particle design using supercritical fluids: Literature and patent survey

    The Journal of Supercritical Fluids

    (2001)
  • C.M. Keck et al.

    Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation

    European Journal of Pharmaceutics and Biopharmaceutics

    (2006)
  • P. Khadka et al.

    Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability

    Asian Journal of Pharmaceutical Sciences

    (2014)
  • P.M. Kris-Etherton et al.

    Bioactive compounds in foods: Their role in the prevention of cardiovascular disease and cancer

    The American Journal of Medicine

    (2002)
  • S.K. Kumar et al.

    Modelling the solubility of solids in supercritical fluids with density as the independent variable

    The Journal of Supercritical Fluids

    (1988)
  • C. Leuner et al.

    Improving drug solubility for oral delivery using solid dispersions

    European Journal of Pharmaceutics and Biopharmaceutics

    (2000)
  • B. Li et al.

    Stability and solubility enhancement of ellagic acid in cellulose ester solid dispersions

    Carbohydrate Polymers

    (2013)
  • B. Li et al.

    Solid dispersion of quercetin in cellulose derivative matrices influences both solubility and stability

    Carbohydrate Polymers

    (2013)
  • Y. Li et al.

    Nanoemulsion-based delivery systems for poorly water-soluble bioactive compounds: Influence of formulation parameters on polymethoxyflavone crystallization

    Food Hydrocolloid

    (2012)
  • Z.H. Loh et al.

    Overview of milling techniques for improving the solubility of poorly water-soluble drugs

    Asian Journal of Pharmaceutical Sciences

    (2015)
  • C. Lucas-Abellán et al.

    Cyclodextrins as resveratrol carrier system

    Food Chemistry

    (2007)
  • E. Merisko-Liversidge et al.

    Nanosizing: A formulation approach for poorly-water-soluble compounds

    European Journal of Pharmaceutical Sciences

    (2003)
  • M. Mosharraf et al.

    The effect of particle size and shape on the surface specific dissolution rate of microsized practically insoluble drugs

    International Journal of Pharmaceutics

    (1995)
  • J.R. Moyano et al.

    Solid-state characterization and dissolution characteristics of gliclazide-β-cyclodextrin inclusion complexes

    International Journal of Pharmaceutics

    (1997)
  • H. Nerome et al.

    Nanoparticle formation of lycopene/β-cyclodextrin inclusion complex using supercritical antisolvent precipitation

    The Journal of Supercritical Fluids

    (2013)
  • P.J. Niebergall et al.

    Dissolution rate studies II. Dissolution of particles under conditions of rapid agitation

    Journal of Pharmaceutical Sciences

    (1963)
  • C.M. Noronha et al.

    Characterization of antioxidant methylcellulose film incorporated with α-tocopherol nanocapsules

    Food Chemistry

    (2014)
  • C.M. Noronha et al.

    Optimization of α-tocopherol loaded nanocapsules by the nanoprecipitation method

    Industrial Crops and Products

    (2013)
  • K.A. Overhoff et al.

    Novel ultra-rapid freezing particle engineering process for enhancement of dissolution rates of poorly water-soluble drugs

    European Journal of Pharmaceutics and Biopharmaceutics

    (2007)
  • M.V. Palmer et al.

    Applications for supercritical fluid technology in food processing

    Food Chemistry

    (1995)
  • A.R. Patel et al.

    Colloidal delivery systems in foods: A general comparison with oral drug delivery

    LWT – Food Science and Technology

    (2011)
  • E. Pinho et al.

    Cyclodextrins as encapsulation agents for plant bioactive compounds

    Carbohydrate Polymers

    (2014)
  • C.W. Pouton

    Formulation of poorly water-soluble drugs for oral administration: Physicochemical and physiological issues and the lipid formulation classification system

    European Journal of Pharmaceutical Sciences

    (2006)
  • C. Qian et al.

    Nanoemulsion delivery systems: Influence of carrier oil on β-carotene bioaccessibility

    Food Chemistry

    (2012)
  • C. Qian et al.

    Formation of nanoemulsions stabilized by model food-grade emulsifiers using high-pressure homogenization: Factors affecting particle size

    Food Hydrocolloid

    (2011)
  • S.L. Raghavan et al.

    Crystallization of hydrocortisone acetate: Influence of polymers

    International Journal of Pharmaceutics

    (2001)
  • D.E. Alonzo et al.

    Understanding the behavior of amorphous pharmaceutical systems during dissolution

    Pharmaceutical Research

    (2010)
  • I. Amar et al.

    Solubilization patterns of lutein and lutein esters in food grade nonionic microemulsions

    Journal of Agricultural and Food Chemistry

    (2003)
  • B.J. Boyd

    Past and future evolution in colloidal drug delivery systems

    Expert Opinion on Drug Delivery

    (2008)
  • Chime, S. A., Kenechukwu, F. C., & Attama, A. A. (2014). Nanoemulsions—Advances in formulation, characterization and...
  • G. Cravotto et al.

    Cyclodextrins as food additives and in food processing

    Current Nutrition & Food Science

    (2006)
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