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Copyright © 2016. De Gruyter. All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or Tharwat F. Tadros applicable copyright law. Nanodispersions | EBSCO Publishing : eBook Collection (EBSCOhost) - printed on 6/28/2019 2:48 AM via NARESUAN UNIVERSITY AN: 1131238 ; Tadros, Tharwat F..; Nanodispersions Account: ns004377

Copyright © 2016. De Gruyter. All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or Author applicable copyright law. Prof. Tharwat F. Tadros 89 Nash Grove Lane Workingham RG40 4HE Berkshire, UK [email protected] ISBN 978-3-11-029033-2 e-ISBN (PDF) 978-3-11-029034-9 e-ISBN (EPUB) 978-3-11-038879-4 Library of Congress Cataloging-in-Publication Data A CIP catalog record for this book has been applied for at the Library of Congress. Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at http://dnb.dnb.de. © 2016 Walter de Gruyter GmbH, Berlin/Boston Cover image: Kesu01/iStock/Thinkstock Typesetting: PTP-Berlin, Protago-TEX-Production GmbH, Berlin Printing and binding: CPI books GmbH, Leck ♾ Printed on acid-free paper Printed in Germany www.degruyter.com EBSCO Publishing : eBook Collection (EBSCOhost) - printed on 6/28/2019 2:48 AM via NARESUAN UNIVERSITY AN: 1131238 ; Tadros, Tharwat F..; Nanodispersions Account: ns004377

Copyright © 2016. De Gruyter. All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or Preface applicable copyright law. It is generally accepted that nanodispersions cover the range 10–200 nm diameter. These systems fall within the colloid range (1 nm–1 μm) and hence one can apply the general theories of colloid stability for these systems. The resulting dispersion can be transparent, translucent or turbid depending on three main factors, namely the par- ticle or droplet radius, the difference in refractive index between the dispersed phase and dispersion medium and the volume fraction of the disperse phase. Several ad- vantages of nanodispersions can be listed: (i) The very small particle or droplet size causes a large reduction in gravity force and Brownian motion may be sufficient for overcoming gravity. This means that no creaming or sedimentation occurs on storage. (ii) The small droplet size also prevents any flocculation of the particles or droplets, due to the small van der Waals attraction between the particles or droplets. The re- pulsive energy produced by surfactants and/or polymers will give nanodispersions a high kinetic stability, particularly when using polymeric surfactants that provide strong steric repulsion. (iii) The small droplets within nanoemulsions will also pre- vent coalescence, since these droplets are nondeformable and hence surface fluctu- ations are prevented. In addition, the significant surfactant film thickness (relative to droplet radius) prevents any thinning or disruption of the liquid film between the droplets. (iv) Nanosuspensions have wide applications in drug delivery systems for poorly insoluble compounds, whereby reduction of particle size to nanoscale dimen- sions enhances the drug bioavailability. This is due to the increase of solubility of the active ingredient on reduction of particle radius. (v) Nanoemulsions are suitable for efficient delivery of active ingredients through the skin. The large surface area of the emulsion system allows rapid penetration of actives. (vi) Due to their small size, nanoemulsions can penetrate through the “rough” skin surface and this enhances penetration of actives. (vii) The transparent nature of the system, their fluidity (at rea- sonable oil concentrations) as well as the absence of any thickeners may give them a pleasant aesthetic character and skin feel. (viii) Nanoemulsions can be prepared us- ing reasonable surfactant concentration. For a 20 % O/W nanoemulsion, a surfactant concentration in the region of 5 % may be sufficient. (ix) The small size of the droplets allows them to deposit uniformly on substrates. Wetting, spreading and penetration may also be enhanced as a result of the low surface tension of the whole system and the low interfacial tension of the O/W droplets. (x) Nanoemulsions can be applied for delivery of fragrants which may be incorporated in many personal care products. (xi) Nanoemulsions may be applied as a substitute for liposomes and vesicles (which are much less stable) and in some cases it is possible to build lamellar liquid crys- talline phases around the nanoemulsion droplets. Two methods can be applied for preparation of nanosuspensions: (i) The bottom- up approach where one starts with molecular components and builds up the particles by a process of nucleation and growth. (ii) The top-down process where one starts EBSCO Publishing : eBook Collection (EBSCOhost) - printed on 6/28/2019 2:48 AM via NARESUAN UNIVERSITY AN: 1131238 ; Tadros, Tharwat F..; Nanodispersions Account: ns004377

Copyright © 2016. De Gruyter. All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or VI | Preface applicable copyright law. with the bulk material (which may consist of aggregates and agglomerates), this is dis- persed into single particles (using a wetting/dispersing agent) and then the large par- ticles are subdivided into smaller units that fall within the required nanosize. This pro- cess requires the application of intense mechanical energy that can be applied using bead milling, high pressure homogenization and/or application of ultrasonics. The preparation of nanopolymer colloids using emulsion and suspension polymerization can be considered a bottom-up process since one starts with the monomer which is then polymerized using an initiator. The preparation of biodegradable nanoparticles by aggregation of A–B block copolymers (such as polylactic polyglycolic block copoly- mer) can also be considered a bottom-up process. A special case for producing nan- odispersions is the formation of liposomes and vesicles. Liposomes are multilamellar structures consisting of several bilayers of lipids (several μm). They are produced by simply shaking an aqueous solution of phospholipids, e.g. egg lecithin. When soni- cated, these multilayer structures produce unilamellar structures (with size range of 25–50 nm) that are referred to as liposomes. There are generally two methods for stabilizing nanodispersions. The first method depends on charge separation and formation of an electrical double layer whose ex- tension (double layer thickness) depends on electrolyte concentration and valency of the counter and co-ions. When the particles approach to a distance h that is smaller than twice the double layer extension, strong repulsion occurs, particularly when the 1 : 1 electrolyte (e.g. NaCl) is lower than 10−2 mol dm−3. This repulsion can overcome the van der Waals attraction at intermediate particle separation resulting in an en- ergy barrier (maximum) that prevents particle approach and hence flocculation is prevented. The second and more effective mechanism is obtained by using nonionic surfactants or polymers (referred to as polymeric surfactant). When two particles or droplets approach to a distance h that is smaller than 2δ, the stabilizing chains may overlap or become compressed resulting in very strong repulsion as a result of two main effects, namely unfavourable mixing of the stabilizing chains when these are in good solvent conditions and unfavourable loss of configurational entropy of the sta- bilizing chains on significant overlap. Combination of these two effects is referred to as steric repulsion which, when combined with the van der Waals attraction, results in an energy-distance with only one shallow minimum. The formation of nanosuspensions by a bottom-up or top-down process seldom results in monodisperse particles. By proper control of the method of preparation, one may at best produce a narrow size distribution which still consists of small and larger particles. The smaller size particles will have a higher solubility than the larger ones. On storage, molecular diffusion will occur from the smaller to the larger particles and this results in a shift in the particle size distribution to larger values. This process is referred to as Ostwald ripening and the driving force is the difference in solubility be- tween the small and the large particles. Several industrial applications of nanodispersions have emerged in the last few decades. One of the most important applications is in drug delivery of poorly soluble EBSCO Publishing : eBook Collection (EBSCOhost) - printed on 6/28/2019 2:48 AM via NARESUAN UNIVERSITY AN: 1131238 ; Tadros, Tharwat F..; Nanodispersions Account: ns004377

Copyright © 2016. De Gruyter. All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or Preface | VII applicable copyright law. drugs. By reducing the size of the particles to values in the nanosize range, the solubil- ity of the drug is greatly enhanced and this enhances bioavailability. Another impor- tant application of nanodispersions is the use of biodegradable polymer nanoparticles for targeted delivery of drugs, e.g. in cancer treatment. Another important area of ap- plication of nanodispersions is in the field of cosmetics and personal care. Sunscreen dispersions of semiconductor TiO2 require particles in the range 30–50 nm which need to be stable against aggregation in the formulation and on application. Nanoemul- sions are applied in many hand creams for efficient delivery of anti-wrinkle agents. Liposomes and vesicles are also used in many formulations for efficient delivery of ceramides that protect the skin from ageing. Several other industrial applications of nanoparticles can be mentioned such as preparation of nanosize catalyst particles, nanopolymer colloids, ceramics, etc. The present text addresses the topic of nanodispersions at a fundamental level and some of their industrial applications. Chapter 1 gives a general introduction of the definition of nanodispersions, their main advantages and general applications in in- dustry. Chapter 2 deals with the colloid stability of nanodispersions, both electrostatic and steric stabilization. The interaction between particles or droplets containing dou- ble layers is described and when combined with the van der Waals attraction results in the general theory of colloid stability due to Deryaguin–Landau–Verwey–Overbeek (DLVO theory). This is followed by describing the interaction between particles or droplets containing adsorbed surfactant or polymer layers. Steric interaction is de- scribed in terms of the unfavourable mixing of the adsorbed layers (when these are in good solvent conditions) and the unfavourable loss of entropy on significant over- lap of the adsorbed layers. Combining these two effects with van der Waals attraction results in the theory of steric stabilization. Chapter 3 describes the Ostwald ripen- ing of nanodispersions and its prevention. It starts with the Kelvin theory that de- scribes the effect of curvature (particle or droplet size) on the solubility of the disperse phases. It shows the rapid increase in solubility when the particle or droplet size is reduced below 500 nm. The kinetics of Ostwald ripening is described showing the change of the cube of the mean radius with time and the effect of oil solubility on the rate. This is followed by the methods that can be applied to reduce Ostwald ripen- ing for both nanosuspensions and nanoemulsions. Chapter 4 describes the methods of preparation of nanosuspensions by the bottom-up process. The theory of nucle- ation and growth is described with particular reference to the effect of supersaturation and presence of surfactants and polymers. The preparation of nanopolymer colloids (lattices) using miniemulsion polymerization is described. This is followed by a sec- tion on the application of microemulsions for the preparation of nanopolymer col- loids. Chapter 5 describes the methods of preparation of nanosuspensions using the top-down process. The process of wetting of powder aggregates and agglomerates is described with special reference to the role of surfactants (wetting agents). The dif- ferent classes of surfactants for enhancing wetting are described. This is followed by a section on dispersion of the aggregates and agglomerates using high speed stir- EBSCO Publishing : eBook Collection (EBSCOhost) - printed on 6/28/2019 2:48 AM via NARESUAN UNIVERSITY AN: 1131238 ; Tadros, Tharwat F..; Nanodispersions Account: ns004377

Copyright © 2016. De Gruyter. All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or VIII | Preface applicable copyright law. rers. Finally, the methods that can be applied for size reduction are described with reference to microfluidization (using high pressure homogenizers) and bead milling. The main factors responsible for maintenance of colloid stability are described. Chap- ter 6 describes the industrial applications of nanosuspensions. Two main areas will be considered in some detail, namely the use of nanosuspensions for size reduction of highly insoluble drugs to enhance their bioavailability and application of nanosus- pensions of semiconductor titanium dioxide in sunscreens. Chapter 7 deals with the application of nanoparticles as drug carriers for targeted delivery of the active in- gredient. It deals with the formation of liposomes (multilamellar lipid bilayers) and vesicles (unilamellar lipid bilayer) and the nature and structure of lipids used in their preparation. The formation of vesicles by sonication of liposomes is described and the origin of their stability by application of thermodynamic principles is analyzed. The use of block copolymers for stabilization of the lipid bilayer is described at a fun- damental level. The application of liposomes and vesicles in drug delivery is briefly described. The use of model nanolatex particles for investigating the circulation of the nanoparticles and preventing their engulfment by the Kupffer cells in the liver is described. The influence of particle surface charge, size and presence of adsorbed polymer layers on particle circulation is discussed. The use of biodegradable poly- mers of polylactic polyglycolic A–B block copolymers for preparation of biodegradable nanoparticles is described followed by the methods of synthesis and characterization of the block copolymer. The characterization of the resulting nanoparticles using light scattering and rheological techniques is briefly described. The prevention of protein adsorption by the hydrophilic chain is explained at a fundamental level. This is fol- lowed by an investigation of the circulation of the nanoparticle using radio labelled particles. Chapter 8 describes the preparation of nanoemulsions using high pressure homogenizers. The selection of emulsifiers and description of their role in prevention of coalescence during emulsification are analyzed at a fundamental level. The meth- ods of emulsification and application of high pressure and ultrasonic techniques for formation of the nanoemulsions are described with particular reference to the influ- ence of the formulation variables such as the disperse volume fraction, nature and concentration of the emulsifier on the property of the nanoemulsion. The character- ization of the nanoemulsion using dynamic light scattering technique is described. Chapter 9 deals with the preparation of nanoemulsions using low energy techniques. Three methods are described, namely the phase inversion composition, the phase inversion temperature and dilution of microemulsion methods. A comparison of na- noemulsions prepared using low energy emulsification and high energy methods is given. Particular attention is given to the effect of polydispersity and Ostwald ripening rates. Chapter 9 also describes some practical examples of nanoemulsions with par- ticular reference to the effect of oil solubility and nature of the emulsifier. Chapter 10 deals with the topic of solubilized systems and swollen micelles (microemulsions). The thermodynamic definition of microemulsions, their spontaneous formation and stability are described at a fundamental level. This is followed by describing the theo- EBSCO Publishing : eBook Collection (EBSCOhost) - printed on 6/28/2019 2:48 AM via NARESUAN UNIVERSITY AN: 1131238 ; Tadros, Tharwat F..; Nanodispersions Account: ns004377

Preface | IX Copyright © 2016. De Gruyter. All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or ries of microemulsion formation and stability and the need for using two surfactants to applicable copyright law. produce ultra-low interfacial tension. The characterization of microemulsions using scattering, conductivity and NMR techniques is described. Chapter 10 also describes the methods that can be applied for formulation of microemulsions and the impor- tance of the partition of the cosurfactant between the oil and water phases. The various methods that can be applied for selecting emulsifiers for microemulsion formation are described. The application of microemulsions in several industries is briefly de- scribed. The present book provides the reader with the fundamental principles of prepa- ration of nanodispersions and their stabilization. It could be valuable for research workers in academia as well as in industrial research laboratories. It also provides the reader with various practical applications of nanoemulsions in various fields such as pharmaceuticals, cosmetics, agrochemicals, the oil industry, etc. The text is cer- tainly valuable for formulation scientists, chemical engineers and research scientists involved in this important topic. Tharwat Tadros November, 2015 EBSCO Publishing : eBook Collection (EBSCOhost) - printed on 6/28/2019 2:48 AM via NARESUAN UNIVERSITY AN: 1131238 ; Tadros, Tharwat F..; Nanodispersions Account: ns004377

Copyright © 2016. De Gruyter. All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or applicable copyright law. EBSCO Publishing : eBook Collection (EBSCOhost) - printed on 6/28/2019 2:48 AM via NARESUAN UNIVERSITY AN: 1131238 ; Tadros, Tharwat F..; Nanodispersions Account: ns004377

Copyright © 2016. De Gruyter. All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or Contents applicable copyright law. Preface | V 1 Nanodispersions – general introduction | 1 1.1 Definition of colloids | 1 1.2 Definition of nanodispersions | 1 1.3 Main advantages of nanodispersions | 2 1.4 General methods for preparation of nanodispersions | 4 1.5 General stabilization mechanisms for nanodispersions | 5 1.6 Ostwald ripening in nanodispersions | 6 1.7 Industrial applications of nanodispersions | 6 1.8 Outline of the book | 7 2 Colloid stability of nanodispersions | 11 2.1 Introduction | 11 2.2 Electrostatic stabilization | 12 2.3 Steric stabilization | 25 3 Ostwald ripening in nanodispersions | 33 3.1 Driving force for Ostwald ripening | 33 3.2 Kinetics of Ostwald ripening | 34 3.3 Reduction of Ostwald ripening | 39 3.3.1 Reduction of Ostwald ripening in nanosuspensions | 39 3.3.2 Reduction of Ostwald ripening in nanoemulsions | 39 3.4 Influence of initial droplet size of nanoemulsions on the Ostwald ripening rate | 41 4 Preparation of nanosuspensions by the bottom-up process | 45 4.1 Introduction | 45 4.2 Preparation of nanosuspensions by precipitation | 46 4.2.1 Nucleation and growth | 47 4.2.2 Precipitation kinetics | 49 4.2.3 Seeded nucleation and growth | 54 4.2.4 Surface modification | 54 4.2.5 Other methods for preparation of nanosuspensions by the bottom-up process | 55 4.3 Characterization of nanoparticles | 62 4.3.1 Visual observations and microscopy | 62 4.3.2 Electron microscopy | 63 4.3.3 Scattering techniques | 65 4.3.4 Measurement of charge and zeta potential | 70 EBSCO Publishing : eBook Collection (EBSCOhost) - printed on 6/28/2019 2:48 AM via NARESUAN UNIVERSITY AN: 1131238 ; Tadros, Tharwat F..; Nanodispersions Account: ns004377

XII | Contents Copyright © 2016. De Gruyter. All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or 5 Preparation of nanosuspensions using the top-down process | 77 applicable copyright law. 5.1 Wetting of the bulk powder | 77 5.2 Breaking of aggregates and agglomerates into individual units | 81 5.3 Wet milling or comminution | 83 5.4 Stabilization of the suspension during dispersion and milling and the resulting nanosuspension | 88 5.5 Prevention of Ostwald ripening (crystal growth) | 92 6 Industrial application of nanosuspensions | 95 6.1 Introduction | 95 6.2 Application of nanosuspensions for drug delivery | 95 6.2.1 Preparation of drug nanosuspensions using the top-down process | 96 6.2.2 Optimization of wetting/dispersant agent using PVP-SDS as model | 103 6.2.3 Protocol for preparation of nanosuspensions of water insoluble drugs | 109 6.3 Application of nanosuspensions in cosmetics | 109 6.3.1 Adsorption isotherms | 112 6.3.2 Dispersant demand | 113 6.3.3 Quality of dispersion UV-vis attenuation | 114 6.3.4 Solids loading | 114 6.3.5 SPF Performance in emulsion preparations | 116 6.3.6 Criteria for preparation of a stable sunscreen dispersion | 116 6.3.7 Competitive interactions in formulations | 120 6.4 Application of nanosuspensions in paints and coatings | 121 7 Nanoparticles as drug carriers | 131 7.1 Introduction | 131 7.2 Liposomes as drug carriers | 132 7.3 Polymeric nanoparticles | 139 7.3.1 Surface modified polystyrene latex particles as model drug carriers | 141 7.3.2 Biodegradable polymeric carriers | 142 7.3.3 The action mechanism of the stabilizing PEG chain | 146 7.3.4 Synthesis and characterization of PLA-PEG block copolymers | 149 7.3.5 Preparation and characterization of PLA-PEG nanoparticles | 152 7.3.6 Rheology of PLA-PEG dispersions | 174 7.3.7 Small angle neutron scattering (SANS) of PLA-PEG nanoparticles | 179 7.3.8 Biological performance of PLA-PEG nanoparticles | 184 EBSCO Publishing : eBook Collection (EBSCOhost) - printed on 6/28/2019 2:48 AM via NARESUAN UNIVERSITY AN: 1131238 ; Tadros, Tharwat F..; Nanodispersions Account: ns004377

Contents | XIII Copyright © 2016. De Gruyter. All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or 8 Preparation of nanoemulsion using high pressure homogenizers | 189 applicable copyright law. 8.1 Introduction | 189 8.2 Thermodynamics of emulsion formation and breakdown | 189 8.3 Adsorption of surfactants at the liquid/liquid interface | 191 8.4 Mechanism of emulsification | 194 8.5 Methods of emulsification | 196 8.6 Role of surfactants in emulsion formation | 197 8.7 Role of surfactants in droplet deformation | 199 8.8 Selection of emulsifiers | 203 8.8.1 The hydrophilic-lipophile balance (HLB) concept. | 203 8.8.2 The phase inversion temperature (PIT) concept. | 206 8.8.3 The cohesive energy ratio (CER) concept | 207 8.8.4 The critical packing parameter (CPP) for emulsion selection | 209 8.9 Preparation of nanoemulsions using high energy methods | 210 8.10 Emulsification process functions | 213 8.11 Enhancing of the process of forming nanoemulsions | 214 9 Low energy methods for preparation of nanoemulsions and practical examples of nanoemulsions | 217 9.1 Introduction | 217 9.2 Phase inversion composition (PIC) Principle | 218 9.3 Phase inversion temperature (PIT) Principle | 218 9.4 Preparation of nanoemulsions by dilution of microemulsions | 220 9.5 Steric stabilization and the role of the adsorbed layer thickness | 222 9.6 Ostwald ripening in nanoemulsions | 222 9.7 Practical examples of nanoemulsions | 223 9.8 Nanoemulsions based on polymeric surfactants | 232 10 Swollen micelles or microemulsions and their industrial applications | 239 10.1 Introduction | 239 10.2 Thermodynamic definition of microemulsions | 240 10.3 Mixed film and solubilization theories of microemulsions | 241 10.3.1 Mixed film theories [4] | 241 10.3.2 Solubilization theories | 243 10.4 Thermodynamic theory of microemulsion formation | 245 10.4.1 Reason for combining two surfactants | 245 10.4.2 Free energy of formation of a microemulsion | 247 10.4.3 Factors determining W/O versus O/W microemulsions | 248 10.5 Characterization of microemulsions using scattering techniques | 250 10.5.1 Time average (static) light scattering | 251 EBSCO Publishing : eBook Collection (EBSCOhost) - printed on 6/28/2019 2:48 AM via NARESUAN UNIVERSITY AN: 1131238 ; Tadros, Tharwat F..; Nanodispersions Account: ns004377