Lipid-Based Nanostructures for Food Encapsulation Purposes, Volume 2: Volume 2 in the Nanoencapsulation in the Food Industry Series 9780128156735, 0128156732

Table of contents :
Front Cover......Page 1
Acknowledgment......Page 2
Dedication......Page 3
LIPID-BASED NANO-STRUCTURES FOR FOOD ENCAPSULATION PURPOSES......Page 6
LIPID-BASED NANO-STRUCTURES FOR FOOD ENCAPSULATION PURPOSES......Page 8
Copyright......Page 9
Contents......Page 10
List of Contributors......Page 16
Preface to the Series......Page 18
Preface to Volume 2......Page 20
1. Introduction......Page 22
2. Nanoemulsions for encapsulation of food ingredients......Page 24
2.1 Single O/W and W/O nanoemulsions......Page 26
2.2 Double nanoemulsions......Page 28
2.3 Microemulsions......Page 30
2.4 Pickering nanoemulsions......Page 32
3.1 Solid lipid nanoparticles......Page 34
3.2 Nanostructured lipid carriers......Page 36
3.3 Nano-organogels (nano-oleogels)......Page 38
4.1 Nanoliposomes......Page 40
4.2 Nanophytosomes......Page 42
5. Nanostructured surfactants for encapsulation of food ingredients......Page 43
5.1 Niosomes......Page 44
5.2 Cubosomes and hexosomes......Page 45
References......Page 46
ONE - Nanoemulsions for encapsulation of food ingredients......Page 56
1. Introduction......Page 58
2.1 Food-grade emulsifiers......Page 61
2.2 Optimizing emulsion stability......Page 69
2.3 Fabrication methods......Page 70
2.3.1 High-energy methods......Page 72
2.3.2 Low-energy methods......Page 74
2.3.3 Mixed approaches......Page 76
3.1 Nanoemulsion characterization......Page 77
3.2 Nanoemulsion properties......Page 78
4. Application of nanoemulsions for encapsulation of food ingredients......Page 80
4.1 Nutraceutical compounds......Page 82
4.2 Micronutrients......Page 85
4.3 Antimicrobial compounds......Page 88
4.4 Flavorings and colorants......Page 93
5. Conclusions and perspectives......Page 94
References......Page 96
1. Introduction......Page 110
2. Classification and structure of double emulsions......Page 112
2.1 Instability sources of double nanoemulsions......Page 114
3. Preparation of double emulsions......Page 116
4.1 Double nanoemulsions......Page 119
4.3 O/W/O double emulsions......Page 123
5.1 Vitamins......Page 124
5.2 Minerals......Page 126
5.3 Proteins and amino acids......Page 127
5.4 Phenolic compounds......Page 128
5.5 Pigments......Page 129
5.7 Microorganisms (probiotics)......Page 132
6. Conclusion and future trends......Page 133
References......Page 142
2. Microemulsions......Page 150
3. Surfactants......Page 151
4. Phase behavior of microemulsions......Page 153
5. Structural characterization of microemulsions......Page 154
6. Comparison of microemulsions with other nanodispersions......Page 155
7. Encapsulation of food ingredients within microemulsions......Page 156
7.1 Fatty acids......Page 157
7.2 Antioxidants......Page 158
7.3 Proteins and other antimicrobial molecules......Page 160
7.4 Other bioactive molecules......Page 161
References......Page 162
1. Introduction......Page 172
2. Food-grade nanoemulsion systems......Page 173
3.1 High-energy methods......Page 174
3.2 Low-energy methods......Page 175
4. Preparation of Pickering nanoemulsions......Page 178
5.1 Inorganic nanoparticles......Page 182
5.2 Lipid-based nanoparticles......Page 183
5.3 Carbohydrate-based nanoparticles......Page 184
5.4 Protein-based nanoparticles......Page 186
7. Use of Pickering nanoemulsions in food industries: benefits and drawbacks......Page 187
8. Conclusions and future perspective......Page 190
References......Page 191
Further reading......Page 197
TWO - Lipid nano carriers for encapsulation of food ingredients......Page 198
1. Introduction......Page 200
2.1 Solid lipid nanoparticles......Page 202
2.2 Nanostructured lipid carriers......Page 203
2.3 Lipid–drug conjugates......Page 204
3.1 Lipids......Page 205
3.2 Surfactants......Page 208
4. Preparation methods......Page 210
4.1.1 Hot homogenization method......Page 211
4.2.2 Microemulsion method......Page 212
4.2.4 Double emulsion technique......Page 213
4.3.3 Solvent dispersion method......Page 214
5.1 Particle size and particle size distribution......Page 215
5.2 Zeta potential......Page 218
5.3 Loading parameters......Page 221
5.4 Release behavior......Page 222
5.5 The crystalline and polymorphism behavior......Page 223
5.6 Morphology of particles......Page 225
6. Applications of SLNs in food fortification......Page 226
References......Page 230
1. Introduction......Page 238
2. Nanostructured lipid carriers ingredients......Page 240
2.1.1 Solid lipids screening......Page 241
2.1.2 Liquid lipids screening......Page 243
2.2 Surfactants......Page 245
3.3 Multiple type NLCs......Page 248
5. Different methods for preparing NLCs......Page 249
5.1 Hot homogenization method......Page 250
5.2 Cold homogenization method......Page 256
5.3 Solvent emulsification/evaporation method......Page 257
5.5 Microemulsion method......Page 258
5.6 Melting-emulsification method......Page 259
5.8 Film-ultrasonic method......Page 260
5.9 Solvent dispersion method......Page 261
5.10 Double emulsion technique......Page 262
6. Food applications of NLCs......Page 263
7.1 Particle size and zeta (ζ) potential......Page 268
7.2 Particle morphology......Page 273
7.3 Encapsulation efficiency, bioactive loading, and chemical stability of bioactive compounds......Page 274
7.4 Crystallinity......Page 275
8. Bioavailability of nutraceuticals within NLCs......Page 276
10. Health aspects of foods enriched with NLCs: safety and efficacy......Page 279
11. Bioactive release from NLC systems......Page 281
12. Concluding and future remarks......Page 282
References......Page 284
1. Introduction......Page 292
2.1 Basic types of food-grade edible oils and organogelators......Page 294
2.1.1 Partially hydrogenated edible oils......Page 295
2.1.2 Fully hydrogenated vegetable oils......Page 297
2.1.3 Organogelators......Page 298
2.2 Lipid Nanocarriers......Page 301
2.3 Gelled lipid nanoparticles......Page 304
2.4 Nanostructured morphologies......Page 307
3. Nanoorganogel structures for encapsulation of food bioactive compounds......Page 308
3.1 Emulgels......Page 309
3.2 Bigels......Page 310
3.3 Lyotropic gels......Page 312
4.1.1 Size and shape of micro- and nanoemulsions......Page 313
4.1.2 Structure and supramolecular organogelator organization......Page 314
4.1.3 Structural and molecular mechanism......Page 316
4.2 Sol–gel and gel–sol phase transition parameters......Page 318
4.3 Light scattering methods......Page 319
4.4 Thermal analyses......Page 320
4.5 Rheological profiling......Page 321
4.6 Stability and storage testing......Page 323
4.7.1 Generalities on organogel release kinetics......Page 324
4.7.1.1 Case of hydrophobic molecules......Page 327
4.7.1.2 Case of hydrophilic molecules......Page 329
4.7.3 Food applications: controlling fat release......Page 330
4.7.4 Food applications: release of nutraceuticals and bioactive molecules......Page 331
4.8.1 General considerations......Page 332
4.8.2 In vitro bioaccessibility experiments......Page 333
4.8.3 Bioavailability......Page 335
5. Nanoorganogels as potential food bioactive delivery systems......Page 336
5.1 Antioxidant-loaded organogel-based nanoemulsions......Page 337
5.2 Organogels loaded with probiotics......Page 338
5.3 Alternative solutions to saturated and trans-fatty acid animal fats......Page 339
5.4 Nanoorganogels as oil and fat nanostructuring agents......Page 340
5.5 Food derivatives–based nanomaterial organogels......Page 342
6. Future trends......Page 343
List of abbreviations......Page 348
References......Page 349
Further reading......Page 364
THREE - Nanostructured phospholipid carriers for encapsulation of food ingredients......Page 366
1. Introduction......Page 368
2. Ingredients used for preparing nanoliposomes......Page 370
3. Production techniques of nanoliposomes......Page 371
4.1 Surface coating of liposomes with biopolymers......Page 377
4.3 Application of membrane stabilizing agents such as cholesterol or glycerol......Page 379
4.5 Lyophilization or freeze drying......Page 380
5.1 Phenolic compounds......Page 381
5.2 Carotenoids......Page 388
5.3 Vitamins......Page 393
5.4 Essential fatty acids......Page 400
5.5 Natural antimicrobial agents and essential oils......Page 404
5.6 Bioactive peptides......Page 408
5.7 Enzymes......Page 412
6. Conclusion and future trends......Page 413
References......Page 414
1. Introduction......Page 426
2. Phytoactive compounds......Page 428
3. Lipid-based nanodelivery systems......Page 432
4. Encapsulation of phytoactive compounds......Page 433
5.1 Structure......Page 434
5.2 Excipients......Page 435
6. Preparation techniques of nanophytosomes......Page 436
7. Nanophytosomes versus nanoliposomes; differences and comparisons......Page 437
8. Effects of food processes on nanophytosomes......Page 438
9. Food ingredients with nanophytosomal-loading abilities......Page 439
10.1.1 Silibinin-loaded phytosomes......Page 441
10.1.2 Sinigrin-loaded phytosomes......Page 442
10.1.5 Luteolin-loaded phytosomes......Page 443
10.2 Antiobesity and weight maintenance......Page 444
10.4 Wound healing effects......Page 445
11.1 Morphology studies......Page 446
11.2.3 Retention time......Page 447
11.3 Crystallinity......Page 448
11.4 Melting point......Page 449
11.8 Antioxidant activity......Page 450
11.9 Vesicular stabilities and releasing profile......Page 451
11.10 Organoleptic evaluations......Page 453
12. Future trends......Page 454
References......Page 456
FOUR -Nanostructured surfactants for encapsulation of food ingredients......Page 466
1. Introduction......Page 468
2. Niosomes......Page 472
3.1.1 Nonionic surfactants......Page 474
3.1.2 Additives......Page 476
3.1.3 Encapsulated drug or bioactive compound......Page 477
4.1 Agitation—sonication method......Page 478
4.2 Thin-film hydration method......Page 479
4.3 Dehydration–rehydration vesicle method......Page 480
4.5 Ether injection method......Page 481
4.8 Hydration of solid surfactants......Page 482
4.14 Microfluidic flow-focusing method......Page 483
4.18 Supercritical carbon dioxide method......Page 484
5. Loading methods for preparing niosomes......Page 485
6. Purification of niosomes......Page 486
6.1 Dialysis......Page 487
6.4 Minicolumns......Page 488
7.4 Morphology......Page 489
8.1 Dermal and transdermal delivery......Page 490
8.4 Ocular delivery......Page 492
8.7 Therapeutics/diagnostics......Page 493
9.1 Yogurts prepared with loaded niosomes......Page 494
9.2 Loaded niosomes with α-tocopherol......Page 495
References......Page 496
Further reading......Page 502
1. Introduction......Page 504
2. Lyotropic nonlamellar liquid crystalline phases......Page 507
3. Self-assemblies of new ω-3 PUFA monoglycerides......Page 511
4. Cubosomes, hexosomes, and related ISAsomes......Page 514
5. Stabilization of ISAsomes......Page 517
6. Characterization of cubosomes, hexosomes, and related ISAsomes......Page 521
7. Nanocarriers based on cubosomes and hexosomes for encapsulation of food ingredients......Page 529
8. Summary and future directions......Page 534
References......Page 535
B......Page 544
C......Page 545
D......Page 546
E......Page 547
F......Page 548
H......Page 550
L......Page 552
M......Page 554
N......Page 555
O......Page 558
P......Page 559
S......Page 561
T......Page 563
W......Page 564
Z......Page 565
Back Cover......Page 566

Citation preview

In the Name of GOD, The Compassionate, The Merciful

Dedication To Iranian martyred nuclear scientists, • Masoud Alimohammadi, • Majid Shahriari, • Darioush Rezaeinejad, • Mostafa Ahmadi Roshan, and all beloved martyrs who sacrificed their life for the development of science and technology in Iran.

A poem by Rumi On the seeker’s path, wise men and fools are one. In His love, brothers and strangers are one. Go on! Drink the wine of the Beloved! In that faith, Muslims and pagans are one

Tomb and Museum of Mevlana, Konya, Turkey Jal
al ad-D
ın Muhammad R
um
ı, also known as Mevl^an^a/Mawl
an
a ( , “our master”), Mevlevî/Mawlaw
ı ( , “my master”), and more popularly simply as Rumi (1207e1273 AC), was a 13th-century Persian poet, jurist, Islamic scholar, theologian, and Sufi mystic originally from Greater Khorasan. Rumi’s influence transcends national borders and ethnic divisions: Iranians, Tajiks, Turks, Greeks, Pashtuns, other Central Asian Muslims, and the Muslims of South Asia have greatly appreciated his spiritual legacy for the past seven centuries. His poems have been widely translated into many of the world’s languages and transposed into various formats. Rumi has been described as the “most popular poet” and the “best selling poet” in the United States. Rumi’s works are written mostly in Persian, and his Masnavi ( ), is considered one of the greatest poems of the Persian language.

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LIPID-BASED NANOSTRUCTURES FOR FOOD ENCAPSULATION PURPOSES

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Nanoencapsulation in the Food Industry

LIPID-BASED NANOSTRUCTURES FOR FOOD ENCAPSULATION PURPOSES Volume 2

Edited by

SEID MAHDI JAFARI Gorgan University of Agricultural Science and Natural Resources Gorgan, Iran

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright Ó 2019 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-815673-5 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Charlotte Cockle Acquisition Editor: Nina Rosa de Araujo Bandeira Editorial Project Manager: Laura Okidi Production Project Manager: Vignesh Tamil Cover Designer: Miles Hitchen Typeset by TNQ Technologies

Contents List of Contributors Preface to the Series Preface to Volume 2

1. An overview of lipid-based nanostructures for encapsulation of food ingredients

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1

Elham Assadpour and Seid Mahdi Jafari 1. 2. 3. 4.

Introduction Nanoemulsions for encapsulation of food ingredients Solid lipid nanocarriers for encapsulation of food ingredients Nanostructured phospholipid carriers for encapsulation of food ingredients 5. Nanostructured surfactants for encapsulation of food ingredients References

Section 1: Nanoemulsions for encapsulation of food ingredients 2. Encapsulation of food ingredients by single O/W and W/O nanoemulsions

1 3 13 19 22 25

35

37

Francesco Donsì and Krassimir P. Velikov 1. Introduction 2. Formulation of nanoemulsions 3. Properties and characterization of nanoemulsions 4. Application of nanoemulsions for encapsulation of food ingredients 5. Conclusions and perspectives References

3. Encapsulation of food ingredients by double nanoemulsions

37 40 56 59 73 75 89

Mohammad Nejatian, Hamed Saberian and Seid Mahdi Jafari 1. 2. 3. 4.

Introduction Classification and structure of double emulsions Preparation of double emulsions Different double emulsions for encapsulation purposes

89 91 95 98

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5. Application of double emulsions for encapsulation of food ingredients 6. Conclusion and future trends References

4. Encapsulation of food ingredients by microemulsions

103 112 121 129

Maria D. Chatzidaki, Vassiliki Papadimitriou and Aristotelis Xenakis 1. Overview 2. Microemulsions 3. Surfactants 4. Phase behavior of microemulsions 5. Structural characterization of microemulsions 6. Comparison of microemulsions with other nanodispersions 7. Encapsulation of food ingredients within microemulsions 8. Food-grade microemulsions and final-product legislation issues References

5. Encapsulation of food ingredients by Pickering nanoemulsions

129 129 130 132 133 134 135 141 141 151

Rezvan Shaddel, Safoura Akbari-Alavijeh and Seid Mahdi Jafari 1. Introduction 2. Food-grade nanoemulsion systems 3. Nanoemulsion preparation techniques 4. Preparation of Pickering nanoemulsions 5. Pickering stabilizers: characteristics and morphology 6. Nanoencapsulation of food ingredients via Pickering emulsification 7. Use of Pickering nanoemulsions in food industries: benefits and drawbacks 8. Conclusions and future perspective References Further reading

151 152 153 157 161 166 166 169 170 176

Section 2: Lipid nano carriers for encapsulation of food ingredients

177

6. Encapsulation of food ingredients by solid lipid nanoparticles (SLNs)

179

Babak Ghanbarzadeh, Fatemeh Keivani and Maryam Mohammadi 1. Introduction 2. Nanoparticles based on solid lipids 3. Solid lipid nanoparticle ingredients

179 181 184

Contents

4. Preparation methods 5. Solid lipid nanoparticle properties 6. Applications of SLNs in food fortification References

7. Encapsulation of food ingredients by nanostructured lipid carriers (NLCs)

xi 189 194 205 209

217

Maryam Mohammadi, Elham Assadpour and Seid Mahdi Jafari 1. Introduction 2. Nanostructured lipid carriers ingredients 3. Structural model of NLCs 4. Advantages of NLCs 5. Different methods for preparing NLCs 6. Food applications of NLCs 7. Characterization and analysis of NLCs 8. Bioavailability of nutraceuticals within NLCs 9. Sensory aspects of NLC systems 10. Health aspects of foods enriched with NLCs: safety and efficacy 11. Bioactive release from NLC systems 12. Concluding and future remarks References

8. Encapsulation of food ingredients by nanoorganogels (nanooleogels)

217 219 227 228 228 242 247 255 258 258 260 261 263

271

Cloé L. Esposito, V Gaëlle Roullin and Plamen Kirilov 1. Introduction 2. Design of nanoorganogel matrices 3. Nanoorganogel structures for encapsulation of food bioactive compounds 4. Characterization of nanoorganogels 5. Nanoorganogels as potential food bioactive delivery systems 6. Future trends List of abbreviations References Further reading

271 273 287 292 315 322 327 328 343

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Contents

Section 3: Nanostructured phospholipid carriers for encapsulation of food ingredients 9. Encapsulation of food ingredients by nanoliposomes

345 347

Khashayar Sarabandi, Zahra Rafiee, Diako Khodaei and Seid Mahdi Jafari 1. Introduction 2. Ingredients used for preparing nanoliposomes 3. Production techniques of nanoliposomes 4. Instability and structural modification of nanoliposomes 5. Nanoencapsulation of different bioactive compounds by nanoliposomes 6. Conclusion and future trends References

10. Encapsulation of food ingredients by nanophytosomes

347 349 350 356 360 392 393 405

Afshin Babazadeh, Seid Mahdi Jafari and Bingyang Shi 1. Introduction 2. Phytoactive compounds 3. Lipid-based nanodelivery systems 4. Encapsulation of phytoactive compounds 5. Nanophytosome technology 6. Preparation techniques of nanophytosomes 7. Nanophytosomes versus nanoliposomes; differences and comparisons 8. Effects of food processes on nanophytosomes 9. Food ingredients with nanophytosomal-loading abilities 10. Pharmaceutical application of nanophytosomes 11. Characterization of nanophytosomes 12. Future trends 13. Conclusion References

405 407 411 412 413 415 416 417 418 420 425 433 435 435

Section 4: Nanostructured surfactants for encapsulation of food ingredients

445

11. Nanoencapsulation of food ingredients by niosomes

447

María Matos, Daniel Pando and Gemma Gutiérrez 1. Introduction 2. Niosomes

447 451

Contents

3. Formation of niosomes 4. Preparation methods of niosomes 5. Loading methods for preparing niosomes 6. Purification of niosomes 7. Niosomal characterization 8. Drug administration by niosomes 9. Food applications of niosomes References Further reading

12. Nanoencapsulation of food ingredients by cubosomes and hexosomes

xiii 453 457 464 465 468 469 473 475 481

483

Anan Yaghmur 1. 2. 3. 4. 5. 6. 7.

Introduction Lyotropic nonlamellar liquid crystalline phases Self-assemblies of new u-3 PUFA monoglycerides Cubosomes, hexosomes, and related ISAsomes Stabilization of ISAsomes Characterization of cubosomes, hexosomes, and related ISAsomes Nanocarriers based on cubosomes and hexosomes for encapsulation of food ingredients 8. Summary and future directions References Index

483 486 490 493 496 500 508 513 514 523

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List of Contributors Safoura Akbari-Alavijeh Department of Food Science and Technology, Isfahan University of Technology, Isfahan, Iran Elham Assadpour Department of Food Science and Technology, Baharan Institute of Higher Education, Gorgan, Iran Afshin Babazadeh Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia Maria D. Chatzidaki Institute of Biology Medicinal Chemistry & Biotechnology, National Hellenic Research Foundation, Athens, Greece Francesco Donsì Department of Industrial Engineering, University of Salerno, Fisciano, SA, Italy Cloé L. Esposito Laboratoire de Nanotechnologies Pharmaceutiques, Faculté de Pharmacie, Université de Montréal, Montréal, QC, Canada Babak Ghanbarzadeh Department of Food Science and Technology, Faculty of Agriculture, University of Tabriz, Tabriz, Iran; Department of Food Engineering, Faculty of Engineering, Near East University, Nicosia, Cyprus, Turkey Gemma Gutiérrez Department of Chemical and Environmental Engineering, University of Oviedo, Oviedo, Spain Seid Mahdi Jafari Department of Food Materials and Process Design Engineering, Gorgan University of Agricultural Science and Natural Resources, Gorgan, Iran Fatemeh Keivani Department of Food Science and Technology, Faculty of Agriculture, University of Tabriz, Tabriz, Iran Diako Khodaei Department of Food Science and Technology, Tarbiat Modares University, Tehran, Iran Plamen Kirilov Université de Lyon, Institut de Biologie et Chimie des Protéines, Laboratoire de Biologie Tissulaire et Ingénierie Thérapeutique UMR 5305, Institut des Sciences Pharmaceutiques et Biologiques Lyon Cedex 08, France

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María Matos Department of Chemical and Environmental Engineering, University of Oviedo, Oviedo, Spain Maryam Mohammadi Department of Food Science and Technology, Faculty of Agriculture, University of Tabriz, Tabriz, Iran; Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Mohammad Nejatian Department of Food Science and Technology, Tarbiat Modares University, Tehran, Iran Daniel Pando Nanovex Biotechnologies SL, Parque Tecnologico de Asturias, CEEI, Llanera, Spain Vassiliki Papadimitriou Institute of Biology Medicinal Chemistry & Biotechnology, National Hellenic Research Foundation, Athens, Greece Zahra Rafiee Department of Food Materials and Process Design Engineering, Gorgan University of Agricultural Science and Natural Resources, Gorgan, Iran V Gaëlle Roullin Laboratoire de Nanotechnologies Pharmaceutiques, Faculté de Pharmacie, Université de Montréal, Montréal, QC, Canada Hamed Saberian Department of Food Additives, Food Science and Technology Research Institute, Academic Center for Education, Culture and Research, Khorasan Razavi, Iran Khashayar Sarabandi Department of Food Materials and Process Design Engineering, Gorgan University of Agricultural Science and Natural Resources, Gorgan, Iran Rezvan Shaddel Department of Food Science and Technology, University of Mohaghegh Ardabili, Ardabil, Iran Bingyang Shi Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia Krassimir P. Velikov Unilever R&D Vlaardingen B.V., The Netherlands; Institute of Physics, University of Amsterdam, The Netherlands; Debye Institute for Nanomaterials Science, Utrecht University, The Netherlands Aristotelis Xenakis Institute of Biology Medicinal Chemistry & Biotechnology, National Hellenic Research Foundation, Athens, Greece Anan Yaghmur Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

Preface to the Series Enthusiasm for the consumption of healthy and functional food products has dramatically expanded with the growth of industrial life and obesity among people. Therefore, many research studies have focused on novel topics such as nanoencapsulation in preparing healthy cuisine. Nanoencapsulation is a new field of science combining different fields of technology in general and encapsulation in particular. Encapsulation can be defined as the technology of encasing bioactive compounds in solid, liquid, or gaseous states in matrices, which can be released under particular circumstances with a controlled rate. Recently, according to perception of material properties and their reaction at the nanoscale research, the encapsulation area has moved to the nanoencapsulation field. The fabricated nanocarriers provide better opportunity for interaction, high bioavailability, solubility, and permeation due to their larger surface area. Also, nanoencapsulated ingredients enable targeted release plus high stability against harsh digestive steps, process conditions, and environment stresses. Selecting the best method for nanoencapsulation of distinct food bioactive ingredients is the main step for designing an efficient delivery system in healthy food and functional products. Considering different techniques applied for fabricating nanoscale carriers, we have classified nanoencapsulation technologies into five groups based on the main mechanism/ingredient in our previous books (Elsevier, 2017). Due to substantial and overwhelming research activities on nanoencapsulation of food bioactive ingredients and nutraceuticals in recent years, it is necessary to work on specialized and in-depth book titles devoted to different groups of nanocarriers. On the other hand, release, bioavailability, characterization, safety, and application of nanoencapsulated ingredients in different food products are some other important topics which deserve to have some relevant book titles to provide more detailed information and discussions. Therefore, the book series Nanoencapsulation in the Food Industry has been defined to address these emerging topics and cover the recent cutting-edge researchers in this field. Seven volumes defined in this series have the titles as following: • Volume 1: Biopolymer Nanostructures for Food Encapsulation Purposes • Volume 2: Lipid-Based Nanostructures for Food Encapsulation Purposes • Volume 3: Nanoencapsulation of Food Ingredients by Specialized Equipment

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• Volume 4: Characterization of Nanoencapsulated Food Ingredients • Volume 5: Release and Bioavailability of Nanoencapsulated Food Ingredients • Volume 6: Application of Nano-/Microencapsulated Ingredients in Food Products • Volume 7: Safety and Regulatory Issues of Nanoencapsulated Food Ingredients This book series would be useful for a diverse group of readers including food technologists, food engineers, nanotechnologists, nutritionists, food colloid experts, pharmacists, cosmetic experts, physicists, chemists, microbiologists, biotechnologists, engineers, and those who are interested in novel technologies in the areas of food formulations, functional foods, and nutraceutical delivery systems. We hope this book series will stimulate further research in this rapidly growing area and will enable scientists to gain more practical knowledge about different nanocarriers and their properties to solve their particular problems. Seid Mahdi Jafari Gorgan, IRAN

Preface to Volume 2 The food industry is one of the most important industries in many countries as there is a very strong link between this industry and food security. On the other hand, due to expanding of the population along with industrialization, the demand for processed foods is increasing very fast. Also, because of changes in the lifestyle of people and a growing tendency to processed foods and limited consumption of healthy foods, it is necessary to incorporate essential nutraceuticals and health-promoting bioactives into food products to preserve normal body health and preventing new lifestyle diseases. Functional and new fortified products are currently provided on a large scale to reduce these diseases and improve the intake of micronutrients. Nutraceutical can be defined as bioactive components that promote both the nutritional and medicinal properties, but their bioavailability is restricted if administered orally. These compounds include a widespread range of essential components such as bioactive peptides, phytosterols, antioxidant compounds (tocopherols and phenolic compounds), carotenoids, essential fatty acids, vitamins, minerals, etc. However, because of the lipophilic nature of many bioactives, it is difficult to introduce them in low-fat and aqueousbased foods. On the other hand, these valuable nutraceuticals are susceptible to oxidation and other deteriorative factors during food processing, storage, and consumption as they need to pass the gastrointestinal tract successfully. Thus these components should be entrapped in a lipid-based nanodelivery system to preserve their nutritional and health-promoting features and improve their water dispersibility. The overall aim of the Lipid-Based Nanostructures for Food Encapsulation Purposes is to present conventional and cutting-edge nanodelivery systems based on lipid formulations which can be applied for encapsulation of various food bioactive ingredients. This book is covering recent and applied research studies in all disciplines of bioactive and nutrient delivery. All chapters emphasize original results relating to experimental, formulation, analysis, and/or applications of lipid-based nanostructures for food encapsulation purposes. After presenting a brief overview of lipid-based nanocarriers in Chapter 1, nanocarriers made via nanoemulsions have been covered in Section 1 including simple oil-in-water or water-in-oil nanoemulsions (Chapter 2), double nanoemulsions (Chapter 3), microemulsions (Chapter 4), and pickering nanoemulsions (Chapter 5). Section 2 has been

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devoted to solid lipid nanocarriers namely solid lipid nanoparticles or SLNs (Chapter 6), nanostructured lipid carriers or NLCs (Chapter 7), and nanoorganogels/nanooleogels (Chapter 8). Another important group of lipidbased nanostructures, i.e., phospholipid-based nanocarriers have been explained in Section 3 including nanoliposomes (Chapter 9), and nanophytosomes (Chapter 10). Finally, Section 4 deals with nanocarriers made from surfactants such as niosomes (Chapter 11), and cubosomes/hexosomes (Chapter 12). All who are engaged in micro-/nanoencapsulation of food, nutraceutical, pharmaceutical, and cosmetic ingredients worldwide can use this book as either a textbook or a reference which will give the readers a good and recent knowledge and potentials of lipid-based nanostructures, as well as their novel applications in developing bioactive delivery systems. We hope this book will stimulate further research in this rapidly growing area and will enable scientists to get familiar with lipid-based nanostructures as an important group of nanocarriers. I really appreciate the great cooperation of all authors of the chapters for taking time from their busy schedules to contribute to this project. Also, it is necessary to express my sincere thanks to all the editorial staff at Elsevier for their help and support throughout the project. Finally, special acknowledgment is to my family for their understanding and encouragement during the editing of this great project. Seid Mahdi Jafari March 2019 Gorgan, IRAN

CHAPTER ONE

An overview of lipid-based nanostructures for encapsulation of food ingredients Elham Assadpour1, Seid Mahdi Jafari2 1

Department of Food Science and Technology, Baharan Institute of Higher Education, Gorgan, Iran Department of Food Materials and Process Design Engineering, Gorgan University of Agricultural Science and Natural Resources, Gorgan, Iran

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1. Introduction Most of the bioactive substances suffer from low stability and decomposition when exposed to unfavorable conditions during food processing and storage (e.g., light, oxygen, and moisture) as well as within the gastrointestinal tract (GIT) which reduces their efficiency and bioactivity (Mokhtari et al., 2017; Abaee et al., 2017). Moreover, they exhibit low water solubility, poor bioavailability, and insufficient dispersibility in food systems; interact with food ingredients; and negatively influence sensory properties of food systems (da Silva et al., 2016; Donsì et al., 2011; Fang and Bhandari, 2010; Gleeson et al., 2016). On the other hand, health concerns have recently increased the tendency for development of functional foods and novel food products fortified with bioactive compounds and nutraceuticals especially phytochemicals (Ting et al., 2014). However, there are some limitations for direct utilization of bioactive compounds in food matrices. Food-grade delivery systems for nanoencapsulation of bioactive compounds represent an efficient way to solve these drawbacks. Among different nanodelivery techniques, lipid-based nanocarriers are a promising strategy for successful delivery of food bioactives. Lipid-based nanostructures have great potentials to accommodate and release various bioactive compounds (hydrophilic, lipophilic, and amphiphilic compounds) in a sustained and controlled manner, improve solubility and encapsulation efficiency of hydrophobic bioactive compounds, decrease their volatility, and enhance their target specificity. Lipid-based nanocarriers Lipid-Based Nanostructures for Food Encapsulation Purposes ISBN: 978-0-12-815673-5 https://doi.org/10.1016/B978-0-12-815673-5.00001-5

© 2019 Elsevier Inc. All rights reserved.

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j

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also promote effectiveness and bioavailability by enhancing stability of entrapped compounds in food mediums and during digestion (de Souza Sim~ oes et al., 2017; Jafari, 2017; Shin et al., 2015). Furthermore, these systems are biocompatible and can be fabricated by inexpensive and safe components for large-scale industrial practices via simple and available production technologies without the use of organic solvents (Jafari, 2017; Katouzian and Jafari, 2016). It should be mentioned that the terminology for nanocarriers is very versatile and various words and expressions are being used in the relevant literature such as nanocarrier, nanocargo, nanovehicle, nanocapsule, nanosphere, nanoparticle, nanodelivery system, nanocomplex, nanodroplet, nanoencapsulant, nanocoating, etc. Although their technical meaning and intention could be different, generally speaking, researchers are using them with a common sense of nanocarriers particularly in the food science field which is not as advances as pharmaceutical field in terms of nanoencapsulation and nanodelivery systems. Many studies have indicated superiority of nanocarriers; as shown in Fig. 1.1, compared with microencapsulation systems, nanosized carriers offer more stability, solubility in different media, functionality, bioavailability, absorption, homogeneity, targeting properties, and the ability of controlled release in food and pharmaceutical practices which are associated with their

Sustained release

Lowering toxicity and side effects

Active packaging

Higher loading capacity

Anti-cancer drug delivery

Chelating and free radical scavenging

Enhanced long term stability

Enhanced particle size and stability

Increased bioavailability

Enhanced cellular uptake

Improved sensory properties

Nanocarreirs for foods

Enhanced solubility and stability

Figure 1.1 Potential advantages of nanocarriers for encapsulation of food bioactive ingredients.

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greater surface area and larger reactivity (Ezhilarasi et al., 2013; Faridi Esfanjani and Jafari, 2016). Briefly: • An increase in surface area may lead to an increase in nutraceutical bioavailability due to faster digestion of the particles within the GIT. • A decrease in particle size may lead to faster penetration through the mucus layer coating the epithelium cells. • A decrease in particle size may lead to direct absorption of undigested nutraceutical-loaded nanoparticles by epithelium cells. • A decrease in particle size may improve the water dispersibility of nonpolar nutraceuticals. • A decrease in particle size may lead to the development of optically transparent products, which is important for some food and beverage applications, such as fortified waters and soft drinks. • Encapsulation of bioactives within nanoparticles may lead to improved protection against chemical or biochemical degradation. • Encapsulation of bioactives within nanoparticles may be used to prevent their adverse interactions with other food ingredients. • Encapsulation of bioactives within nanoparticles may help to mask undesirable flavor profiles. An important result of applying bioactive-loaded nanocarriers is the improvement of bioavailability. Typically, a number of different steps determine the biological fate of bioactive components before and after ingestion (Katouzian and Jafari, 2016), which is summarized in Fig. 1.2. As mentioned before, lipid-based nanostructures (Fig. 1.3) are an important group of nanocarriers for the encapsulation and delivery of food bioactive components. These carriers can be classified into four groups: (1) nanoemulsions, (2) solid lipid nanocarriers, (3) phospholipid nanocarriers, and (4) surfactant-based nanocarriers. This chapter will present an overview of lipid-based nanostructures for encapsulation of food bioactive ingredients, and more details for each group of these nanocarriers along with their preparation methods, properties, applications, characterization, etc. will be provided in the following chapters of the book.

2. Nanoemulsions for encapsulation of food ingredients An emulsion is defined as a system composed of two immiscible liquids (mostly water and oil) where one is dispersed as the droplet form (the dispersed or internal phase) in the other one (the continuous or external

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Design and formulaƟon of bioacƟve-loaded nanocarrier (BLN); Stability of BLN against environmental parameters (light, oxygen, pH, humidity, etc);

Before ingestion

Stability of BLN against processing condiƟons (temperature, pressure, etc); InteracƟon of BLN with food matrix; Stability of BLN during storage and shelf life of food products; Stability of BLN during oral delivery; Stability of BLN inside the stomach.

After ingestion

Release of the bioactive compounds from the dietary matrix; Digestion by enzymes within the intestine; Adherence and uptake by the mucosal layer of the intestine; Transfer across the gut wall (passing through and/or between the epithelium cells) to the lymphatic system or portal vein; Systemic distribution; Systemic deposition (storage); Metabolic and functional use; Excretion (via urine or feces).

Figure 1.2 Different parameters affecting the bioavailability of bioactive ingredients loaded within nanocarriers.

Nanoemulsions

Single O/W and W/O nanoemulsions Double nanoemulsions Microemulsions

Solid lipid nanocarriers

Nano-liposomes Nano-phytosomes

Nanostructured lipid carriers (NLCs) Nano-organogels (nano-oleogels)

Pickering nanoemulsions

Phospholipid nanostructures

Solid lipid nanoparƟcles (SLNs)

Surfactant nanostructures

Niosomes Cubosomes and hexosomes

Figure 1.3 Different lipid-based nanostructures for encapsulating food bioactives.

phase). Emulsions can be classified into three main types in terms of droplet size: microemulsions (10e100 nm), macroemulsions (0.5e100 mm), and nanoemulsions (known as miniemulsions, 100e500 nm) (Jafari et al., 2008; McClements, 2005). Different forms of nanoemulsions can be applied for encapsulation of food bioactives including single oil-in-water (O/W) and water-in-oil (W/O) nanoemulsions (Chapter 2), double nanoemulsions (W/O/W or O/W/O) (Chapter 3), microemulsions (Chapter 4), and

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Pickering nanoemulsions (Chapter 5) which are described briefly in the following sections.

2.1 Single O/W and W/O nanoemulsions Nanoemulsions, differently from microemulsions, are thermodynamically unstable systems, which naturally tend to phase separation (McClements and Jafari, 2018b). However, gravitational separation is hampered by the onset of Brownian motions, which dominate over inertial motion in the typical size range of nanoemulsions. Depending on their formulations, nanoemulsions might undergo other instability phenomena, such as coalescence, Ostwald ripening, or flocculation, which cause the size of their drops to increase with time, ultimately leading to phase separation (Porras et al., 2008). Therefore, an appropriate nanoemulsion formulation is required to impart the long-term kinetic stability (Solans and Solé, 2012), while abiding by the severe constraints, posed by the current food regulations, as well as by possible impact on the organoleptic properties, or by economic considerations. Different methods are currently available for preparing nanoemulsions, which can be classified into high-energy methods, such as high-pressure homogenization, ultrasonication, and colloid milling, and low-energy methods, such as phase inversion temperature or concentration and spontaneous emulsification (Gupta et al., 2016; Jafari et al., 2008). Because nanoemulsions are kinetically stable, thermodynamically unstable systems, their formation is an inherently nonspontaneous process, which requires energy to expand the interfacial surface (Kumar and Kumar, 2018). The required energy input increases with the decreasing particle size because Laplace pressure, required to deform a spherical droplet, is inversely proportional to droplet radius. High-energy methods require a significant energy input (108e1010 W/kg) to produce nanoemulsions (Gupta et al., 2016), with a large fraction that is dissipated in the continuous phase as heat (Abbasi et al., 2019). In contrast, low-energy methods exploit specific properties of the system components, or changes in the chemical potential of the components, to produce nanometric droplets, with a minimum energy input (w103 W/kg), mainly associated with stirring (Gupta et al., 2016; Kumar and Kumar, 2018). The mechanisms of stabilization of nanoemulsion droplets are based on steric or electrostatic stabilization. Steric stabilization is a short-range repulsive interaction and arises upon the overlapping of the interfacial layers of

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two approaching droplets. The intensity of steric interaction grows with the thickness and affinity for the continuous phase of the emulsifier layer (Ozturk and McClements, 2016). Electrostatic stabilization is instead a short- to long-range interaction, depending on the droplets’ electrical charges. The electrostatic repulsion generated between droplets with similar charges depends, therefore, on the surface charge density and the ionic strength of the continuous phase, differently from the steric stabilization (Ozturk and McClements, 2016). The steric interaction is the main mechanism of stabilization of W/O nanoemulsions, for which, instead, the effect of electrostatic repulsion is negligible because of the low electrical conductivity of oil (Tabibiazar and Hamishehkar, 2015). In nanoemulsions, because of the nonnegligible solubility in water of many food oils, or vice versa, Ostwald ripening is considered to be the main mechanism of physical instability (Chang and McClements, 2014; Donsì and Ferrari, 2016). Ostwald ripening can be described as the molecular diffusion of the dispersed liquid in the continuous phase, driven by the higher local solubility around smaller droplets than larger ones (Wooster et al., 2008), which, ultimately, causes the growth of larger droplets at the expense of smaller ones. This thermodynamically driven spontaneous process is caused by the intrinsic factors because the molecules on the surface of a droplet are energetically less stable than the ones in the interior. Because of the high water diffusivity in oil, as well as mobility of water droplets, which can easily coalesce, the stability of W/O nanoemulsion is typically more critical than for O/W nanoemulsions (Tabibiazar and Hamishehkar, 2015). Various food-grade surfactants, such as saponins, sucrose esters, polysorbates, or fatty acids, are available for the formulation of O/W nanoemulsions (McClements and Jafari, 2018a). The formulation of W/O nanoemulsions is typically based on the use of polyglycerol polyricinoleate (PGPR) or Span 80 as primary emulsifiers. It is often required at high concentration (4.0e6.0 wt%), which might not be allowed in some food products by regulatory bodies (Ruan et al., 2018), or might result in unpleasant off-taste (Tekin Pulatsu et al., 2018). The design of nanoemulsions for the encapsulation and delivery of food ingredients is generally based on the desired in-product and in-body behavior (Donsì et al., 2013; Sessa and Donsì, 2015). In particular, the in-product behavior of a nanoemulsion, referred to its addition into food formulations, should be evaluated in terms of (1) the efficient and homogeneous dispersion in the food matrix, as well as the compatibility with it, (2) the physical

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stability of the nanoemulsion in the complex environment of food matrices, where the different O/W interfaces may promote its segregation, (3) the minimization of the reaction of the payload molecules with the food ingredients, which in turn affects their stability and the impact on product quality, (4) the physicochemical stability at the treatment conditions of the food, including temperature or pH extremes, light exposure, or intense shearing, deriving from food processing, preservation or preparation. An optimal in-product behavior should be able to ensure that the encapsulated ingredients can reach the stage of oral consumption in active form. The in-body behavior of the nanoemulsion depends, instead, on (1) the efficient release of the payload compounds, preferably triggered by the digestive environment (from chewing to the digestion process), such as changes in pH or temperature, mechanical shear, enzymatic activity, or moisture addition, and (2) the bioaccessibility and bioavailability of the payload compounds, taking into account their desired fate to target sites. Particularly, in addition to more conventional requirements in terms of physicochemical stability, the digestibility should also become part of the design of nanoemulsions for the delivery of food ingredients (Donsì, 2018). The choice between an O/W or W/O nanoemulsion depends on the properties of the payload ingredient, and in particular if it is prevalently hydrophilic or lipophilic, but also on the characteristics of the food matrix (McClements and Rao, 2011; Sessa and Donsì, 2015). Most foods consist of an aqueous phase and therefore require O/W nanoemulsions. Conversely, W/O nanoemulsions can be used in the encapsulation of bioactive hydrophilic substances or as a structural unit of double W/O/W emulsions, to be added in aqueous-based products (Tabibiazar and Hamishehkar, 2015). Simple W/O nanoemulsions, instead, can find application in oil- and lipid-based foods, such as vegetable oils, butter, spreads, and salad dressings. More details about application of simple nanoemulsions for encapsulation of different food bioactive ingredients have been provided in Chapter 2.

2.2 Double nanoemulsions Double nanoemulsions are a newer system of lipid-based nanocarriers and could be considered as an advanced nanoemulsion delivery technique (Assadpour and Jafari, 2019; Esfanjani et al., 2015). A double nanoemulsion is in fact a ternary system having either water-in-oil-in-water (W/O/W) or oil-in-water-in-oil (O/W/O) structures, where each of the dispersed droplets contains smaller internal droplets of a different immiscible liquid phase.

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For example, in the case of W1/O/W2 emulsion, each droplet of oil dispersed in the external aqueous phase (W2) contains at least one internal water droplet (W1) (Assadpour et al., 2016; Jafari et al., 2017). A double nanoemulsion, typically has inner and outer droplets with a mean diameter below 200 and 1000 nm, respectively. Such relatively complex structures allow coencapsulating of lipophilic compounds (in the lipid phase) and hydrophilic ones (in the inner aqueous compartments). This feature is only seen in a small number of nanocarriers, such as nanoliposomes and polymeric nanomicelles, and have been utilized in many cases, specifically in pharmaceutical and food supplements industry (Kalepu et al., 2013). By producing a synergetic effect due to incorporation of several bioingredients with different natures in the individual carrier, the efficiency of treatment is improved (Hu et al., 2012; Kemp et al., 2016). The preparation of double nanoemulsions offers another unique feature to overcome incompatibility of lipophilic substances used for nanoemulsion formulation. Double nanoemulsions are thermodynamically unstable, and their encapsulation effectiveness is extremely influenced by many forms of instability. It should be noted that these advantages and disadvantages also exist for conventional double emulsions (Gharehbeglou et al., 2019a,b). Indeed, many theoretical basics for conventional double emulsions also exploit to double nanoemulsions. However, droplet size reduction from the microto nanoscale and, then improvement in surface area of droplets, can develop the functionality of bioactive ingredients incorporated into double nanoemulsions (Jafari and McClements, 2018; McClements and Rao, 2011). Various bioactive ingredients can be encapsulated in the core and external phase of double nanoemulsions (i.e., the inner and outer phase, respectively). The middle phase, as a membrane, has a significant role to play in the control of encapsulant release kinetics from inner phase into the outer phase. Technically, this type of emulsions has two different interfacial layers: one layer between the inner and middle phase (for instance, W1/O in W1/O/W2 emulsions) and the other one between the middle and outer phase (O/W2) (Jafari et al., 2017). Therefore, the use of two different surfactants is usually necessary; an oil-soluble and a water-soluble surfactant for stabilization of W1/O and O/W2 interfaces, respectively. The most usual hydrophilic surfactants (with a high hydrophilic-lipophilic balance (HLB)) in the formulation of double nanoemulsions are Tween(s), decaglycerol monolaurate, and biopolymeric emulsifiers such as proteins (whey proteins, sodium caseinate, soy protein isolates) and polysaccharides

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(gum Arabic, gum tragacanth) (Capdevila et al., 2010; Esfanjani et al., 2015). On the other hand, Span(s) and PGPR are the most common lipophilic surfactants (with an HLB value of 4 or less) to make double nanoemulsions (Bonnet et al., 2009; Jafari et al., 2017; Le Révérend et al., 2011; Mehrnia et al., 2017). When choosing surfactants for preparation of double nanoemulsions, their regulatory/safety status and efficacy should be simultaneously considered. For example, PGPR, a high-molecular-weight chemical originated from castor oil, has been frequently applied in studies of duplex emulsions. However, its application requires declaration on the product label, since it is not a natural compound (Lamba et al., 2015). Accordingly, the feasibility of replacing PGPR or other synthetic surfactants with natural ingredients or even decreasing its amount in double nanoemulsion formulations is a dynamic and expanding research area. Similar to conventional microscale double emulsions, double nanoemulsions are usually manufactured through a two-step emulsification technique. In the first step of emulsification, the W/O (or O/W) emulsions would be prepared, and then this primary emulsion is used as oil (or aqueous) phase with another aqueous (or oil) phase, to make a direct second emulsion W1/O/W2 (or O1/W/O2). The first step is typically done under intense homogenization conditions and, as previously mentioned, plays a key role in the characteristics and performance of the final nanoemulsion, so that a double nanoemulsion with small droplet sizes, desirable encapsulation loads, and high stability is obtained when the primary emulsions have enough stability and optimum droplet sizes. On the contrary, secondary step is usually performed under gentle shear conditions in order to prevent the breakup of the internal droplets (the W1 or O1 droplets) within the lipid and water phases, respectively (Garti, 1997; Jafari et al., 2017). Several studies have reported the formation of food bioactiveeloaded double nanoemulsions as a strategy to improve their functional performance which has been covered in Chapter 3 along with destabilization phenomena in these nanocarriers and different strategies to improve their stability.

2.3 Microemulsions Similar to nanoemulsions, microemulsions are also in the nanometric range (typically, with a mean droplet size < 100 nm). However, microemulsions are thermodynamically stable dispersions, which form spontaneously when the aqueous, oil, and amphiphilic components are brought into contact. In general, microemulsions consist of a variety of structures, including

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liquid crystals, gels, and vesicles dispersed in the continuous phase, and require significantly higher amounts of surfactant than emulsions and nanoemulsions, typically over 30 wt% (Porras et al., 2008). Generally, microemulsions are colloidal dispersions that are formed spontaneously in the sense that only small amounts of energy are required for the micellar formation to occur under specific circumstances (Prince, 2012). This occurs due to the fact that the micellar formation is the thermodynamically favorable state; hence it is also stable in time (Langevin, 1988; Moulik and Paul, 1998). In the recent years, microemulsions containing edible lipids and emulsifiers have been proposed as an effective carrier for the delivery of bioactives in food applications. The most important argument on these types of vehicles arises from the fact that these fabricated micellar structures resemble the naturally occurring self-assemblies of phospholipids, proteins, etc., commonly found in foods. Moreover, due to their microenvironment containing different polarities, they are able to increase the solubility of molecules in the interior, interface, or continuous phase of the system depending on the application. There are many different structures that surfactant molecules could form under self-assembly, namely micellar, hexagonal, reverse micellar, lamellar, and other, depending on the dispersal conditions (Lawrence and Rees, 2000). For the specific case of microemulsions, the surfactant structures are considered to be micellar or reverse micellar for O/W or W/O dispersions, respectively. Surfactants are classified in many different ways depending on their chemical nature, structure, polarity, etc. More specifically, these amphiphiles are considered as (1) nonionic, (2) zwitterionic, and (3) ionic depending on the molecule’s nature. In order to choose the most appropriate amphiphile for food applications, not only the nature but also the structure and polarity should be also taken into consideration. Many empirical approaches have been proposed in the literature in order to predict the surfactant molecules self-assembly. Critical packing parameter (CPP) is an approach used for many decades in order to utilize a simplified model of the molecules geometry so as to predict the aggregation. The phase diagram is a commonly used approach to visually assess the monophasic region of mixtures of water, oil, and surfactants under a constant pressure and temperature (Lawrence and Rees, 2012). A typical phase diagram is represented by an equilateral triangle where every corner represents the pure component used (water, oil, and surfactant). The corners are representations of binary mixtures of the relative compounds, and inside the triangle every point is indicative of the percentage of composition of all three

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components. Constructing the phase diagram of water, oil, and surfactant is time-consuming as different binary mixtures are being titrated with the third component and let to equilibrate (Kalaitzaki et al., 2015; Papadimitriou et al., 2008). Since, in most cases, more than three components are being used for the formation of a microemulsion, a so-called pseudoternary phase diagram is constructed with mixtures of surfactant/cosurfactant or solvent/ cosolvent at specific ratios represented at the corner(s) of the triangle. The monophasic region close to the water or oil corner distinguishes the O/W from the W/O microemulsions, respectively. Due to the fact that microemulsions can be fabricated spontaneously or with low energy offer, they are very attractive for several industrial applications, the food sector included. In addition, microemulsions based on foodgrade oils and surfactants are usually compatible with food matrices and do not affect the appearance, taste, flavor, and texture of the product. Finally, increased solubility of poorly soluble compounds and protection from oxidation and degradation of sensitive food bioactives (e.g., a-tocopherol, b-carotene, green tea polyphenols, flavonols) upon encapsulation in the dispersed phase of the microemulsions have been shown by different research groups which will be explained in Chapter 4.

2.4 Pickering nanoemulsions The conventional way to prepare emulsions/nanoemulsions is by means of emulsifiers like surfactants and biopolymers, e.g., applying proteins in the layer between two immiscible phases to decline the surface pressure between them. A comparatively new strategy is to use solid nano-/microscale particles instead of surfactants. Superior stability of these particle-stabilized emulsions (known as Pickering emulsions), which arises from the substantial adsorption energy of the particles at the interfacial layer, is one of their main features that conventional surfactant-stabilized emulsions do not possess. Pickering nanoemulsions have plenty of benefits over conventional emulsions, including a lower toxicity, preferable stability, adjustable permeability, better biocompatibility, and the diversity of available particles, all of which have developed their study and possible usages, today in food industry. Furthermore, the diversity of Pickering emulsions enables a versatility of functionalities to fulfill different demands of application. New Pickering emulsions and dependent materials are persistently emerging, like nonspherical emulsions or those obtained by nonspherical particles. Superior stability

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Elham Assadpour and Seid Mahdi Jafari

against coalescence is the primary advantage of particle-stabilized systems (Frelichowska et al., 2009). The second advantage of these systems is their surfactant-free feature (Leal-Calderon and Schmitt, 2008; Wu and Ma, 2016). Surfactants are the type of compounds which are recognized to be environmentally problematic (Braisch et al., 2009) or representing detrimental influences (Chevalier and Bolzinger, 2013) which can be substituted by other particles as Pickering stabilizers. Most Pickering nanoemulsions are made by high-energy preparation techniques like high-pressure homogenization, ultrasonic homogenization, microfluidization, and high-speed homogenization methods. The use of spontaneous emulsification as a low-energy nanoemulsion preparation technique has also been reported for their fabrication (Richter et al., 2018). Stability of Pickering emulsions is superior than that of surfactant-stabilized emulsions as a higher energy is needed to remove adsorbed particles from the interfacial layer (Whitby et al., 2016). Besides this, in the majority of cases, the high-energy barrier also is necessary to be conquered or declined by using external forces or selecting the proper conditions to develop a stable Pickering emulsion. Silica and its derivatives are the most commonly used particles in Pickering emulsions. However, these particles are widely utilized as model stabilizers in nonefood-grade Pickering nanoemulsions, and the purpose of such studies is modeling the mechanism of formation and stabilization of the systems (Berton-Carabin and Schroën, 2015). Nevertheless, the European Food Safety Authority (EFSA) and the US Food and Drug Administration (FDA) have introduced the insoluble derivatives of silicates as generally recognized as safe (GRAS) food ingredients (EFSA, 2009; FDA, 1979). Lipid-based particles called fat crystals are known as efficient stabilizers for W/O emulsions (Dickinson, 2012). In general, lipid-based particles are colloidal systems with a mean particle diameter lower than 500 nm and finite particle size distribution. Typically, they include lipids which are physiological, biodegradable, safe, affordable, and notably dispersible in aqueous media. All these properties facilitate the preparation and scaleup processes (Gupta and Rousseau, 2012). Furthermore, their high hydrophobicity makes them good candidates to settle at the interfacial layer between oil and water of Pickering nanoemulsions with an angle greater than 90 , enhancing the stability of the aqueous phase in a lipid-based phase (Paunov et al., 2007).

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Carbohydrate-based nanostructures form another category of nanoparticles stabilizing the Pickering emulsions. Among all carbohydrates, modified starch represents a desirable candidate for Pickering stabilization of O/W emulsions. Starch granules of different biological sources have been utilized for such applications. Other carbohydrate nanostructures include microcrystalline cellulose, aminated nanocellulose (ANC) particles, cellulose nanofibers, alginate nanoparticles, etc. Different protein-based nanoparticles have also been widely utilized as Pickering stabilizers for O/W emulsions. Various protein sources (plant or dairy proteins) may be used for development of the particles via different processes (Berton-Carabin and Schroën, 2015; Liu and Tang, 2014). More information about these nanoparticles and application of Pickering nanoemulsions for encapsulation of food bioactive ingredients has been provided in Chapter 5.

3. Solid lipid nanocarriers for encapsulation of food ingredients Solid lipid nanocarriers including solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and nanostructured polymeric lipid carriers are colloidal carriers which are extensively under investigations as bioactive carrier systems for different food ingredients. SLNs (Chapter 6) are based on melt-emulsified lipids which are solid at room temperature and are obtained from physiologically well-tolerated and biodegradable raw renewable materials. NLCs (Chapter 7) are characterized by a solid lipid matrix in which a liquid lipid is also added. They are the second generation of SLNs permitting a more efficient bioactive loading, a modulation of the bioactive delivery profile, and a prolonged bioactive entrapment during storage. On the other hand, the interest of using colloidal dispersions of gelled lipid nanoparticles (GLNs) such as nano-oleogels (Chapter 8) for different fields of applications has been increased in recent years, notably in cosmetics, dermatology, and/or pharmaceutics due to their capacity to immobilize poorly water-soluble compounds. The following sections give a brief overview of these nanocarriers.

3.1 Solid lipid nanoparticles SLNs have gained an increasing attention in the pharmaceutical and food technology because of their ability to combine the advantages of polymeric particles, liposomes, and emulsions and overcoming some of their

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deficiencies. SLNs are colloidal particles made from a lipid matrix that can fully or partially crystallize at a desired temperature (body/room temperature), and they are stabilized by a single surfactant or a mixture of surfactants. SLNs consist of a core of solid lipid that can be purified triglycerides or complex mixtures; the bioactive material is a part of the lipid matrix. In contrast to nanoemulsions, in SLN systems, lipid droplets have a highly ordered crystalline structure which increases the stability of core bioactive compounds and since the bioactive substance has a much lower diffusion rate, its prolonged release is possible (Weiss et al., 2008). SLNs have some limitations such as a relatively low loading capacity and potential expulsion of bioactive material. Crystallization of lipids in SLN structures leads to a more or less perfect crystalline lattice (Muchow et al., 2008). The highly organized crystal lattice structures are orderly and tightly packed together leaving very limited space for incorporation of bioactive material (Feng and Mumper, 2013). In addition, the bioactive loading capacity of SLNs depends on the solubility of bioactive material in the lipid phase, the structure, and the polymorphic state of the lipid matrix. The use of highly similar molecules (i.e., tristearin) as lipid phase leads to the formation of a perfect crystalline structure with few imperfections for incorporation of bioactive compounds. Therefore, the use of more complex lipids (i.e., a mixture of different mono-, di-, triglycerides) will result in a higher loading capacity (Wissing et al., 2004). On the other hand, when a lipid forms a highly crystalline particle, sudden expulsion of bioactive components may occur due to the transition of lipids crystals to highly ordered lipid particles (i.e., a-crystal / bʹ-crystal / b-crystal). In addition to polymorphic transition, the formation of bioactive componenteenriched shell leads to a burst release. These disadvantages limit the use of SLNs as delivery systems for food applications (Tamjidi et al., 2013). SLNs are basically composed of a lipid phase containing 100% solid lipids that have a melting point above ambient and body temperature and the aqueous phase containing surface-active materials (surfactants) (Mehnert and M€ader, 2012; Mitri et al., 2011). Therefore, an efficiently engineered nanodelivery system for encapsulating of bioactive by SLNs can be provided by the accurate selection of lipids and surfactants (Katouzian et al., 2017). Different solid lipids can be used in SLN preparation including highly saturated pure triglycerides, the oil and fats containing high amounts of saturated triglycerides (such as cacao butter, butter, palm oil), saturated fatty acids, steroids, and waxes.

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The main factors that influence the application of surfactant for preparing SLNs are surfactant concentration and chemical structure of surfactants. From the aspect of concentration, low concentrations of surfactant during the crystallization process cannot fully cover all the new surfaces and due to a poor repulsion between particles, the aggregation will occur in the system. On the other hand, in a higher concentration of surfactant, the excessive surfactant molecules form the micelles which cause instability and particle aggregation during storage due to the depletion flocculation mechanism (Pezeshki et al., 2014). The most used emulsifiers in SLN preparation have been small molecule surfactants individually or rarely, the combination of them and biopolymers (Liu et al., 2012). Three classes of hydrophilic surfactants are used in the preparation of SLNs including neutral surfactants, e.g., lecithin (Faergemand and Krog, 2003); ionic surfactants, e.g., sodium dodecyl sulfate (SDS), sodium lauryl sulfate, sodium oleate, and sodium taurodeoxycholate (Shah et al., 2015); and nonionic surfactants, in which most common ones are Poloxamer 188, Poloxamer 407, polysorbates (Tween 20, Tween 40, Tween 80), and sucrose esters (Fang et al., 2008). A number of interesting protocols have been developed for SLN preparations. These protocols are divided in three classes: (1) High-energy methods which need a high energy and high shear provided by mechanical instruments such as high-pressure homogenizers (hot and cold homogenization), high-speed Ultra-Turrax homogenizers and sonication (Ganesan and Narayanasamy, 2017); (2) Low-energy approaches including spontaneous nanoemulsification, microemulsification, coacervation, and double nanoemulsification; (3) SLN preparation with organic solvents including solvent emulsification/evaporation, solvent emulsificationediffusion, solvent dispersion, and supercritical fluid techniques. Most reports on SLNs have been in pharmaceutical applications; however, in recent years, using of food-grade SLN delivery systems has been evaluated for encapsulation of food ingredients. Several research works have been published on encapsulation of food ingredients such as plant extracts, essential oils, pure polyphenols, carotenoids, and polyunsaturated fatty acids (PUFAs) in SLNs which will be discussed in Chapter 6 along with more details about their preparation methods, characterization, and analysis.

3.2 Nanostructured lipid carriers As mentioned in Section 3.1, drawbacks of SLNs can be dissolved by using blends of solid lipids with liquid lipids. Actually by adding the oil into SLNs,

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the highly ordered crystalline structures of SLNs are shifted to more disordered solid matrices which results in less expulsion of surrounded bioactives and consequently a low tendency toward undesirable changes in particle morphology, aggregation, and gelation (Gonçalves et al., 2018). This sort of colloidal nanodelivery systems is often referred to as a NLC or oilloaded SLN. The NLCs contain partially crystallized lipid droplets and have an amorphous crystalline structure (Hung et al., 2011; Tamjidi et al., 2013). NLCs are a kind of oil-in-water (O/W) emulsion system which are composed of both liquid lipids with melting points much lower than the ambient temperature (30%) and solid lipids with melting points above the room temperature (70%) within the inner phase along with suitable emulsifiers in outer phase for attaining a fine dispersion of these lipids in aqueous medium (Akhavan et al., 2018). In this system, the bioactive compounds are dissolved in the oil phase and all together are encapsulated in the less ordered crystalline structures of solid matrix. Thus, the loading capacity of NLCs increases compared with other colloidal delivery systems. The key factors which should be considered for selection of a suitable lipidic blend being utilized in the NLC structures are (1) the good solubility of encapsulated bioactive in lipidic matrix; (2) the solid and liquid lipids used in NLC structures should have a good miscibility and compatibility with each other; (3) the lipidic blend should be resistant against chemical oxidative degradations; and (4) the lipidic matrix should be biodegradable and food grade (Katouzian et al., 2017). Solid lipids which can be applied in preparation of NLCs are similar to SLNs. In terms of liquid oils, medium chain triglycerides such as miglyol 812, octyl octanoate, and oleic acid are some common ingredients. In order to provide more therapeutic benefits and improve delivery properties, different healthful oils such as olive oil (Soleimanian et al., 2018), fish oil (Lacatusu et al., 2013), and grape seed oil (Lacatusu et al., 2012) have also been utilized successfully as liquid lipids for NLC production. Applied surfactants are also similar to those described for SLNs (Section 3.2). Based on the lipids used in the NLC structure and the preparation parameters, three kinds of structures have been proposed for NLCs (Katouzian et al., 2017): imperfect structure (when various lipids with different structures are used); amorphous (by mixing the solid lipid with special lipids); and multiple type (the oil concentration is higher than the other structures). More details along with preparation methods, food applications,

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characterization, bioavailability, and health aspects of NLCs have been provided in Chapter 7.

3.3 Nano-organogels (nano-oleogels) Organogels can be defined as organized organogelator molecules selfassembled into supramolecular structures entrapping a hydrophobic solvent and resulting in a change of state, from sol to gel (Esposito et al., 2018). A subclass of these organogels are nano-organogels; organogels which are organized in specific nanostructures through noncovalent interactions (John et al., 2006). Due to their outstanding thermoreversible properties, organogels, and particularly nano-organogels, have found numerous applications in fields as diverse as material research (Fujita et al., 2006; Lv et al., 2017), pharmaceutical drug delivery (Park et al., 2016), sensors and nanowires (Xie et al., 2017), or water purification systems (Prathap et al., 2018). Because of their exclusive thermal, rheological and nutritional properties, oleogels made from edible oils have drawn the attention of the food and pharmaceutical industries. Organogelators are categorized into two main groups, low-molecularmass organic gelators (M  3000 Da) and polymeric organic gelators (M  3000 Da) (Kirilov et al., 2015). In food applications, edible oil organic gelators (EDOGs) present new promising systems which exclude the use of additional hydrogenated or saturated fats. They are used to retain the oil migration and mobility, factors with a main importance in food preparation and storage. EDOGs have been designed to replace unhealthy fats in oilcontained products and goods, such as baking fats (margarine and shortening), processed meat and sauces, dairy products, confections, ice cream, and food-based dispersions. EDOGs are also recognized to have a good organogel functionality, are low cost, are easy to handle, and have effectiveness at small quantities (Chaves et al., 2018; Pandolsook and Kupongsak, 2017). Among the food-grade organogelators, ethyl cellulose is the most promising organogelator for replacing the saturated fats in different foods. Among low-molecular organogelators, D-benzylidene sorbitol (DBS) derivatives are promising organogelators for edible oils. DBS and its derivatives are commonly applied in different domains from pharmaceuticals to cosmetic products (Kirilov et al., 2015). It is a derivative of D-sorbitol, with a butterfly-shaped structure with both hydrophilic and lipophilic groups, which lend self-assembly properties. hydroxy stearic acid, another

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promising low-molecular organogelator has been employed in the formulation of organogels. GLNs are prepared in two successive steps: (1) organogel formation and (2) its dispersion in aqueous medium. Organogel is prepared by dissolving the organogelator, and eventually other lipophilic additives (bioactive substances, photosensitizer agents, fragrances, etc.) in the corresponding organic liquid. For a complete dissolution of the oily ingredients, the mixture is homogenized (stirring, sonication, rotor stator homogenization) by heating above the melting point of the corresponding organogelator and then cooling at room temperature to form a compact and translucent gel (Lv et al., 2017). The next step for obtaining GLN dispersion is to add the water containing stabilizing/emulsifying agents into the previously obtained organogels. The mixture is heated to above Tgel of the starting organogel and the melting led to an oily layer at the surface of the solution. Then, the hot mixture is homogenized (sonication, rotor stator homogenization). The emulsion formed is then cooled at room temperature, leading to the dispersion of organogel particles. Nano-organogel structures are classified into three elemental groups including emulgels, bigels, and lyotropic gels (Carranca et al., 2017): (1) Emulgel is a biphasic system and a soft-solid material composed of either O/W or W/O emulsions gelled by gelling agents (Ashara et al., 2014; Wan et al., 2018). Gels obtained from the gelation of W/O emulsions are named as emulsion organogel, and the gels formed from the O/W emulsions are known as emulsion hydrogel. (2) Bigels are innovative semisolid twophase gel systems able to properly control the delivery of active ingredients. They possess the advantages typical of both gels. On structural point of view, bigels differ from emulsions, creams, or emulgels. They possess significantly improved properties, which makes them a potential candidate to be used in pharmaceutical, cosmeceutical, or nutraceutical products. Their stable structural organization is a result of entrapment of the internal liquid phase of emulsion gels within the 3D network. (3) Liquid crystals are chemical systems which are prepared by self-assembly of solids and liquids. They are mesophases between the two phases and possess intermediate properties between those of a liquid and a solid. Liquid crystals are majorly divided into two types, (1) thermotropic liquid crystals and (2) lyotropic liquid crystals. Lyotropic liquid crystals are explored as potential bioactive delivery vehicles due to their favorable biological and physicochemical properties. The delivery of bioactive molecules and nutraceuticals is one of the newest and most promising applications of nanostructured organogels in the

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food industry. In particular, protecting and targeting the release of nutrients or active ingredients to suitable portions of the digestive system can be achieved by their entrapment in an organic gelled matrix (Norton et al., 2015). Chapter 8 presents a full coverage of nano-organogels, their preparation methods, characterization, and applications in the food industry particularly for the nanoencapsulation of food bioactive ingredients and improvement in their bioavailability and bioaccessibility.

4. Nanostructured phospholipid carriers for encapsulation of food ingredients Among lipid-based nanodelivery systems, nanostructures based on phospholipids are one of the most common carriers for encapsulation, preservation, and controlled release of hydrophilic and hydrophobic bioactive compounds due to the use of edible ingredients in their formulations (Ghorbanzade et al., 2017; Mozafari et al., 2008a). These carriers are formed through hydration of phospholipid emulsifiers when they are mixed in the water under little shear forces. Phospholipid molecules initially form regular sheets, which, after interconnection of hydrophobic tails, form a bilayer membrane resulting in some water entrapped within the interior of phospholipid vesicles which form nanoliposomes, as described in Chapter 9 (Katouzian et al., 2017). These properties render liposomes the targetability and simultaneous transport of both hydrophilic (inside the vesicles) and hydrophobic (in the bilayer membrane) compounds (Mozafari et al., 2008a). In addition to nanoliposomes, nanophytosomes with similar structures are used for loading different types of phenolic ingredients (Chapter 10). Following sections provide a brief overview of phospholipid nanocarriers.

4.1 Nanoliposomes Nanoliposomes are produced in food and pharmaceutical industries from surfactants (phospholipids) with moderate HLB ratios and optimum curvatures close to zero. The most commonly applied phospholipids for preparation of liposomes in the food industry are isolated and prepared from eggs, soybeans, sunflower, and milk. Commercial lecithin contains a blend of various phospholipids and other compounds such as free fatty acids, triglycerides, and sterols (Mozafari et al., 2008b; Taylor et al., 2005). Phosphatidyl ethanolamine and phosphatidyl inositol are among the most important lecithin-forming phospholipids. Natural lecithins are basically hydrophobic molecules with an HLB w8, so they are not suited alone for stabilization of

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lipid carriers, but can be used for these purposes due to their structural properties in the composition of other surfactants. Two lecithin fatty acids can be isolated enzymatically or chemically to produce lysolecithin as a highly hydrophilic compound capable of stabilizing oil dispersions in water. Lecithins are zwitterionic surfactants, hence, they may have positive, negative, or neutral charges based on electrolyte content or the pH value. On the other hand, lecithins possibly bear large amounts of unsaturated fatty acids and are, therefore, unstable against oxidation. These compounds have been announced to be safe for extensive commercial use in food and pharmaceutical practices (Ghorbanzade et al., 2017; Tavakoli et al., 2018). Beside the above compounds, other natural materials like squalene and vitamin E have also been utilized as liquid lipids in the composition and production of nanoliposomes. Different structural shapes and sizes can be designed for nanoliposomes depending on the components, production techniques, and environmental circumstances (Sarabandi et al., 2019). Unilamellar liposomes (UL) show a balloonlike structure consisting of a simple monolayer while multilamellar liposomes possess an onionlike structure composed of several single-layer cases. UL liposomes may be classified as small unilamellar vesicles with diameters below 100 nm, or large unilamellar vesicles with diameters over 100 nm. The multivesicular vesicles include several smaller vesicles entrapped in a bigger vesicle (Taylor et al., 2005). Although phospholipids turn into unilamellars spontaneously when applied in the aqueous mediums, they could not have a structure with desirable features and good stability. Proper production processes should be used to produce liposomes with desirable properties such as apparent structure, loading capacity, particle size, and encapsulation entrapment (Maherani et al., 2011; McClements, 2014; Rafiee and Jafari, 2018). Some common methods for the production of nanoliposomes are thin film hydration, reverse-phase evaporation, microfluidization, heating method, solvent/surfactant displacement, homogenization/sonication, and extrusion which will be explained in Chapter 9. Different factors such as mean particle size, phase-transition temperature, zeta potential, phospholipid membrane composition, storage conditions, and environmental tensions (e.g., temperature and pH) affect the stability and efficiency of nanoliposomal encapsulation during storage. Some strategies such as coating with other biopolymers, lyophilization, application of stabilizers, etc. have been proposed for improving the stability and structural modification of nanoliposomes. These topics along with application of nanoliposomes for

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encapsulation of various food bioactive ingredients will be discussed in Chapter 9.

4.2 Nanophytosomes Most of the biologically active phytocompounds such as flavonoids have affinity to the aqueous phase or polar compounds. Poor lipid solubility limits their ability to pass across the biological membranes which are composed of lipid-based materials. Moreover, multiple phenolic rings cause a large molecular size, which again limits absorption via a simple diffusion (Walle, 2004). Also, it is possible that some decomposing phenomena for multiconstituent herbal extracts will occur in the gastric conditions. Delivering an efficient level of phytoconstituents to the body improves the effectiveness of any herbal extracts. It is reported that nanocarriers can potentially improve the bioavailability and physicochemical stability of bioactive compounds (Assadpour and Jafari, 2018; Jafari and McClements, 2017; Rostamabadi et al., 2019; Vinod et al., 2010). Phytosomes are a new type of herbal extract formulations providing better absorption and enhanced bioavailability in comparison with standard plant extracts (Acharya et al., 2011; Karimi et al., 2015). The main interaction occurred in the phytosomal platforms is interaction between the herbal extract constituents and phospholipids, which is also known as phytoe phospholipid interaction. This interaction generates water- and lipidsoluble complexes, which is the major advantage of phytosomal systems. Phytosome technology has been sufficiently enhanced the bioavailability of many herbal extracts such as curcumin (Zhang et al., 2013), silymarin (Amit et al., 2013; Yanyu et al., 2006), Ginkgo biloba (Panda and Naik, 2014), grape seed, green tea, ginseng, and olive oil polyphenols (Kareparamban et al., 2012). Thus, this technology could be potentially established for designing and producing new dietary supplements of medicinalefunctional foods. Phytosomes are formulated by incorporating the standardized plant extract or the phytoactive compounds into phospholipids, mainly phosphatidylcholine (PC), to generate lipid-compatible molecular structures (Shyam and Kumar, 2012; Theodosiou et al., 2014). They are similar to cell membranes in the case of chemical structures and are considered as phytolipid delivery system (Bhosale et al., 2015). Nonpolar solvents such as dioxane, methylene chloride, acetone, and ethyl acetate, which are used for production of the phytosomes, provide proper interactions between phospholipids

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and polyphenols (Guliani et al., 2016). In order to produce the phytosomes for food applications, the food-grade solvents such as ethanol can be used, although the number of such solvents is very limited. Formation of the phytosomes is based on the hydrogen bonds (H-bonds), the main interaction occurred in phytosomal structures, that are placed between the polar parts of the phospholipids (i.e., phosphate groups) and the bioactive substance. In general, the structure of phytosomes shows some similarities to liposomes when exposed to water. Mixing bioactive ingredients with PC in specific ratios is the major step in the production of phytosomes and liposomes (Patel et al., 2014). Although liposomes and phytosomes have some similarities, there are differences between them in terms of chemical structure. In liposome, there is no H-bond founded between the polar group of phospholipid molecules and bioactive substances. The phospholipid molecules surround the bioactive components instead of making chemical interactions through H-bonds. On the other side, in phytosomes, the phospholipid and the phytoactive components make H-bonds to each other at the polar parts. Optimum molar ratios for this reaction are reported as 1:1 or 2:1 (phospholipid: bioactive). These differences result in phytosomes to have much better absorption and more bioavailability than liposomes (Babazadeh et al., 2018; Semalty et al., 2010). Chapter 10 gives more information about nanophytosome properties, their applications for encapsulation of bioactive ingredients, characterization, and preparation methods.

5. Nanostructured surfactants for encapsulation of food ingredients Surfactants are amphiphilic molecules with two distinct regions consisting of a structural group that has very little attraction for the solvent, and other group that has strong attraction for the solvent. The hydrophilic part is referred as the head group and the hydrophobic part as the tail. Depending on the nature of hydrophilic group, surfactants can be classified as ionic or nonionic. In the case of nonionic surfactants, the surface-active portion has no apparent ionic charges. Surfactant-based nanocarriers are vesicles/ nanostructures formed from the self-assembly of different surfactants in aqueous media resulting in different nanodelivery systems such as niosomes (Chapter 11), cubosomes, hexosomes (Chapter 12), etc. The following sections briefly describe these nanocarriers as a high-potential group of nanodelivery systems for the food bioactive ingredients.

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5.1 Niosomes Niosomes are vesicles formed from the self-assembly of nonionic surfactants in aqueous media resulting in closed bilayer structures similar to liposomes (Uchegbu and Vyas, 1998). Niosomes are formed based on the unfavorable interactions between surfactants and water molecules, and they can also entrap hydrophilic, lipophilic, and amphiphilic compounds (Mahale et al., 2012; Moghassemi and Hadjizadeh, 2014). Niosome size is ranged from 10 nm to 3 mm (Moghassemi and Hadjizadeh, 2014). The main advantages of niosomes with respect to liposomes are better skin permeation potential, sustained release characteristics, higher stability, and lower cost (Marianecci et al., 2014; Uchegbu and Vyas, 1998). Niosomes are mainly used for encapsulation of bioactive compounds in order to enhance their solubility and bioavailability. Lipophilic compounds are incorporated at the lipidic membrane while hydrophilic compounds are encapsulated in the hydrophilic inner compartment. The structure of the nonionic surfactant plays an important role in niosome formation. Normally, to form a bilayer membrane in aqueous media, a surfactant with a higher contribution of the hydrophobic parts is necessary. However, with an optimum level of hydrophobic membrane stabilizer (e.g., cholesterol), it seems that niosomes are indeed formed from hydrophilic surfactants (Santucci et al., 1996). In order to select the appropriate surfactant, there are two interesting parameters to consider: HLB and CPP. Also, in order to obtain niosomes with a high stability, the use of additives in niosomal formulation is very common such as membrane additives, surface additives, and steric additives (Chapter 11). Niosomal formation is not spontaneous and some energy input is required. There are more than 20 different methods reported to produce niosomes (Moghassemi and Hadjizadeh, 2014; Walde and Ichikawa, 2001) and the most common techniques have been discussed in Chapter 11. Generally, there are two main loading methods into niosomal vesicles, active and passive loading. Most of niosomal preparation methods implies passive loading of biocompounds. Just transmembrane pH gradient method corresponds active loading due to a change of pH between each side of niosome. Regarding passive loading methods, there are some appropriate techniques for encapsulation of lipophilic surfactants or hydrophilic ones. As a normal trend, it can be concluded that the encapsulation of lipophilic bioactives obtains larger encapsulation efficiencies than the encapsulation of hydrophilic ones. As it was mentioned, the encapsulation of lipophilic

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compounds is within the vesicle membrane, while the encapsulation of hydrophilic compounds takes place in the inner part of the vesicle. Since hydrophilic bioactives are soluble in external aqueous media, their encapsulation is being hindered and moreover their release is enhanced. Selection of the most appropriate method of preparation is performed according to the surfactants and stabilizers selected, as well as the bioactive compound that will be encapsulated, and the characteristics required depending on their final application. Once the bioactive compound is encapsulated, a solution which contains the bioactive-loaded vesicles, surfactant and stabilizer molecules, and free bioactives is obtained. In order to study the effect of the encapsulated compound, it is necessary to remove the unencapsulated ingredients from the solution. Moreover, this effect is also important on the calculation of encapsulation efficiency, depending on the method used. Five different methods are commonly used for the purification of niosomes: dialysis, gel filtration, centrifugation and ultracentrifugation, and minicolumns, which will be discussed in Chapter 11.

5.2 Cubosomes and hexosomes Cubosomes and hexosomes are nano-self-assemblies in the form of nonlamellar liquid crystalline nanoparticles which can be used for encapsulation of different food bioactives. The produced nanodispersions possess unique structural properties and high interfacial area (400 m2/g surfactant) similar to those of their corresponding bulk (nondispersed) lyotropic nonlamellar liquid crystalline phases (Angelova et al., 2017; Azmi et al., 2015, 2016, 2018; Wibroe et al., 2015; Yaghmur and Glatter, 2009). These nanocarriers are capable of enhancing the solubilization of poorly water-soluble drugs and nutraceuticals and therefore are attractive for various delivery applications. Lyotropic lamellar and inverse nonlamellar (type 2) liquid crystalline phases of surfactant-like lipids and their corresponding aqueous nanostructured dispersions have received much attention owing to their attractiveness in various fields. For pharmaceutical and food delivery applications, lamellar phase-forming phospholipids are commonly used in the literature to prepare nanoliposomes (Chapter 9). The inverse nonlamellar phases are divided into micellar and bicontinuous structures and include highly ordered bicontinuous cubic (Q2) and discontinuous hexagonal (H2) liquid crystals (Hyde et al., 1997; Larsson, 2009; Luzzati et al., 1993; Yaghmur and Rappolt, 2013; Yaghmur et al., 2012). The inverse bicontinuous cubic phases are 3D complex fluids consisting of curved lipid bilayers forming two

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nonintersecting water nanochannels. The inverse hexagonal (H2) phase is arranged in a two-dimensional (2D) lattice of dense-packed cylindrical rodlike hydrophilic nanochannels with the polar headgroups of the single amphiphilic lipid (or the amphiphilic lipid combination) directed inward, toward the core of these hydrophilic domains; whereas the acyl chains are directed outward. This unique family of structured nanodispersions are known in the literature as ISAsomes (Internally Self-Assembled somes) and can be used in the development of promising platforms for the solubilization and delivery of nutraceuticals, particularly poorly water-soluble food additives and bioactive materials (Yaghmur et al., 2005; Yaghmur and Glatter, 2009). In the production of cubosomes, the most widely used amphiphilic compounds are phytantriol, and the mono- and di-unsaturated monoglycerides of monoolein (MO) and monolinolein (MLO) (Azmi et al., 2015; Nilsson et al., 2014). For the preparation of hexosomes and other ISAsomes, we generally use these main lipid constituents in combinations with hydrophobic additives (e.g., vitamin E, oleic acid, R(þ)-limonene, and triglycerides) (Azmi et al., 2015; Wibroe et al., 2015). It is also possible to form such nanodispersions by using a single more wedge-shaped amphiphilic lipids as compared with MO and MLO such as u-3 PUFA monoacylglycerols (Shao et al., 2018; Yaghmur et al., 2017). Cubosomes, hexosomes, and related ISAsomes are usually prepared following a top-down approach, where the single lipid (or a lipid combination) is subjected to a high-energy emulsification method such as ultrasonication and microfluidization in the presence of an efficient stabilizer (secondary emulsifier) and excess water (Azmi et al., 2015; Gustafsson et al., 1997; Yaghmur and Glatter, 2009). In recent studies, possible production of cubosomes, hexosomes, and other structurally tunable ISAsomes by means of a low-energy emulsification method has been reported based on vortexing soybean phospholipid with Citrem at different lipid compositions (Azmi et al., 2016). More details about cubosomes and hexosomes, their preparation, stabilization, characterization, and application for encapsulating food bioactives has been provided in Chapter 12.

References Abaee, A., Mohammadian, M., Jafari, S.M., 2017. Whey and soy protein-based hydrogels and nano-hydrogels as bioactive delivery systems. Trends in Food Science & Technology, 70 (Supplement C), 69e81. Abbasi, F., Samadi, F., Jafari, S.M., Ramezanpour, S., Shams Shargh, M., 2019. Ultrasoundassisted preparation of flaxseed oil nanoemulsions coated with alginate-whey protein for targeted delivery of omega-3 fatty acids into the lower sections of gastrointestinal tract to enrich broiler meat. Ultrasonics Sonochemistry 50, 208e217.

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Acharya, N., Parihar, G., Acharya, S., 2011. Phytosomes: novel approach for delivering herbal extract with improved bioavailability. International Journal of Pharmaceutical Sciences 2, 144e160. Akhavan, S., Assadpour, E., Katouzian, I., Jafari, S.M., 2018. Lipid nano scale cargos for the protection and delivery of food bioactive ingredients and nutraceuticals. Trends in Food Science & Technology 74, 132e146. Amit, P., Tanwar, Y., Rakesh, S., Poojan, P., 2013. Phytosome: phytolipid drug dilivery system for improving bioavailability of herbal drug. Journal of Pharmaceutical Science and Bioscientific Research 3 (2), 51e57. Angelova, A., Garamus, V.M., Angelov, B., Tian, Z., Li, Y., Zou, A., 2017. Advances in structural design of lipid-based nanoparticle carriers for delivery of macromolecular drugs, phytochemicals and anti-tumor agents. Advances in Colloid and Interface Science 249, 331e345. Ashara, K.C., Paun, J.S., Soniwala, M.M., Chavada, J.R., Mori, N.M., 2014. Microemulsion based emulgel: a novel topical drug delivery system. Asian Pacific Journal of Tropical Disease 4, S27eS32. Assadpour, E., Jafari, S.M., 2018. A systematic review on nanoencapsulation of food bioactive ingredients and nutraceuticals by various nanocarriers. Critical Reviews in Food Science and Nutrition 1e47. Assadpour, E., Jafari, S.M., 2019. Chapter 3 e Nanoencapsulation: techniques and developments for food applications. In: L opez Rubio, A., Fabra Rovira, M.J., Martínez Sanz, M., G omez-Mascaraque, L.G. (Eds.), Nanomaterials for Food Applications. Elsevier, pp. 35e61. Assadpour, E., Maghsoudlou, Y., Jafari, S.-M., Ghorbani, M., Aalami, M., 2016. Optimization of folic acid nano-emulsification and encapsulation by maltodextrin-whey protein double emulsions. International Journal of Biological Macromolecules 86, 197e207. Azmi, I.D., Moghimi, S.M., Yaghmur, A., 2015. Cubosomes and hexosomes as versatile platforms for drug delivery. Therapeutic Delivery 6 (12), 1347e1364. Azmi, I.D., Wibroe, P.P., Wu, L.P., Kazem, A.I., Amenitsch, H., Moghimi, S.M., Yaghmur, A., 2016. A structurally diverse library of safe-by-design citremphospholipid lamellar and non-lamellar liquid crystalline nano-assemblies. Journal of Controlled Release 239, 1e9. Azmi, I.D.M., Ostergaard, J., Sturup, S., Gammelgaard, B., Urtti, A., Moghimi, S.M., Yaghmur, A., 2018. Cisplatin encapsulation generates morphologically different multicompartments in the internal nanostructures of nonlamellar liquid-crystalline selfassemblies. Langmuir 34 (22), 6570e6581. Babazadeh, A., Zeinali, M., Hamishehkar, H., 2018. Nano-phytosome: a developing platform for herbal anti-cancer agents in cancer therapy. Current Drug Targets 19 (2), 170e180. Berton-Carabin, C.C., Schroën, K., 2015. Pickering emulsions for food applications: background, trends, and challenges. Annual Review of Food Science and Technology 6 (1), 263e297. Bhosale, A.P., Patil, A., Swami, M., 2015. Herbosomes as a Novel Drug Delivery System for Absorption Enhancement. Bonnet, M., Cansell, M., Berkaoui, A., Ropers, M.H., Anton, M., Leal-Calderon, F., 2009. Release rate profiles of magnesium from multiple W/O/W emulsions. Food Hydrocolloids 23 (1), 92e101. Braisch, B., K€ ohler, K., Schuchmann, H.P., Wolf, B., 2009. Preparation and flow behaviour of oil-in-water emulsions stabilised by hydrophilic silica particles. Chemical Engineering & Technology 32 (7), 1107e1112.

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SECTION ONE

Nanoemulsions for encapsulation of food ingredients

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CHAPTER TWO

Encapsulation of food ingredients by single O/W and W/O nanoemulsions Francesco Donsì1, Krassimir P. Velikov2, 3, 4 1

Department of Industrial Engineering, University of Salerno, Fisciano, SA, Italy Unilever R&D Vlaardingen B.V., The Netherlands 3 Institute of Physics, University of Amsterdam, The Netherlands 4 Debye Institute for Nanomaterials Science, Utrecht University, The Netherlands 2

1. Introduction Nanoemulsions can be defined as a biphasic colloidal disperse system in the submicron size range, where one liquid phase is intimately dispersed as fine droplets in another liquid phase. The term refers to both dispersions of oil droplets in a continuous aqueous phase (oil-in-water or O/W nanoemulsions) and water droplet in a continuous oil phase (water-in-oil or W/O nanoemulsions). Nanoemulsions are kinetically stable colloidal dispersions (Gupta et al., 2016), consisting of droplets of the disperse phase stabilized in the immiscible continuous phase (external phase or continuous phase), through the use of an emulsifying agent, typically made of surfactant molecules, (bio)polymers, or solid particles, which form a film around the emulsion droplets, referred to as intermediate phase or interphase (Kumar and Kumar, 2018). Nanoemulsions are also known as miniemulsions, submicron emulsions, nanoscale emulsions, and colloidal emulsions (McClements and Rao, 2011); often they are simply called emulsions. Although there is a common understanding that the nanoemulsion droplets fall in the submicrometer size, a harmonized definition of the distinction of nanoemulsions from conventional (macro)emulsions is still lacking: perhaps also difficult to establish. According to different literature sources, the size range (as droplet diameter) that identifies a nanoemulsion is reported to vary from a lower limit of 20 nm to an upper limit spanning between 100 and 500 nm. These definitions are grounded on the evidence that some macroscopic properties, such as physical stability against sedimentation or creaming, optically transparent Lipid-Based Nanostructures for Food Encapsulation Purposes ISBN: 978-0-12-815673-5 https://doi.org/10.1016/B978-0-12-815673-5.00002-7

© 2019 Elsevier Inc. All rights reserved.

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appearance, rheology, reactivity, or biological activity, change when the droplet size is decreased from micrometer to nanometer range, and therefore are significantly different between an emulsion and a nanoemulsion, even if formulated with the same constituents (McClements, 2011; Solans and Solé, 2012). However, considering that the variation of such properties depends on the intended application, and the required formulation, this issue is still open (Solans and Solé, 2012). According to the EU regulatory framework (Regulation (EU) No 1363/2013), any manufactured material is considered as a nanomaterial if 50% of the number-based size distribution of its constituents exhibits one or more external dimensions in the nanoscale range, intended in the 1e100 nm range (Martins et al., 2015). In this chapter, we will adopt a less strict convention that a nanoemulsion is characterized by a mean droplet diameter below 1000 nm. We will, however, emphasize the cases where the use of much smaller droplets is beneficial or desired. Similar to nanoemulsions, microemulsions are also in the nanometric range (typically, with a mean droplet size < 100 nm). However, microemulsions are thermodynamically stable dispersions, which form spontaneously when the aqueous, oil, and amphiphilic components are brought into contact. In general, microemulsions consist of a variety of structures, including liquid crystals, gels, and vesicles dispersed in the continuous phase, and require significantly higher amounts of surfactant than emulsions and nanoemulsions, typically over 30 wt% (Porras et al., 2008). Therefore, nanoemulsions are finding application in diverse food, cosmetic, and pharmaceutical products. One of the main distinctive properties of nanoemulsions is the capability to encapsulate/localize different payload compounds in combination with excellent stability and efficient delivery and high bioaccessibility from food matrices ( Jafari et al., 2017). In particular, nanoemulsions enable to significantly increase the dispersibility of molecules, which are insoluble in the continuous phase, and increase their bioaccessibility and bioavailability, thanks to their submicron size, high surface area, as well as protection and controlled release of a wide range of compounds (Donsì et al., 2013b; Donsì and Ferrari, 2016; Kumar and Kumar, 2018). The stability of a colloidal dispersion against gravitational separation, by creaming or sedimentation, tends, in fact, to significantly increase for droplet diameters below about 180 nm, when Brownian motion becomes dominating over gravitational forces (McClements and Rao, 2011). Remarkably, also transparency depends nonlinearly on droplet size: the appearance of a colloidal dispersion is reported to become translucent

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or transparent only for droplet diameters below about 60 nm (Wooster et al., 2008). The unique properties of nanoemulsions reflect, even though indirectly, also on the uptake of the payload compounds upon ingestion (Faridi Esfanjani et al., 2018; Jafari and McClements, 2017). As an example, it was shown that when curcumin is delivered in nanoemulsions, its uptake was significantly promoted, in comparison with curcumin solubilized in a solvent (Gupta et al., 2016). However, nanoemulsions are more efficient in promoting the uptake of payload compounds, also in comparison with conventional emulsions. Experimental evidence was, in fact, reported that the bioavailability of lipophilic compounds is significantly enhanced when delivered by emulsions with a mean droplet diameter below about 200 nm, which was likely ascribed to the steep increase in the local water solubility in close proximity to the droplet surface of lipophilic components, because of the increased Laplace pressure (McClements, 2012). This observation should be coupled to another remarkable experimental evidence: the main mechanism of absorption of the nanoemulsion payload compounds is based on the preliminary release of the compounds in the gastric fluid, rather than occurring from intact micelles (Feeney et al., 2016). Several studies have shown that the compounds delivered by nanoemulsions are absorbed at different sites of the gastrointestinal tract, i.e., the gastric lumen, stomach, and small intestine (Katamreddy et al., 2018). Moreover, it was also shown that the diffusion through biological membranes is inversely proportional to the mucin concentration in the mucous layer deposited on the membrane surfaces (Katamreddy et al., 2018). Therefore, the role of nanoemulsions on payload compound absorption concerns the direct interaction with mucins, in function of nanoemulsion composition, viscosity, size, and surface charge, which influence the rate of diffusion through the mucous layer. Subsequently, emulsion and nanoemulsion droplets play an important role in enhancing the electrostatic interaction with cellular surfaces, which are dominated by negatively charged sulfated proteoglycans. Considering that colloidal systems with a higher surface charge are able to bind more strongly to the cell membranes, this explains why nanoemulsions, with significantly larger surface area than conventional emulsions, promote the cellular uptake of the payload compounds via pinocytosis, nonspecific or receptor-mediated endocytosis or phagocytosis (Katamreddy et al., 2018). The unique properties of nanoemulsions in comparison with conventional emulsions extend also to the nanoconfinement effects on the disperse phase during freezingethawing. Recent data showed that the crystallization

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of both phytosterols and lipids in nanoemulsion droplets was completely suppressed due to the nanoscale confinement, where no suppression was observed in conventional emulsions (Ribeiro et al., 2016). In this chapter, the formulation and fabrication of O/W and W/O nanoemulsions, and their use as delivery systems for food ingredients will be discussed.

2. Formulation of nanoemulsions The main formulations and fabrication strategies for nanoemulsions, projected against the main restrictions posed by the food industry, such as food compatibility of the ingredients, use of nontoxic solvents, as well as low-cost and scalable processes, are discussed in this section. Nanoemulsions, differently from microemulsions, are thermodynamically unstable systems, which naturally tend towards phase separation (McClements and Jafari, 2018b). However, gravitational separation is hampered by the onset of Brownian motions, which dominate over inertial motion in the typical size range of nanoemulsions. Depending on their formulations, nanoemulsions might undergo other instability phenomena, such as coalescence, Ostwald ripening or flocculation, which cause the size of their drops to increase with time, ultimately leading to phase separation (Porras et al., 2008). Therefore, an appropriate nanoemulsion formulation is required to impart the long-term kinetic stability (Solans and Solé, 2012), while abiding by the severe constraints, posed by the current food regulations, as well as by possible impact on the organoleptic properties, or by economic considerations.

2.1 Food-grade emulsifiers Emulsifiers are surface-active substances, which are able to form monomolecular, multimolecular, or particulate films around the dispersed droplets, contributing to emulsion formation, and promoting emulsion stability. Different synthetic and natural emulsifiers are currently utilized in the food industry, such as proteins, polysaccharides, phospholipids, and surfactants (Sessa and Donsì, 2015). Monolayer films are generally formed by surfactants and phospholipids, which adsorb at the watereoil interface, significantly reducing the interfacial tension ( Jaiswal et al., 2015). The combination of different surfactants, although not always preferred from an industrial point of view, might offer some functional advantages over a single surfactant (McClements and Jafari,

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2018a; Porras et al., 2004) because of the combination of a hydrophilic surfactant in the aqueous phase and a hydrophobic surfactant in the oil phase to form a complex film at the interface of both O/W or W/O nanoemulsions. Multimolecular films are, instead, generally formed by macromolecules around the oil droplets in O/W emulsions. These films are stronger and more coherent than monolayer films, but they cause a lower effect on the interfacial tension ( Jaiswal et al., 2015). However, the use of macromolecules as emulsifier might also cause depletion flocculation, induced by the presence of nonadsorbed polymers or micelles in the aqueous phase, which generates an osmotic attraction that promotes droplet aggregation (Helgeson, 2016). Solid particulate films are formed by small solid particles, which are wetted by both the oil and aqueous phases. Therefore, they concentrate at the oilewater interface, forming a film around the dispersed droplets, which is very effective in preventing coalescence ( Jaiswal et al., 2015). The mechanisms of stabilization of nanoemulsion droplets are based on steric or electrostatic stabilization. Steric stabilization is a short-range repulsive interaction, which arises upon the overlapping of the interfacial layers of two approaching droplets. The intensity of steric interaction grows with the thickness and affinity for the continuous phase of the emulsifier layer (Ozturk and McClements, 2016). Electrostatic stabilization is instead a short- to long-range interaction, depending on the droplets’ electrical charges. The electrostatic repulsion generated between droplets with similar charges depend, therefore, on the surface charge density and the ionic strength of the continuous phase, differently from the steric stabilization (Ozturk and McClements, 2016). The steric interaction is the main mechanism of stabilization of W/O nanoemulsions, for which, instead, the effect of electrostatic repulsion is negligible because of the low electrical conductivity of oil (Tabibiazar and Hamishehkar, 2015). Fig. 2.1 schematically shows the main types of emulsifiers, and their classification, used in food applications. There is a growing demand in the food industry for natural food-grade emulsifiers. However, for their effective use in the food industry, they are required to possess a high surface activity, fast adsorption kinetics to adsorb onto oilewater interfaces (Donsì et al., 2012b), capability of high surface coverage and of steric or electrostatic repulsion to prevent droplet recoalescence during homogenization and stabilize the nanoemulsions over their shelf life (Ozturk and McClements, 2016).

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Figure 2.1 Classification of the main food-grade emulsifiers.

Small-molecule surfactants can be characterized by a specific hydrophilicelipophilic balance (HLB) number, which gives some empirical indication on their surface activity, by determining the prevalence of the hydrophilic head groups or of the hydrophobic tails (Maali and Mosavian, 2013). In general, surfactants with HLB numbers between 8 and 18 are able to form monolayers at O/W interface with a curvature toward the oil phase, significantly lowering the interfacial tension, and hence promoting the conditions needed for the formation of nanometer-sized O/W droplets (Donsì and Ferrari, 2016). Conversely, a HLB number between 3 and 6 promotes the formation of W/O emulsions. However, the HLB number does not give any clear prediction of the amount of surfactant to be used to form a stable emulsion (Macedo et al., 2006) and provides only limited information about the behavior of the surfactant at muting environmental conditions or changing system composition (Komaiko and McClements, 2016; McClements, 2015). Finally, because of its definition, the HLB number cannot be determined for other types of emulsifiers. Different food-grade surfactants, such as saponins, sucrose esters, polysorbates, or fatty acids, are available for the formulation of O/W nanoemulsions, as shown in Table 2.1. The formulation of W/O nanoemulsions is typically based on the use of polyglycerol polyricinoleate (PGPR) or Span 80 as primary emulsifiers. It is often required at high concentration (4.0e6.0 wt%), which might not be allowed in some food products by regulatory bodies (Ruan et al., 2018), or might result in unpleasant off-taste (Tekin Pulats€ u et al., 2018). Proteins are surface-active macromolecules, which, thanks to their hydrophilic and hydrophobic amino acids along with their polypeptide chains, are particularly suitable to adsorb onto oilewater interfaces of oil droplets,

References

Surfactants

Tween 80 Tween 60 Tween 20

Tween 20 Span 20 Span 80 Span 80 PGPR (polyglycerol polyricinoleate) PGPR (polyglycerol polyricinoleate) Sugar esters (sucrose palmitate) Sugar esters (sucrose palmitate)

10% wt sunflower oil in water nanoemulsion (3% wt emulsifier): dH ¼ 168 nm, PdI ¼ 0.15 2% wt water in olive oil nanoemulsions (4% wt emulsifier): dH ¼ 130 nm, PdI ¼ 0.2 6% wt peanut oil in water nanoemulsions containing resveratrol (3% wt emulsifier, made of Tween 20:glycerol monooleate ¼ 1:1): dH ¼ 128 nm, PdI ¼ 0.12 2% wt water in olive oil nanoemulsions (6% wt emulsifier): dH ¼ 100 nm, PdI ¼ 0.12 2% wt water in olive oil nanoemulsions (4% wt emulsifier): dH ¼ 110 nm, PdI ¼ 0.07 2% wt water in olive oil nanoemulsions (6% wt emulsifier): dH ¼ 130 nm, PdI ¼ 0.05 17% wt water in soybean oil nanoemulsions (9% wt emulsifier): dH ¼ 19 nm, PdI ¼ N.A. 20% wt water in soybean oil nanoemulsions (5% wt emulsifier): dH ¼ 15 nm, PdI ¼ N.A. 30% wt skim milk in sunflower oil nanoemulsions (1% wt emulsifier): dH ¼ 15 nm, PdI ¼ N.A. 6% wt peanut oil in water nanoemulsions containing resveratrol (1.3% wt emulsifier, in combination with soy lecithin): dH ¼ 137 nm, PdI ¼ 0.22 8% wt sunflower oil and 2% wt essential oil in water nanoemulsions (1% wt emulsifier): dH ¼ 123e168 nm, PdI ¼ 0.07e0.12

Calligaris et al. (2018) Polychniatou and Tzia (2014) Sessa et al. (2014)

Polychniatou and Tzia (2014) Polychniatou and Tzia (2014) Polychniatou and Tzia (2014) Gharehbeglou et al. (2019b) Gharehbeglou et al. (2019a) Gharehbeglou et al. (2019a)

Encapsulation of food ingredients by single O/W and W/O nanoemulsions

Table 2.1 Examples of emulsifiers used in the preparation of food-grade nanoemulsions. Emulsifier Nanoemulsion characteristics

Sessa et al. (2014)

Donsì et al. (2012b)

43

(Continued)

Sugar esters (sucrose monopalmitate) Saponins (tea and Quillaja) Quillaja saponins Ginger saponins

10% wt lemon oil in water nanoemulsion (5% wt emulsifier): dH ¼ 84 nm, PdI ¼ N.A. 10% wt medium-chain triglycerides in water nanoemulsions (1% wt emulsifier): dH ¼ 200 nm, PdI ¼ N.A. 5% vol orange oil (30% ester gum) in water nanoemulsions (20% wt emulsifier): dH ¼ 75 nm, PdI ¼ N.A. 5% wt soybean oil in water nanoemulsions containing astaxanthin (0.6% wt emulsifier): dH ¼ 140 nm, PdI ¼ N.A.

References

44

Table 2.1 Examples of emulsifiers used in the preparation of food-grade nanoemulsions.dcont'd Emulsifier Nanoemulsion characteristics

Rao and McClements (2011) Zhu et al. (2019) Zhang et al. (2016) Shu et al. (2018)

Phospholipids

Soy lecithin

Soy lecithin

Donsì et al. (2012b)

Arancibia et al. (2017)

Proteins

Whey protein isolates

Sodium caseinate b-Lactoglobulin

3% sunflower oil and 3% wt carvacrol in water nanoemulsion (6% wt emulsifier): dH ¼ 115 nm, PdI ¼ 0.24 1% wt eugenol in water nanoemulsions (2% wt emulsifier): dH ¼ 117 nm, PdI ¼ N.A. 5% wt medium-chain triglycerides oil in water nanoemulsions (1% wt emulsifier): dH ¼ 200 nm, PdI ¼ N.A.

Tastan et al. (2016)

Zhang et al. (2018) Ali et al. (2016)

Francesco Donsì and Krassimir P. Velikov

8% wt sunflower oil and 2% wt cinnamaldehyde in water nanoemulsions (1% wt emulsifier): dH ¼ 196 nm, PdI ¼ 0.35 10% wt avocado oil in water nanoemulsions (7.5% wt emulsifier): dH ¼ 180 nm, PdI ¼ 0.17

Soy protein isolates

Bhushani et al. (2016)

Donsì et al. (2010)

Polysaccharides

Gum Arabic Mesquite gum Modified starch (succinylated waxy maize starch) Modified starch (succinylated waxy maize starch) Modified starch (succinylated waxy maize starch) Pectin (high methoxyl pectin)

10% sunflower oil in water nanoemulsion (10% wt emulsifier): dH ¼ 137 nm, PdI ¼ N.A. 10% wt fish oil in water nanoemulsions (20% wt emulsifier): dH ¼ 165 nm, PdI ¼ 0.1 10% wt medium-chain triglycerides oil in water nanoemulsions (15% wt emulsifier): dH ¼ 130 nm, PdI ¼ N.A. 9% vol flax seed oil and 1% vol. eugenol in water nanoemulsions (15% wt emulsifier): dH ¼ 186 nm, PdI ¼ 0.07 5% vol orange oil (30% ester gum) in water nanoemulsions (20% wt emulsifier): dH ¼ 160 nm, PdI ¼ N.A.

Bai et al. (2016) García-Marquez et al. (2017) Donsì et al. (2011c)

Sharif et al. (2017)

Zhang et al. (2016)

2% vol essential oil in water nanoemulsions (1% wt emulsifier, together with 5% wt Tween 80): dH ¼ 200 nm, PdI ¼ N.A.

Guerra-Rosas et al. (2017)

20% wt hexadecane in water nanoemulsions (1% wt emulsifier): dH ¼ 350 nm, PdI ¼ N.A.

Jiménez Saelices and Capron (2018)

Encapsulation of food ingredients by single O/W and W/O nanoemulsions

Pea proteins

5% sunflower oil in water nanoemulsion containing green tea catechins (4% wt emulsifier): dH ¼ 244 nm, PdI ¼ N.A. 6% sunflower oil in water nanoemulsion (4% wt emulsifier): dH ¼ 150 nm, PdI ¼ N.A.

Solid particles

Nanocellulose (nanocrystals and TEMPO-oxidized nanofibrils)

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Francesco Donsì and Krassimir P. Velikov

forming thick interfacial layers. In addition, thanks to the charges of some amino acids of the protein backbone, proteins may generate also an electrostatic repulsion (Ozturk and McClements, 2016). Currently, the natural proteins mostly used as emulsifiers in the food industry include caseins and whey proteins (Ozturk and McClements, 2016), which are specifically suitable for stabilizing O/W nanoemulsions (Tastan et al., 2016). The use of proteins from plant sources as food emulsifiers has stimulated several studies, especially concerning pea, lupin, soy, and corn germ proteins (Donsì et al., 2010; Ozturk and McClements, 2016). However, the successful exploitation of plant proteins as emulsifiers should take into account the availability of the protein sources, their costs, and the definition of viable methods of protein isolation, fractionation, and purification (Ozturk and McClements, 2016). Only few examples of nanoemulsions prepared with vegetable proteins are reported in literature, as shown in Table 2.1. Despite most polysaccharides are only moderately surface-active, they can be modified by chemical or enzymatic reactions, by attaching nonpolar groups to their hydrophilic backbones, as in modified starches. However, some natural polysaccharides have good emulsifying properties in unmodified forms, such as gum Arabic (Hosseini et al., 2015) and other gum exudates (i.e., almond gum (Mahfoudhi et al., 2014), and apricot gum (Shamsara et al. 2015, 2017), or pectins (i.e., highly methylesterified citrus pectin and sugar beet pectin (Schmidt et al., 2015). Currently, gum Arabic is the most widely used natural polysaccharide in emulsions for the food and beverage industry, despite the interest for other natural gum exudates is continuously increasing (Mahfoudhi et al., 2014). Polysaccharides are specifically suitable to stabilize O/W emulsions, where they form, because of their generally large molecules, thick hydrophilic layers on oil droplets, hence requiring higher surface loads than proteins (Ozturk and McClements, 2016). The mechanism of stabilization of polysaccharide films is by steric repulsion, driven by the large hydrophilic groups protruding in the continuous phase (Ozturk and McClements, 2016), often associated with electrostatic repulsion. As shown in Table 2.1, polysaccharides are required in significantly larger amounts than other emulsifiers (i.e., surfactants or proteins) to stabilize emulsions at the nanoscale. Phospholipids, such as lecithin from soybeans, egg yolk, milk, sunflower kernels, or rapeseeds, are natural amphiphilic molecules, with a high surface activity because they have hydrophobic fatty acid tail groups and hydrophilic heads (Ozturk and McClements, 2016; Sessa et al., 2014, 2011). Thanks to their amphiphilic behavior, lecithins, containing varying concentrations of

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phosphatidylcholine, phosphatidylinositol, and phosphatidylethanolamine, and therefore of varying HLB, are suitable for the stabilization of both O/W and W/O emulsions (Donsì et al., 2011c; Sessa et al., 2011; Tekin Pulats€ u et al., 2018), mainly by electrostatic repulsion (Ozturk and McClements, 2016). They are often used in combination with other emulsifiers, but nanoemulsions can be produced with lecithin alone, as shown in Table 2.1. Solid particles are increasingly used as emulsifiers, with the main advantages of forming a more stable film than other emulsifiers. The emulsions stabilized by solid particles are called Pickering emulsions (Chapter 5). Different from surface-active molecules, whose adsorption at oilewater interface is in dynamic equilibrium with the emulsifier dissolved in the continuous phase, the solid particles adsorb irreversibly at interfaces because of their higher energy of adsorption. Therefore, the film of solid particles provide a better steric stabilization (Duffus et al., 2016; Fujisawa et al., 2017), due to the high energy of attachment of the particles (thousands of kT/particle), which anchors them onto the O/W interface (Frasch-Melnik et al., 2010). Depending on the solid particle properties, which can be characterized in terms of three-phase contact angle at solide oilewater interfaces, and which can eventually be tailored by surface modification, the fine particles can effectively stabilize both O/W (more hydrophilic particles) and W/O emulsions (more hydrophobic particles) (Levine et al., 1989). Among various solid stabilizers suitable for food applications, nanocellulose has gathered a significant interest because of its unique nanosize, amphiphilicity, chemical stability, and biocompatibility (Fujisawa et al., 2017), which make it suitable also for the fabrication of nanoemulsions. Additionally, also hydrophobically modified starch particles, different flavonoids (i.e., rutin hydrate and naringin), fat crystals and wax, protein and chitosan particles, as well as corn-peptide-functionalized calcium phosphate particles have been exploited in the stabilization of Pickering emulsions (Duffus et al., 2016; Frasch-Melnik et al., 2010; Ruan et al., 2018). However, none of these particles enabled the formation of nanosized droplets. As reported in Table 2.1, very recently nanocellulose, in the form of cellulose nanocrystals or TEMPO-oxidized cellulose nanofibrils, was exploited in the fabrication of food-grade Pickering O/W nanoemulsions ( Jiménez Saelices and Capron, 2018). Promising results were obtained in the formation of Pickering W/O nanoemulsions, exploiting the condensation of

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water vapor on a nanoparticle-infused subcooled oil that spreads on water (Kang et al., 2018). Therefore, among the main factors affecting the stability of Pickering emulsions, the particle characteristics, and in particular particle size and wettability by oil and water, are the most important. Particles with a better water-wetting capability, with a three-phase (at the particle surface in contact with water and oil phases) contact angle 90 degrees (largely lipophilic) facilitate the formation of W/O emulsions (Duffus et al., 2016; Ferrari et al., 2017; Mustafa et al., 2018). Finally, the particles with a three-phase contact angle of 90 degrees do not exhibit a net curvature of the interface, and therefore can be used in both types of emulsions. Moreover, the particle size significantly affects the mean droplet size of the Pickering emulsions (Duffus et al., 2016), as well as the cohesion forces of the particulate film (Mustafa et al., 2018). The formation of a Pickering nanoemulsion obviously requires the use of particles with a size distribution well below that of the desired nanoemulsion droplet. It is, however, possible to reduce the size of the emulsifying particles by physical processing or chemical modification (Jiménez Saelices and Capron, 2018). More discussion about application of Pickering nanoemulsions for encapsulation of food ingredients has been provided in Chapter 5. Surfactants, such as monoolein, or PGPR, or lecithins are often used concurrently to the particles, to increase their polarity, are improving the adsorption at O/W interfaces (Frasch-Melnik et al., 2010).

2.2 Optimizing emulsion stability In nanoemulsions, because of the nonnegligible solubility in water of many food oils, or vice versa, Ostwald ripening is considered to be the main mechanism of physical instability (Chang and McClements, 2014; Donsì and Ferrari, 2016). Ostwald ripening can be described as the molecular diffusion of the dispersed liquid in the continuous phase, driven by the higher local solubility around smaller droplets than larger ones (Wooster et al., 2008), which, ultimately, causes the growth of larger droplets at the expense of smaller ones. This thermodynamically driven spontaneous process is caused by intrinsic factors because the molecules on the surface of a droplet are energetically less stable than the ones in the interior. Because of the high water diffusivity in oil, as well as mobility of water droplets, which can easily

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49

coalesce, the stability of W/O nanoemulsion is typically more critical than for O/W nanoemulsions (Tabibiazar and Hamishehkar, 2015). In principle, Ostwald ripening could be accelerated by the presence of surfactant micelles in the continuous phase, which enhance the rate of the mass transfer, through two different mechanisms: one is based on the collision of micelles with the emulsion droplets, the other on the dynamic equilibrium between the micelles and the oil droplets (Kabalnov, 2001). In O/W nanoemulsions, long-chain triglyceride oils, which exhibit a negligible aqueous phase solubility, can be added to the oil phase as ripening inhibitors (Rao and McClements, 2012). Alternatively, the oil droplets can be gelled, by adding a gelator agent, such as stearic acid, to the lipid phase, hence reducing the partition of the payload compounds into the aqueous phase (Zahi et al., 2014). Similarly, W/O nanoemulsions can be stabilized against Ostwald ripening by inducing the gelation of the aqueous droplets (Harwansh et al., 2015), by adding suitable gelling agents (mainly proteins or hydrocolloids), such as gelatin (Oppermann et al., 2018). Moreover, Ostwald ripening can also be inhibited by forming a biopolymeric layer on the droplet surfaces, hence mechanically preventing the shrinkage or growth of the droplets (Pan et al., 2014; Shah et al., 2012; Wu et al., 2014). Similarly, also multiple layers of biopolymers around the droplets, deposited by the layer-by-layer method, are reported to contribute to stabilizing the nanoemulsions against Ostwald ripening, as shown for multiple chitosan layers (Grigoriev and Miller, 2009). Also inorganic salt can positively contribute to stabilizing W/O emulsions (Zhu et al., 2018).

2.3 Fabrication methods Different methods are currently available for preparing nanoemulsions, which can be classified into high-energy methods, such as high-pressure homogenization (HPH), ultrasonication, and colloid milling, and low-energy methods, such as phase inversion temperature (PIT) or concentration and spontaneous emulsification (Jafari et al., 2008; Gupta et al., 2016). Because nanoemulsions are kinetically stable, thermodynamically unstable systems, their formation is an inherently nonspontaneous process, which requires energy to expand the interfacial surface (Kumar and Kumar, 2018). The required energy input increases with the decreasing particle size because Laplace pressure (P), required to deform a spherical droplet, is inversely proportional to droplet radius (r).

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Francesco Donsì and Krassimir P. Velikov

2$g (2.1) r Eq. (2.1) also explains why the use of an efficient emulsifier, which reduces the interfacial tension g, is beneficial for the nanoemulsion formation. It also explains how low-energy methods of fabrication of nanoemulsions, which are based on the use of surfactants, under specific environmental conditions, significantly reduce the interfacial tension, until a thermodynamically stable system (microemulsion or lyotropic fluid) is formed, before suddenly changing the environmental conditions to those of final use, forcing a transition through the metastable phase of nanoemulsion (Kumar and Kumar, 2018). Figs. 2.2 and 2.3 schematically represents some of the possible approaches for the fabrication of O/W and W/O nanoemulsions. High-energy methods (Fig. 2.2) require a significant energy input (108e1010 W/kg) to produce nanoemulsions (Gupta et al., 2016), with a large fraction that is dissipated in the continuous phase as heat. In contrast, low-energy methods (Fig. 2.3) exploit specific properties of the system components, or changes in P¼

Figure 2.2 Main high-energy methods of nanoemulsion fabrication.

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Figure 2.3 Main low-energy methods of nanoemulsion fabrication.

the chemical potential of the components, to produce nanometric droplets, with a minimum energy input (w103 W/kg), mainly associated with stirring (Gupta et al., 2016; Kumar and Kumar, 2018). 2.3.1 High-energy methods Nanoemulsion production via high-energy methods typically exploits mechanical processes, such as colloid milling (also known as high-shear mixing), HPH, and ultrasonication, to generate intense fluid-mechanical stresses in the continuous phase, which are transmitted to the dispersed phase as disruptive forces (McClements and Jafari, 2018a,b). As shown in Eq. (2.1), the smaller the droplet size, the higher the required energy input. In addition, at decreasing the droplet size, also the efficiency of transmission of the disruptive forces to the droplets decreases, while larger fractions of energies, either as kinetic or pressure energy, are dissipated as heat. In particular, it is estimated that only 0.1% of the energy required by one of the abovementioned high-energy devices is used for emulsification (Solans and Solé, 2012). Colloid milling consists of a high-speed rotor/stator device, which is able to form coarse emulsions, through the dispersion and emulsification of two

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immiscible fluids, due to the intense shear stresses, friction, and highfrequency vibrations generated during the rotor movement (Sessa and Donsì, 2015). Because of their simplicity, colloid mills enable an economically viable and easily scalable emulsion fabrication. However, the intrinsic relatively low-energy density transferred to the fluid, associated to moving parts (rotors and stators or gear-rim dispersers, and intensive mixers), prevents the formation of very fine particles (Sessa and Donsì, 2015). Ultrasonication enables the formation of nanoemulsions mainly by cavitation, due to the generation of alternating low-pressure and high-pressure waves at high frequency (>18 kHz), which induces the repeated formation of vapor bubbles, followed by their immediate collapse (Gharibzahedi and Jafari, 2018). The emulsion droplets are disrupted by the shock waves produced by imploding bubbles, whose local pressure may peak up to 1350 bars (Maa and Hsu, 1999). Because of these characteristics, ultrasonication is suitable for producing emulsions in the nanometric range (Kumar and Kumar, 2018), but its industrial application is limited by scale-up issues concerning the treatment chamber and the sonicator devices ( Jafari et al. 2006, 2007b). Moreover, ultrasound treatments are reported to cause oxidation and degradation of some typical nanoemulsion components. For example, sonication was reported to cause significant lipid oxidation in refined sunflower oil and the formation of some off-flavor compounds, such as hexanal and limonene, from the ultrasonic degradation of the oil (Chemat et al., 2004). In comparison with colloid milling and ultrasonication, the HPH offers easier industrial scalability, better reproducibility, and higher throughput for producing nanometric O/W or W/O nanoemulsions (Sessa and Donsì, 2015; Silva et al., 2018b). The HPH process consists of continuously driving a primary coarse emulsion, compressed up to 50e400 MPa, through a specifically designed homogenization valve, whose geometry can vary from a simple orifice plate to colliding jets and radial diffuser assemblies (Coccaro et al., 2018; Donsì et al., 2013a, 2012b, 2009). Emulsification by HPH is based on droplet breakup in the homogenization valve, followed by the rapid emulsifier adsorption onto the newly formed interfaces, to prevent recoalescence phenomena ( Jafari et al., 2008). HPH-induced droplet breakup is generally attributed to cavitation or shear stresses (Håkansson et al., 2011; Lee and Norton, 2013). However, the efficiency of the emulsification process depends also on the kinetics of adsorption of the emulsifier at O/W interfaces. Often, also other HPH techniques are used, such as microfluidization, which is based on a colliding-jet assembly ( Jafari et al., 2007a;

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Villalobos-Castillejos et al., 2018). The process fluid under pressure is split into two microchannels, which collide in a reaction chamber, dissipating the pressure energy input almost instantaneously at the point of impact into heat and fluid-mechanical stresses (Donsì et al., 2013b). The advantages in terms of narrow droplet size distribution and reproducibility are counterbalanced by the risk of valve clogging and the high capital costs. 2.3.2 Low-energy methods Low-energy emulsification methods make use of the internal chemical energy of the system (Sessa and Donsì, 2015; Solans and Solé, 2012). Therefore, low-energy methods enable the fabrication of nanoemulsions of comparable size to high-energy methods, requiring only energy for stirring. Hence, these methods are suitable for heat- and shear-sensitive compounds and enable significant energy savings in large-scale production, at the cost of severe formulation requirements (Yukuyama et al., 2018), and in particular they work only with small-molecule surfactants and cannot be applied to proteins, polysaccharides, and particles, or that they require the use of organic solvents. The different low-energy emulsification methods can be classified depending on the occurrence of changes in the surfactant spontaneous curvature during the process. Fig. 2.3 schematically depicts the main available processes. The self-emulsification process is based on the diffusion of surfactant, solvent, and/or cosurfactant molecules from the dispersed phase into the continuous phase, without any change of the spontaneous curvature of the surfactant (Solans and Solé, 2012). This diffusion, often triggered by the dilution of the continuous phase, causes a dramatic increase in the interfacial area, resulting in the formation of a metastable emulsion. Nanometric droplets are formed at a very high solvent to continuous phase ratio, which accelerates the solvent diffusion and induces the required turbulence at O/W interface. Both O/W and W/O nanoemulsions can be formed through the self-emulsification method (Mohammadi et al., 2016a,b; Solans and Solé, 2012). It offers the advantages of protecting heat-sensitive compounds, as well as of minimizing surfactant, removing the cosurfactants (Mehrnia et al., 2016). Solvent demixing methods are based on the dissolution of the oil and payload molecules in a suitable organic solvent, such as acetone or methylene chloride, followed by their spontaneous separation in nanometric droplets through the dilution of the continuous phase, or the addition of an

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antisolvent in the presence of emulsifiers (Sessa and Donsì, 2015). This method is, however, limited to water-miscible solvents and requires the careful purification of the organic solvents used in the process (Silva et al., 2012). Phase inversion methods, such as PIT and phase inversion composition (PIC), involving changes in the surfactant spontaneous curvature, with a shift from a predominantly lipophilic behavior to predominantly hydrophilic behavior, or vice versa, in response to changes in system temperature or composition, respectively (Rao and McClements, 2010; Solans and Solé, 2012; Yukuyama et al., 2018). PIT nanoemulsions are fabricated by mixing the required ingredients at the PIT, which also corresponds to the temperature of HLB. Under these conditions, the hydrophilic and lipophilic properties of the system are balanced, the mean spontaneous curvature of the surfactant is close to zero, and extremely low O/W interfacial tensions are obtained (102e105 mN/m), hence promoting the formation of very small droplets, but also the coalescence rate. Therefore, stable nanoemulsions can be obtained only if, after emulsification, the temperature is quickly changed from the PIT by rapid cooling or heating (Solans and Solé, 2012). Similarly, PIC nanoemulsions can be obtained by adding water or oil into a mixture of the other two components mixed in a microemulsion. The absence of rapid heating/cooling makes the PIC method to be more suitable for large-scale productions than the PIT, as well as for heatsensitive compounds. Furthermore, the PIC method is suitable for both O/W and W/O nanoemulsions (Silva et al., 2012). During the dilution, the surfactant spontaneous curvature changes, forming at zero curvature a bicontinuous or lamellar structure, which, upon further dilution, separates into metastable small regions (Sessa and Donsì, 2015; Solans and Solé, 2012). However, the nanoemulsions become highly susceptible to coalescence when they are brought close to the conditions of phase inversion (Rao and McClements, 2010). Moreover, it is important to note that in several applications of the low-energy methods, proposed in the literature for the preparation of nanoemulsions (especially PIT, PIC, and self-emulsification), the required compositions are so rich in emulsifiers that the boundaries that differentiate the obtained nanoemulsions from microemulsions become increasingly thinner, and in some cases they are completely indistinguishable.

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In many practical cases, the fabrication procedure of nanoemulsions is based on a combination of low-energy methods, such as phase inversion and self-emulsification, into a two-step emulsification process. For example, under conditions at which a bicontinuous microemulsion or a lamellar liquid crystalline phase is formed, dilution with water is performed at a constant temperature, resulting in the formation of a nanoemulsion, upon a change of surfactant curvature (Solans and Solé, 2012). Another method is based on surfactant-phase emulsification (Yukuyama et al., 2018). It enables the formation of temperature- and compositionstable O/W nanoemulsions, using different vegetable oils and at relatively low surfactant concentrations. The surfactant-phase emulsification method requires the use of an alkyl polyol, such as glycerin (Yukuyama et al., 2018). It must be remarked that most of the low-energy methods require the use of small-molecule surfactants or lecithins and are not possible to achieve by using biopolymers (e.g., proteins, gums) or solid particles. The only exception is the solvent demixing method, where biopolymers or particles can be used (Silva et al., 2012), but it requires the use of organic solvents for the creation of the dispersed phase at the nanoscale. 2.3.3 Mixed approaches Different mixed approaches, combining low- and high-energy methods have been proposed to improve the efficiency of the emulsification process. For example, stable and transparent W/O nanoemulsions were obtained by combining the isothermal low-energy method of self-emulsification with the high-energy ultrasonication (Kumar and Kumar, 2018). In the case of O/W nanoemulsions, molecular assembly and comminution processes are combined to produce multiple-layer polyelectrolyte nanoemulsions, by exploiting the layer-by-layer method. First, highenergy emulsification is applied to produce a nanometric emulsion, stabilized by a charged emulsifier. Subsequently, the spontaneous deposition of an oppositely charged polyelectrolyte is triggered at the nanoemulsion interface, driven by the electrostatic attraction between the droplet surface and the polyelectrolytes dissolved in the continuous phase. This procedure can be repeated several times, for the deposition of multiple biopolymer layers (Grigoriev and Miller, 2009; McClements and Rao, 2011), which are reported to significantly improve the stability to environmental stresses in comparison with conventional single-layer systems (Silva et al., 2018a).

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3. Properties and characterization of nanoemulsions The design of nanoemulsions for the encapsulation and delivery of food ingredients is generally based on the desired in-product and in-body behavior (Donsì et al., 2013b; Sessa and Donsì, 2015). In particular, the in-product behavior of a nanoemulsion, referred to its addition into food formulations, should be evaluated in terms of (1) the efficient and homogeneous dispersion in the food matrix, as well as the compatibility with it, (2) the physical stability of the nanoemulsion in the complex environment of food matrices, where the different O/W interfaces may promote its segregation, (3) the minimization of the reaction of the payload molecules with the food ingredients, which in turn affects their stability and the impact on product quality, (4) the physicochemical stability at the treatment conditions of the food, including temperature or pH extremes, light exposure, or intense shearing, deriving from food processing, preservation, or preparation. An optimal in-product behavior should be able to ensure that the encapsulated ingredients can reach the stage of oral consumption in active form. The in-body behavior of the nanoemulsion depends, instead, on (1) the efficient release of the payload compounds, preferably triggered by the digestive environment (from chewing to the digestion process), such as changes in pH or temperature, mechanical shear, enzymatic activity, or moisture addition, (2) the bioaccessibility and bioavailability of the payload compounds, taking into account their desired fate to target sites. Particularly, in addition to more conventional requirements in terms of physicochemical stability, also the digestibility should also become part of the design of nanoemulsions for the delivery of food ingredients (Donsì, 2018).

3.1 Nanoemulsion characterization The droplet size analysis of nanoemulsions is routinely carried out by counting techniques, such as static light scattering, which relies on the projected area of the particles and their optical properties, or by dynamic light scattering, also known as correlation spectroscopy, which is instead based on the fluctuation in light scattering due to the Brownian motion of the droplets (Donsì et al., 2012b). These measurements can be expressed directly as size distribution, or as a mean droplet size (or hydraulic diameter) and a polydispersity index (PDI) ( Jafari and Esfanjani, 2017).

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Polydispersity indicates the wideness of the droplet size distribution: the higher the value of the PDI, the lower the uniformity of the droplet size distribution (Donsì et al., 2012b). In addition to the droplet size distribution data, obtained from the counting techniques, scanning or transmission electron microscopy in cryo-mode (cryo-SEM and cryo-TEM) offers the possibility of the morphological characterization of the system (Jaiswal et al., 2015). Zeta potential measurement, which is related to the surface charge of nanoemulsion droplets, can be conducted through the quantification of their electrophoretic mobility, with different instruments, such as Brookhaven Zeta PALS or Malvern Panalytical Zetasizer Nano Series (Jaiswal et al., 2015; Tastan et al., 2016). The encapsulation efficiency of payload compounds in nanoemulsions is often based on the assessment of both the payload compounds dissolved in the continuous phase and those effectively encapsulated in the nanoemulsion droplets, by separation using suitable filters or washing in dialysis membranes. In certain cases, it might be required the emulsion breakup using suitable solvents, prior to the analysis by spectrophotometer, HPLC and GC against standard solution (Jaiswal et al., 2015). The physical stability of the nanoemulsions is typically assessed over time either at the conditions of usage, or under accelerated conditions, i.e., at extremes of temperature, pH, shear, light exposure, in centrifugal fields, or eventually upon repeated cycles of freezingethawing, in terms of variation of mean droplet size, polydispersity, zeta potential, or light transmittance (Sessa et al., 2011).

3.2 Nanoemulsion properties Despite the fact that structure of a nanoemulsion droplet is extremely simple, unique functionalities may arise as a consequence of the collective behavior of the emulsion droplets, or from the structural complexity of the droplet core or interfacial layer (Sessa and Donsì, 2015). Fig. 2.4 schematically describes the effect of some of the main, and more easily to determine, nanoemulsion characteristics on the nanoemulsion behavior at the macroscale. The size distribution of the nanoemulsion droplets, together with their composition and concentration, is directly responsible of several relevant properties, such as the kinetic stability against gravitational separation, the optical transparency, the transport through biological membranes, or porous matrices (Donsì et al., 2014; Sessa et al., 2014), as well as the rate of digestion

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Figure 2.4 Schematics of the correlation between microscopic (white panels) and macroscopic properties (dark gray panels) of nanoemulsions.

(Sessa et al., 2011). Additionally, the droplet size distribution, through the specific surface area of the nanoemulsion, controls the reaction rate with other food ingredients or interfaces, as well as with biological cells, and all the phenomena, which involve surface forces, such as gelation (Helgeson, 2016) or capillary forces (Sessa and Donsì, 2015). Consequently, digestibility and, hence, bioaccessibility of the payload compounds are enhanced by finer droplets and higher specific surface areas, which facilitate the enzymatic action (Salvia-Trujillo et al., 2017). The surface composition and charge significantly affects the interaction of nanoemulsion droplets with the surrounding matrix. In particular, the selection of a suitable emulsifier, or combination of emulsifiers and stabilizers may impart significant steric and/or electrostatic stability, which contributes to prevent the phenomena of flocculation or to promote the adsorption at and the interaction with interfaces. This last aspect is of particular interest in some applications, such as the delivery of essential oils as natural antimicrobials because the interaction with the target microorganisms might be enhanced (Donsì and Ferrari, 2016). Finally, the composition of the dispersed phase, where the payload compounds are embedded, is crucial for protecting their chemical stability, to prevent physical instability phenomena due to Ostwald ripening, as well as for controlling their release in the continuous phase (Donsì et al., 2012a; Donsì and Ferrari, 2016). In particular, what is referred to as payload affinity in Fig. 2.4, which takes into account the interaction between the payload compounds and the dispersed phase, including the oil or water phase and the emulsifier (i.e., when lipophilic compounds are mixed with

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the oil phase in O/W nanoemulsions) affects significantly the partition between the nanoemulsion droplets and the continuous phase, in turn influencing the release rate, the Ostwald ripening, and the biological behavior of the nanoemulsion. For example, it has been shown that, depending on the composition of the oil droplets, the equilibrium concentration in the aqueous phase of nanoemulsions of essential oils mixed with vegetable oils can be controlled, and consequently the resulting antimicrobial activity (Donsì et al., 2012a).

4. Application of nanoemulsions for encapsulation of food ingredients In food applications, O/W emulsions can be found in many different products, such as mayonnaise, salad creams, desserts, and beverages, because of their important role on texture, rheology, and organoleptic properties (McClements, 2015). The development, in recent years, of O/W nanoemulsions has considerably expanded their range of applications because of their capability to efficiently deliver into aqueous matrices a wide range of lipophilic or hydrophobic compounds, such as oil-soluble vitamins, colors, flavors, and aromas, bioactive compounds, as well as essential oils (Donsì and Ferrari, 2016; Jaiswal et al., 2015; Akhavan et al., 2018; Rafiee and Jafari, 2018). However, also W/O nanoemulsions exhibit a considerable potential of application, even though not as well developed as for O/W nanoemulsions, especially in the fortification of lipid-based food formulations with hydrophilic bioactives or vitamins, which need to be protected from degradation because they are easily susceptible to thermal degradation or reaction with other ingredients. In addition, their encapsulation also enables the controlled release of the payload compounds and the improved bioavailability (Assadpour et al., 2016b). Currently, W/O emulsions are important structural components of different foods, such as butter and spreads, as well as of pharmaceutical and cosmetic formulations. The nanometric size might contribute to improving the product properties, as well as the improved bioavailability of the payload. In addition to the efficient delivery of bioactive compounds, W/O nanoemulsions can be exploited in the design of stable double emulsions (Chapter 3), such as water-in-oil-in-water emulsions (Gharehbeglou et al., 2019b; Mehrnia et al., 2016). The compartmentalized structure of double emulsions is especially suitable for the delivery and controlled release

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of hydrophilic components, for reduced-calorie and reduced-salt products, and for masking off-flavors (Tabibiazar and Hamishehkar, 2015). Remarkably, although a stable primary emulsion is critical to the stability of double emulsions, to date, only a few studies have addressed the issue of formulation and fabrication of stable W/O nanoemulsions, using natural ingredients (Tabibiazar and Hamishehkar, 2015). The market of nanotechnology products for the food industry, which include nanoencapsulated bioactive compounds for packaging, healthpromoting products, as well as beverages, was worth about US$ 1 billion in 2007 (Chau et al., 2007), and it is foreseen to grow to more than US$ 1 trillion in the next years (Kumari and Yadav, 2014; Salvia-Trujillo et al., 2017). From an industrial point of view, a nanoemulsion-based delivery system for food ingredients, should be (1) formulated with food-grade, possibly allnatural, ingredients, as efficient as polymers and surfactants used in the pharmaceutical industry, (2) able to disperse the payload compounds in the food, ensuring high physicochemical stability and minimizing the impact on the quality perception of the product, (3) protect the payload from the degradation due to extremes in temperature, light, or pH, as well as from the interaction with other ingredients, (4) enhance the payload uptake upon consumption, eventually in combination with controlled release in response to specific environmental stimulus (Donsì et al., 2011a,b; McClements et al., 2007). It must, however, be remarked that the implementation of nanoemulsion technology in the food industry has been slowed down by (1) the high capital costs of the emulsification systems required for high throughput (Donsì et al., 2013a), (2) the scarcity of all-natural, food-compatible emulsifiers (McClements, 2017), (3) the concerns about the use of nanotechnology in foods, together with the generally conservative position of the food industry compared with other industries (Silva et al., 2012), (4) the interactions with complex food systems (Donsì et al., 2014; Donsì and Ferrari, 2016), (5) and specific issues concerning nanoemulsion stability (mainly against Ostwald ripening or flocculation) over the expected shelf life of food products (Gutiérrez et al., 2008). Thanks to the introduction of different naturally delivered agents with a high emulsifying ability, such as saponins, phospholipids, or biopolymers (natural gums, vegetable or animal proteins, modified starches) (Chen et al., 2006), the use of nanoemulsions in foods can be expected to

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exponentially increase in the near future, toward foods with enhanced functionality and sensorial attributes (Donsì, 2018). The choice between an O/W or W/O nanoemulsion depends on the properties of the payload ingredient, and in particular if it is prevalently hydrophilic or lipophilic, but also on the characteristics of the food matrix (McClements and Rao, 2011; Sessa and Donsì, 2015). Most foods consist of an aqueous phase and therefore require O/W nanoemulsions. Conversely, W/O nanoemulsions can be used in the encapsulation of bioactive hydrophilic substances or as a structural unit of double W/O/W emulsions, to be added in aqueous-based products (Tabibiazar and Hamishehkar, 2015). Simple W/O nanoemulsions, instead, can find application in oil- and lipid-based foods, such as vegetable oils, butter, spreads, and salad dressings. In the following sections, some examples of the use of nanoemulsions in the encapsulation of bioactive compounds, micronutrients, and essential oils are discussed.

4.1 Nutraceutical compounds Driven by the growing consumers’ demand for more natural and healthier food products, the interest in the encapsulation of naturally derived, health-beneficial food ingredients has exponentially increased in recent years (Donsì, 2018). Table 2.2 reports some examples of the application of nanoemulsion for the encapsulation of nutraceutical compounds, either as plant extracts, such as green tea, olive leaf, saffron, raspberries, or grape marcs or as isolated compounds, such as b-carotene, curcumin, naringenin, quercetin, resveratrol, or phenolic acids. In particular, Table 2.2 describes the main formulation and fabrication techniques and highlights the advantages of using the nanoemulsions in terms of ingredient functionality. The main challenge in the encapsulation of bioactive ingredients is the use of edible ingredients, which, in addition to good encapsulation efficiency, ensure also the protection from the reaction with other food ingredients and controlled release of the payload, for maximized bioaccessibility and bioavailability (McClements and Rao, 2011). O/W food nanoemulsions are ideal for lipophilic bioactive compounds, or for scarcely water-soluble compounds, if specific stabilizers for the oil phase are used, such as lecithin (Sessa et al., 2014) or milk fats (Kumar et al., 2016). In particular, bioactive compounds are typically dosed at low

Table 2.2 Examples of nanoemulsions used to encapsulate and deliver bioactive compounds in foods. Compound Formulation Fabrication Functionality

b-Carotene b-Sitosterol Curcumin

Ellagic acid

Ferulic acid

Naringenin

Quercetin

O/W nanoemulsion: Corn oil (oil phase) and whey proteine dextran conjugates (emulsifiers) O/W nanoemulsion: Algae oil (oil phase), soybean lecithin (emulsifier) O/W nanoemulsion: Medium-chain triglycerides and milk fat (oil phase), sodium caseinate (emulsifier)

7 HPH (Microfluidizer) passes at 100 MPa at 15 C

O/W nanoemulsion: Ellagic acid complexed with phospholipids, captex 500 (oil phase), cremophor RH 40 (surfactant), PEG 400 (cosurfactant) O/W nanoemulsion: Isostearyl isostearate (oil phase), labrasol and acconon CC-6 (surfactant), transcutol CG and plurol isostearique (cosurfactant) O/W nanoemulsion: Triacetin (oil phase), Tween 80 (surfactant), and Transcutol HP (co-surfactant) O/W nanoemulsion: polyoxyethylene(20) oleyl (hydrophilic surfactant), polyoxyethylene(3) oleyl ether (lipophilic surfactant), trimethyl ammonium chloride (cationic surfactant), caprylic/capric triglyceride (oil phase)

Self-emulsification by water dilution at 25 C

Ultrasonication at 20 kHz and 14 kW/kg for 5 min at 5 C 1 HPH pass at 20 MPa at room temperature

Improved physical stability, control of lipolysis, and release of b-carotene Structuring the lipid phase of emulsion and improving the protection of other oils High stability of curcumin at different temperature, pH, ionic strength. Good compatibility with sensory properties of ice cream (Kumar et al., 2016) Increased bioaccessibility of ellagic acid

References

Fan et al. (2017) Chen et al. (2016) Kumar et al. (2016)

Avachat and Patel (2015)

Self-emulsification by water dilution at 25 C

Improved biological activity, permeability, absence of cytotoxic effect

Harwansh et al. (2015)

Self-emulsification by water dilution at 37 C

Enhanced release and increased bioavailability of naringenin

Khan et al. (2015)

PIT method: Heating at 80 C, followed by cooling to room temperature under stirring

Improved of thermal and photostability of quercetin; enhanced delivery

Dario et al. (2016).

Resveratrol

Black raspberry extracts

Grape marc extracts

Green tea catechins

Olive leaf extracts Saffron aqueous extracts Steroid glycosides

O/W nanoemulsion: soy lecithin (lipophilic emulsifier), sugar esters (hydrophilic emulsifier), peanut oil (oil phase) W/O nanoemulsion: Soybean oil (continuous phase), gelatin and gum Arabic (gelling agents), Tween 80 (hydrophilic emulsifier), and polyglycerol polyricinoleate (lipophilic emulsifier) O/W nanoemulsion: Sunflower oil (oil phase), gelatin soybean lecithin(emulsifier) O/W nanoemulsion: Solubilization of green catechins in sunflower oil and lecithin. Further addition of Tween 80 as coemulsifier. W/O nanoemulsion: Soybean oil (continuous phase) and Span 80 (lipophilic emulsifier) W/O nanoemulsion: Olive oil (continuous phase) and Span 80 (lipophilic emulsifier)

10 HPH passes at 300 MPa and 5 C

Enhanced cell permeation of resveratrol in Caco-2 cells

Sessa et al. (2014)

Wet milling by Ultra-Turrax at 12,500 rpm for 4 min

Improved thermal and storage stability of the extracts

Shaddel et al. (2018)

5 HPH passes at 150 MPa and 5 C

Improved compatibility with a hazelnut cream and enhanced antioxidant activity of the encapsulated extracts Increased storage stability of catechins

Spigno et al. (2013)

6 HPH passes at 100 MPa and 25 C

Gadkari et al. (2017)

Improved protection and antioxidant Mohammadi Self-emulsification by activity of the extracts et al. (2016a) dropwise addition of olive leaf extracts at 25 C Formation of nanometric droplets in Mehrnia et al. Self-emulsification by oil to encapsulate crocin (2016) dropwise addition of aqueous phase and emulsifier to the oil phase at 25 C O/W nanoemulsion: Tween 80 or whey 5 HPH (Microfluidizer) passes at Improved stability against creaming, Melnikov et al. coalescence, and Ostwald ripening (2017) protein isolates (hydrophilic emulsifier), 120 MPa and 20e30 C Econa oil (oil phase)

HPH, high-pressure homogenization.

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concentration, and therefore they are often dispersed into a carrier oil phase, which might eventually contribute to regulated chemical stability, release properties, as well as bioavailability (Donsì, 2018; Sessa and Donsì, 2015). In contrast, W/O nanoemulsions are needed in the case of hydrophilic bioactive compounds, or aqueous extracts. The further stabilization in water-based food products requires the formation of W/O/W double emulsions, where the W/O nanoemulsions are formed in a primary stage, followed by the dispersion in the external aqueous phase (Esfanjani et al., 2017, 2015; Mehrnia et al., 2017; Mohammadi et al., 2016a). Interestingly, in the case of W/O nanoemulsions, most of the formulations are based on ecioleate PGPR or Span 80, which are food grade, but whose use in food is subject to limitation. In fact, more natural emulsifiers are not able to ensure the desired physical stability of the W/O nanoemulsions and to counteract the high molecular diffusivity of water.

4.2 Micronutrients Differently from nutraceutical compounds, which are incorporated in foods because of their health-beneficial properties, vital micronutrients, such as fatty acids, vitamins, dietary fibers, and minerals, contribute also to the nutritive profile of the food. Nanoemulsions can be exploited for their efficient delivery to the gastrointestinal tract, but also for the protection from interaction with the food, to prevent undesirable changes in appearance or the development of off-flavors. Table 2.3 provides some examples of the nanoemulsions used in the encapsulation of different micronutrients, with details on their formulation and fabrication processes, as well as on the advantages in terms of ingredient functionality. The encapsulation in O/W nanoemulsions is used for fatty acids, liposoluble vitamins, and phytosterols, mainly to make them dispersible in waterbased products; protect them from undesired reactions during the phases of food transformation, storage, or preparation; as well as regulate their gastrointestinal absorption. Because they are required at higher concentrations than bioactive compounds, some of these micronutrients are generally used in nanoemulsions at high concentrations, without the need for a carrier oil phase. In contrast, liposoluble vitamins, such as A, D, and E, are usually preliminarily mixed with a carrier oil, such as palm oil, medium-chain triglycerides, or orange oil, which also contributes to their preservation (Mehmood, 2015) (Katouzian and Jafari, 2016).

Table 2.3 Examples of nanoemulsions used to encapsulate and deliver micronutrients in foods. Compound Formulation Fabrication Functionality

Algae oil b-Sitosterol

Conjugated linoleic acid

Fish oil

Skim milk

High-oleic palm oil (Vitamin A)

Riboflavin (Vitamin B)

O/W nanoemulsion: Algae oil (oil phase), Quillaja saponins (emulsifier) O/W nanoemulsion: Algae oil (oil phase), soybean lecithin (emulsifier)

7 HPH passes (Microfluidizer) Improved digestibility at 100 MPa and 4 C

Structuring the lipid phase of emulsion and improving the protection of other oils Reduced oxidation of O/W nanoemulsion: Conjugated 1 HPH pass at 200 MPa conjugated linoleic acid, linoleic acid and 25 C minimized impact on a and soybean oil (1:5, oil phase), soy milk-based beverage protein isolate (emulsifier) O/W nanoemulsion: Fish Self-emulsification by Improved physical and oil and lemon oil (1:1, oil phase), buffered water dilution or 3 oxidative stability Tween 80 (emulsifier) HPH passes (Microfluidizer) at 80 MPa W/O nanoemulsion: Skim milk Ultrasonication at 20 kHz Increased encapsulation of (aqueous phase), polyglycerol and 1.3 kW/kg for 90 s skim milk in the inner polyricinoleate or lecithin (lipophilic phase at decreasing emulsifiers), sunflower oil emulsification intensity (continuous phase) O/W nanoemulsion: Palm 1-3 HPH passes Improved protection of oil (oil phase), Tween 20 and (Microfluidizer) at oleic acid from chemical, whey powder (emulsifiers) 100e200 MPa enzymatic and/physical instability Improved encapsulation W/O nanoemulsion: NaCl and Self-emulsification by and stability of riboflavin riboflavin aqueous solution (aqueous dropwise addition of phase), polyglycerol polyricinoleate aqueous solution to the (lipophilic emulsifier), chia oil lipid phase at 25 C (continuous phase) Ultrasonication at 20 kHz and 14 kW/kg for 5 min at 5 C

References

Karthik and Anandharamakrishnan (2016) Chen et al. (2016)

Fernandez-Avila et al. (2017)

Walker et al. (2015)

Leong et al. (2018)

Ricaurte et al. (2016).

Katouzian and Jafari (2016)

(Continued)

Table 2.3 Examples of nanoemulsions used to encapsulate and deliver micronutrients in foods.dcont'd Compound Formulation Fabrication Functionality

Folic acid (Vitamin B9)

Vitamin D3 Vitamin E

FeSO4

MgCl2

W/O nanoemulsion: Folic acid aqueous solution (aqueous phase), canola oil (continuous phase), and Span 80 (lipophilic emulsifier) O/W nanoemulsion: Medium-chain triglycerides and vitamin D3 (oil phase), Quillaja saponin (emulsifiers) O/W nanoemulsion: Orange oil and vitamin E-acetate (oil phase), soy lecithin or Quillaja saponin (emulsifiers) W/O nanoemulsion: FeSO4 aqueous solution (aqueous phase), gelatin (aqueous gelling agent), polyglycerol polyricinoleate (lipophilic emulsifier), sunflower oil (continuous phase) W/O nanoemulsion: MgCl2 aqueous solution (aqueous phase), polyglycerol polyricinoleate (lipophilic emulsifier), soybean oil (continuous phase)

References

Protection of folic acid Self-emulsification by from degradation dropwise addition of aqueous solution mixed with emulsifier in oil at 25 C 3 HPH passes (Microfluidizer) Improved bioaccessibility at 80 MPa of vitamin D3 during simulated digestion 3 HPH passes (Microfluidizer) Improved permeability at 80 MPa of vitamin E through epidermal barriers, controlled release Better encapsulation and Self-emulsification by taste masking when dropwise addition of further incorporated in aqueous solution mixed W/O/W emulsions with emulsifier in oil at 25 C

Ozturk et al. (2014)

1 HPH pass at 60 MPa

Zhu et al. (2018)

Concentration-dependent encapsulation and stability of Mg2þ in the inner water phase

(Assadpour et al., 2016a, 2016b)

Ozturk et al. (2015)

Simiqueli et al. (2019)

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67

In the case of hydrophilic compounds, such as vitamin B2 and B9, but also for skim milk, they are typically encapsulated in W/O nanoemulsions and then in double emulsions for their long-term stabilization in aqueous food matrices (Assadpour et al., 2016a,b). The fortification of foods with FeSO4 represents an effective strategy for preventing iron deficiency anemia. However, direct addition of FeSO4 to foods causes undesired sensory changes, in particular, the darkening of the matrix and unpleasant off-flavors. The encapsulation in W/O/W double emulsions, which may contribute to effectively prevent these changes, requires the fabrication of extremely stable W/O nanoemulsions, for embedding FeSO4, or other salts, such as MgCl2, in the internal aqueous phase (Simiqueli et al., 2019).

4.3 Antimicrobial compounds Recently, the interest in the use of essential oils as natural antimicrobial compounds has considerably increased, especially for applications related to food preservation against pathogens and spoilage microorganisms. Moreover, the essential oils also exhibit another significant advantage, with respect to synthetic antimicrobial compounds: because of their multitarget antimicrobial action against microbial cells, they substantially prevent the development of microbial resistance (Donsì and Ferrari, 2016; Seow et al., 2014). In particular, the antimicrobial activity of essential oils can be mainly attributed to their molecular hydrophobicity, which affects the cell membrane structure, increasing its permeability and causing the leakage of cytoplasmic content (Donsì and Ferrari, 2016; Salvia-Trujillo et al., 2015a). Therefore, the essential oils typically exhibit a low, but nonnegligible, solubility in water. The nanoemulsions enable not only to disperse the essential oils at high concentration in the aqueous phase, where microorganisms grow but also to improve their stability against degradation reactions or volatilization (Donsì et al., 2012a, 2011a; Donsì and Ferrari, 2016). Because of the nonnegligible solubility in water, the encapsulation of essential oils requires a special attention to prevent the Ostwald ripening phenomena, which is typically achieved through the addition of a ripening inhibitor in the oil phase, such as long-chain triglycerides (Sessa and Donsì, 2015). In addition, the nanoemulsions should also be able to promote, or at least, to leave it unchanged, the antimicrobial activity of the essential oils (Donsì et al., 2011a; Donsì and Ferrari, 2016).

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In vitro studies, against different microorganisms, with extremely promising results, have revealed that O/W nanoemulsions might be extremely efficient, especially in promoting the mass transfer across the cellular membranes, because of their submicrometric size, and the fusion with the microbial membranes, due to the hydrophilic nature of the emulsifying agents (Shah et al., 2013; Wu et al., 2014). Moreover, some studies suggested that the encapsulation in nanoemulsions might affect also the mechanism of bacterial inactivation, and therefore different antimicrobial efficiencies are observed against Gram-positive (such as Lactobacillus delbrueckii) and Gram-negative microorganisms (such as Escherichia coli) (Donsì et al., 2012a, 2011a). For similar reasons, the observed inactivation of yeast cells by essential oil nanoemulsions resulted to be of smaller extent in comparison with bacterial inactivation, as demonstrated for Saccharomyces cerevisiae (Donsì et al., 2012a) and for Zygosaccharomyces bailii (Zhang et al., 2014). The use of essential oil-loaded nanoemulsions in real food products, however, is limited by different constraints, related to the complexity of the food matrices, the different endogenous flora, as well as to the perception of the pungent aroma of the essential oils. Therefore, different strategies have been adopted, varying not only the type of essential oils but also the nanoemulsions formulation, mean droplet size, and surface charge (Donsì and Ferrari, 2016). Table 2.4 reports the formulation and fabrication processes of O/W nanoemulsions used to encapsulate different types of essential oils, for their incorporation in food products. Table 2.4 also highlights the main advantages of using nanoemulsions, in comparison with free essential oils. It must be highlighted that an efficient antimicrobial system for food products is required to exhibit a wide spectrum of activity because of the large, and often varying from batch to batch, spoilage and pathogenic microorganism count. In addition, the possible interaction with proteins, carbohydrates, lipids, and minerals constituting the food, might promote the degradation, or the adsorption at O/W interfaces, of the highly reactive essential oil molecules, and hence the reduction of their antimicrobial activity (Gyawali and Ibrahim, 2014). Finally, the high volatility and intense flavor of essential oils should not impact on the sensory properties of food products (Gyawali and Ibrahim, 2014; Kim et al., 2013). Concerning this last aspect, the use of nanoemulsions might contribute to reduce the required essential oil concentration, by increasing their dispersibility in food and enhancing the antimicrobial activity (Donsì et al., 2012a). In addition, by altering the partition of the essential oils into the aqueous phase,

References

Thyme oil

O/W nanoemulsion: Thyme oil (oil phase), lecithin and sodium caseinate (emulsifiers)

Colloid milling at 15,000 rpm for 3 min

Xue et al. (2015)

Eugenol

O/W nanoemulsion: Eugenol in sesame oil (oil phase), Tween 20 and Tween 80 (emulsifiers)

Tea tree oil

O/W nanoemulsion: tea tree oil (oil phase), soybean lecithin (emulsifier)

Ultrasonication at 20 kHz, 750 W (specific energy and time not available) 10 HPH passes at 350 MPa and 5 C

Higher antibacterial activity against Escherichia coli, Listeria monocytogenes, Salmonella enteritidis in milk than free essential oil Increased antimicrobial activity against native cultivable bacteria in orange juice

Donsì et al. (2011a)

Cinnamaldehyde

O/W nanoemulsion: Cinnamaldehyde (oil phase), Tween 80 (emulsifier)

2 HPH (Microfluidizer) passes at 140 MPa

Oregano oil

O/W nanoemulsion: Oregano oil (oil phase), Tween 80 (emulsifier)

Ultrasonication at 750 W for 10 min (specific energy not available)

Lemongrass

O/W nanoemulsion: Lemongrass oil (oil phase), Tween 80 and sodium caseinate (emulsifier)

3 HPH (Microfluidizer) passes at 150 MPa and 20 C

Enhanced antimicrobial activity against L. delbrueckii, E. coli, Saccharomyces cerevisiae in pear and orange juice, and minimized impact on the appearance Enhanced antimicrobial activity against Salmonella typhimurium, Staphylococcus aureus in watermelon juice Antimicrobial activity by immersion of fresh lettuce leaves against E. coli, L. monocytogenes, S. typhimurium, Salmonella enterica Inhibition of E. coli and endogenous flora upon application as coating on apple pieces, while maintaining the product quality

Ghosh et al. (2014)

Jo et al. (2015)

Bhargava et al. (2015)

Encapsulation of food ingredients by single O/W and W/O nanoemulsions

Table 2.4 Examples of nanoemulsions used to encapsulate essential oils for applications in food. Essential oil Formulation Fabrication Functionality

Salvia-Trujillo et al. (2015b) 69 (Continued)

Citrus oils

Mandarin oil

Lemon oil

Ginger oil

O/W nanoemulsion: Ginger oil (oil phase), Tween 80 (emulsifier)

10 HPH passes at 350 MPa and 5 C

Enhanced antimicrobial activity against L. monocytogenes upon application as coating on broccoli florets

Severino et al. (2014b)

10 HPH passes at 350 MPa and 5 C

Enhanced antimicrobial activity against Listeria innocua upon application as coating on green beans

Donsì et al. (2015) and Severino et al. (2014a)

3 HPH passes at 200 MPa and 5 C

Enhanced antimicrobial activity against endogenous flora upon application as coating on rucola leaves

Sessa et al. (2015).

Ultrasonication at 20 kHz, 400 W (specific energy not available) for 10 min Ultrasonication at 20 kHz, 200 W (specific energy not available) for 5 min

Increased antibacterial and antifungal properties upon application as a coating on sliced bread Increased antibacterial properties against endogenous flora when applied onto chicken breast fillet

Otoni et al. (2014)

Noori et al. (2018)

Francesco Donsì and Krassimir P. Velikov

Clove bud oil

O/W nanoemulsion: Citrus oil and sunflower oil (oil phase), glycerol monooleate (lipophilic emulsifier), Tween 20 (hydrophilic emulsifier) O/W nanoemulsion: Mandarin oil and sunflower oil (oil phase), glycerol monooleate (lipophilic emulsifier), Tween 20 (hydrophilic emulsifier) O/W nanoemulsion: Lemon oil (oil phase), glycerol monooleate or soybean lecithin (lipophilic emulsifiers), whey proteins or Tween 20 (hydrophilic emulsifiers) O/W nanoemulsion: Clove bud oil (oil phase), Tween 80 (emulsifier)

References

70

Table 2.4 Examples of nanoemulsions used to encapsulate essential oils for applications in food.dcont'd Essential oil Formulation Fabrication Functionality

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71

through the use of a carrier vegetable oil, nanoemulsions can also contribute to partly mask the essential oil taste and aroma (Donsì and Ferrari, 2016), as well as reduce the reaction with other food components (Shah et al., 2012). The interfacial properties of essential oil-loaded nanoemulsions can be also influenced by their interfacial stabilization layer, especially when biopolymers are used, which, through the physical or chemical interaction with the essential oil molecules, principally affect the release rate (Donsì and Ferrari, 2016). From Table 2.4 it can be observed that the main applications of essential oil-loaded nanoemulsions for the preservation of real foods are based on (1) direct mixing or infusion into food matrices, (2) washing of food surfaces, (3) application of edible coatings. Direct mixing with liquid foods has been reported for milk and fruit juices. The use of nanoemulsions with fine droplet sizes contributes not only to minimizing the impact on the organoleptic properties of food (Donsì et al., 2011a) but also to enhance the in-product antimicrobial activity because nanoemulsions enable the homogeneous distribution of the antimicrobial compounds in the food above the solubility concentration level (Shah et al., 2013; Xue et al., 2015). In the case of solid food matrices, the nanoemulsions can be directly mixed with the food ingredients, or infused, as in the case of meat (Noori et al., 2018). The infusion rate of essential oil nanoemulsions is mainly a function of the mean droplet size (Donsì et al., 2014). Washing of foods with nanoemulsions has been investigated especially for leaf vegetables. The main contribution of nanoemulsions is to increase the essential oil concentration in the washing solutions, as well as to improve the wettability of the leaves (Donsì and Ferrari, 2016). An additional advantage is that nanoemulsions also might reduce the interaction of the essential oils with the product (Bhargava et al., 2015). Finally, the incorporation of nanoemulsions within biopolymer coatings applied on the food product surfaces has been reported to offer significant advantages because such antimicrobial coatings constitute a physical barrier against microbial contamination, from which essential oils are released over time (Vahedikia et al., 2019). In addition, the antimicrobial coatings enable to concentrate the presence of essential oils, where it is needed, at the produce surface, with minimal impact on produce appearance (Donsì et al., 2015; Otoni et al., 2014; Severino et al., 2014a,b).

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4.4 Flavorings and colorants The delivery of flavoring agents in food systems poses several challenges concerning the preservation and persistence of the highly volatile odorous molecules composing the aroma during manufacturing, storage, packing, and controlled release until they are perceived by consumers (Zuidam and Heinrich, 2010; Ghasemi et al., 2018). Aroma molecules are generally constituted by alcohols, aldehydes, ketones, esters, or acids of small molecular weight (100e250 Da) (Trifkovic et al., 2016). Flavor emulsions represent the standard approach to the incorporation of flavoring agents in different food formulations, such as dressings, marinades, sauces, condiments, and beverages. However, conventional flavor emulsions contain also toxic weighing agents, such as ester gum, brominated vegetable oil, added to the oil phase to increase its density and reduce the extent of creaming caused by the density difference between the water phase and the oil phase (Chanamai and McClements, 2000). Nanoemulsions, due to their long-term physical stability against creaming, enable to eliminate toxic weighting agents, for label-friendly formulations (Yalçın€ oz and Erçelebi, 2018). For example, a patent was filed to protect the use of food-grade flavor nanoemulsion, using Tween 80 as an emulsifier and C2eC8 alcohol as a cosolvent (Monsalve-Gonzalez and Ochomogo, 2008). Flavor nanoemulsions were also prepared using more natural emulsifiers, such as Quillaja saponins (Schultz and Monnier, 2013). However, the nanometric scale of flavor nanoemulsions is reported to facilitate undesirably rapid flavor diffusion (Trifkovic et al., 2016). To date, the sensory impact of the incorporation of flavor nanoemulsions in foods has been only speculatively investigated, based on the effect on the release of essential oils (Majeed et al., 2016). One of the main challenges to the use of flavor emulsions in foods is the preservation of aroma compounds, such as citral, in acidic beverages. Citral, which is an important lemon-like aroma compound of wide interest to the food and drink industry, is highly susceptible to degradation in the low-pH environment of carbonated beverages (Tian et al., 2017). Different citral nanoemulsions were developed, using different emulsifiers (Choi et al., 2010; Djordjevic et al., 2008), investing the deposition of multiple layers of biopolymers (Yang et al., 2012), and the addition of antioxidant molecules (Yang et al., 2011), which all resulted in the efficient preservation of citral.

Encapsulation of food ingredients by single O/W and W/O nanoemulsions

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Flavor nanoemulsions were also exploited in controlling the aroma profile of citrus oil (Yang et al., 2017), as well as in controlling the release triggered by the contact with saliva, through the incorporation of the nanoemulsions in soluble hydrogels (Kwan and Davidov-Pardo, 2018). Color delivery is also a great interest to the food industry, especially when involving natural colorants (Akhavan Mahdavi et al., 2016; Mahdavi et al., 2014). The key challenge in color delivery is the protection of colorant molecules from interaction with other food ingredients, as well as from harsh processing conditions. Remarkably, the optical behavior of a colorant emulsion depends on its mean droplet size, refractive index, and concentration of the dispersed phase, by affecting light scattering, and hence opacity or lightness, or absorption, and hence the chromatic properties of the dispersion, such as blueness, greenness, and redness (McClements, 2002). The chromaticness increases at higher particle size and concentration of colorant molecules (Chanamai and McClements, 2001). A nanoemulsion with a mean droplet size below 60e100 nm is reported to be optically transparent, which is required for clear beverages (McClements, 2002). Therefore, the use of nanoemulsions to deliver chromophoric molecules requires the specific design of the nanoemulsions, and, in particular, droplet size distribution, refractive index, and concentration of the disperse phase. For example, lutein- or b-carotene-loaded nanoemulsions, prepared with b-lactoglobulin, successfully protected the payload colorant molecules from degradation, hence reducing the rate of color fading (Qian et al., 2012). Lutein-loaded nanoemulsions were formulated also with Tween 80 and medium-chain triglycerides by spontaneous emulsification (Surh et al., 2017). The use of the layer-by-layer electrostatic deposition was exploited to prepare O/W nanoemulsions encapsulating Nile red as lipophilic colorant, resulting in a significant slowdown of the rate of color fading (Selig et al., 2018).

5. Conclusions and perspectives O/W and W/O nanoemulsions are simple but highly effective delivery systems for different food ingredients, ranging from bioactive compounds with health-beneficial or technological functionality to micronutrients, such as fatty acids, vitamins, or minerals, to natural antimicrobial agents, such as essential oils. The encapsulation of these food ingredients in nanoemulsions enables an efficient solution to promote their

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homogeneous dispersion in phases where they are not soluble, such as lipophilic compounds in aqueous-based foods, or hydrophilic compounds in oil-based matrices. In addition, nanoemulsions offer a unique contribution in the efficient transport to the biological membranes, where release and payload compounds absorption takes place, while still enabling the protection of the encapsulated ingredients from the interaction with other ingredients, or degradation during food processing, storage and preparation, and minimizing the impact on the organoleptic quality of the foods, to which they are added. In the case of W/O nanoemulsions, these can be exploited as a structured oil phase of O/W emulsions to make double emulsions, where the internal aqueous phase embeds and segregates from the external aqueous phase (i.e., the food system) sensitive hydrophilic food ingredients. Currently, food nanoemulsions, both of O/W and W/O type, represent a simple yet effective delivery system for food ingredients because of their ease of production, the flexibility of formulation with several food-grade emulsifiers available to date, as well as compatibility with both food products and biological systems. Different emulsifiers are currently available, of natural origin or naturally derived, which have significantly expanded the possibility of a natural formulation for food nanoemulsions, in comparison to the recent past. In addition, also in terms of formulation, significant advancements have been recently registered. In particular, food nanoemulsions can be produced through high-energy methods, characterized by robustness, repeatability, and industrial scalability, or through low-energy methods, characterized by strict constraints in terms of ingredients (emulsifiers, coemulsifiers, solvents), but significantly less energy intensive. Both formulation and fabrication contribute to the design of nanoemulsions with well-defined properties, to enhance their properties. For example, one frequent objective is to protect the encapsulated functional ingredients in product, or to control their behavior, in terms of stability and release, in body after ingestion, by suitable selection of the emulsifier and stabilizer ingredients. Within this frame, one of the main challenges for the successful use of nanoemulsions in foods is the formulation with natural or naturally derived ingredients, characterized by a significant compatibility with food matrices, and which are able to control the rate of release and intestinal absorption of the encapsulated compounds, while allowing for a clean and consumer-friendly label. Therefore, tailor-designed nanoemulsions will contribute to developing novel functionalities in the food matrices, as well as novel food products for personalized nutrition targeted

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to groups of the population with specific dietetic requirements, such as young or elderly people. Despite the limited current use in commercial food products, nanoemulsions have the potential to bring great benefits in several areas because of their intrinsic constitutive simplicity, their ability to generate novel functionalities, and, above all, the capability to encapsulate and deliver a wide range of food ingredients, such as bioactive molecules, micronutrients, colorants, flavorings, or antimicrobial agents.

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the physico chemical characteristics of flax seed oil-eugenol nanoemulsions. Food Hydrocolloids 66, 365e377. https://doi.org/10.1016/J.FOODHYD.2016.12.002. Shu, G., Khalid, N., Chen, Z., Neves, M.A., Barrow, C.J., Nakajima, M., 2018. Formulation and characterization of astaxanthin-enriched nanoemulsions stabilized using ginseng saponins as natural emulsifiers. Food Chemistry 255, 67e74. https://doi.org/10.1016/ J.FOODCHEM.2018.02.062. Silva, H.D., Cerqueira, M.A., Vicente, A.A., 2012. Nanoemulsions for food applications: development and characterization. Food and Bioprocess Technology. https://doi.org/ 10.1007/s11947-011-0683-7. Silva, H.D., Poejo, J., Pinheiro, A.C., Donsì, F., Serra, A.T., Duarte, C.M.M., Ferrari, G., Cerqueira, M.A., Vicente, A.A., 2018a. Evaluating the behaviour of curcumin nanoemulsions and multilayer nanoemulsions during dynamic in vitro digestion. Journal of Functional Foods 48, 605e613. https://doi.org/10.1016/J.JFF.2018.08.002. Silva, W., Torres-Gatica, M.F., Oyarzun-Ampuero, F., Silva-Weiss, A., Robert, P., Cofrades, S., Giménez, B., 2018b. Double emulsions as potential fat replacers with gallic acid and quercetin nanoemulsions in the aqueous phases. Food Chemistry 253, 71e78. https://doi.org/10.1016/J.FOODCHEM.2018.01.128. Simiqueli, A.A., Lima Filho, T., Minim, L.A., de Oliveira, E.B., Torres, I.V., Vidigal, M.C.T.R., Minim, V.P.R., 2019. The W/O/W emulsion containing FeSO4 in the different phases alters the hedonic thresholds in milk-based dessert. LWT 99, 98e104. https://doi.org/10.1016/J.LWT.2018.09.020. Solans, C., Solé, I., 2012. Nano-emulsions: formation by low-energy methods. Current Opinion in Colloid & Interface Science 17, 246e254. https://doi.org/10.1016/ J.COCIS.2012.07.003. Spigno, G., Donsì, F., Amendola, D., Sessa, M., Ferrari, G., De Faveri, D.M., 2013. Nanoencapsulation systems to improve solubility and antioxidant efficiency of a grape marc extract into hazelnut paste. Journal of Food Engineering 114, 207e214. https:// doi.org/10.1016/j.jfoodeng.2012.08.014. Surh, J., Decker, E.A., McClements, D.J., 2017. Utilisation of spontaneous emulsification to fabricate lutein-loaded nanoemulsion-based delivery systems: factors influencing particle size and colour. International Journal of Food Science and Technology 52, 1408e1416. https://doi.org/10.1111/ijfs.13395. Tabibiazar, M., Hamishehkar, H., 2015. Formulation of a food grade water-in-oil nanoemulsion: factors affecting on stability. Pharmaceutical Sciences 21, 220e224. https:// doi.org/10.15171/PS.2015.40. € Ferrari, G., Baysal, T., Donsì, F., 2016. Understanding the effect of formulation Tastan, O., on functionality of modified chitosan films containing carvacrol nanoemulsions. Food Hydrocolloids 61, 756e771. https://doi.org/10.1016/j.foodhyd.2016.06.036. Tekin Pulats€ u, E., Sahin, S., Sumnu, G., 2018. Characterization of different double-emulsion formulations based on food-grade emulsifiers and stabilizers. Journal of Dispersion Science and Technology 39, 996e1002. https://doi.org/10.1080/ 01932691.2017.1379021. Tian, H., Li, D., Xu, T., Hu, J., Rong, Y., Zhao, B., 2017. Citral stabilization and characterization of nanoemulsions stabilized by a mixture of gelatin and Tween 20 in an acidic system. Journal of the Science of Food and Agriculture 97, 2991e2998. https://doi.org/ 10.1002/jsfa.8139. Trifkovic, K., ÐorCevic, V., Balanc, B., Kalusevic, A., Levic, S., Bugarski, B., Nedovic, V., 2016. Novel approaches in nanoencapsulation of aromas and flavors. In: Encapsulations. Academic Press, pp. 363e419. https://doi.org/10.1016/B978-0-12-804307-3.000090. Vahedikia, N., Garavand, F., Tajeddin, B., Cacciotti, I., Jafari, S.M., Omidi, T., Zahedi, Z., 2019. Biodegradable zein film composites reinforced with chitosan nanoparticles and

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Zhu, Q., Feng, L., Saito, M., Yin, L., 2018. Preparation and characterization of W/O/W double emulsions containing MgCl2. Journal of Dispersion Science and Technology 39, 349e355. https://doi.org/10.1080/01932691.2017.1318076. Zhu, Z., Wen, Y., Yi, J., Cao, Y., Liu, F., McClements, D.J., 2019. Comparison of natural and synthetic surfactants at forming and stabilizing nanoemulsions: tea saponin, Quillaja saponin, and Tween 80. Journal of Colloid and Interface Science 536, 80e87. https:// doi.org/10.1016/J.JCIS.2018.10.024. Zuidam, N.J., Heinrich, E., 2010. Encapsulation of aroma. In: Encapsulation Technologies for Active Food Ingredients and Food Processing. Springer New York, New York, NY, pp. 127e160. https://doi.org/10.1007/978-1-4419-1008-0_5.

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CHAPTER THREE

Encapsulation of food ingredients by double nanoemulsions Mohammad Nejatian1, Hamed Saberian2, Seid Mahdi Jafari3 1

Department of Food Science and Technology, Tarbiat Modares University, Tehran, Iran Department of Food Additives, Food Science and Technology Research Institute, Academic Center for Education, Culture and Research, Khorasan Razavi, Iran 3 Department of Food Materials and Process Design Engineering, Gorgan University of Agricultural Science and Natural Resources, Gorgan, Iran 2

1. Introduction There has been a growing trend in the study of encapsulation of bioingredients over the last decades (Assadpour and Jafari, 2018; Rezaei et al., 2019). This academic interest is related to practical and commercial importance of such systems. First, nowadays, because of increasing knowledge, consumers prefer the food products promoting human health and well-being. Food scientists are therefore producing foods with healthpromoting ingredients, including vitamins and various nutraceuticals, being at the same time as low-caloric as possible (Nejatian et al., 2018; Shahidi, 2004; Wang and Bohn, 2012). Second, there is a pressure of regulatory organizations to reduce the level of synthetic additives, such as preservatives and artificial antioxidants, present in food. Then, a new trend has been created in the food industry toward removing or replacing synthetic substances with natural alternatives (Bondi et al., 2017; Falag
an et al., 2016). Both goals can be addressed by exploiting food-grade systems for the encapsulation of bioactive compounds, including various nutraceuticals, antioxidants, vitamins, colorants, flavorings, and antimicrobials, into foods (Assadpour and Jafari, 2018; Ezhilarasi et al., 2013; Jafari, 2017). Nanotechnology is representing new insights to develop these kinds of delivery systems so that the global market for nanoencapsulation of food products is projected to reach US$10.1 billion by 2024 (Global Industry Analyst, 2018). Accordingly, research groups are actively endeavoring to apply new techniques and materials to prepare various advanced encapsulation systems.

Lipid-Based Nanostructures for Food Encapsulation Purposes ISBN: 978-0-12-815673-5 https://doi.org/10.1016/B978-0-12-815673-5.00003-9

© 2019 Elsevier Inc. All rights reserved.

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The use of many mentioned bioactive ingredients in the food industry remains as a major challenge, as they suffer from some restriction such as short shelf life in the food formulations because of their weak chemical stability and low bioavailability due to their poor absorption and low water solubility (Faridi Esfanjani et al., 2018; Ghasemi et al., 2018; Rafiee et al., 2018). Lipid-based nanostructures are considered as helpful tools with a substantial potential for the delivery of food ingredients (Rafiee and Jafari, 2018). They are usually categorized as phospholipid-based (nanoliposomes and nanophytosomes), surfactant-based (including niosomes and hexosomes), and molecule-based (such as nanoemulsions, solid lipid nanoparticles, and nanostructured lipid carriers) (Akhavan et al., 2018; Shrestha et al., 2014). This capability of lipid-based nanocarriers is related to two factors (Rezaei et al., 2019; Rostamabadi et al., 2019): (1) the most food bio-ingredients have a hydrophobic nature, (2) coincorporation of bioactive ingredients within a lipid phase via a lipid-based delivery system facilitates the absorption of these components in the small intestine, since edible lipids present in their nanostructure amplifies the formation of mixed micelles responsible for the solubilization and transference of hydrophobic compounds (Porter et al., 2007; Pouton, 2006) (Jafari and McClements, 2017). In comparison with other lipid-based nanocarriers, double nanoemulsions are newer systems and could be considered as an advanced nanoemulsion delivery technique (Assadpour and Jafari, 2019; Esfanjani et al., 2015). A double nanoemulsion is in fact a ternary system having either water-inoil-in-water (W/O/W) or oil-in-water-in-oil (O/W/O) structures, where each of the dispersed droplets contains smaller internal droplets of a different immiscible liquid phase (Gharehbeglou et al., 2019a). For example, in the case of W1/O/W2 emulsion, each droplet of oil dispersed in the external aqueous phase (W2), contains at least one internal water droplet (W1) (Assadpour et al., 2016; Jafari et al., 2017). A double nanoemulsion typically has inner and outer droplets with a mean diameter below 200 and 1000 nm, respectively. Such relatively complex structures allow coencapsulating of lipophilic compounds (in the lipid phase) and hydrophilic ones (in the inner aqueous compartments). This feature is only seen in a small number of nanocarriers, such as nanoliposomes and polymeric nanomicelles, and has been utilized in many cases, specifically in pharmaceutical and food supplements industry (Kalepu et al., 2013). By producing a synergetic effect due to incorporation of several bio-ingredients with different natures in the individual carrier, the efficiency of treatment is improved (Hu et al., 2012; Kemp et al., 2016). The

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preparation of double nanoemulsions offers another unique feature to overcome incompatibility of lipophilic substances used for nanoemulsion formulation. It is not possible, for example, to incorporate vitamin E and coenzyme Q10 together in conventional nanoemulsions, since these two lipophilic compounds are not compatible, and consequently react to each other by electron transfer processes, and the solution turns dark brown. It should be noted that simultaneous use of coenzyme Q10 and tocopherol (vitamin E) is necessary to improve its bioactivity because coenzyme Q10 is obtained in its oxidized form and must therefore be reduced in the cell to act as an antioxidant (Zuelli et al., 2006; Zulli et al., 2005). Additionally, double nanoemulsions, due to using directly in hydrophilic and lipophilic phases, provide a considerable encapsulation efficiency of both hydrophilic and lipophilic ingredients (Esfanjani et al., 2015; Mohammadi et al., 2016a). Despite the potential usefulness, double nanoemulsions are thermodynamically unstable, and their encapsulation effectiveness is extremely influenced by many forms of instability. It should be noted that advantages and disadvantages also exist for conventional double emulsions. Indeed, many theoretical basics for conventional double emulsions also exploit to double nanoemulsions. However, droplet size reduction from the micro- to nanoscale and then improvement in surface area of droplets can develop the functionality of bioactive ingredients incorporated into double nanoemulsions ( Jafari and McClements, 2018; McClements and Rao, 2011). First scientific report about double emulsions as complex multiphase structures was published in 1925, and since then, more studies have been conducted on these complex emulsions over the years (Seifriz, 1924). Hence, this chapter discusses the newest advancements created in the nanoencapsulation of ingredients into double nanoemulsion networks so that researchers can have detailed information on their various aspects, including formation and stability. Moreover, the potential food and pharmaceutical applications of conventional double emulsions and double nanoemulsions are separately underlined.

2. Classification and structure of double emulsions Double nanoemulsions belong to a group of advanced emulsions named structural emulsions. In this type of emulsions, functionality of emulsion-based products is extended applying structural design techniques including layering, imbedding, and clustering. A double nanoemulsion applies the imbedding of the droplets inside larger droplets consisted of another

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liquid phase to control functional performance of the system ( Jafari et al., 2017; McClements, 2012). This member of the emulsions family is made up of three separate phases including inner aqueous or lipid phase, middle lipid (W/O/W) or aqueous (O/W/O) phase, and outer continuous phase as well as hydrophilic and hydrophobic surfactants (Mehrnia et al., 2017; Mohammadi et al., 2016a). The aqueous phase is usually composed of water; however, it can be composed of other polar components, such as cosolvents (organic acids), carbohydrates, proteins and minerals. Different nonpolar components, including triglycerides (long-chain, medium-chain, and short-chain), essential oils, mineral oils, fat substitutes, waxes, or combination of them, can be used as lipid phase in the formulation of double nanoemulsions ( Jafari and McClements, 2018). Various bioactive ingredients can be encapsulated in the core and external phases of double nanoemulsions (i.e., the inner and outer phase, respectively). The middle phase, as a membrane, has a significant role to play in the control of encapsulant release kinetics from inner phase into the outer phase. Technically, this type of emulsions has two different interfacial layers; one layer between the inner and middle phase (for instance, W1/O in W1/O/W2 emulsions) and the other one between the middle and outer phase (O/W2) ( Jafari et al., 2017). Therefore, the use of two different surfactants is usually necessary; an oil-soluble and a water-soluble surfactant for stabilization of W1/O and O/W2 interfaces, respectively. The most usual hydrophilic surfactants (with a high hydrophilic to lipophilic balance (HLB)) in the formulation of double nanoemulsions are Tween(s), decaglycerol monolaurate, and biopolymeric emulsifiers such as proteins (whey proteins, sodium caseinate, soy protein isolates) and polysaccharides (gum Arabic, gum tragacanth) (Capdevila et al., 2010; Esfanjani et al., 2015). On the other hand, Span(s) and polyglycerol polyricinoleate (PGPR) are the most common lipophilic surfactants (with an HLB values of 4 or less) to make double nanoemulsions (Bonnet et al., 2010; Jafari et al., 2017; Le Révérend et al., 2011; Mehrnia et al., 2017). When choosing surfactants for preparation of double nanoemulsions, their regulatory/safety status and efficacy should be simultaneously considered. For example, PGPR, a high-molecular-weight chemical originated from castor oil, has been frequently applied in studies of duplex emulsions. However, its application requires declaration on the product label, since it is not a natural compound (Lamba et al., 2015). Accordingly, the feasibility of replacing PGPR or other synthetic surfactants with natural ingredients or even decreasing its

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amount in double nanoemulsion formulations is a dynamic and expanding research areas.

2.1 Instability sources of double nanoemulsions Despite the potential usefulness of double nanoemulsions, the major restriction which decreases their extensive application is the stability. Double nanoemulsions are thermodynamically unstable systems and each of their constituent phases tends to undergo coalescence, flocculation, and creaming. In addition, they are highly sensitive to migration of water molecules between phases; subsequently a large part of the encapsulants is gradually lost ( Jafari et al., 2017). Therefore, it is crucial to maintain the stability of double nanoemulsions because it may influence functional performance of the encapsulated bio-ingredients (such as the bioactivity and bioavailability). The presence of two different surfactants in double nanoemulsion formulation can obviously be a potential source of instability, since they, especially small molecule surfactants, often have a tendency to move between phases (Garti, 1997; McClements and Jafari, 2018). Other reason of instability is the great increase of Laplace pressure within the inner droplets, when the size reaches scales lower than 100 nm. Such effect in double W/O/W nanoemulsions provides the driving force for migration of water from the internal to the external aqueous phase. As a result, outer droplets start to swell and gradually reach the point where further expansion results in bursting of them with subsequent loss of encapsulant from nanocarrier (Ding et al., 2017; Jafari et al., 2017). Another major source of instability for double nanoemulsions over storage is osmotic pressure imbalance between both sides of the intermediate lipid phase due to the presence of solids (encapsulants) within internal droplets. If the osmotic pressure difference is large enough to induce a diffusive flow from the external to the internal water phase, size of the internal aqueous droplets will gradually increase. Extensive promotion of inner droplet size leads to rupture of the double nanoemulsions and consequently release of encapsulant into the outer continuous phase ( Jafari et al., 2017; Pawlik et al., 2010). Some strategies have been reported to reinforce the double structure and control the destabilization mechanisms in double nanoemulsions. A popular strategy is to replace amphiphilic block copolymers with conventional lowmolecular-weight surfactants. As an example, in an early reference to such strategy, Hanson et al. (2008) manufactured double nanoemulsions of

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silicone oil with outer droplet sizes below 200 nm, accompanied with a long stability, using single-component synthetic amphiphilic diblock copolymer surfactants. The emulsification process involved ultrasonication followed by high-pressure homogenization. These copolypeptides were made up of poly(L-lysine HBr) and poly(racemic-leucine) monomers, as hydrophilic and hydrophobic segments, respectively. After adding oil phase into the aqueous solutions containing copolymer, they are adsorbed at the interfaces with the lipophilic poly(racemic-leucine) blocks protruded onto the oil side, and the hydrophilic poly(L-lysine HBr) block protruded onto the water side, providing the effective emulsion stabilization via hydrogen bonding among the hydrophobic segments at the inner interface with those at the outer interface, thus inhibiting internal droplet coalescence. The prepared nanoscale double emulsions were very stable and displayed no substantial structural changes over a storage date of 9 months (Hanson et al., 2008). Another strategy for stability enhancement of food-relevant double nanoemulsion systems is decreasing the clash of dispersed droplets and subsequently creaming, through viscosity increase or gelation. Accordingly, Mehrnia et al. (2017) employed Persian gum, whey protein concentrate (WPC), and gum Arabic for stabilizing the outer water phase of W1/O/ W2 nanoemulsions. They observed that Persian gumestabilized double nanoemulsions had the lowest droplet diameter increment after 1-month storage and then concluded that Persian gum produced more stable emulsions than gum Arabic and WPC, which was attributed to high viscosity and gel-like structure of Persian gum emulsions. Furthermore, viscosity increasing and gelation of the internal phase of a W1/O/W2 nanoemulsion can led to a significant improvement in overall stability of systems, meanwhile, decreasing the PGPR content that is needed to prepare the primary W1/O emulsions (Mehrnia et al., 2017). Moreover, there is evidence suggesting that the viscose internal water phase clearly reduces the level of sensitivity to sources of imbalance in osmotic pressure (Mezzenga et al., 2004). Generally, the first point that should be considered about the preparation and overall stability of double nanoemulsions is the stability of the primary emulsion, which in turn hinges to formulation parameters including amount and type of the surfactants used, and the nature of the oil phase and encapsulants. For example, encapsulants that contain electrolytes with small molecules can quickly diffuse across the lipid layer. So, the stability of double nanoemulsions can be increased by careful selection of formulation ingredients, especially surfactants ( Jafari et al., 2017).

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3. Preparation of double emulsions Similar to conventional microscale double emulsions, double nanoemulsions are usually manufactured through a two-step emulsification technique. In the first step of emulsification, the W/O (or O/W) emulsions would be prepared and then this primary emulsion is used as oil (or aqueous) phase with another aqueous (or oil) phase to make a direct second emulsion W1/O/W2 (or O1/W/O2). The first step is typically done under intense homogenization conditions and, as previously mentioned, plays a key role in the characteristics and performance of the final nanoemulsion so that a double nanoemulsion with small droplet sizes, desirable encapsulation loads, and high stability is obtained when the primary emulsions have enough stability and optimum droplet sizes. On the contrary, secondary step is usually performed under gentle shear conditions in order to prevent the breakup of the internal droplets (the W1 or O1 droplets) within the lipid and water phases, respectively (Garti, 1997; Jafari et al., 2017). In the food studies, a number of high-energy techniques are used to form stable double nanoemulsions including ultrasonication devices, rotorestator homogenizers, high-pressure homogenizers, and microfluidizers. The mild dispersing conditions for the secondary emulsification step is provided by increasing the gap and reducing the shear rate in rotorestator apparatus or by decreasing the pressure and sonication time/power in high-pressure homogenizers and ultrasound devices, respectively ( Jafari et al., 2017). Table 3.1 lists the range of operating conditions for different preparation techniques that have been applied to manufacture W/O/W nanoemulsions. Mohammadi et al. (2016a,b) used a moderate rotation speed of 8000 rpm in 5 min for dispersing the primary W/O nanoemulsion into the outer water phase of a W/O/W emulsion (Mohammadi et al., 2016a,b). Assadpour et al. (2016) and Faridi Esfanjani et al. (2017) also performed the second emulsification step through two successive homogenizations with a rotorestator homogenizer. At first, primary W/O nanoemulsion was added into the external aqueous phase of mixed biopolymeric surfactants while blending at 12,000 rpm for 5 min, and then these coarse emulsions were further emulsified at 15,000 rpm for 8 min (Assadpour et al., 2016; Faridi Esfanjani et al., 2017). In contrast, Mehrnia et al. (2017) combined the Ultra-Turrax homogenization (8000 rpm, 10 min) with a high-pressure valve homogenizer (10,000 psi for three cycles and ambient temperature) (Mehrnia et al., 2017). In another similar work, a primary W/O (medium-chain triglyceride oil) nanoemulsion was fabricated in the presence of PGPR

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Table 3.1 Emulsification techniques used for the production of double nanoemulsions. Method classification First stage Second stage

Phase inversion temperature Sonication (5 min) Spontaneous emulsification Microemulsion method (stirring) Microemulsion method (stirring)

Low-energy method/rotorestator/high energy methods

Microemulsion method (stirring)

Rotorestator/high-energy method/low-energy method

Ultra-Turrax (24,000 rpm for 3 min) þ microfluidizer (1200 psi þ 1 cycle)

Phase inversion temperature Sonication (10 min) Spontaneous emulsification Homogenization under 8000 rpm for 5 min Two successive homogenizations with a rotorestator homogenizer (12,000 rpm for 5 min and then 15,000 rpm for 8 min) Ultra-Turrax homogenizer (at 8000 rpm for 10 min) and then high-pressure valve homogenizer (10,000 psi for 3 cycles) Microemulsion method (stirring)

Schwarz et al. (2012) Divakaran (2012) Shakeel et al. (2014) Mohammadi et al. (2016a) Assadpour et al. (2016), Faridi Esfanjani et al. (2017)

Mehrnia et al. (2017)

Ding et al. (2017)

Mohammad Nejatian et al.

Low-energy methods High-energy methods Low-energy methods Low-energy method/rotorestator Low-energy method/rotorestator

References

Encapsulation of food ingredients by double nanoemulsions

97

and maltodextrin in lipid and aqueous phase, respectively, and by the combination of Ultra-Turrax operating at 24,000 rpm for 3 min, with microfluidizer operating at 1200 psi and one passage. After the low-energy emulsification in the second step of the process (see the following paragraph), the authors obtained inner and outer droplets with a mean diameter of lower than 100 and 200 nm, respectively, and an encapsulation efficiency up to 58% (Ding et al., 2017). An alternative technique to make primary or secondary emulsions is applying low-energy methods (microemulsion techniques). Contrary to high-energy methods, these techniques apply the internal chemical energy of the mixture of oilewateresurfactant and only a simple stirring for emulsification. These methods can be classified as either phase inversion by simple phase mixing (emulsion phase inversion and spontaneous emulsification) or by changing the hydrophilicelipophilic balance through altering the system conditions (inversion temperature and phase inversion composition) such as composition or temperature ( Jafari and McClements, 2018; Jafari et al., 2017). For example, Mehrnia et al. (2017) have used spontaneous emulsification to prepare the W/O primary nanoemulsion in which 10 wt% aqueous phase containing encapsulant was added dropwise into the mixture of PGPR and olive oil in 1.5 h while magnetically stirring at 700 rpm (Mehrnia et al., 2017). Similarly, Assadpour et al. (2016), Mohammadi et al. (2016a,b), and Faridi Esfanjani et al. (2017) by using this method and Span 80, prepared primary W/O nanoemulsions (Assadpour et al., 2016; Faridi Esfanjani et al., 2017; Mohammadi et al., 2016a). For both emulsification steps of W/O/W nanoemulsion preparation, Schwarz et al. (2012) followed the low-energy methods based on the phase inversion temperature (the so-called PIT method). Weighed amounts of Miglyol 815 (neutral oil), the lipophilic surfactant (Span 80), and the active ingredient (aciclovir) were first mixed together in a beaker and stirred for 2 h to ensure incorporation into the reverse micelles. In the next step, the hydrophilic surfactant (Solutol HS15) was dissolved in a 40 wt% water phase containing sodium chloride and then heated to a temperature above the PIT to about 85 C using a water bath. Once that temperature was reached, the oil phase was added dropwise. Finally, the mixture was rapidly cooled to the room temperature and diluted abruptly with the remaining part of the water phase (Schwarz et al., 2012). Similarly, Shakeel et al. (2014) successfully prepared both primary (W/O) and secondary (W/O/W) nanoemulsions by using microemulsion technique based on spontaneous emulsification (titration method) (Shakeel et al., 2014).

98

Mohammad Nejatian et al.

4. Different double emulsions for encapsulation purposes As mentioned above, the unique structure of double nanoemulsions makes them suitable for encapsulation of both hydrophilic and hydrophobic molecules (polar and nonpolar) simultaneously. Additionally, they provide a controlled release of core materials when the nanoemulsion droplet is in the environments of different natures. The encapsulation of bio-ingredients into conventional double emulsions has been extensively investigated; however, there is a growing attention for the encapsulation and delivery of nutraceuticals into double nanoemulsions. Therefore, some important and recent food applications of these lipid-based nanoformulations are separately summarized in the following sections.

4.1 Double nanoemulsions Several studies have reported the formation of food ingredienteloaded double nanoemulsions as a strategy to improve their functional performance (as shown in Table 3.2). In a study by Mohammadi et al. (2016a,b), they incorporated olive leaf phenolic extracts into double W/O/W nanoemulsions with a mean inner droplet diameter of 6 nm and outer droplet sizes 675 nm. Compared with free olive leaf extract, these nanodroplets increased the extract antioxidant activity, so that oxidation protection offered by encapsulated extract was almost equivalent to the capacity of Tertiary butylhydroquinone (TBHQ), a widely used synthetic antioxidant (Mohammadi et al., 2016a,b). Double nanoemulsions have also been reported to be an appropriate vehicle to increase the physical and chemical stability against various environmental stresses that are usual in the processing of products. In this sense, Assadpour et al. (2017) investigated the application of W/O/W nanoemulsions for encapsulation of folic acid using mixed solutions of WPC and maltodextrin (hydrophilic surfactant), Span 80 (lipophilic surfactant), and canola oil (lipid phase). In another study, Faridi Esfanjani et al. (2017) prepared double nanoemulsions of sunflower oil using Span 80 and a mixture of pectin and whey protein, as lipophilic and hydrophilic surfactants, respectively, depicting a high efficacy to preserve the encapsulated saffron extract (crocin, safranal, and picrocrocin) after 22 days storage. Under the best conditions, the inner and outer droplet size of resulting saffron-loaded nanocarriers were 174 and 601 nm, respectively, and encapsulation efficiency of about 90% was achieved (Faridi Esfanjani et al., 2017). These authors, in a

References

Lecithin Tween 80 þ Span 80 Span 80

Lecithin WPC

Coenzyme Q10/vitamin E Aqueous strawberry extract

40e63 e

68.6 297e315

Zulli et al. (2005) Divakaran (2012)

WPC/Pectin

Olive leaf phenolics

6

675

Span 80

WPC

Folic acid